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Aims/introduction: To investigate whether sarcopenic obesity is associated with the progression of atherosclerotic lesions in older patients with diabetes and to identify the obesity components of sarcopenic obesity that best reflect atherosclerosis., Materials and Methods: In 118 inpatients aged ≥75 years with diabetes mellitus, sarcopenia defined as a low skeletal muscle mass and low grip strength was assessed, and sarcopenia coexisting with a high body-fat percentage or visceral fat area was defined as sarcopenic obesity. Correlations between the obesity components and atherosclerotic markers, including the carotid intima-media thickness, were analyzed; the intima-media thickness was analyzed in four groups with and without obesity and sarcopenia, and a multiple linear regression analysis adjusted for covariates was conducted to investigate whether sarcopenic obesity was independently associated with the intima-media thickness., Results: The visceral fat area and intima-media thickness showed positive correlations in the overall patients (P = 0.032) and the sarcopenia (P = 0.016) group but showed no associations in participants without sarcopenia. The intima-media thickness in the group showing sarcopenia with a high visceral fat area was significantly higher than that in the control group (P = 0.012). Sarcopenic obesity defined by a high body-fat percentage and high visceral fat area was independently associated with the intima-media thickness even after adjusting for age, sex, and atherogenic risk factors. However, sarcopenic obesity defined by a high visceral fat area was more strongly associated with the intima-media thickness (β = 0.384, P = 0.002) than that defined by the high body-fat percentage (β = 0.237, P = 0.068)., Conclusions: Sarcopenic obesity, especially that defined by visceral fat accumulation, reflected the risk of atherosclerotic lesion progression in older patients with diabetes., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Older patients with diabetes mellitus are more susceptible to frailty. Although some imaging markers of appendicular skeletal muscle mass obtained using dual-energy X-ray absorptiometry or computed tomography (CT) imaging can reflect frailty status, the association between imaging indices obtained by abdominal CT scans and frailty in older inpatients has not been reported., Methods: A total of 151 older inpatients with diabetes mellitus (median age, 79 years; men, 42%) who underwent abdominal CT scans close to the admission date were studied to examine the associations between abdominal CT indices and frailty. Two frailty definitions were used: the modified Cardiovascular Health Study (mCHS) criteria and Kihon Checklist (KCL) criteria. Using the imaging analysis software SYNAPSE VINCENT®, we compared the cross-sectional areas (CSA) of four truncal muscles (erector spinae, iliopsoas, rectus abdominis, and abdominal oblique muscles) and the liver-to-spleen ratio (L/S), the ratio of the CT values of the liver and spleen between frail and non-frail patients. The muscle areas that showed the strongest associations with frailty were also investigated in relation to grip strength and walking speed. Finally, multivariate binominal logistic regression analyses were performed to assess the independent associations of CSA of muscle and L/S with the prevalence of frailty., Results: The prevalence of frailty defined by the mCHS and KCL criteria was 55% and 52%, respectively. The CSA of the erector spinae muscle was most significantly associated with frailty, and was significantly smaller in both sexes of mCHS-defined frail patients and in men with KCL-defined frailty. The CSA of erector spinae muscle was also positively correlated with grip strength and walking speed. In contrast, the L/S was higher in men with KCL-defined frailty. Multivariate logistic regression analyses revealed that the CSA of the erector spinae muscle was independently associated with mCHS-defined frailty in women, and the L/S was associated with KCL-defined frailty in men., Conclusions: The CSA of erector spinae muscle and low liver fat content could be indices of frailty in older patients with diabetes., (© 2023. The Author(s).)

Streptococcus dysgalactiae subsp. equisimillis (SDSE) is classified as a group G streptococcus (GGS). In systemic SDSE infection, septic shock is easily induced and has a high mortality of 44%. The case was a 78-year-old man presented with fever and chills of 20 hours duration. He was in shock at the presentation and developed melena on day nine. CT images showed bowel wall thickening with emphysema and bedside colonoscopy showed active bleeding in the descending colon and rectum. Blood cultures were positive for Streptococcus dysgalactiae and a diagnosis of streptococcal toxic shock syndrome (STSS) due to SDSE was made. Urgent Hartmann procedure with laparotomy for removal of descending and rectal colon was performed to relieve his shock status. His shock status was reversed after surgery. Surgical specimens confirmed the presence of SDSE on the intestinal mucosa. This is the first case of STSS due to SDSE infection of the intestinal wall. Resection of infected tissue in the setting of multiple organ dysfunction syndrome and necrotizing enterocolitis is indicated in such cases., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Matsuoka et al.)

Background: Although physical performance tests of the lower extremities are used to assess sarcopenia and frailty, little is known about the mechanisms by which the parameters of ground reaction force (GRF) measured during sit-to-stand motion affect the frailty status in older adults. We aimed to examine the association between GRF parameters during sit-to-stand motion and the incidence of frailty in older adults., Methods: This longitudinal study evaluated 319 outpatients aged ≥ 65 years with cardiometabolic diseases. The GRF parameters were measured using a motor function analyzer, in which the power, speed, and balance scores were calculated. Frailty was diagnosed using the modified version of the Cardiovascular Health Study (mCHS) and the Kihon Checklist (KCL). The independent associations between scores and frailty indices were assessed using multivariate binomial logistic regression analyses. Cox regression analysis was used to examine whether power and speed scores were associated with the incidence of frailty after adjusting for covariates., Results: Logistic regression analyses adjusted for covariates showed that the power and speed scores were associated with frailty according to the mCHS criteria (power: OR = 0.37, 95% CI = 0.22-0.63; speed: OR = 0.64, 95% CI = 0.52-0.79) and KCL criteria (power: OR = 0.40, 95% CI = 0.26-0.62; speed: OR = 0.81, 95% CI = 0.69-0.96) at baseline. Receiver operating characteristic analyses revealed that the area under the curve values of power and speed scores for discriminating mCHS-defined frailty were 0.72 and 0.73. The Cox regression analysis showed that the speed score predicted the incidence of mCHS-defined (HR = 0.45, 95% CI = 0.22-0.92, P = 0.029) and KCL-defined (HR = 0.77, 95% CI = 0.60-0.99, P = 0.039) frailty, whereas the power score was associated with the incidence of KCL-defined frailty (HR = 0.72, 95% CI = 0.55-0.95, P = 0.02) after adjusting for covariates., Conclusions: The speed and power scores measured during sit-to-stand motion are predictive of frailty in older adults with cardiometabolic disease. Therefore, the GRF parameters measured during sit-to-stand motion could be an important indicator of frailty. Further studies are necessary to examine whether the GRF parameters can be improved by exercise or whether the changes in these parameters are associated with the improvement of frailty status., (© 2023. The Author(s).)

Introduction: Frailty and depression may play important roles in the management of older patients with cardiometabolic diseases. We explored the determinants of depressive symptoms and their association with frailty among patients with cardiometabolic diseases (hypertension, diabetes, and atrial fibrillation) in a cross-sectional study., Methods: A total of 633 outpatients aged 65 years or older with cardiometabolic disease and suspected symptoms of frailty participated in this study. Depressive symptoms, physical activity, and social network were assessed using the Geriatric Depression Scale (GDS)-15, International Physical Activity Questionnaire, and Lubben Social Network Scale-6 (LSNS-6), respectively. Frailty was evaluated using the Kihon Checklist (KCL) based on the Comprehensive Geriatric Assessment (CGA), the modified Cardiovascular Health Study (mCHS), and the Clinical Frailty Scale (CFS). Binomial logistic regression analysis was used to examine the determinants of depressive symptoms and their association with frailty., Results: Depressive symptoms with GDS-15 scores ≥ 5 were present in 43.6% of the patients. In logistic regression, after adjusting for covariates, the determinants of depressive symptoms in all patients were lack of social network, low years of education, and frailty. In contrast, in logistic regression with frailty as the dependent variable, depressive symptoms were independently associated KCL-defined frailty (OR = 6.28, 95% CI: 4.13-9.55) and mCHS-defined frailty (OR = 2.66, 95% CI: 1.70-4.17), but not with CFS. Similarly, significant associations between depression and frailty were observed in patients with hypertension, diabetes, or atrial fibrillation., Conclusions: Lack of social networks, low education, and frailty based on the KCL and mCHS were important determinants of depressive symptoms in all patients. The relatively strong associations between depressive symptoms and frailty based on CGA in patients with hypertension, diabetes, or atrial fibrillation suggest that the assessment of depressive symptoms is of great importance in clinical practice in those patients at high risk of frailty., Competing Interests: AA has received a speaker honoraria from Merck Sharp & Dohme, Sumitomo Parma Co. Ltd., Ono Pharmaceutical Co.Ltd., Takeda Pharmaceutical Co. Ltd., and Novo Nordisk Pharma Ltd. The other authors declare no conflict of interest., (Copyright: © 2023 Yorikawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Diffusion tensor imaging (DTI) can be used for the early detection of abnormal changes in the integrity of cerebral white matter tracts, and we have previously reported that these changes are associated with indices of early atherosclerotic lesions. Although these changes have been demonstrated to be associated with the incidence of frailty in older adults, no studies have investigated this relationship in patients at high risk for vascular disease. In this longitudinal study, we followed outpatients with cardiometabolic diseases for a maximum of 6 years (median, 3 years) and evaluated the association of baseline DTI data of seven white matter tracts with the incidence of frailty. The modified version of the Cardiovascular Health Study criteria and the Kihon Checklist were used as indices of frailty; fractional anisotropy (FA) and mean diffusivity (MD) were used as indices of white matter changes. Patients who developed frailty based on both indices had low FA and high MD in many of the tracts tested, with the most significant difference found in the MD of the anterior thalamic radiation (ATR). Cox proportional hazard model analysis revealed a significantly high risk of frailty defined by both indices in the groups with high MD values in the left ATR. Similar results were found in patients with diabetes mellitus but not in those without diabetes mellitus. Therefore, abnormalities in the integrity of the left ATR could be associated with the progression of frailty in older adults with cardiometabolic disease, particularly those with diabetes mellitus., Competing Interests: AA has received speaker honoraria from Merck Sharp & Dohme, Sumitomo Parma Co. Ltd., Tanabe Mitsubishi Pharma Corporation, Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Novo Nordisk Pharma Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tamura, Shimoji, Ishikawa, Murao, Yorikawa, Kodera, Oba, Toyoshima, Chiba, Tokumaru and Araki.)

Cadmium (Cd) is an industrial and environmental pollutant that targets the vascular endothelium. The vascular system is critically affected by Cd toxicity. Recent studies have indicated an association between Cd and vascular diseases, although the mechanisms of Cd implications in vascular diseases are not clear. The purpose of the present study was to determine whether epalrestat (EPS), which is used for the treatment of diabetic neuropathy, protects against Cd-induced cytotoxicity in bovine aortic endothelial cells (BAECs). In the present study, the effects of EPS at near-plasma concentration were examined on Cd-induced cytotoxicity in BAECs. Cd-induced cytotoxicity was suppressed by pretreatment with EPS. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that serves a role in regulating the expression of glutamate cysteine ligase, the rate-limiting enzyme in glutathione (GSH) synthesis. In a previous study, EPS was demonstrated to increase GSH levels in BAECs in association with the Nrf2 pathway. In the present study, EPS increased GSH levels in BAECs exposed to Cd. The protective ability of EPS against the Cd-induced cytotoxicity disappeared following Nrf2 small interfering RNA transfection. In addition, EPS affected the intracellular levels of Cd, Cd transporter ZIP8 and metallothionein. To the best of our knowledge, the current study demonstrated, for the first time, that EPS suppresses Cd-induced cytotoxicity in BAECs. The upregulation of GSH may be associated with the suppression of Cd-induced cytotoxicity by EPS. From these findings, it may be proposed that the regulation of GSH, ZIP8 and metallothionein by EPS is a promising therapeutic approach to prevent Cd-induced toxicity., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Aim: An index that accurately measures intravascular volume is paramount for the optimal resuscitation of sepsis. Selecting an adequate indicator to substitute for central venous pressure (CVP) has remained an issue. The objective of our study was to compare the usefulness of standard early goal-directed therapy (EGDT) with CVP (EGDT-CVP) and modified EGDT with global end-diastolic volume index (GEDI; EGDT-GEDI) for sepsis., Methods: This was a multicenter prospective randomized controlled study. All patients with sepsis who were expected to require mechanical ventilator support for a minimum of 48 h were included. The patients were classified into an EGDT-CVP group and an EGDT-GEDI group. All participants underwent the extubation protocol. The primary outcome was the ventilator-free days over a 28-day period., Results: The ventilator-free days was not significantly different between the two groups ( P  = 0.59). However, the EGDT-GEDI group showed a trend of shorter ventilator support duration (5.1 days [2.0-8.7 days] versus 3.9 days [2.4-5.7 days], P  = 0.27) and length of stay in the intensive care unit (7.2 days [3.8-10.7 days] versus 5.1 days [3.7-8.8 days], P  = 0.05) and a smaller 3-day infusion balance than the EGDT-CVP group (4,405 mL [1,092-8,163 mL] versus 3,046 mL [830-6,806 mL], P  = 0.34), but the differences were not statistically significant., Conclusion: Although there was no significant efficacy, EGDT guided by GEDI showed a trend of shorter length of stay in the intensive care unit and lower 3-day infusion balance than the EGDT-CVP group in sepsis. The GEDI monitoring did not appear to improve the ventilator-free days over a 28-day period., Competing Interests: Approval of the research protocol: This study was approved by the institutional research committees of all participating institutions. Informed consent: Written informed consent to participate was obtained from the patients, their families, or their legally authorized proxies. Registry and registration no.: The study was registered with the University Medical Information Network Clinical Trial Registry (UMIN‐CTR ID000011493). Animal studies: N/A. Conflict of interest: YT was a member of the medical advisory board of Pulsion Medical Systems. The other authors declare no competing interests., (© 2019 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Interleukin (IL)-10, a cytokine with anti-inflammatory effects, is produced by blood cells and cells of various organs. Ischemia-reperfusion injury (IRI) is a systemic inflammatory disease caused by a systemic circulation of pro-inflammatory cytokines and chemokines produced from blood cells or organs damaged by ischemia. Apoptosis, a key event after IRI, is correlated with the degree of injury. Here we investigated the effects and mechanism of IL-10 in renal IRI. Compared to wild-type (WT) mice with a renal IRI, IL-10 knockout (IL-10 KO) mice with IRI demonstrated decreased renal function as represented by blood urea nitrogen and serum creatinine, upregulated early acute kidney injury (AKI) biomarkers such as kidney injury molecule-1 (Kim-1), increased mRNA expression of the pro-inflammatory cytokines IL-1β, IL-6, and IL-18 and a chemokine (regulated on activation, normal T cell expressed and secreted; RANTES), and increased expression of the pro-apoptosis factors Bax and cleaved caspase-3. When tubular epithelial cells (TECs) from IL-10 KO mice were put in a hypoxic state and added with recombinant IL-10, their expression of Bax decreased. Our findings demonstrated that IL-10 suppressed the production of pro-inflammatory cytokines, renal dysfunction, and the expression of pro-apoptosis factors after IRI.

Heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions. Recent studies have shown that the upregulation of HO-1 is beneficial to counteract neuroinflammation, making HO-1 a new therapeutic target for neurological diseases. We have reported that epalrestat (EPS), which is currently used for the treatment of diabetic neuropathy, increases HO-1 levels through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in bovine aortic endothelial cells. In this study, we tested the hypothesis that EPS upregulates HO-1 via Nrf2 activation in the component cells of the nervous system, by using rat Schwann cells and human SH-SY5Y cells. Treatment of Schwann cells with EPS at near-plasma concentration led to a dramatic increase in HO-1 levels. Nrf2 knockdown by small interfering RNA (siRNA) suppressed the EPS-induced HO-1 expression. EPS did not promote the intracellular accumulation of free ferrous ion and reactive oxygen species, by increasing ferritin via Nrf2 during HO-1 induction. Moreover, EPS stimulated the expression of superoxide dismutase 1 and catalase, which also are Nrf2 target gene products. It also markedly increased HO-1 levels in SH-SY5Y cells through the activation of Nrf2. We demonstrated for the first time that EPS upregulates HO-1, superoxide dismutase, and catalase by activating Nrf2. We suggest that EPS has the potential to prevent several neurological diseases.

Schwann cell injury is caused by diabetic neuropathy. The apoptosis of Schwann cells plays a pivotal role in diabetic nerve dysfunction. Glycolaldehyde is a precursor of advanced glycation end products that contribute to the pathogenesis of diabetic neuropathy. In this study, we examined whether glycolaldehyde induces endoplasmic reticulum (ER) stress and apoptosis in rat Schwann cells. Schwann cells treated with 500 μM glycolaldehyde showed morphological changes characteristic of apoptosis. Glycolaldehyde activated apoptotic signals, such as caspase-3 and caspase-8. Furthermore, it induced ER stress response involving RNA-dependent protein kinase-like ER kinase (PERK), inositol-requiring ER-to-nucleus signal kinase 1α (IRE1α), and eukaryotic initiation factor 2α (eIF2α). In addition, glycolaldehyde activated CCAAT/enhancer-binding homologous protein (CHOP), an ER stress response factor crucial to executing apoptosis. Knockdown of nuclear factor E2-related factor 2 (Nrf2), which is involved in the promotion of cell survival following ER stress, enhanced glycolaldehyde-induced cytotoxicity, indicating that Nrf2 plays a protective role in the cytotoxicity caused by glycolaldehyde. Taken together, these findings indicate that glycolaldehyde is capable of inducing apoptosis and ER stress in Schwann cells. The ER stress induced by glycolaldehyde may trigger the glycolaldehyde-induced apoptosis in Schwann cells. This study demonstrated for the first time that glycolaldehyde induced ER stress.

Epalrestat (EPS) is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH) in rat Schwann cells. GSH plays a crucial role in protecting endothelial cells from oxidative stress, thereby preventing vascular diseases. Here we show that EPS increases GSH levels in not only Schwann cells but also endothelial cells. Treatment of bovine aortic endothelial cells (BAECs), an in vitro model of the vascular endothelium, with EPS caused a dramatic increase in intracellular GSH levels. This was concomitant with the up-regulation of glutamate cysteine ligase, an enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Moreover, EPS stimulated the expression of thioredoxin and heme oxygenase-1, which have important redox regulatory functions in endothelial cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of antioxidant genes. EPS increased nuclear Nrf2 levels in BAECs. Nrf2 knockdown by siRNA suppressed the EPS-induced glutamate cysteine ligase, thioredoxin-1, and heme oxygenase-1 expression. Interestingly, LY294002, an inhibitor of phosphatidylinositol 3-kinase, abolished the EPS-stimulated GSH synthesis, suggesting that the kinase is associated with Nrf2 activation induced by EPS. Furthermore, EPS reduced the cytotoxicity induced by H2O2 and tert-butylhydroperoxide, indicating that EPS plays a role in protecting cells from oxidative stress. Taken together, the results provide evidence that EPS exerts new beneficial effects on endothelial cells by increasing GSH, thioredoxin, and heme oxygenase-1 levels through the activation of Nrf2. We suggest that EPS has the potential to prevent several vascular diseases caused by oxidative stress., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Epalrestat (EPS), approved in Japan, is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Here we report that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH), which is important for protection against oxidative injury, through transcription regulation. Treatment of Schwann cells with EPS caused a dramatic increase in intracellular GSH levels. EPS increased the mRNA levels of γ-glutamylcysteine synthetase (γ-GCS), the enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that plays a central role in regulating the expression of γ-GCS. ELISA revealed that EPS increased nuclear Nrf2 levels. Knockdown of Nrf2 by siRNA suppressed the EPS-induced GSH biosynthesis. Furthermore, pretreatment with EPS reduced the cytotoxicity induced by H2O2, tert-butylhydroperoxide, 2,2'-azobis (2-amidinopropane) dihydrochloride, and menadione, indicating that EPS plays a role in protecting against oxidative stress. This is the first study to show that EPS induces GSH biosynthesis via the activation of Nrf2. We suggest that EPS has new beneficial properties that may prevent the development and progression of disorders caused by oxidative stress.

The clinical characteristics of perimesencephalic nonaneurysmal subarachnoid hemorrhage (SAH) caused by physical exertion were analyzed to investigate the causes and mechanisms of perimesencephalic nonaneurysmal SAH. Nine of 209 patients with spontaneous SAH were identified as having perimesencephalic nonaneurysmal SAH. Perimesencephalic nonaneurysmal SAH in four males and three females was precipitated by exertion. Age, sex predominance, type of exertion, symptoms, loss of consciousness during bleeding, clinical grade, angiographic spasm, hydrocephalus, delayed ischemic deficit, rebleeding, hypertension, and outcome were evaluated in these seven patients. Outcomes were assessed using the Glasgow Outcome Scale. Patients showed male predominance (57.1%), relatively young age (mean 50 years), low frequency of hypertension (28.6%), good clinical grade (World Federation of Neurological Surgeons grade I or II), and excellent outcomes including no rebleeding, no symptomatic hydrocephalus, and no delayed ischemic deficits. The type of exertion was swimming in two patients, golfing in two patients, heavy lifting in two patients, and bending forward during gymnastics in one patient. Physical exertion including components of the Valsalva maneuver is an important predisposing factor for perimesencephalic nonaneurysmal SAH. Such physical exertion produces increased intrathoracic pressure, which blocks the internal jugular venous return, resulting in elevated intracranial venous pressure or mechanical swelling of the intracranial veins, and leads to venous or capillary breakdown.

Recent studies have shown that hypertonic saline (HS) resuscitation can reduce hemorrhage-induced lung damage by preventing neutrophil activation. In this study, we examined whether this protective effect can be improved by increasing the HS dose used for resuscitation. The protective effect of two HS doses was tested in a mouse model of hemorrhagic shock. BALB/c mice were bled to a mean arterial blood pressure of 35 +/- 5 mmHg for 1 h. Then the animals were resuscitated with lactated Ringer's (LR) or with HS (7.5% NaCl) at doses of 4 mL/kg or 6 mL/kg body weight, sacrificed after 24 h, and lung tissue samples were collected. Evidence of lung injury was evaluated morphologically by scoring histology specimens in a blinded fashion. In a separate set of mice, plasma Na+ and osmolarity were determined 15 min after resuscitation. Resuscitation of hemorrhaged mice with 4 and 6 mL/kg HS increased plasma Na+ concentrations by 5 and 11 mM, respectively. LR treatment reduced plasma Na+ concentrations by 6 mM and resulted in a lung injury score of 6.1 +/- 0.8, accompanied by focal thickening of alveolar membranes, congestion, pulmonary edema, and interstitial and intra-alveolar neutrophil infiltration. HS at 4 mL/kg decreased focal thickening, congestion, pulmonary edema, and neutrophil infiltration, and the injury score to 3.8 +/- 0.9, which was not significantly different from controls (3.6 +/- 0.8), and lung damage was lowest in animals that received 6 mL/kg HS (2.5 +/- 0.2, P < 0.005 vs. LR). Lung damage scores inversely correlated with plasma Na+ concentrations (r > 0.9999). Our data suggest that the protective effect of HS may be a function of the plasma Na+ concentration and that HS at 6 mL/kg is at least equally effective in reducing hemorrhage-induced lung damage compared to the more commonly used HS dose of 4 mL/kg.

The effect of hypertonic saline resuscitation on intestinal damage and the incidence of apoptosis after hemorrhagic shock were investigated. After anesthesia, male BALB/c mice weighing 24-34 g were hemorrhaged to the mean arterial pressure of 40 +/- 5 mmHg for 90 min. Animals were randomly assigned to four groups: 1) resuscitation with 4 mL/kg of 7.5% NaCl (hypertonic saline; HS) + shed blood (SB); 2) resuscitation with two times the volume of shed blood of lactated Ringer's solution (2LR) + SB; 3) sham (catheter only); or 4) control (no treatment). Intestinal damage was graded based on the extent of the vacuolation at the basal area of the intestinal villi. Apoptosis of the small intestines was examined with the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling method and with DNA laddering. Caspase-3 activation, heat shock protein (HSP) 70, and HSP40 were assessed by western blotting. Apoptosis of the small intestine and intestinal damage were significantly lower (P < 0.01) in the HS+SB group compared with the 2LR+SB group 2 h and 6 h after hemorrhagic shock and resuscitation, respectively. This corresponded with more DNA fragmentation in the small intestine of the 2LR+SB group compared with the HS+SB group 2 h after hemorrhage and resuscitation. In addition, we observed less caspase-3 activation in the small intestine of the HS+SB group compared with the 2LR+SB group at 2 h after resuscitation. The content of HSP40 and HSP70 in the HS+SB group was similar to that in controls, but slightly decreased in the 2LR+SB group. HS resuscitation reduced intestinal damage and apoptosis after hemorrhagic shock, suggesting that HS resuscitation may improve the outcome after hemorrhagic shock by reducing apoptosis and damage to the small intestine.

Brachial plexus injury is very rare in neurosurgical practice, so many neurosurgeons have never experienced this problem in Japan. This study describes a clinical analysis of 16 patients aged 5 to 62 years (mean 32.9 years) who presented at our institution with brachial plexus injuries. Nine patients presented with paralysis and seven with paresis. Head injury was the most common associated injury in eight of 16 patients. Six patients were managed conservatively. All patients with C8-T1 paresis spontaneously recovered to a useful level. Surgery was performed in 10 patients: six neurolysis, two neurotization, and three nerve grafting procedures. All six patients who underwent neurolysis of the brachial plexus attained useful recovery. Four of five patients achieved useful recovery after nerve repair. Nerve grafting achieved a better outcome than neurotization in this study. The difference of outcome was attributed to the graft length. The management of brachial plexus injury is a great challenge, but surgical outcome can be improved if the optimal repair procedure is selected for brachial plexus injury.

With the aim of preparing a stationary phase with a high shape-recognition ability for liquid chromatography, a new bonded phase was synthesized by coupling multiply dodecylamino-substituted beta-cyclodextrin (beta-CD) to 3-glycidoxypropyl-derivatized silica gel. The stationary phase prepared in this way was expected to have increased shape selectivity compared with that of conventional reversed-phase materials, due to solute interactions with the alkyl chain piles built up on the beta-CDs bonded to silica. The separation characteristics of the bonded phase were investigated using polycyclic aromatic hydrocarbons (PAHs) with different molecular shapes and compared with those of monomeric ODS and native beta-cyclodextrin-bonded phases. The newly developed stationary phase was found to be highly selective for PAHs.

A one-year-old boy presented with orbitocranial penetrating injury by a chopstick. Neurological examination did not reveal abnormal findings. Skull radiography did not reveal any sign of fracture and there were no abnormal findings. Initially, computed tomography (CT) of the head did not reveal any intracranial lesions. However, bone window CT showed a well-defined low-density abnormality measuring 2.5 cm in length in the right orbit and parasellar region. Magnetic resonance imaging clearly revealed a low-intensity structure extending from the orbit to the prepontine area. Surgical exploration was emergently performed and the wooden fragment was removed. The postoperative course was uneventful. Transorbital penetrating injury by a wooden foreign body is relatively rare. The wound may be superficial and trivial. Major neurological deficit does not usually manifest immediately, so the penetrating injury may be overlooked. If the foreign body is retained in the orbit and cranium, severe infectious complications may occur later.

Hypertonic saline (HS) resuscitation has been reported to prevent lung damage by suppressing neutrophil activation in animal models. Data on the effectiveness of HS to prevent organ damage in the clinical setting are inconsistent. We investigated whether the timing of HS administration relative to neutrophil activation could affect its potential to block neutrophil responses. Different likely clinical circumstances were simulated in vitro by exposing human neutrophils to HS at different time points before and after activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP). The in vivo effect of using HS as a secondary resuscitation fluid was determined with a mouse model of hemorrhage. BALB/c mice were hemorrhaged (40 +/- 5 mmHg) for 1 h and partially resuscitated with HS or Lactated Ringer's (LR) 20 min before completing resuscitation with LR or HS, respectively. Neutrophil activation parameters were determined 2 h after complete resuscitation and lung damage was assessed after 24 h. The length of exposure to physiologically relevant HS levels (20 mM) determined the suppressive effect on in vitro neutrophil superoxide formation. HS treatment caused a transient state of suppression during which neutrophil activation was suppressed; however, HS was unable to suppress cells that were stimulated with fMLP before HS was added. Accordingly, in vivo lung damage was greater in animals that received HS after they had been partially resuscitated with LR compared to mice that received HS before LR (P < 0.05). We conclude that timing of exposure to HS affects neutrophil responses in vitro and may reduce the potential of HS resuscitation to prevent lung injury in vivo.

We measured the plasma levels of adrenomedullin (AM), a novel vasodilating peptide, in 89 patients with various forms of systemic inflammatory response syndrome (SIRS) and 13 healthy volunteers serving as controls. Plasma levels of AM in SIRS (burns: 20.5 +/- 3. 2 fmol/ml [mean +/- SEM]; pancreatitis: 13.8 +/- 3.8 fmol/ml; trauma: 14.9 +/- 2.5 fmol/ml; traumatic shock: 41.1 +/- 7.8 fmol/ml; severe sepsis: 59.9 +/- 11.2 fmol/ml; septic shock: 193.5 +/- 30.1 fmol/ml) were significantly increased over those of controls (5.1 +/- 0.2 fmol/ml). The patients with traumatic shock or septic shock especially had higher levels of plasma AM than those with trauma or severe sepsis, respectively. These data showed that in patients with SIRS, plasma AM levels increased in proportion to the severity of illness. Subsequently, we measured the plasma levels of mediators such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, plasminogen activator inhibitor (PAI)-1, and thrombomodulin (TM) in patients with traumatic shock and septic shock. A significant correlation was observed between plasma AM and TNF-alpha levels in patients with septic shock, suggesting an important role for AM as well as of TNF-alpha in the pathophysiology of inflammation. Plasma AM and IL-8 levels correlated positively with Acute Physiology and Chronic Health Evaluation (APACHE) II score, peak multiple organ failure (MOF) score during the first month and prognosis in patients with septic shock, as did plasma IL-6 levels in patients with traumatic shock. The plasma AM level might serve as a useful marker for evaluating the severity of disease and as an early predictor of subsequent organ failure and outcome in septic shock.