Inter-rater reliability of the Conversational Assessment of Neurocognitive Dysfunction.

BACKGROUND: Cognitive assessment through communication has been the focus of recent studies because the conventional cognitive tests are often considered invasive for older people. Although the Conversational Assessment of Neurocognitive Dysfunction is designed to assess cognitive function non-invasively, inter-rater reliability remains unclear. The current study investigated the Conversational Assessment of Neurocognitive Dysfunction's reliability. METHODS: The Conversational Assessment of Neurocognitive Dysfunction was used by four clinical psychologists, who evaluated 38 older people with and without cognitive dysfunction. One clinical psychologist evaluated the assessment based on face-to-face communication with participants, while the other clinical psychologists evaluated it according to the audio data in the digital voice recorder. All clinical psychologists were blind to the results of other conventional cognitive tests and details surrounding participants' daily living activities. RESULTS: The univariate correlation scores of the Conversational Assessment of Neurocognitive Dysfunction among evaluators ranged from 0.61 to 0.79, all of which were significant (P < 0.001). The intraclass correlation coefficient was 0.64 (P < 0.001, 95% CI: 0.53-0.79 for agreement) and 0.67 (P < 0.001, 95% CI: 0.45-0.77 for consistency). The Conversational Assessment of Neurocognitive Dysfunction score of all evaluators was significantly associated with conventional cognitive tests like the Mini-Mental State Examination (P < 0.001). CONCLUSIONS: The findings suggested that the Conversational Assessment of Neurocognitive Dysfunction has moderate to good inter-rater reliability and high concurrent validity as a cognitive assessment tool, and it would be useful in clinical practice.

Recombinant Antithrombin Attenuates Acute Respiratory Distress Syndrome in Experimental Endotoxemia.

Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1ß was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury.

Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model.

Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otcspf-ash ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8-mediated delivery of a short hairpin RNA in Otcspf-ash mice diminished hyperammonemia and reduced lethality. Knockdown of Gls2 but not Glud1 in Otcspf-ash mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that Gls2 hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.

Hepatic Glucagon Signaling Regulates PCSK9 and Low-Density Lipoprotein Cholesterol.

RATIONALE: Glucagon is a key hormone that regulates the adaptive metabolic responses to fasting. In addition to maintaining glucose homeostasis, glucagon participates in the regulation of cholesterol metabolism; however, the molecular pathways underlying this effect are incompletely understood. OBJECTIVE: We sought to determine the role of hepatic Gcgr (glucagon receptor) signaling in plasma cholesterol regulation and identify its underlying molecular mechanisms. METHODS AND RESULTS: We show that Gcgr signaling plays an essential role in LDL-C (low-density lipoprotein cholesterol) homeostasis through regulating the PCSK9 (proprotein convertase subtilisin/kexin type 9) levels. Silencing of hepatic Gcgr or inhibition of glucagon action increased hepatic and plasma PCSK9 and resulted in lower LDLR (LDL receptor) protein and increased plasma LDL-C. Conversely, treatment of wild-type (WT) mice with glucagon lowered LDL-C levels, whereas this response was abrogated in Pcsk9-/- and Ldlr-/- mice. Our gain- and loss-of-function studies identified Epac2 (exchange protein activated by cAMP-2) and Rap1 (Ras-related protein-1) as the downstream mediators of glucagon's action on PCSK9 homeostasis. Moreover, mechanistic studies revealed that glucagon affected the half-life of PCSK9 protein without changing the level of its mRNA, indicating that Gcgr signaling regulates PCSK9 degradation. CONCLUSIONS: These findings provide novel insights into the molecular interplay between hepatic glucagon signaling and lipid metabolism and describe a new posttranscriptional mechanism of PCSK9 regulation.

Glucagon contributes to liver zonation.

Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/ß-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/ß-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/ß-catenin. The glucagon and Wnt/ß-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counterplay with the Wnt/ß-catenin signaling pathway.

Multiple trauma including pelvic fracture with multiple arterial embolization: an autopsy case report.

BACKGROUND: Pelvic fracture with high energy trauma has a high mortality rate, especially in men. In addition, severe multiple trauma, major hemorrhage, and administration of red blood cells predict mortality in elderly patients with pelvic fracture. We herein report a rare case in which multiple arterial embolization occurred after pelvic fracture. CASE PRESENTATION: An 83-year-old male cyclist was transported to our hospital after being struck by a car. On arrival, he was diagnosed with multiple trauma, including rib fractures with hemothorax, lumbar fractures of the transverse process, and injuries in the right acetabulum, left adrenal gland, and liver. He underwent massive transfusion and transcatheter arterial embolization due to extravasation from the right superior gluteal artery and left adrenal gland. On the second day, owing to right lower leg ischemia, serum creatinine kinase and myoglobin levels were markedly elevated from the reference value; hence, a right above-knee amputation was performed 12 h after the accident. However, both protein levels remained high after amputation, resulting in acute renal injury, which was treated via hemodiafiltration on hospital day 3. In addition, sustained low efficiency hemodialysis and plasma exchange were performed on hospital day 4. Despite these treatments, the patient's hemodynamics did not improve, and he died on hospital day 8. The autopsy revealed necropsy of the iliopsoas muscles and the digestive tract. CONCLUSIONS: The causes of the patient's death were considered to be persistent rhabdomyolysis and severe hypotension due to iliopsoas necrosis and peritonitis due to digestive tract necrosis. Multiple arterial embolization caused by consumption coagulopathy associated with multiple trauma may account for severe outcomes in this case.

Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice.

Inactivating mutations in the insulin receptor results in extreme insulin resistance. The resulting hyperglycemia is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. We used the insulin receptor antagonist S961 to induce severe insulin resistance, hyperglycemia, and ketonemia in mice. Using this model, we show that glucagon receptor (GCGR) inhibition with a monoclonal antibody normalized blood glucose and ß-hydroxybutyrate levels. Insulin receptor antagonism increased pancreatic ß-cell mass threefold. Normalization of blood glucose levels with GCGR-blocking antibody unexpectedly doubled ß-cell mass relative to that observed with S961 alone and 5.8-fold over control. GCGR antibody blockage expanded α-cell mass 5.7-fold, and S961 had no additional effects. Collectively, these data show that GCGR antibody inhibition represents a potential therapeutic option for treatment of patients with extreme insulin-resistance syndromes.

Angptl4 does not control hyperglucagonemia or α-cell hyperplasia following glucagon receptor inhibition.

Genetic disruption or pharmacologic inhibition of glucagon signaling effectively lowers blood glucose but results in compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Ben-Zvi et al. recently reported that angiopoietin-like protein 4 (Angptl4) links glucagon receptor inhibition to hyperglucagonemia and α-cell proliferation [Ben-Zvi et al. (2015) Proc Natl Acad Sci USA 112:15498-15503]. Angptl4 is a secreted protein and inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. We report that Angptl4-/- mice treated with an anti-glucagon receptor monoclonal antibody undergo elevation of plasma glucagon levels and α-cell expansion similar to wild-type mice. Overexpression of Angptl4 in liver of mice caused a 8.6-fold elevation in plasma triglyceride levels, but did not alter plasma glucagon levels or α-cell mass. Furthermore, administration of glucagon receptor-blocking antibody to healthy individuals increased plasma glucagon and amino acid levels, but did not change circulating Angptl4 concentration. These data show that Angptl4 does not link glucagon receptor inhibition to compensatory hyperglucagonemia or expansion of α-cell mass, and that it cannot be given to induce such secretion and growth. The reduction of plasma triglyceride levels in Angptl4-/- mice and increase following Angptl4 overexpression suggest that changes in plasma triglyceride metabolism do not regulate α-cells in the pancreas. Our findings corroborate recent data showing that increased plasma amino acids and their transport into α-cells link glucagon receptor blockage to α-cell hyperplasia.

Characterization of glucose-stimulated insulin release protocols in african green monkeys (Chlorocebus aethiops).

BACKGROUND: Management of diabetes remains a major health and economic challenge, demanding test systems in which to develop new therapies. These studies assessed different methodologies for determining glucose tolerance in green monkeys. METHODS: Twenty-eight African green monkeys between 4 and 24 years old underwent single or repeat intravenous glucose tolerance testing (IVGTT), oral glucose tolerance testing (OGTT), and/or graded glucose infusion testing. RESULTS: Geriatric monkeys exhibited glucose intolerance with impaired glucose-stimulated insulin secretion following IVGTT. Repeat IVGTT and OGTT assessments were inconsistent. Monkeys with low glucose-stimulated insulin secretion after graded glucose infusion exhibited elevated blood glucose levels. CONCLUSION: IVGTT and graded glucose infusion protocols revealed differences in glucose tolerance among green monkeys at single time points, including age-dependent differences suggestive of shifts in pancreatic beta-cell functional capacity, but care should be applied to study design and the interpretation of data in the setting of longitudinal studies.

Efficacy and Safety of the Ultra-Short-Acting ß1-Selective Blocker Landiolol in Patients With Recurrent Hemodynamically Unstable Ventricular Tachyarrhymias　- Outcomes of J-Land II Study.

BACKGROUND: We aimed to investigate the efficacy and safety of landiolol in Japanese patients with recurrent hemodynamically unstable ventricular tachycardia or recurrent ventricular fibrillation (recurrent VT/VF).Methods and Results:This was an open-label, uncontrolled, multicenter study. Patients with hemodynamically unstable VT or VF 24 h prior to providing informed consent, and who were refractory to class III antiarrhythmic drugs, were enrolled. Landiolol was started at a dose of 1 µg/kg/min, after VT/VF was suppressed with electrical defibrillation. Landiolol was titrated up to 10 µg/kg/min in 1 h and adjusted between 1 and 40 µg/kg/min for the efficacy assessment (1-49 h). The primary efficacy endpoint was the proportion of patients free from recurrent VT/VF. Secondary efficacy endpoints included the number of recurrent VT/VF events and the survival rate 30 days after the start of landiolol treatment. Adverse events (AEs) were assessed for safety; 27 and 29 patients were analyzed for efficacy and safety, respectively. The proportion of patients free from recurrent VT/VF was 77.8% (95% CI 57.1-89.3). The mean (±standard deviation) number of recurrent VT/VF events was 9.3±7.9. The survival rate was 96.3%. The overall incidence of AEs and of serious AEs was 72.4% and 6.9%, respectively. CONCLUSIONS: Landiolol may be useful for Japanese patients with recurrent VT/VF who do not respond to class III antiarrhythmic drugs.

Use of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells.

This study provides an assessment of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells. The system combines microfluidic technology and nanoliter-scale reactions. We sequenced 622 cells, allowing identification of 341 islet cells with high-quality gene expression profiles. The cells clustered into populations of α-cells (5%), ß-cells (92%), δ-cells (1%), and pancreatic polypeptide cells (2%). We identified cell-type-specific transcription factors and pathways primarily involved in nutrient sensing and oxidation and cell signaling. Unexpectedly, 281 cells had to be removed from the analysis due to low viability, low sequencing quality, or contamination resulting in the detection of more than one islet hormone. Collectively, we provide a resource for identification of high-quality gene expression datasets to help expand insights into genes and pathways characterizing islet cell types. We reveal limitations in the C1 Fluidigm cell capture process resulting in contaminated cells with altered gene expression patterns. This calls for caution when interpreting single-cell transcriptomics data using the C1 Fluidigm system.

Recombinant antithrombin attenuates acute kidney injury associated with rhabdomyolysis: an in vivo animal study.

BACKGROUND: Rhabdomyolysis is characterized by the destruction and necrosis of skeletal muscle tissue, resulting in acute kidney injury (AKI). Recombinant antithrombin (rAT) has DNA repair and vascular endothelial-protection properties. Herein, we investigated whether rAT therapy has beneficial effects against rhabdomyolysis-induced AKI. Ten-week-old male B6 mice were injected with 5 mL/kg of 50% glycerol intramuscularly in the left thigh after 24 h of fasting to create a rhabdomyolysis mouse model. Further, 750 IU/kg rAT was injected intraperitoneally at 24 and 72 h after the rhabdomyolysis model was established. The mice were euthanized after 96 h for histological analysis. Saline was administered to mice in the control group. RESULTS: Blood tests show elevated serum creatinine, urea nitrogen, and neutrophil gelatinase-associated lipocalin levels in rhabdomyolysis. Loss of tubular epithelial cell nuclei and destruction of the tubular luminal surface structure was observed in the untreated group, which improved with rAT treatment. Immunostaining for Ki-67 showed increased Ki-67-positive nuclei in the tubular epithelial cells in the rAT group, suggesting that rAT may promote tubular epithelial cell regeneration. The microvilli of the brush border of the renal tubules were shed during rhabdomyolysis, and rAT treatment reduced this injury. The vascular endothelial glycocalyx, which is usually impaired by rhabdomyolysis, became functional following rAT treatment. CONCLUSIONS: Treatment with rAT suppressed rhabdomyolysis-induced AKI, suggesting that rAT therapy may be a novel therapeutic approach.

Serum syndecan-1 concentration in hemolysis, elevated liver enzymes, and low platelets syndrome: A case report.

Background: Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome occurs in pregnant and postpartum individuals. We observed serum syndecan-1 (SDC-1) levels, which is a component of the glycocalyx, in a patient with HELLP syndrome from admission to the postpartum period and examined their association as reflecting the pathophysiology related to endothelial injury. Case presentation: A 31-year-old primiparous female patient without a previous medical history at a gestational age of 37 weeks and 6 days was transferred to our hospital the morning after a visit to a previous hospital with headache and nausea. Elevated transaminase, platelet count, and proteinuria were noted. Head magnetic resonance imaging revealed a caudate nucleus hemorrhage and posterior reversible encephalopathy syndrome. After she delivered her newborn through an emergency cesarean section, she was admitted to the intensive care unit. On day 4 post-delivery, the patient's D-dimer concentration was elevated, and contrast-enhanced computed tomography was performed. The results indicated pulmonary embolism, and heparin administration was initiated. The serum SDC-1 level was highest on day 1 post-delivery and quickly decreased subsequently; however, it remained elevated during the postpartum period. Her condition gradually improved, and she was extubated on day 6 and discharged from the ICU on day 7 post-delivery. Conclusion: We measured SDC-1 concentration in a patient with HELLP syndrome and found that the clinical course correlated with SDC-1 levels, indicating that SDC-1 is elevated immediately before and after pregnancy termination in patients with HELLP syndrome. Therefore, SDC-1 fluctuations, combined with the elevation of the D-dimer level, may be a potential marker for the early detection of HELLP syndrome and estimation of the syndrome's severity in the future.

Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice.

Introduction: Common variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in heterozygous individuals only, are protective against the disease, even though knockout of the homologous SLC30A8 gene in mice leads to unchanged or impaired glucose tolerance. Here, we aimed to determine how one or two copies of the mutant R138X allele in the mouse SLC30A8 gene impacts the homeostasis of zinc at a whole-body (using non-invasive 62Zn PET imaging to assess the acute dynamics of zinc handling) and tissue/cell level [using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to map the long-term distribution of zinc and manganese in the pancreas]. Methods: Following intravenous administration of [62Zn]Zn-citrate (~7 MBq, 150 µl) in wild-type (WT), heterozygous (R138X+/-), and homozygous (R138X+/+) mutant mice (14-15 weeks old, n = 4 per genotype), zinc dynamics were measured over 60 min using PET. Histological, islet hormone immunohistochemistry, and elemental analysis with LA-ICP-MS (Zn, Mn, P) were performed on sequential pancreas sections. Bulk Zn and Mn concentration in the pancreas was determined by solution ICP-MS. Results: Our findings reveal that whereas uptake into organs, assessed using PET imaging of 62Zn, is largely unaffected by the R138X variant, mice homozygous of the mutant allele show a substantial lowering (to 40% of WT) of total islet zinc, as anticipated. In contrast, mice heterozygous for this allele, thus mimicking human carriers of LoF alleles, show markedly increased endocrine and exocrine zinc content (1.6-fold increase for both compared to WT), as measured by LA-ICP-MS. Both endocrine and exocrine manganese contents were also sharply increased in R138X+/- mice, with smaller increases observed in R138X+/+ mice. Discussion: These data challenge the view that zinc depletion from the beta cell is the likely underlying driver for protection from type 2 diabetes development in carriers of LoF alleles. Instead, they suggest that heterozygous LoF may paradoxically increase pancreatic ß-cell zinc and manganese content and impact the levels of these metals in the exocrine pancreas to improve insulin secretion.

Starvation-induced elevation of taste responsiveness and expression of a sugar taste receptor gene in Drosophila melanogaster.

Animals increase their feeding motivation under starved conditions. Here the authors test if the starvation-induced increase of feeding motivation is different among wild-derived strains of Drosophila melanogaster. In behavioral experiments comparing the feeding behaviors of the strains Mel6 and TW1, only TW1 exhibited a decreased feeding threshold to sucrose following a 24-h starvation period. Starved TW1 preferably ingested a low concentration of sucrose. Starved TW1 also exhibited significant elevation of taste responsiveness to low concentrations of sucrose and enhanced expression of the Gr64a sucrose sugar receptor gene. TW1 survived longer than Mel6 when provided a less nutritious food (10 mM sucrose). Thus, the starvation-induced decrease in the behavioral and the sensory thresholds could be an advantage in searching for and utilizing less nutritious foods. These results show that the starvation-induced functional change in the taste sensory system is a possible strategy for survival during starvation or suboptimal nutrient periods.

A pediatric case of axial rotary fixation associated with severe head trauma requiring emergency craniotomy for hematoma removal.

Background: Atlantoaxial rotatory fixation (AARF) causes the atlantoaxial joint to be fixed in a rotated position, resulting in painful torticollis. We report a case of pediatric AARF associated with severe head trauma requiring emergency craniotomy and was treated with conservative treatment. Case presentation: A 10-year-old boy was struck by a van while walking across the street. Upon admission to our trauma care center, his Glasgow Coma Scale score was 11 points (E3V3M5), pupils were 4 mm bilateral regular circles, and other vital signs were stable. Plain computed tomography (CT) revealed left acute epidural hematoma, traumatic subarachnoid hemorrhage, cerebral contusion, pneumoencephalopathy, and rightward deviation of the axial vertebra. We performed an emergency craniotomy due to an enlarged hematoma on a repeat head CT scan and decreased level of consciousness. Based on imaging studies, rightward deviation of the axial vertebra was diagnosed as AARF; however, since the patient was already on ventilatory management and no physical findings were obtained, conservative treatment with cervical collar fixation was started. His condition improved, and he was extubated on day 3, released from the cervical collar on day 10, discharged from the hospital on day 17, and followed-up until day 32. Conclusions: AARF is often caused by minor trauma or inflammation in children; however, we experienced a case complicated by severe head trauma, which was treated conservatively and showed a good clinical progress. Since AARF treatment depends on the length of time from onset, early diagnosis, in trauma care, carefully assessing factors other than major trauma, will lead to improved prognosis.

Leriche syndrome diagnosed due to polytrauma: a case report.

BACKGROUND: Leriche syndrome is caused by atherosclerosis and is often characterized by symptoms such as intermittent claudication and numbness and coldness of the lower limbs. Its exact prevalence and incidence are unknown because it is a rare disease. We report a case of Leriche syndrome diagnosed incidentally on trauma pan-scan computed tomography (CT). CASE PRESENTATION: A 61-year-old Asian male was driving a passenger car and had a head-on collision with a dump truck that required an emergency call. The patient was transported to our hospital in a doctor's helicopter. Physical examination revealed the following vital signs: respiratory rate, 23 breaths per min; SpO2, 98% under a 10-L administration mask; pulse rate, 133 beats per min; blood pressure, 142/128 mmHg; Focused Assessment with Sonography for Trauma, positive; Glasgow Coma Scale assessment, E3V5M6; and body temperature, 35.9 °C. Trauma pan-scan CT showed bilateral mandibular fractures, bilateral multiple rib fractures, bilateral pneumothorax, sternal fractures, hematoma around thoracic spine, small bowel perforation, mesenteric injury, right clavicle fracture, right ankle debridement injury, and thrombotic occlusion from just above the abdominal aortic bifurcation to the bilateral common iliac arteries. Although thrombotic occlusion needed to be differentiated from traumatic aortic injury, the presence of collateral blood vessels led to the diagnosis of Leriche syndrome, and conservative treatment was performed. Damage control surgery was required for the small bowel injuries. From the second day of admission, the patient was treated with continuous intravenous heparin and prostaglandin preparations. However, impaired blood flow and reperfusion injury in the right lower extremity progressed. On the fifth day of admission, right thigh amputation was performed. The patient required renal replacement therapy for 2 weeks starting from the third day of admission. CONCLUSIONS: In this case, conservative therapy was initially chosen for Leriche syndrome. However, the complex factors in the acute phase of trauma led to development of hemorrhagic necrosis, requiring amputation of the lower extremity. Our findings indicate the need to carefully consider the unique factors affecting Leriche syndrome patients when considering treatment indications and choices for trauma.

Recombinant thrombomodulin may protect cardiac capillary endothelial glycocalyx through promoting Glypican-1 expression under experimental endotoxemia.

Introduction: Myocardial dysfunction occurs in patients with sepsis due to vascular endothelial injury. Recombinant human thrombomodulin (rhTM) attenuates vascular endothelial injuries through endothelial glycocalyx (eGC) protection. Hypothesis: We hypothesized that rhTM attenuates myocardial dysfunction via the inhibition of vascular endothelial injury during sepsis. Methods: Ten-week-old male C57BL6 mice were injected intraperitoneally with 20 mg/kg of lipopolysaccharide (LPS). In rhTM-treated mice, rhTM was injected intraperitoneally at 3 and 24 h after LPS injection. Saline was injected intraperitoneally as control. To assess for eGC injury, intensity score was measured 48 h after the LPS injection. To confirm vascular endothelial injuries, ultrastructural analysis was performed using scanning (SEM) and transmission electron microscopy (TEM). Results: The survival rate of the rhTM group at 48 h after LPS injection was significantly higher than that of the control group (68% vs. 17%, p < 0.05). The serum level of troponin I in the rhTM group was lower than that in the control (2.2 ± 0.4 ng/dL vs 9.4 ± 1.1 ng/dL, p < 0.05). The expression of interleukin-6 (IL-6) was attenuated in the rhTM-treated group than in the control (65.3 ± 15.3 ng/mL vs 226.3 ± 19.4 ng/mL, p < 0.05). The serum concentration of syndecan-1, a marker of glycocalyx damage, was significantly decreased 48 h post-administration of LPS in the rhTM-treated group than in the control group. In ultrastructural analysis using SEM and TEM, eGC peeled off from the surface of the capillary lumen in the control. Conversely, the eGC injury was attenuated in the rhTM group. Gene set enrichment analysis revealed that osteomodulin, osteoglycin proline/arginine-rich end leucine-rich repeat protein, and glypican-1, which are proteoglycans, were preserved by rhTM treatment. Their protein expression was retained in endothelial cells. Conclusion: rhTM attenuates sepsis-induced myocardial dysfunction via eGC protection.

The Economic Burden of Dementia: Evidence from a Survey of Households of People with Dementia and Their Caregivers.

Although a cognitive impairment such as dementia causes serious economic problems among older people, its impact on economic activities is unclear. This study investigated the actual conditions of economic activities and the current status of the financial support systems among people with dementia and caregivers. One hundred and five dyads participated in the survey. Each dyad consisted of an older person with Alzheimer's disease and their caregiver. The Mini-Mental State Examination (MMSE) and Functional Assessment Staging (FAST) were used to evaluate the cognitive functions of people with dementia. The caregivers were asked questions concerning the financial status of the household and their utilization of the financial support systems available to people with dementia. Average monthly care costs significantly increased according to the severity of dementia, while household income and spending incurred no significant changes. People with dementia experienced financial problems (including a large amount of erroneously purchased, unnecessary shopping), even though their assets were informally managed by their caregivers. Financial support systems such as adult guardianship and civil trust systems were rarely known and used. We proposed the propagation of the adult guardianship and civil trust systems and the development of contract guidelines for elderly customers including people with dementia.

Glucagon Receptor Inhibition Reduces Hyperammonemia and Lethality in Male Mice with Urea Cycle Disorder.

The liver plays a critical role in maintaining ammonia homeostasis. Urea cycle defects, liver injury, or failure and glutamine synthetase (GS) deficiency result in hyperammonemia, serious clinical conditions, and lethality. In this study we used a mouse model with a defect in the urea cycle enzyme ornithine transcarbamylase (Otcspf-ash) to test the hypothesis that glucagon receptor inhibition using a monoclonal blocking antibody will reduce the hyperammonemia and associated lethality induced by a high-protein diet, which exacerbates disease. We found reduced expression of glutaminase, which degrades glutamine and increased expression of GS in livers of Otcspf-ash mice treated with the glucagon receptor blocking antibody. The gene expression changes favor ammonia consumption and were accompanied by increased circulating glutamine levels and diminished hyperammonemia. Otcspf-ash mice treated with the glucagon receptor-blocking antibody gained lean and body mass and had increased survival. These data suggest that glucagon receptor inhibition using a monoclonal antibody could reduce the risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle, liver injury, or failure and GS deficiency.