BACKGROUND/AIM: This study aimed to elucidate a surrogate marker of sarcopenia in patients with liver cirrhosis (LC). METHODS: A total of 424 patients were assessed for handgrip strength (HGS) and skeletal muscle index (SMI). They were divided into two groups: sarcopenia (Group S; n = 80) and nonsarcopenia (Group NS; n = 344). RESULTS: Group S showed significantly lower HGS, SMI, and hemoglobin (Hb) levels in males and females; and lower serum levels of albumin, cholinesterase, and zinc (all p < 0.001), along with significantly higher serum levels of procollagen Type III-N-peptide and type IV collagen 7S-domain (p < 0.001 and p < 0.0017) than Group NS. The risk factors for sarcopenia were age <= 65 years, female, Child-Pugh class C, and Hb levels < 10.9 g/dL in females and < 12.4 g/dL in males (p = 0.012, p < 0.001, p = 0.031 p < 0.001). Significant positive correlations were found between the Hb level and the SMI and HGS (r = 0.4 p < 0.001, r = 0.4 p < 0.001). Sarcopenia, low HGS, and low SMI were significantly associated with overall survival in patients with LC (all p < 0.001). The predictive accuracy of Hb levels for predicting sarcopenia was significantly higher than that for predicting SMI and tended to be higher than that for predicting HGS (p = 0.014 and p = 0.059, respectively). CONCLUSION: Hb levels are predictive of sarcopenia in patients with LC and warrants further investigation as a biomarker for sarcopenia in LC. This article is protected by copyright. All rights reserved.
Although organophosphorus agents are used worldwide as pesticides, there have been many reports of pesticide poisoning. Nerve agents are organophosphorus agents that interfere with neurotransmission and have been used as chemical weapons in wars. These agents mainly irreversibly inhibit the action of acetylcholinesterase, an enzyme that breaks down acetylcholine, a neurotransmitter, and are believed to cause acute symptoms of poisoning. However, in recent years, the presence of subacute, delayed toxicity independent of acetylcholinesterase inhibition has been reported for some organophosphorus agents. We analyzed the subacute and delayed toxicity of bis(isopropylmethyl)phosphonate (BIMP), which has the same phosphonate group as sarin. BIMP rounded out the morphology of the cells and reduced the proportion of cells in the G1 phase of the cell cycle over time. No DNA damage was observed, suggesting that BIMP may affect cell division.
We aimed to prospectively identify the risk factors of sarcopenia in patients with cirrhosis.Patients (n=193) included in a discovery cohort (January 2011 and December 2014) were categorized into alcoholic (A1; n=55) and non-alcoholic cirrhosis (NA; n=138) groups, and those (n=235) in a validation cohort (January 2015 to December 2019) were categorized into alcoholic (n=92), non-alcoholic steatohepatitis-related (n=27), and hepatitis C virus-related cirrhosis groups (n=116). Skeletal muscle mass index (SMI) was determined using computed tomography (SMI-CT) and bioelectrical impedance analysis (SMI-BIA). Endotoxin activity (EA) was measured with an EA assay.SMI-CT correlated with grip strength in all the groups but significantly correlated with SMI-BIA of the men in group A1 (R=0.64, P<.0001) and both sexes in group NA (male: R=0.44, P=.0001; female: R=0.35, P=.003). SMI-CT inversely correlated with the EA levels of the men in group A1 (R=-0.67, P<.0001) and myostatin levels in group NA (R=-0.53, P<.0001). Lower extremity SMI had a strong negative correlation with the EA levels of the men in group A1 (R=-0.58, P<.001), whereas upper extremity SMI showed an inverse trend with EA levels (R=-0.28, P=.08). SMI-CT also inversely correlated with the EA levels in groups A2 (R=-0.52, P=.003) and N (R=-0.67, P<.0001) and myostatin levels in group C (R=-0.65, P<.0001). Moreover, SMI-CT correlated with nutritional factors, including cholinesterase (R=0.50, P=.005), zinc (R=0.45, P=.01), branched amino acid-to-tyrosine ratio (R=0.39, P=.02), and triglyceride (R=0.33, P=.03) in group N.Sarcopenia risk factors differ among cirrhosis etiologies. Alcohol-induced, intestine-mediated peripheral endotoxemia could participate in sarcopenia development in patients with alcoholic cirrhosis.
In our research program to identify cholinesterase and beta-secretase inhibitors, we investigated Ginseng (root of Panax ginseng), a crude drug described as a multifunctional drug in the ancient Chinese herbal book Shennong Ben Cao Jing. Results from hexane and methanol extracts showed moderate inhibitory activities. This suggests that ginseng roots may be effective for the prevention of and therapy for dementia. We then focused on hexane extracts of raw ginseng root and dried ginseng root since the determination of hexane extract constituents has not been studied extensively. Activity-guided fractionation and purification led to the isolation of 4 polyacetylene compounds; homopanaxynol, homopanaxydol, (9Z)-heptadeca-1, 9-diene-4,6-diyn-3-one, and (8E)-octadeca-1,8-diene-4,6-diyn-3,10-diol. The chemical structures of these compounds, including stereochemistry, were determined. This is the first study to identify the structure of homopanaxynol and homopanaxydol. Moreover, the modes of action of some compounds were characterized as competitive inhibitors. This study showed, for the first time, that polyacetylene compounds possess acetylcholinesterase inhibitory activities.
Title: The Sarin-like Organophosphorus Agent bis (isopropyl methyl)phosphonate Induces Apoptotic Cell Death and COX-2 Expression in SK-N-SH Cells Arima Y, Yoshimoto K, Namera A, Makita R, Murata K, Nagao M Ref: Hiroshima J Med Sci, 65:1, 2016 : PubMed
Organophosphorus compounds, such as sarin, are highly toxic nerve agents that inhibit acetylcholinesterase (AChE), but not cholinesterase, via multiple mechanisms. Recent studies have shown that organophosphorus compounds increase cyclooxygenase-2 (COX-2) expression and induce neurotoxicity. In this study, we examined the toxicity of the sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate (BIMP) and the effects of BIMP on COX-2 expression in SK-N-SH human neuroblastoma cells. Exposure to BIMP changed cell morphology and induced caspase-dependent apoptotic cell death accompanied by cleavage of caspase 3, caspase 9, and poly (ADP-ribose) polymerase (PARP). It also increased COX-2 expression, while pretreatment with a COX inhibitor, ibuprofen, decreased BIMP-dependent cell death and COX-2 expression in SK-N-SH cells. Thus, our findings suggest that BIMP induces apoptotic cell death and upregulates COX-2 expression.
Organophosphorus (OP) compounds such as sarin are toxic agents that irreversibly inhibit the enzyme acetylcholinesterase. A recent study showed that OP compounds also have multiple toxicity mechanisms, and another suggested that endoplasmic reticulum (ER) dysfunction contributes to OP toxicity. However, the signaling pathway and mechanisms involved are poorly understood. We examined whether the sarin-like OP agent bis(isopropyl methyl)phosphonate (BIMP), which exhibits toxicity similar to that of sarin, induced ER stress in human astrocytoma CCF-STTG1 cells. Our results demonstrate that BIMP exposure reduced cell viability. Moreover, it induced changes in mitochondrial membrane potential and increased cleavage of caspase 3. Treatment with BIMP increased the mRNA levels of the ER stress marker genes binding immunoglobulin protein (BiP) and the transcription factor C/EBP homologous protein (CHOP). Furthermore, BIMP increased the protein expressions and phosphorylation of BiP, CHOP, and protein kinase RNA-like ER kinase and the phosphorylation of eukaryotic translation initiation factor 2. Compared to BIMP treatment alone, pretreatment with the CHOP siRNA, siCHOP, decreased BIMP-dependent CHOP expression and improved CCF-STTG1 cell viability. Our findings suggest that BIMP induced mitochondrial dysfunction and apoptotic cell death event mediated by ER stress in CCF-STTG1 cells and that treatment targeted at managing ER stress has the potential to attenuate the toxicity of OP nerve agents.
BACKGROUND: Trelagliptin, an oral DPP-4 inhibitor, which is administered once per week and characterized by a long half-life in blood. The effects of trelagliptin on vascular endothelial functions have not been clarified to date. The objective of the present study was to examine the effects of trelagliptin on vascular endothelial functions in patients with type 2 diabetes mellitus (DM) using flow-mediated dilatation (FMD), adiponectin, and asymmetric dimethylarginine (ADMA) as evaluation indicators. METHODS: This study was a preliminary single-arm prospective pilot study. The subjects of this study were type 2 DM patients aged 20-74 years, who visited our outpatient department. The patients were treated with trelagliptin, and their FMD, adiponectin, and ADMA levels were measured at baseline and at 12 weeks after initial treatment to determine the changes during the study period. RESULTS: A total of 27 patients, excluding three dropouts, were included in the population for analysis. Trelagliptin treatment showed no significant changes in FMD (2.42 +/- 2.7% at baseline vs. 2.66 +/- 3.8% post-treatment, P = 0.785) and ADMA (0.41 +/- 0.0 microg/mL at baseline vs. 0.40 +/- 0.0 microg/mL post-treatment, P = 0.402). Trelagliptin treatment resulted in a significant increase of serum adiponectin level (7.72 +/- 6.9 microg/mL at baseline vs. 8.82 +/- 8.3 microg/mL post-treatment, P < 0.002). CONCLUSIONS: In this pilot study, trelagliptin treatment showed no significant changes in FMD. On the other hand, it was believed that trelagliptin treatment may increase serum adiponectin level. Trial Registration http://www.umin.ac.jp (Trial ID UMIN000018311).
The therapeutic agents for dementia are limited due to the complex system underlying the mechanisms. Taking a preventive point of view, we focused on the inhibition of beta-secretase and acetylcholinesterase (AChE). In addition, plant resources including herbs and spices have been widely consumed, and further, may be consumed for a long period over a lifetime. Considering this background, we screened beta-secretase and AChE inhibitors from curry spices. Amongst them, curry leaf, black pepper, and turmeric extracts were effective to inhibit beta-secretase. Furthermore, black pepper and turmeric extracts were also effective to inhibit AChE. Having these results in hand, we focused on the investigation of beta-secretase inhibitors since the inhibitor of this enzyme has not previously been well investigated. As a result, alpha- and beta-caryophyllene, beta-caryophyllene oxide (from curry leaf), piperine (from black pepper), curcumin, demethoxycurcumin, and bisdemethoxycurcumin (from turmeric) were successfully identified as low molecular inhibitors. This is the first report to determine alpha- and beta-caryophyllene, beta-caryophyllene oxide, and piperine as beta-secretase inhibitors. These compounds may pass through the blood brain barrier since their molecular weights are relatively low.
Clinical trials have shown the benefits of acetylcholinesterase inhibitors, such as donepezil and galantamine, and an N-methyl-D-aspartate receptor antagonist, memantine, in patients with Alzheimer's disease (AD). However, little is known regarding the effects of switching from donepezil 5 mg/day to galantamine 16 or 24 mg/day, or regarding the effects of adding memantine to established therapy compared with increasing the dose of donepezil. This report discusses two studies conducted to evaluate treatment with galantamine and memantine with respect to cognitive benefits and caregiver evaluations in patients with AD receiving donepezil 5 mg/day for more than 6 months. Patients with mild or moderate AD (scores 10-22 on the Mini-Mental State Examination) were enrolled in the Galantamine Switch study and switched to galantamine (maximum doses 16 mg versus 24 mg). Patients with moderate to severe AD (Mini-Mental State Examination scores 3-14) were enrolled in the Donepezil Increase versus Additional Memantine study and either had their donepezil dose increased to 10 mg/day or memantine 20 mg/day added to their existing donepezil dose. Patients received the study treatment for 28 weeks and their Disability Assessment for Dementia, Mental Function Impairment Scale, Cohen-Mansfield Agitation Inventory, and Neuropsychiatric Inventory scores were assessed with assistance from their caregivers. For the Galantamine Switch study after 8 weeks, agitation evaluated by the Cohen-Mansfield Agitation Inventory improved in both the 16 mg and 24 mg groups compared with baseline. However, there were no significant differences between the two galantamine groups. Agitation was also less in patients in the additional memantine group than in the donepezil increase group. In summary, switching to galantamine from donepezil and addition of memantine in patients with AD receiving donepezil were both safe and meaningful treatment options, and particularly efficacious for suppression of agitation.
OBJECTIVE: While acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastig-mine, are beneficial in treating behavioral symptoms of patients with Alzheimer's disease (AD), their dose-limiting effects include gastrointestinal disturbances, such as nausea, vomiting, and diarrhea. We aimed to predict the occurrence of these gastrointestinal disturbances with rivastigmine therapy for optimal drug choice and improved compliance. MATERIALS AND METHODS: Thirty patients with mild-to-moderate AD (scores 10-22 on the MiniMental State Examination) were administered a rivastigmine 18 mg patch with domperidone 30 mg (RWD) and without domperidone (RWOD; n = 15 each) for 20 weeks. Gastrointestinal disturbances were evaluated using a frequency scale for symptoms of gastroesophageal reflux disease (FSSG), Bristol stool form scale, laboratory data (hemoglobin, albumin, total cholesterol), body weight, and amount of food intake. RESULTS: After 12 weeks, FSSG scores were higher in the RWOD group compared to baseline scores; however, no significant differences were noted between the RWD and RWOD groups. We then subdivided each group based on high and low baseline scores; the RWOD high-score (>/=4) subgroup showed increased FSSG after 12 weeks compared with the baseline score. In both RWD and RWOD groups, the low-score (</=3) subgroups showed no changes during the dose-escalation phase. CONCLUSION: For AD patients with higher FSSG scores at baseline, domperidone was effective in preventing rivastigmine-related gastrointestinal disturbances.
BACKGROUND: Prenatal environmental factors might influence the risk of developing cardiovascular disease later in life. The HDL-associated enzyme paraoxonase 1 (PON1) has anti-oxidative functions that may protect against atherosclerosis. It also hydrolyzes many substrates, including organophosphate pesticides. A common polymorphism, PON1 Q192R, affects both properties, but a potential interaction between PON1 genotype and pesticide exposure on cardiovascular risk factors has not been investigated. We explored if the PON1 Q192R genotype affects cardiovascular risk factors in school-age children prenatally exposed to pesticides. METHODS: Pregnant greenhouse-workers were categorized as high, medium, or not exposed to pesticides. Their children underwent a standardized examination at age 6-to-11 years, where blood pressure, skin folds, and other anthropometric parameters were measured. PON1-genotype was determined for 141 children (88 pesticide exposed and 53 unexposed). Serum was analyzed for insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP3), insulin and leptin. Body fat percentage was calculated from skin fold thicknesses. BMI results were converted to age and sex specific Z-scores. RESULTS: Prenatally pesticide exposed children carrying the PON1 192R-allele had higher abdominal circumference, body fat content, BMI Z-scores, blood pressure, and serum concentrations of leptin and IGF-I at school age than unexposed children. The effects were related to the prenatal exposure level. For children with the PON1 192QQ genotype, none of the variables was affected by prenatal pesticide exposure. CONCLUSION: Our results indicate a gene-environment interaction between prenatal pesticide exposure and the PON1 gene. Only exposed children with the R-allele developed adverse cardiovascular risk profiles thought to be associated with the R-allele.
We performed interventional treatments on 50 patients with hepatocellular carcinoma (HCC) and analyzed the relationship between these treatments and the exacerbation of liver function after treatment. The different treatments included transcatheter arterial embolization (TAE), percutaneous ethanol injection therapy (PEIT), selective segmental sclerotherapy (SSS), combined TAE and PEIT, or transcatheter arterial chemo-injection (TAI). Thirteen patients showed an exacerbation of liver function after treatment. The laboratory data on admission, showed the lower levels of serum albumin and cholinesterase in this group. In comparison to patients who did not show any exacerbation of liver function, these 13 patients had undergone combined TAE and PEIT. An analysis of cases after TAE and PEIT treatment revealed that the time from TAE to PEIT was shorter in the exacerbation group than in the non-exacerbation group, however, there was no significant difference in the amount of injected ethanol between the two groups. It is assumed that the values of albumin and cholinesterase before treatment, or the period from TAE to PEIT are related to liver failure after treatment. Combining TAE and PEIT treatment may be effective for HCC, however, we should pay special attention to liver failure after treatment.
Title: A preliminary study on delayed vestibulo-cerebellar effects of Tokyo Subway Sarin Poisoning in relation to gender difference: frequency analysis of postural sway Yokoyama K, Araki S, Murata K, Nishikitani M, Okumura T, Ishimatsu S, Takasu N Ref: J Occup Environ Med, 40:17, 1998 : PubMed
To evaluate delayed (long-term) effects of acute sarin poisoning on postural balance, nine male and nine female victims of the Tokyo Subway Sarin Poisoning in Japan (sarin cases) were examined by computerized posturography 6-8 months after the poisoning. Their plasma cholinesterase activities (ChE) on the day of the poisoning (March 20, 1995) were 13-95 (mean 68.2) IU/l for females and 19-131 (mean 75.9) IU/l for males, which were not significantly different between the two sexes. In females, the postural sway of low frequency (0-1 Hz) in the anterior-posterior direction and area of sway with eyes open was significantly larger in the cases than in the controls. Romberg quotients for the low-frequency sway in the anterior-posterior direction for females and low-frequency sway and length of sway in the medio-lateral direction for males were significantly related to log ChE. It is suggested that a delayed effect on the vestibulo-cerebellar system was induced by acute sarin poisoning; females might be more sensitive than males.
Chronic neurobehavioral effects of acute sarin poisoning were evaluated in 9 male and 9 female patients who were exposed to sarin poisoning in the Tokyo subway incident in Japan. The investigators used nine neurobehavioral tests, as well as a posttraumatic stress disorder checklist, 6-8 mo after the poisoning occurred. Serum cholinesterase activity in patients on the day of poisoning (i.e., March 20, 1995) ranged from 13 to 131 IU/l (mean=72.1 IU/l). The results of analysis covariance, in which age, education level, alcohol consumption, and smoking status (covariates) were controlled in 18 sarin cases and in 18 controls, showed that the score on the digit symbol (psychomotor performance) test was significantly lower in the sarin cases than in controls. Nonetheless, the scores for the General Health Questionnaires, fatigue of Profile of Mood States, and posttraumatic stress disorder checklist were significantly higher in the sarin cases than controls. The investigators added posttraumatic stress disorder to the covariates, and only the score on the digit symbol test was significantly lower in sarin cases. In addition, the results of stepwise multiple regression analysis in 18 sarin cases revealed that scores for the General Health Questionnaires, fatigue of Profile of Mood States (i.e., fatigue, tension-anxiety, depression, and anger-hostility)-together with the paired-associate learning test-were associated significantly with posttraumatic stress disorder. The association did not remain significant for the digit symbol test score. Perhaps a chronic effect on psychomotor performance was caused directly by acute sarin poisoning; on the other hand, the effects on psychiatric symptoms (General Health Questionnaire) and fatigue (Profile of Mood States) appeared to result from posttraumatic stress disorder induced by exposure to sarin.
Title: Long term follow-up for patients with liver cirrhosis after partial splenic embolization Murata K, Shiraki K, Takase K, Nakano T, Tameda Y Ref: Hepato-Gastroenterology, 43:1212, 1996 : PubMed
Fifteen cases of liver cirrhosis (LC) were examined to determine whether the partial splenic embolization (PSE), done to improve hematological disorders, could also improve liver function for at least 12 months.
MATERIALS AND METHODS:
Peripheral blood count, serological and coagulatory examination were retrospectively examined before PSE, 6 months and 12 months after PSE.
RESULTS:
Hematological disorders were improved (p < 0.01) and persisted at improved levels in all cases. In patients in Child A or Child B classification, the levels of cholinesterase, total cholesterol and prothrombin time were also improved significantly after PSE (p < 0.05). However, those parameters were not improved in Child C classification.
CONCLUSION:
PSE may improve not only hematological disorders but also liver functions for at least one year.
