Individual dipeptidyl peptidase-4 inhibitors and acute kidney injury in patients with type 2 diabetes: A systematic review and network meta-analysis.

This network meta-analysis of randomized controlled trials aimed to determine whether any individual dipeptidyl peptidase-4 (DPP-4) inhibitors increase the risk of acute kidney injury (AKI). The Medical Literature Analysis and Retrieval System Online via PubMed, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were systematically searched to identify relevant studies. The primary outcome was AKI. A frequentist network meta-analysis was performed using a random-effects model to account for heterogeneity. Twenty-nine studies involving 56 117 participants were included. There were 918 cases of AKI (1.63%). The risk of bias was generally considered to be low. The only DPP-4 inhibitor that significantly increased the frequency of AKI when compared with placebo was sitagliptin (risk ratio 1.65, 95% confidence interval 1.22-2.23). However, because one study showed significant outliers in the funnel plot, in a highly heterogeneous population composed solely of patients undergoing surgery for coronary artery bypass graft, we conducted a post-hoc sensitivity analysis to exclude this study. The results showed no statistically significant difference in the risk of AKI between sitagliptin and placebo. Individual DPP-4 inhibitors do not appear to increase the risk of AKI. However, sitagliptin may be associated with AKI in patients with underlying severe cardiovascular disease.

Efficacy and safety of alcohol reduction pharmacotherapy according to treatment duration in patients with alcohol dependence or alcohol use disorder: A systematic review and network meta-analysis.

BACKGROUND AND AIMS: Relapse is common in alcohol dependence (AD) and alcohol use disorder (AUD), so alcohol reduction therapy should be measured over as long a period as possible; however, existing reviews do not consider the duration of treatment and therefore alcohol reduction therapy may not have been appropriately evaluated. This review evaluated the efficacy and safety of alcohol reduction pharmacotherapy in patients with AD or AUD according to the duration of treatment. METHODS: We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) that assessed 15 pharmacological agents. MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov and the International Clinical Trials Registry Platform were searched for eligible trials through to May 2021. Outcomes were heavy drinking days (HDD), total alcohol consumption (TAC), any adverse event and days without drinking. RESULTS: Fifty-five RCTs (n = 8891) were included. Nalmefene was superior to placebo for reducing HDD (standard mean difference [SMD] -0.28, 95% confidence interval [CI] -0.37, -0.18) and TAC (SMD -0.25, 95% CI -0.35, -0.16) in the long-term, but not in the short-term. Topiramate was superior to placebo for reducing HDD (SMD -0.35, 95% CI -0.59, -0.12) and days without drinking (SMD 0.46, 95% CI 0.11, 0.82), and baclofen was superior for reducing TAC (SMD -0.70, 95% CI -1.29, -0.11), in the short-term. The frequency of adverse events was higher with nalmefene and topiramate than with placebo. CONCLUSION: Nalmefene, topiramate and baclofen may be effective as alcohol reduction pharmacotherapy; however, only nalmefene has demonstrated long-term efficacy, and nalmefene and topiramate have a significantly higher frequency of adverse events compared with placebo.

Urate-Lowering Drugs and Muscle Injury: A Systematic Review and Network Meta-Analysis.

Several urate-lowering drugs have been linked to muscle injury. This study investigated the association of oral urate-lowering drugs with the risk of muscle injury by performing a network meta-analysis of randomized and non-randomized controlled trials. A systematic search of MEDLINE, via PubMed, the ClinicalTrials.gov website, and the Cochrane Central Register of Controlled Trials was conducted to identify relevant studies with a primary outcome of "all muscle injuries." A random-effects model was used to perform a frequentist network meta-analysis to estimate whether there was significant heterogeneity among the studies. In total, 32 studies including 28,327 participants with 2694 (9.5%) "all muscle injuries" were assessed, and the overall risk of bias was judged to be low to moderate. No statistically significant differences were found between placebo and 6 urate-lowering therapies: allopurinol (risk ratio, RR, 1.05; 95% confidence interval, 95%CI, 0.63-1.73), febuxostat (RR 1.10, 95%CI 0.71-1.70), lesinurad (RR 7.00, 95%CI 0.31-160.36), lesinurad concomitant with allopurinol (RR 0.85, 95%CI 0.34-2.11), lesinurad concomitant with febuxostat (RR 1.97, 95%CI 0.55-7.03), and topiroxostat (RR 0.99, 95%CI 0.37-2.65). The findings suggest that there is little need to consider the risk of muscle injury when using urate-lowering drugs in the clinical setting.

Association of silodosin, tamsulosin, and naftopidil with delirium: analysis of the pharmacovigilance database in Japan.

BACKGROUND: An association between adrenergic alpha-1 receptor antagonists and delirium has been suggested, but the details are unclear. AIM: This study investigated the association between adrenergic alpha-1 receptor antagonists and delirium in patients with benign prostatic hyperplasia using the Japanese Adverse Drug Event Report database. METHOD: First, disproportionality analysis compared the frequency of delirium in the adrenergic alpha-1 receptor antagonists silodosin, tamsulosin, and naftopidil. Next, multivariate logistic analysis was performed to examine the association between delirium and adrenergic alpha-1 receptor antagonists where disproportionality was detected. RESULTS: A disproportionality in delirium was observed in patients receiving tamsulosin (reporting odds ratio [ROR] 1.85, 95% confidence interval [CI] 1.38-2.44, P < 0.01) compared with those who did not, and also in patients receiving naftopidil (ROR 2.23, 95% CI 1.45-3.28, P < 0.01) compared with those who did not. Multivariate logistic analysis revealed that in addition to previously reported risk factors for delirium, delirium in patients receiving tamsulosin was significantly increased with concomitant use of anticholinergics (odds ratio 2.73, 95% CI 1.41-5.29, P < 0.01) and delirium in patients receiving naftopidil was significantly increased with concomitant use of beta3-adrenergic receptor agonists (odds ratio 4.19, 95% CI 1.66-10.6, P < 0.01). CONCLUSION: Anticholinergics or beta3-adrenergic receptor agonists to treat overactive bladder in patients receiving tamsulosin and naftopidil was strongly associated with delirium. Confirming the medical history and concomitant medications of patients receiving tamsulosin or naftopidil may contribute to preventing delirium in patients with benign prostatic hyperplasia and to improving their outcomes.

Association between misoprostol and nonsteroidal anti-inflammatory drug-induced kidney injury: A systematic review and meta-analysis.

AIMS: Misoprostol is a prostaglandin E1 analogue that is used to prevent nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal disorders. The aim of this systematic review and meta-analysis was to evaluate whether use of misoprostol also decreases the risk of NSAID-induced kidney injury. METHODS: Randomized controlled trials that compared misoprostol vs. placebo in an adult patient population were selected. The primary outcome was kidney injury and the secondary outcome was severe adverse events. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Twelve studies were eligible for inclusion. Although the rates of kidney injury and severe adverse events did not differ significantly between misoprostol and placebo, a posthoc subgroup analysis that excluded studies in which different NSAIDs were used in the misoprostol and placebo groups suggested that misoprostol may reduce the risk of NSAID-induced kidney injury (risk difference -0.09, 95% confidence interval -0.15 to -0.03, P < .01, I2  = 87%; evidence of very low certainty). CONCLUSION: There is limited evidence that misoprostol reduces the risk of NSAID-induced kidney injury. Misoprostol possibly contributes to reducing the risk of kidney injury associated with chronic NSAID use. The findings of this meta-analysis suggest further high-quality clinical trials are warranted.

Yokukansan (TJ-54) in patients undergoing surgery: A systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy and safety of Yokukansan (TJ-54) in patients undergoing surgery. METHODS: Efficacy was assessed by the onset of delirium, delirium rating scales, anxiety evaluated by Hospital Anxiety and Depression Scale-Anxiety (HADS-A) score, and safety was assessed by any reported adverse events. RESULTS: Six studies were included. There were no significant differences between the groups in the onset of delirium (risk ratio 1.15, 95% confidence interval [CI] 0.77-1.72), delirium rating scales (early postoperative period: standardized mean difference [SMD] -0.24, 95% CI -1.11 to 0.63; late postoperative period: SMD -0.06, 95% CI -1.56 to 1.45), HADS-A score (mean difference -0.47, 95% CI -1.90 to 0.96), and any adverse events (risk ratio 1.18, 95% CI 0.35-4.00). CONCLUSIONS: The use of TJ-54 in patients undergoing surgery is not an effective strategy for postoperative delirium and anxiety. Further research considering target patients and durations of administration should be conducted.

Identification of Risk Factors for Phlebitis in Patients Treated with Nafamostat Mesylate.

The proteolytic enzyme inhibitor nafamostat mesylate is widely used for the treatment of acute pancreatitis and disseminated intravascular coagulation. This drug may be a risk factor for phlebitis, but this risk has not been studied. Therefore, we aimed to investigate the frequency of phlebitis and its risk factors in patients treated with nafamostat mesylate in intensive care units (ICU) or high care units (HCU). During the study period, 83 patients met the inclusion criteria, and 22 of them (27%) experienced phlebitis. A multivariate logistic regression analysis was performed for severe acute pancreatitis, administration duration, and administration concentration of nafamostat mesylate in ICU or HCU. As a result, the administration of nafamostat mesylate for ≥3 d in the ICU or HCU was an independent predictor of phlebitis caused by nafamostat mesylate [odds ratio (OR), 10.3; 95% confidence interval (CI), 1.28-82.5; p=0.03]. This study suggests that the number of days of nafamostat mesylate administration is associated with phlebitis in patients treated with the drug, and it may be necessary to pay attention to its administration for ≥3 d in ICU or HCU.

Evaluation of Risk of Cardiac or Cerebrovascular Events in Romosozumab Users Focusing on Comorbidities: Analysis of the Japanese Adverse Drug Event Report Database.

Background: Romosozumab is associated with an increased risk of cardiac or cerebrovascular events. Identifying the risk factors for these events could contribute to the safe use of romosozumab. Objective: This study aimed to investigate risk factors for cardiac or cerebrovascular events in romosozumab users. Methods: First, disproportionality analysis was performed to compare the frequency of cardiac or cerebrovascular events, using data from the Japanese Adverse Drug Event Report database. Next, multivariate logistic analysis was performed to investigate risk factors for cardiac or cerebrovascular events in romosozumab users. Results: In total, 859 romosozumab users were identified. A disproportionality of both cardiac and cerebrovascular events was observed in only romosozumab users. Multivariate logistic analysis revealed that the risk of cardiac events in romosozumab users was significantly increased in patients with cardiac disease (odds ratio [OR]: 5.9, 95% confidence interval [CI] 3.5-9.9; P < 0.01) and hypertension (OR: 1.6, 95% CI 1.0-2.7; P = 0.047). In addition, the risk of cerebrovascular events in romosozumab users was significantly increased in the presence of cerebrovascular disease (OR: 2.7, 95% CI 1.2-6.2; P = 0.02) and hypertension (OR: 2.6, 95% CI 1.7-3.9; P < 0.01). Conclusion: Our findings suggest that hypertension may increase the risk of cardiac or cerebrovascular events in romosozumab users. Although additional studies are needed to assess other associated factors, these findings may contribute to the appropriate use of romosozumab and limit adverse events.

Association between use of febuxostat and muscle injury: A disproportionality analysis and meta-analysis of randomized controlled trials.

AIMS: Several reports have suggested an association between febuxostat and muscle injury. The purpose of this study was to determine whether febuxostat increases the risk of muscle injury. This study included an analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database and a systematic review/meta-analysis of randomized controlled trials. METHODS: First, evaluation of the FAERS data included a disproportionality analysis that compared patients with and without rhabdomyolysis according to whether they were receiving febuxostat or allopurinol. Second, a systematic review/meta-analysis was performed to assess the risk of rhabdomyolysis and muscle injury in patients who used febuxostat or allopurinol. RESULTS: Analysis of the FAERS data revealed disproportionality for increasing rhabdomyolysis in patients who received febuxostat (reporting odds ratio 4.49, 95% confidence interval [CI] 3.72-5.38, P < .01) and allopurinol (reporting odds ratio 2.49, 95% CI 2.25-2.75, P < .01). Nineteen studies were eligible for inclusion in the systematic review/meta-analysis. Rhabdomyolysis was reported in only 1 study. The risk of any type of muscle damage was not significantly increased with febuxostat compared with placebo (risk ratio 0.92, 95% CI 0.73-1.17, P = .52, I2  = 0%; 8 studies including 2597 participants, high-certainty evidence) or allopurinol (risk ratio 1.03, 95% CI 0.94-1.11, P = .56, I2  = 0%; 9 studies including 17 644 participants, moderate-certainty evidence). CONCLUSION: Febuxostat does not seem to affect the risk of muscle injury. However, the findings of this meta-analysis indicate a need for further high-quality observational studies with long-term follow-up.

Efficacy of Hangeshashinto in the Prevention of Chemotherapy-Induced Diarrhea: A Systematic Review and Meta-Analysis.

Hangeshashinto has attracted attention owing to its potential to prevent chemotherapy-induced diarrhea. However, studies on the efficacy of Hangeshashinto have had conflicting results. Evaluating the efficacy of Hangeshashinto may contribute to reducing the use and adverse events caused by drug therapy for chemotherapy-induced diarrhea. Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed, Ichushi, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov were searched to retrieve all the relevant studies. Randomized controlled trials (RCTs) comparing the administration of Hangeshashinto with that of other treatments in patients with cancer receiving chemotherapy were included. The primary outcome was severe (grade 3-4) diarrhea assessed using the Common Terminology Criteria for Adverse Events. The secondary outcome was mild (grade 0-2) diarrhea. Out of 324 records identified, three studies were selected for the meta-analysis. Irinotecan was used for chemotherapy in all these studies. Hangeshashinto did not reduce the incidence of severe diarrhea compared with other treatments (risk ratio (RR) 0.40, 95% confidence interval (CI) 0.11-1.41, P = 0.15; low-quality evidence). Moreover, Hangeshashinto did not reduce the incidence of mild diarrhea (RR 1.35, 95% CI 0.87-2.09, P = 0.18; low-quality evidence). However, in the subgroup analysis compared with no treatment, the Hangeshashinto group had a significantly lower incidence of severe diarrhea (RR 0.17, 95% CI 0.03-0.88, P = 0.03; low-quality evidence). At present, insufficient evidence exists to support the claim that Hangeshashinto prevents diarrhea caused by irinotecan-based chemotherapy.

Risks of serious adverse events and kidney injury in patients treated with ibandronate: A systematic review and meta-analysis.

BACKGROUND: Several reports suggest that adverse events caused by ibandronate are less serious than those associated with the other bisphosphonates. The purpose of this systematic review and meta-analysis was to determine whether ibandronate has low rates of serious adverse events and kidney injury. METHODS: Randomized controlled trials were selected, and the study populations consisted of adult patients with osteoporosis. The primary outcome was all serious adverse events and the secondary outcome was kidney injury. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of evidence. RESULTS: Nineteen studies were eligible for inclusion. No significant difference in the rate of serious adverse events or that of kidney injury was found between ibandronate and placebo or between ibandronate and other bisphosphonates. However, a sensitivity analysis, which excluded studies at "high risk" of detection bias, found that the risk of serious adverse events was significantly lower for ibandronate than for the other bisphosphonates (risk ratio 0.79, 95% confidence interval 0.66-0.94, p < 0.01). This finding was assessed as high-quality evidence when the GRADE criteria were applied. Only five studies (26%) reported kidney injury as an adverse event. CONCLUSIONS: Limited evidence was found to suggest that ibandronate may carry a lower risk of serious adverse events compared with other bisphosphonates. Further high-quality randomized controlled trials are needed to compare the risk of kidney injury associated with the various bisphosphonates.

Successful Resuscitation of Cardiac Arrest After Refeeding Syndrome Associated with Hiatal Hernia: A Case Report.

BACKGROUND Refeeding syndrome (RFS) is a life-threatening syndrome, which can cause sudden death. RFS has been reported frequently in young patients with anorexia without organic disease; however, there are few reports in elderly patients with organic disease. Herein, we report a case of cardiac arrest after refeeding syndrome associated with hiatal hernia. CASE REPORT We report the case of a 59-year-old woman who had a diagnosis of RFS during treatment for anorexia secondary to hiatal hernia. She was hospitalized with hypothermia, anemia, and hypovolemic shock and treated with electrolytes, hydration, and transfusion at the Emergency Department. Upper gastrointestinal endoscopy revealed hiatal hernia with severe reflux esophagitis. We initiated parenteral nutrition (8.7 kcal/kg/day). However, QTc prolongation caused pulseless ventricular tachycardia. Temporary cardiac pacing was performed to prevent recurrence. Her nutritional status steadily improved, and she was transferred to another hospital without complications. CONCLUSIONS Patients with gastrointestinal comorbidities are more likely to have inadequate food intake and to be undernourished on admission and therefore should be carefully started on nutritional therapy, considering their risk of RFS.

Lamotrigine in the maintenance treatment of bipolar disorder.

BACKGROUND: Bipolar disorder is a chronic mental disorder with repetitive mania/hypomania as well as depressive episodes, which eventually results in marked impairment in overall functioning and health-related quality of life.  A worldwide prevalence rate of 2.4% has been reported. The risk of suicide is higher in people with bipolar disorder than those with other mental disorders. Therefore, effective management of bipolar disorder in the maintenance period is warranted to minimize the risk of relapse or recurrence. Although lithium has been the standard treatment of bipolar disorder for many years, it is associated with adverse effects and teratogenicity. Lamotrigine is approved to be expected for prevention of recurrence for the maintenance treatment of bipolar disorder. In addition, lamotrigine is as effective as lithium. Therefore, we performed a systematic review to confirm the efficacy and safety of lamotrigine in the maintenance treatment of bipolar disorder. OBJECTIVES: To assess the efficacy and tolerability of lamotrigine in the maintenance treatment of bipolar disorder. SEARCH METHODS: We searched Ovid MEDLINE, Embase, PsycINFO, the Cochrane Common Mental Disorders Group's Specialized Register (CCMDCTR) and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to 21 May 2021. We also searched international trial registries and contacted experts in the field. SELECTION CRITERIA: We included randomized controlled trials enrolling adults with bipolar disorder who were treated with lamotrigine, placebo or lithium. DATA COLLECTION AND ANALYSIS: Two reviews authors independently checked the eligibility of studies and extracted data using a standardized form. Data extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in the term of efficacy and tolerability. Study information were then entered into RevMan web. MAIN RESULTS: We included 11 studies with a total of 2314 participants in this review; 1146 were randomized to lamotrigine, 869 were randomized to placebo and, 299 to lithium. We rated all studies as having an unclear risk of bias in at least one domain of Cochrane's tool for assessing risk of bias, with the most commonly observed weakness being selection bias (random sequence generation and allocation concealment). We judged five studies to be at a high risk of detection bias (blinding of outcome assessment). These potential biases pose as major threat to the validity of the included studies in this review. Outcomes of efficacy showed a possible advantage of lamotrigine over placebo. The estimated risk ratio (RR) for recurrence of manic symptom at one year as measured by the Young Mania Rating Scale (YMRS) was 0.67, (95% confidence interval (CI) 0.51 to 0.87; 3 studies, 663 participants; low-certainty evidence) in favor of lamotrigine. The RR of clinical worsening with the need for additional psychotropic treatment (RR 0.82, 95% CI 0.70 to 0.98; 4 studies, 756 participants) based on moderate-certainty evidence. The possible benefits of lamotrigine were also seen for the outcome of treatment withdrawal due to any reason at 6-12 months after treatment (RR 0.88, 95% CI 0.78 to 0.99; 4 studies, 700 participants; moderate-certainty evidence). Regarding tolerability, our analyses showed that the incidence rates of adverse effects were similar between the lamotrigine group and the placebo group (short-term effect: RR 1.07, 95% CI 0.81 to 1.42; 5 studies, 1138 participants; very low-certainty evidence; long-term effect: RR 0.97, 95% CI 0.77 to 1.23; 4 studies, 756 participants; moderate-certainty evidence). In the comparison between lamotrigine and lithium, efficacy was similar between groups except for recurrence of mania episode at one year. Recurrence of manic symptoms was higher in the lamotrigine group than that of the lithium group (RR 2.13, 95% CI 1.32 to 3.44; 3 studies, 602 participants; moderate-certainty evidence). Analysis of adverse effects at 6-12 months showed that a lower proportion of participants experienced at least one adverse effect when treated with lamotrigine compared to lithium (RR 0.70, 95% CI 0.51 to 0.96; 4 studies, 691 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Low- to moderate-certainty evidence collectively suggests that lamotrigine may be superior to placebo as a treatment modality for bipolar disorder. In comparison to lithium, people with bipolar disorder seem to tolerate lamotrigine better in the long run; however, the demonstrated efficacy in the maintenance of bipolar disorder was similar between the two groups.

Factors Determining the Efficacy of Recombinant Human Thrombomodulin in the Treatment of Sepsis-Induced Disseminated Intravascular Coagulation.

Recombinant human thrombomodulin (rhTM) is an anti-coagulant used to treat disseminated intravascular coagulation (DIC). The efficacy of rhTM in patients with sepsis-induced DIC has been proved in some clinical trials, but the determining factors are not known. The aim of this study was to identify patients for whom rhTM will be effective and the factors that determine rhTM efficacy in alleviating DIC. A single-center, retrospective, observational study was conducted in patients with sepsis-induced DIC who were treated with rhTM in Okayama Saiseikai General Hospital (Okayama, Japan) between January 2010 and December 2019. Among 67 patients who were treated with rhTM, DIC was resolved in 24 patients. The multivariate logistic regression analysis revealed that age (odds ratio (OR) 1.05; 95% confidence interval (CI) 1.00-1.10; p < 0.05) and acute physiology and chronic health evaluation II scores (OR 0.88; 95% CI 0.78-0.98; p < 0.05) were factors that determined rhTM efficacy in alleviating DIC. Overall, our study provides valuable information on factors that should be considered before rhTM administration to patients with sepsis-induced DIC for a better management of healthcare costs.

Cholinergic Crisis Owing to Distigmine Bromide Complicated by Hyperosmolar Hyperglycemic State.

Distigmine bromide is widely used to treat neurogenic bladder and causes cholinergic crisis, a serious side effect. We herein report about a patient with distigmine bromide-induced cholinergic crisis complicated by a hyperosmolar hyperglycemic state (HHS). On admission, the patient was diagnosed with HHS based on the medical history and laboratory test results. However, she also had bradycardia, miosis, and low plasma cholinesterase activity. We later found that she had received distigmine bromide, which led to a diagnosis of cholinergic crisis. We suggest that the exacerbation of pathology, including HHS, can cause cholinergic crisis in patients receiving distigmine bromide.

Loss of bone mineral density following sepsis using Hounsfield units by computed tomography.

AIM: To examine the change in vertebral bone mineral density (BMD) using abdominal computed tomography in patients treated for sepsis. METHODS: A single-center, retrospective, observational study was undertaken to evaluate BMD after critical care at Okayama Saiseikai General Hospital (Okayama, Japan) from January 2016 to April 2018. Sepsis was defined as an absolute increase of ≥2 in Sequential Organ Failure Assessment score in the intensive care unit or high care unit. Bone mineral density was evaluated in Hounsfield units (HU) by computed tomography. Patients were divided into groups based on the presence or absence of osteoporosis, which was defined as average vertebral body HU <110. Paired t-tests were used to compare the mean BMD of each vertebra between before and after critical care. We also analyzed accidental bone fracture events after discharge. The survival rate was analyzed as an outcome using the Kaplan-Meier method. RESULTS: Fifty-two of 188 patients met the inclusion criteria. We found significant differences between admission and follow-up vertebral BMD values in the spine at the thoracic 12, lumbar 1-5, and sacrum 1 levels (P < 0.05), especially in the non-osteoporosis groups. No difference in mortality was observed between patients with osteoporosis and those without. Two of 19 patients with osteoporosis developed a bone fracture. CONCLUSION: We found that sepsis was associated with loss in BMD following critical care.

Polyethyleneimine renders mitochondrial membranes permeable by interacting with negatively charged phospholipids in them.

Polyethyleneimines (PEIs) are used for transfection of cells with nucleic acids. Meanwhile, the interaction of PEI with mitochondria causes cytochrome c release prior to apoptosis; the mechanisms how PEI causes this permeabilization of mitochondrial membranes and the release of cytochrome c remain unclear. To clarify these mechanisms, we examined the effects of branched-type PEI and linear-type PEI, each of which was 25 kDa in size, on mitochondria. The permeabilization potency of mitochondrial membranes by branched PEI was stronger than that by linear PEI. The permeabilization by PEIs were insensitive to permeability-transition inhibitors, indicating that PEI-induced permeabilization was not attributed to permeability transition. Meanwhile, PEIs caused permeabilization of artificial lipid vesicles; again, the permeabilization potency of branched PEI was stronger than that of linear PEI. Such a difference in this potency was close to that in the case of isolated mitochondria, signifying that the PEI-induced permeabilization of mitochondrial membranes could be attributed to PEI's interaction with the phospholipid phase. Furthermore, this PEI-induced permeabilization of the lipid vesicles was observed only in the case of lipid vesicles including negatively charged phospholipids. These results indicate that PEIs interacted with negatively charged phospholipids in the mitochondrial membranes to directly lead to their permeabilization.