Risk factors associated with increased incidences of catheter-related bloodstream infection

We have implemented several preventive measures to reduce central line-associated bloodstream infection (CLABSI) in the general intensive care unit (ICU) of a university hospital in Japan. Here, we analyzed the factors associated with CLABSI in patients with central venous catheter (CVC) insertions and evaluated the effects of our implemented preventive measures. From July 2013 to June 2018, data was collected from the medical records of 1472 patients with 1635 CVC insertions, including age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, duration of ICU stay, duration of catheter insertion, insertion site, and mechanical ventilation status. During weekly conferences, a surveillance team comprising intensive care and infection control doctors and nurses determined the patients’ CLABSI status. The analyzed factors were compared between CLABSI and central line patients without bloodstream infection. Multivariate analysis revealed three factors associated with CLABSI. Adjusted odds ratios with 95% confidence intervals were as follows: duration of ICU stay, 1.032 (1.019–1.044); duration of catheter insertion, 1.041 (1.015–1.066); and APACHE II score, 1.051 (1.000–1.105). The prominent risk factors were associated with the severity of the initial condition and exacerbation of the clinical condition of the patients during their stays in the ICU. Further strategies to reduce CLABSI must be developed.     

Roles of Src family kinase,Ras, and mTOR signaling in intestinal epithelial homeostasis and tumorigenesis

The turnover of intestinal epithelial cells (IECs) is relatively rapid (3‐5 days in mouse and human), and this short existence and other aspects of the homeostasis of IECs are tightly regulated by various signaling pathways including Wnt‐β‐catenin signaling. Dysregulation of IEC homeostasis likely contributes to the development of intestinal inflammation and intestinal cancer. The roles of receptor protein tyrosine kinases and their downstream signaling molecules such as Src family kinases, Ras, and mTOR in homeostatic regulation of IEC turnover have recently been evaluated. These signaling pathways have been found to promote not only the proliferation of IECs but also the differentiation of progenitor cells into secretory cell types such as goblet cells. Of note, signaling by Src family kinases, Ras, and mTOR has been shown to oppose the Wnt‐β‐catenin signaling pathway and thereby to limit the number of Lgr5⁺ intestinal stem cells or of Paneth cells. Such cross‐talk of signaling pathways is important not only for proper regulation of IEC homeostasis but for the development of intestinal tumors and potentially for anticancer therapy.     

Aberrant maspin expression in gallbladder epithelium is associated with intestinal metaplasia in patients with cholelithiasis

OBJECTIVE: Aberrant expression of maspin protein related to DNA hypomethylation in the promoter region is frequently observed in gallbladder carcinomas, whereas the non-tumorous gallbladder epithelium is maspin negative. We investigated maspin expression in non-tumorous gallbladder epithelium in patients with cholelithiasis. METHODS: An immunohistochemical study of maspin expression was performed in 69 patients with cholelithiasis and 30 patients with gastric cancer without cholelithiasis. RESULTS: Immunoreactivity for maspin was observed in focal and patchy regions of the gallbladder epithelium. Positive immunoreactivity for maspin was significantly associated with the presence of intestinal metaplasia in patients with cholelithiasis (p<0.05). CONCLUSION: The high incidence of aberrant maspin expression in both intestinal metaplasia and carcinoma of the gallbladder supports the assumption that intestinal metaplasia of the gallbladder may predispose to gallbladder carcinoma.     

Association of variations in the FTO, SCG3 and MTMR9 genes with metabolic syndrome in a Japanese population

Metabolic syndrome is defined as a cluster of multiple risk factors, including central obesity, dyslipidemia, hypertension and impaired glucose tolerance, that increase cardiovascular disease morbidity and mortality. Genetic factors are important in the development of metabolic syndrome, as are environmental factors. However, the genetic background of metabolic syndrome is not yet fully clarified. There is evidence that obesity and obesity-related phenotypes are associated with variations in several genes, including NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, SH2B1, FTO, MAF, MC4R, KCTD15, SCG3, MTMR9, TFAP2B, MSRA, LYPLAL1, GCKR and FADS1. To investigate the relationship between metabolic syndrome and variations in these genes in the Japanese population, we genotyped 33 single-nucleotide polymorphisms (SNPs) in 19 genes from 1096 patients with metabolic syndrome and 581 control individuals who had no risk factors for metabolic syndrome. Four SNPs in the FTO gene were significantly related to metabolic syndrome: rs9939609 (P=0.00013), rs8050136 (P=0.00011), rs1558902 (P=6.6 × 10(-5)) and rs1421085 (P=7.4 × 10(-5)). rs3764220 in the SCG3 gene (P=0.0010) and rs2293855 in the MTMR9 gene (P=0.0015) were also significantly associated with metabolic syndrome. SNPs in the FTO, SCG3 and MTMR9 genes had no SNP × SNP epistatic effects on metabolic syndrome. Our data suggest that genetic variations in the FTO, SCG3 and MTMR9 genes independently influence the risk of metabolic syndrome.     

Control of angiogenesis by VEGF and endostatin-encapsulated protein microcrystals and inhibition of tumor angiogenesis

Encapsulation of cytokines within protein microcrystals (polyhedra) is a promising approach for the stabilization and delivery of therapeutic proteins. Here, we investigate the influence of vascular endothelial growth factor (VEGF) microcrystals and endostatin microcrystals on angiogenesis. VEGF was successfully encapsulated into microcrystals derived from insect cypovirus with overexpression of protein disulfide bond isomerase. VEGF microcrystals were observed to increase the phosphorylation of p42/p44 MAP kinase and to stimulate the proliferation, migration, and network and tube formation of human umbilical vein endothelial cells (HUVECs). Endostatin was also successfully encapsulated into microcrystals. Endostatin microcrystals showed antiangiogenesis activities and inhibited the migration, and network and tube formation of HUVECs. Local administration of endostatin microcrystals in mice inhibited both angiogenesis and tumor growth with clear significant differences between treatment and control groups. Endostatin microcrystals only affected angiogenesis, but had no significant effect on lymphangiogenesis compared to controls. Local therapy using endostatin microcrystals offers a potential approach to achieve sustained therapeutic release of antiangiogenic molecules for cancer treatment.     

A simple scoring system based on neutrophil count in sepsis patients

Background

The assessment of critically ill patients is often a challenge for clinicians. There are a number of scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and C-reactive protein test (CRP), which have been shown to correlate with outcome in a variety of Intensive Care Unit (ICU) patients. Therefore, use of repeated measures of these preexisting scores over time is a reasonable attempt to assess the severity of organ dysfunction and predict outcome in critically ill patients. Several reports suggest that the neutrophil is a useful marker of sepsis. However, since both a large number and a small number of neutrophils indicate a severe situation, neutrophil count is difficult to use to directly predict patients’.

The hypothesis

We proposed a novel scoring system identify predictive factors using a simple blood cell count that may be associated with mortality in ICU patients. Our novel scoring system (n-score) was calculated as follows: ranges of neutrophils of 0–4999 cells/mm³ and 5000–9999 cells/mm³ were defined as 3 and 1 points, respectively. When the neutrophil count was over 10,000 cells/mm³, the score was calculated by dividing the number of cells by 10,000. Then, 1 or 2 points were added when patients were female or male, respectively. We hypothesize that n-score may be a simple and easy scoring system to estimate mortality of the patients with sepsis and severe sepsis/septic shock without requirement of special methods or special measuring equipment, and may be as reliable as the APACHE II score or SOFA score.

Evaluation of the hypothesis

The retrospective evaluation was conducted at the Department of Emergency, Disaster and Critical Care Medicine at the Hyogo College of Medicine. Seventy-seven patients who were admitted to the emergency center and diagnosed sepsis or severe sepsis/septic shock between June 2007 and December 2012 and gave informed consent were enrolled. The n-score was significantly higher in non-survivors of sepsis and severe sepsis/septic shock (p < 0.01, t-test) than in survivors. The ROC curve showed a sensitivity of 61.5% and a specificity of 80.4% at an n-score of 3.8 points; the area under the curve was 0.736. In addition, n-score correlated with APACHE II score (p < 0.01, R = 0.378) and SOFA score (p < 0.05, R = 0.256) on admission.

Conclusion

Based on these preliminary evaluations, we hypothesize that n-score may be a useful scoring system to detect risk of death in sepsis and severe sepsis/septic shock.     

Molecular and structural studies of the GM2 gangliosidosis 0 variant

To determine the molecular basis of the GM2 gangliosidosis 0 variant, we constructed a three-dimensional structure of the human β-hexosaminidase β-subunit by homology modeling. It is composed of two domains, domains I and II, and has three disulfide bonds. C534 is located on an extra helix in domain II and forms a disulfide bond with C551. The extra helix is structurally located near domain I. C534Y, identified in a patient with the infantile form of the disease, was deduced to cause disruption of the disulfide bond, which results in a large conformational change of the extra helix, stabilizing the two domains. The drastic change in the protein structure results in a deficiency of the mature β-subunit, and deficient activities of β-hexosaminidases A (αβ) and B (ββ), followed by abundant accumulation of GM2 ganglioside in the patient's cells. R505 is located on the eighth helix of domain II. R505Q, found in a patient with the chronic form of the disease, is predicted to influence the surface structure of the β-subunit, although it does not affect the active site. The amino acid substitution causes a partial processing defect and decreased enzyme activities, which result in moderate accumulation of GM2 ganglioside in the patient's cells. The structural defects well reflect biochemical and phenotypic abnormalities of the disease. Received: November 26, 2001 / Accepted: January 25, 2002     

Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women

Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women.     

A biomechanical and histological evaluation of a bioresorbable lumbar interbody fusion cage

Novel spinal interbody fusion cages made of bioactive and bioresorbable composites by a unique forging process were developed. Previous in vitro study demonstrated that these cages marked excellent biomechanical values. The purpose of the present in vivo study was to evaluate the viability and advantage of this forged composite of uncalcined hydroxyapatite/poly L-Lactide (F-u-HA/PLLA) cage radiographically, biomechanically, and histologically, when compared to conventional autologous iliac bone (AIB) and carbon fiber cage (CFC). Twenty-five mature sheep underwent posterior lumbar interbody fusion at L2-3 level with pedicle screws system made of titanium. Three types of interbody fusion implants were grafted: AIB (n = 7), CFCs (n = 9), F-u-HA/PLLA cages (n = 9). Two types of cages were packed with autologous fragmented cancellous bone harvested locally. All animals were euthanized at 120 days after surgery. The fusion scoring using the coronal view CT scans was designed to three-dimensionally evaluate fusion quality within and around cages. The mean CT scores of three groups were 33.3 points, 35.0 points, and 33.6 points in AIB, CFC, and F-u-HA/PLLA cage groups, respectively (full-score: 56 points). Statistical differences were not detected among the three groups. The mean range of motion values among fused groups had no significant difference under all pure loadings. The range of motion showed strong and significant correlation with the CT fusion scores. Histologic results demonstrated that F-u-HA/PLLA cages contacted with the surrounding bone directly, and CFC was encircled with thick fibrous tissue layers without any sign of inflammation around cages. The fusion quality of fused spinal segment using F-u-HA/PLLA cages was equal to that of AIB or CFCs both radiographically and biomechanically. In the histological observation, biocompatibility of F-u-HA/PLLA cage was obviously superior to CFC. It has been confirmed that the novel bioactive and bioresorbable cages had valuable advantages over existing CFC for use in spinal reconstructive surgery.