Longitudinal micro-endoscopic monitoring of high-success intramucosal xenografts for mouse models of colorectal cancer.

Colorectal cancer (CRC) is one of the most frequently lethal forms of cancer. Intramucosal injection allows development of better mouse models of CRC, as orthotopic xenografts allow development of adenocarcinoma in the submucosa of the mouse colon wall. In this paper, a method of orthotopic injection is monitored longitudinally using cellular-resolution real-time in vivo fluorescence microendoscopy, following the injection of three different cell lines: 3T3-GFP to confirm immunosuppression and HCT116-RFP cells to model CRC. Adenoma formation is first observable after 7 to 10 days, and by use of 33 G needles a tumor induction rate of greater than 85% is documented. An additional experiment on the injection of rapamycin reveals drug efficacy and localization between 24 and 48 hours, and suggests the promise of real-time cellular-resolution fluorescence micro-endoscopy for developing longitudinal therapy regimes in mural models of CRC.

Whole kidney engineering for clinical translation.

PURPOSE OF REVIEW: Renal transplantation is currently the only definitive treatment for end-stage renal disease; however, this treatment is severely limited by the shortage of implantable kidneys. To address this shortcoming, development of an engineered, transplantable kidney has been proposed. Although current advances in engineering kidneys based on decellularization and recellularization techniques have offered great promises for the generation of functional kidney constructs, most studies have been conducted using rodent kidney constructs and short-term in-vivo evaluation. Toward clinical translations of this technique, several limitations need to be addressed. RECENT FINDINGS: Human-sized renal scaffolds are desirable for clinical application, and the fabrication is currently feasible using native porcine and discarded human kidneys. Current progress in stem cell biology and cell culture methods have demonstrated feasibility of the use of embryonic stem cells, induced pluripotent stem cells, and primary renal cells as clinically relevant cell sources for the recellularization of renal scaffolds. Finally, approaches to long-term implantation of engineered kidneys are under investigation using antithrombogenic strategies such as functional reendothelialization of acellular kidney matrices. SUMMARY: In the field of bioengineering, whole kidneys have taken a number of important initial steps toward clinical translations, but many challenges must be addressed to achieve a successful treatment for the patient with end-stage renal disease.

Diet control to achieve euglycemia induces significant loss of heart and liver weight via increased autophagy compared with ad libitum diet in diabetic rats.

Intensive glucose control increases the all-cause mortality in type 2 diabetes mellitus (T2DM); however, the underlying mechanisms remain unclear. We hypothesized that strict diet control to achieve euglycemia in diabetes damages major organs, increasing the mortality risk. To evaluate effects on major organs when euglycemia is obtained by diet control, we generated a model of end-stage T2DM in 13-week-old Sprague-Dawley rats by subtotal pancreatectomy, followed by ad libitum feeding for 5 weeks. We divided these rats into two groups and for the subsequent 6 weeks provided ad libitum feeding to half (AL, n=12) and a calorie-controlled diet to the other half (R, n=12). To avoid hypoglycemia, the degree of calorie restriction in the R group was isocaloric (g per kg body weight per day) compared with a sham-operated control group (C, n=12). During the 6-week diet control period, AL rats ate three times more than rats in the C or R groups, developing hyperglycemia with renal hyperplasia. R group achieved euglycemia but lost overall body weight significantly compared with the C or AL group (49 or 22%, respectively), heart weight (39 or 23%, respectively) and liver weight (50 or 46%, respectively). Autophagy levels in the heart and liver were the highest in the R group (P<0.01), which also had the lowest pAkt/Akt levels among the groups (P<0.05 in the heart; P<0.01 in the liver). In conclusion, glycemic control achieved by diet control can prevent hyperglycemia-induced renal hyperplasia in diabetes but may be deleterious even at isocaloric rate when insulin is deficient because of significant loss of heart and liver mass via increased autophagy.

Markers of poor outcome in patients with acute hypoxemic respiratory failure.

PURPOSE: This study described the acute hypoxemic respiratory failure (AHRF) population and identified potential modifiable markers of outcome. METHODS: A prospective, multicenter study was performed in 22 intensive care units (ICUs). The clinical outcomes of patients with acute respiratory distress syndrome (ARDS) were compared to the outcomes in patients with non-ARDS AHRF, and a propensity score matched analysis was performed. RESULTS: A total 837 patients with an arterial oxygen tension/fraction of inspired oxygen ratio (Pao2/Fio2) less than 300 mm Hg on ICU admission were included. Of these, 163 patients met the criteria defining ARDS, whereas the remaining 674 patients who had unilateral or no pulmonary opacities were classified as non-ARDS AHRF. Baseline Pao2/Fio2 ratio, thrombocytopenia, increased positive end-expiratory pressure (PEEP) were significantly associated with the 60-day mortality in hypoxemic respiratory failure after multivariate analysis. However, ARDS was not associated with increased 60-day mortality when independent predictors for the 60-day mortality and propensity score were controlled. In the case-control study, the 60-day mortality rate was 38.6% in the ARDS group and 32.3% in the non-ARDS AHRF group. In both patients with ARDS and non-ARDS AHRF, the mortality rate increased proportionally to a lower baseline Pao2/Fio2. CONCLUSION: Lower baseline oxygenation (Pao2/Fio2) is a poor prognostic marker in acute hypoxemic respiratory failure.

Body mass index and mortality in Korean intensive care units: a prospective multicenter cohort study.

BACKGROUND: The level of body mass index (BMI) that is associated with the lowest mortality in critically ill patients in Asian populations is uncertain. We aimed to examine the association of BMI with hospital mortality in critically ill patients in Korea. METHODS: We conducted a prospective multicenter cohort study of 3,655 critically ill patients in 22 intensive care units (ICUs) in Korea. BMI was categorized into five groups: <18.5, 18.5 to 22.9, 23.0 to 24.9 (the reference category), 25.0 to 29.9, and ≥30.0 kg/m2. RESULTS: The median BMI was 22.6 (IQR 20.3 to 25.1). The percentages of patients with BMI<18.5, 18.5 to 22.9, 23.0 to 24.9, 25.0 to 29.9, and ≥30.0 were 12, 42.3, 19.9, 22.4, and 3.3%, respectively. The Cox-proportional hazard ratios with exact partial likelihood to handle tied failures for hospital mortality comparing the BMI categories <18.5, 18.5 to 22.9, 25.0 to 29.9, and ≥30.0 with the reference category were 1.13 (0.88 to 1.44), 1.03 (0.84 to 1.26), 0.96 (0.76 to 1.22), and 0.68 (0.43 to 1.08), respectively, with a highly significant test for trend (p = 0.02). CONCLUSIONS: A graded inverse association between BMI and hospital mortality with a strong significant trend was found in critically ill patients in Korea.

A case of acute motor and sensory axonal neuropathy following hepatitis a infection.

Acute motor and sensory axonal neuropathy (AMSAN) are recently described subtypes of Guillain-Barre syndrome characterized by acute onset of distal weakness, loss of deep tendon reflexes, and sensory symptoms. A 21-yr-old male was transferred to our hospital due to respiration difficulties and progressive weakness. In laboratory findings, immunoglobulin M antibodies against hepatitis A were detected in blood and cerebrospinal fluid. The findings of motor nerve conduction studies showed markedly reduced amplitudes of compound muscle action potentials in bilateral peroneal, and posterior tibial nerves, without evidence of demyelination. Based on clinical features, laboratory findings, and electrophysiologic investigation, the patient was diagnosed the AMSAN following acute hepatitis A viral infection. The patient was treated with intravenous immunoglobulin and recovered slowly. Clinicians should consider this rare but a serious case of AMSAN following acute hepatitis A infection.

Improvement of ß-cell function after achievement of optimal glycaemic control via long-term continuous subcutaneous insulin infusion therapy in non-newly diagnosed type 2 diabetic patients with suboptimal glycaemic control.

BACKGROUND: Achieving euglycaemia by continuous subcutaneous insulin infusion (CSII) therapy alone has been shown to restore ß-cell function in patients with newly diagnosed type 2 diabetes. However, the efficacy has not been evaluated in patients with non-newly diagnosed type 2 diabetes and suboptimal glycaemic control. METHODS: Of the 1220 patients with type 2 diabetes who began CSII therapy from March 2000 to March 2007, we retrospectively selected patients using the following inclusion criteria: glycosylated haemoglobin (HbA1c ) ≥ 7.0%, diabetes duration ≥ 1 year before CSII therapy, and duration of CSII therapy ≥ 6 months. We evaluated sequential changes in HbA1c and serum C-peptide levels measured at a 6- to 12-month intervals during CSII therapy. RESULTS: In the 521 subjects included in this study [median diabetes duration 10 years; interquartile range (IQR) 6.0-17.0; CSII therapy ≤ 30 months], median HbA1c decreased from 8.7% (IQR 7.7-10.0) at baseline to 6.3% (IQR 5.9-6.9) after 6 months of CSII therapy (p < 0.0001). During the subsequent 24 months, median HbA1c levels were maintained between 6.3% and 6.5% (p < 0.0001 for all time points vs baseline). At 12 months after CSII therapy, median C-peptide levels began to increase compared with baseline (fasting level 23% increase, p < 0.0001; 2-h postprandial level 26% increase, p = 0.022), and the increase was maintained at 30 months (fasting level 39%; 2-h postprandial level 53%; p < 0.0001 for all vs baseline). CONCLUSIONS: ß-Cell function was significantly improved in patients with non-newly diagnosed and suboptimally controlled type 2 diabetes after achieving and maintaining optimal glycaemic control with long-term CSII therapy alone.

The impact of implementing critical care team on open general intensive care unit.

BACKGROUND: There are a plethora of literatures showing that high-intensity intensive care unit (ICU) physician staffing is associated with reduced ICU mortality. However, it is not widely used in ICUs because of limited budgets and resources. We created a critical care team (CCT) to improve outcomes in an open general ICU and evaluated its effectiveness based on patients' outcomes. METHODS: We conducted this prospective, observational study in an open, general ICU setting, during a period ranging from March of 2009 to February of 2010. The CCT consisted of five teaching staffs. It provided rapid medical services within three hours after calls or consultation. RESULTS: We analyzed the data of 830 patients (157 patients of the CCT group and 673 patients of the non-CCT one). Patients of the CCT group presented more serious conditions than those of the non-CCT group (acute physiologic and chronic health evaluation II [APACHE II] 20.2 vs. 15.8, p<0.001; sequential organ failure assessment [SOFA] 5.5 vs. 4.6, p=0.003). The CCT group also had significantly more patients on mechanical ventilation than those in the non-CCT group (45.9% vs. 23.9%, p<0.001). Success rate of weaning was significantly higher in the CCT group than that of the non-CCT group (61.1% vs. 44.7%, p=0.021). On a multivariate logistic regression analysis, the increased ICU mortality was associated with the older age, non-CCT, higher APACHE II score, higher SOFA score and mechanical ventilation (p<0.05). CONCLUSION: Although the CCT did not provide full-time services in an open general ICU setting, it might be associated with a reduced ICU mortality. This is particularly the case with patients on mechanical ventilation.

Review of natural products actions on cytokines in inflammatory bowel disease.

The purpose of this review is to provide an overview of the effects that natural products have on inflammatory bowel disease (IBD) and to provide insight into the relationship between these natural products and cytokines modulation. More than 100 studies from the past 10 years were reviewed herein on the therapeutic approaches for treating IBD. The natural products having anti-IBD actions included phytochemicals, antioxidants, microorganisms, dietary fibers, and lipids. The literature revealed that many of these natural products exert anti-IBD activity by altering cytokine production. Specifically, phytochemicals such as polyphenols or flavonoids are the most abundant, naturally occurring anti-IBD substances. The anti-IBD effects of lipids were primarily related to the n-3 polyunsaturated fatty acids. The anti-IBD effects of phytochemicals were associated with modulating the levels of tumor necrosis factor α (TNF-α), interleukin (IL)-1, IL-6, inducible nitric oxide synthase, and myeloperoxide. The anti-IBD effects of dietary fiber were mainly mediated via peroxisome proliferator-activated receptor-γ, TNF-α, nitric oxide, and IL-2, whereas the anti-IBD effects of lactic acid bacteria were reported to influence interferon-γ, IL-6, IL-12, TNF-α, and nuclear factor-κ light-chain enhancer of activated B cells. These results suggest that the anti-IBD effects exhibited by natural products are mainly caused by their ability to modulate cytokine production. However, the exact mechanism of action of natural products for IBD therapy is still unclear. Thus, future research is needed to examine the effect of these natural products on IBD and to determine which factors are most strongly correlated with reducing IBD or controlling the symptoms of IBD.

Acorus gramineus inhibits microglia mediated neuroinflammation and prevents neurotoxicity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Acorus gramineus Solander (Acoraceae, AG), is a widely distributed plant in Asian countries. Rhizome part of this plant has long been used as a traditional medicine for treating various symptoms including central nervous system (CNS) disorders. AIM OF STUDY: The anti-neuroinflammatory effect of AG aqueous extract was investigated using in vitro cellular and in vivo Parkinson's disease (PD) mouse model. MATERIALS AND METHODS: Lipopolysaccharide (LPS) is used to stimulate BV-2 microglial cells in vitro and the changes in neuroinflammatory expressional levels were measured using ELISA, Western blotting, RT-PCR and immunofluorescence techniques. In in vivo experiments, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD was developed followed by immunohistochemical analysis of specific brain tissues. RESULTS: LPS-stimulation to BV-2 cells increased the production of nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß. Pretreatment with AG extract inhibited the increased levels of NO and pro-inflammatory cytokines in LPS-stimulated BV-2 cells. Mechanistic study revealed that AG acts via the regulation of nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPKs) and TRIF-dependent signaling pathways. Further, AG protected MPTP-induced neuronal cell death and inhibited neuroinflammation in vivo. CONCLUSION: Our results indicated that AG extract exerted anti-neuroinflammatory effects against activated microglia mediated insults through multiple signaling pathways and prevented in vivo neuronal cell death in mouse model of PD substantiating the traditional claims for its use in CNS disorders.

De novo generation of short antimicrobial peptides with simple amino acid composition.

As potential therapeutic agents, antimicrobial peptides with shorter length and simpler amino acid composition can be better candidates for clinical and commercial development. Here, we attempted de novo design of short (5- to 11-residue) antimicrobial peptides with three kinds of amino acids. Amphipathic helical properties were conferred by using leucines and lysines and two tryptophan residues were positioned at the critical amphipathic interface between the hydrophilic ending side and the hydrophobic starting side. According to this specified rule, 12 model peptides were generated and their helical propensity was confirmed by circular dichroism spectroscopy. Antimicrobial and hemolytic activities were compared with those of the known 12-residue peptide agent, omiganan, which is currently under therapeutic and commercial development. Antimicrobial activities against Gram-negative and Gram-positive bacteria, including a multi-drug resistant strain, were observed for certain 7- to 11-residue models. Among them, the most potent activity was found for a 9-residue peptide (L5K2W2), although it also had severe hemolytic activity. Alternatively, an 11-residue peptide (L4K5W2) with little hemolytic activity was potentially the most useful agent, as it showed higher antibacterial activity than omiganan. These results not only suggest useful candidates for novel antibiotic development, but also provide an efficient strategy to design such peptides.

Spontaneous left external iliac vein rupture.

We report a 72-year-old female patient with spontaneous rupture of the left external iliac vein. She visited our hospital for abdominal and back pain. She had the abnormal finding of hemoperitoneum. We performed an emergency operation with diagnosis of left ovarian cyst rupture though she suffered from spontaneous rupture of the left external iliac vein. This case provides insight to the experience of spontaneous rupture of the left external iliac vein.

Venous hemodynamic changes in the surgical treatment of primary varicose vein of the lower limbs.

Venous hemodynamic changes after the surgery of primary varicose veins were evaluated. (Materials and methods) We retrospectively analyzed 1,211 patients (1,407 limbs) who underwent surgery for primary varicose veins from 1994 to 2002. The venous hemodynamics were evaluated using air- plethysmography (APG) preoperatively and one month postoperatively in the viewpoints of ambulatory venous pressure (AVP), venous volume (VV), venous filling index (VFI), and ejection fraction (EF). (Results) The surgical modalities included 958 cases of greater saphenous vein high ligation (GSV HL) and stripping with varicosectomy (VS), 222 cases of short saphenous vein (SSV) HL and VS, 143 cases of external banding valvuloplasty of GSV and VS, and 44 cases using VNUS and VS. The reduction rate of VV was 20.9 +/- 14.1% in the GSV stripping group, 12.0 +/- 14.7% in the GSV valvuloplasty group, 18.3 +/- 16.1% in the VNUS group, and 20.6 +/- 15.9% in the SSV group. The reduction rate of VFI was 63.6 +/- 20.7% in the GSV stripping group, 38.8 +/- 40.9% in the GSV valvuloplasty group, 60.1 +/- 23.9% in the VNUS group, and 37.6 +/- 30.2% in the SSV group. The increasing rate of EF was 25.0 +/- 28.2% in the GSV stripping group, 21.0 +/- 30.0% in the GSV valvuloplasty group, 29.4 +/- 31.9% in the VNUS group, and 30.0 +/- 36.5% in the SSV group. The reduction rate of AVP was 25.4 +/- 32.2% in the GSV stripping group, -6.1 +/- 58.1% in the GSV valvuloplasty group, 28.4 +/- 38.5% in the VNUS group, and 14.1 +/- 49.0% in the SSV group. All of the patients showed improvements in venous hemodynamics by showing a decrease in VV, VFI, AVP, and an increase in EF. However, there was no difference in the change of venous hemodynamics according to the type of surgery.