Risk factors for in-hospital acquisition of carbapenem-resistant Enterobacterales in patients with severe burns.

BACKGROUND: Although patients with severe burns are prone to severe infections with antibiotic-resistant bacteria and inevitably have some risk factors for carbapenem-resistant Enterobacterales (CRE) acquisition, risk factors for CRE infection or colonization in these patients have not been investigated. AIM: To identify the independent risk factors for CRE acquisition in patients with severe burns. METHODS: Patients admitted to the burn intensive care unit (BICU) for acute burn care were categorized based on culture results during BICU care into the CRE group and non-CRE group, which included the carbapenem-susceptible Enterobacterales (CSE) and control groups. Clinical and microbiological factors were compared between the CRE and non-CRE groups, and between the CRE and CSE groups to identify independent risk factors for in-hospital CRE acquisition. FINDINGS: Among the included 489 patients, 101 (20.7%) and 388 (79.3%) patients were classified in the CRE and non-CRE groups, respectively. The non-CRE group included 91 (18.6%) and 297 (60.7%) patients in the CSE and control groups, respectively. In multivariate analysis between the CRE and non-CRE groups, exposure to other CRE-acquired patients (P = 0.018), abbreviated burn severity index score ≥9 (P = 0.012), and mechanical ventilation (P < 0.001) were associated with CRE acquisition. In multivariate analysis between the CRE and CSE groups, exposure to other CRE-acquired patients was associated with CRE acquisition (P = 0.048). CONCLUSION: Considering the limitation of controlling the burn severity in hospitalized patients, enhanced infection control measures for preventing in-hospital CRE transmission among patients with severe burns should be emphasized.

Prospective evaluation of dietary and lifestyle pattern indices with risk of colorectal cancer in a cohort of younger women.

BACKGROUND: Although colorectal cancer (CRC) incidence in the USA is declining overall, its incidence is increasing among those younger than 50 years of age. The reasons underlying the increasing trend are largely unknown, although behavioral changes, such as unhealthy diet and lifestyle factors, may be partially responsible. DESIGN: A prospective cohort study included 94 217 women aged 26-45 years at baseline. Validated anthropometric measures and lifestyle information were self-reported biennially. Exposures were four recommendation-based dietary indices-the prime diet quality score and three plant-based dietary indices; and two mechanism-based indices-the empirical dietary and lifestyle index for hyperinsulinemia (EDIH and ELIH). We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall CRC and for early-onset (before age 50) and after age 50 CRC separately. RESULTS: We documented 332 cases of CRC during 24 years of follow-up (2 113 655 person-years), with an average age of 52 ± 7 years at diagnosis. Hyperinsulinemic dietary and lifestyle patterns were associated with a higher risk of CRC. Multivariable-adjusted HRs (95% CIs) comparing participants in the highest versus lowest quartile were: 1.67 for EDIH (95% CI: 1.15-2.44, P-trend = 0.01) and 1.51 for ELIH (95% CI: 1.10-2.08, P-trend = 0.01). Moreover, per 75% increment in rank, ELIH appeared to be a stronger risk factor for early-onset CRC (HR = 1.86, 95% CI: 1.12-3.07) than after age 50 CRC (HR = 1.20, 95% CI: 0.83-1.73, P-heterogeneity = 0.16). The four recommendation-based indices were not significantly associated with overall, early-onset, or after age 50 CRC risk (per 75% increment in rank, HRs ranged from 0.75 to 1.28). CONCLUSION: Dietary and lifestyle patterns contributing to hyperinsulinemia were associated with greater CRC risk in younger women. Moreover, the hyperinsulinemic lifestyle showed a suggestively stronger positive association with early-onset CRC risk, compared with after age 50 CRC. Our findings suggest that dietary and lifestyle interventions to reduce insulinemic potential may be effective for CRC prevention among younger women.

Toll-like receptors and inflammation in metabolic neuropathy; a role in early versus late disease?

Neuropathy is a common, morbid complication of the metabolic syndrome, prediabetes, and diabetes. Recent studies have indicated a potential role for the immune system in the development of neuropathy. In particular, toll-like receptors (TLR) 2 and 4 have been linked to metabolic dysfunction, and blocking TLR4 is proposed as a treatment for neuropathic pain. In the current study, we investigated the role of the immune system, particularly TLRs 2 and 4, in the pathogenesis and progression of neuropathy. Sural or sciatic nerve gene expression arrays from humans and murine neuropathy models of prediabetes and diabetes were first analyzed to identify differentially expressed TLR2- and TLR4-associated genes within the KEGG (Kyoto Encyclopedia of Genes and Genomes) database. We observed that genes associated with TLRs 2 and 4, particularly lipopolysaccharide binding protein (LPB) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB), were dysregulated across species and across multiple murine models of prediabetic and diabetic neuropathy. To further understand the role of these pathways in vivo, TLR 2 and 4 global knockout mice placed on a 60% high fat diet (HFD-TLR2/4-/-) were compared with wild type (WT) mice on a high fat diet (HFD-WT) and WT controls on a standard diet (CON). Mice then underwent metabolic, neuropathic, and immunological phenotyping at two time points to assess the impact of TLR signaling on neuropathy and immunity during metabolic dysfunction over time. We found that HFD-TLR2/4-/- and HFD-WT mice weighed more than CON mice but did not have increased fasting blood glucose levels. Despite normal blood glucose levels, HFD-TLR2/4-/- mice eventually developed neuropathy at the later time point (28 wks of age) but were somewhat protected from neuropathy at the early time point (16 wks of age) as measured by shorter hind paw withdraw latencies. This is in contrast to HFD-WT mice which developed neuropathy within 11 wks of being placed on a high fat diet and were neuropathic by all measures at both the early and late time points. Finally, we immunophenotyped all three mouse groups at the later time point and found differences in the number of peripheral blood Ly6C-myeloid cells as well as F4/80+ expression. These results indicate that TLR signaling influences early development of neuropathy in sensory neurons, potentially via immune modulation and recruitment.

Abnormal RNA stability in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA-binding protein TDP-43. TDP-43 regulates RNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We use Bru-seq and BruChase-seq to assess genome-wide RNA stability in ALS patient-derived cells, demonstrating profound destabilization of ribosomal and mitochondrial transcripts. This pattern is recapitulated by TDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in postmortem samples from ALS and FTD patients. Proteomics and functional studies illustrate corresponding reductions in mitochondrial components and compensatory increases in protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, and may ultimately cause cell death by disrupting energy production and protein synthesis pathways.

Administration of Cripto in GRP78 overexpressed human MSCs enhances stem cell viability and angiogenesis during human MSC transplantation therapy.

OBJECTIVES: The purpose of this study was to explore the effectiveness of concurrent GRP78 overexpression combined with Cripto on hMSC proliferation and migration both in vitro and in vivo. Specifically, we explored whether the treatment enhances effectiveness of hMSC transplantation in ischaemic tissue. MATERIALS AND METHODS: Human MSCs obtained from human adipose tissue were cultured in α-minimum essential medium (Hyclone, Logan, UT, USA) supplemented with 10% (v/v) foetal bovine serum (Hyclone), 100 U mL-1 penicillin and 100 µg mL-1 streptomycin. Murine hindlimb ischaemic model was generated with 8-week-old male nude BALB/c mice (Biogenomics, Seoul, Korea) maintained under a 12-h light/dark cycle following the established protocol with minor modification. Cellular injection was performed no later than 3 hour after surgery. Lipofectamine transfection, single-cell cultivation assay, transwell assay, scratch wound-healing migration assay, immunohistochemistry and western blotting assays were performed. RESULTS: Overexpression of GRP78 along with Cripto enhanced hMSC proliferation, migration and invasion. It increased interaction of surface GRP78 receptor with Cripto via JAK2/STAT3 pathway. We confirmed our proposed mechanism by showing that treatment with GRP78 antibody blocks the enhancement in vitro. In vivo, we observed that Cripto induced by the hypoxic environment in hindlimb ischaemic model interacts with the overexpressed GRP78 and increases hMSC proliferation, migration and invasion potentials as well as angiogenesis around transplanted ischaemic site via cytokine secretions. CONCLUSIONS: These results demonstrate supporting evidences that GRP78-Cripto combination technique offers novel strategy to enhance MSC proliferation, migration and invasion potentials as well as angiogenesis around ischaemic site, ultimately facilitating MSC-based transplantation therapy in ischaemic conditions.

Endophytic and endolichenic fungal diversity in maritime Antarctica based on cultured material and their evolutionary position among Dikarya.

Fungal endophytes comprise one of the most ubiquitous groups of plant symbionts. They live asymptomatically within vascular plants, bryophytes and also in close association with algal photobionts inside lichen thalli. While endophytic diversity in land plants has been well studied, their diversity in lichens and bryophytes are poorly understood. Here, we compare the endolichenic and endophytic fungal communities isolated from lichens and bryophytes in the Barton Peninsula, King George Island, Antarctica. A total of 93 fungal isolates were collected from lichens and bryophytes. In order to determine their identities and evolutionary relationships, DNA sequences of the nuclear internal transcribed spacer (ITS), nuclear ribosomal small subunit (nuSSU), nuclear large subunit (nuLSU), and mitochondrial SSU (mtSSU) rDNA were obtained and protein coding markers of the two largest subunit of RNA polymerase II (RPB1 and RPB2) were generated. Multilocus phylogenetic analyses revealed that most of the fungal isolates were distributed in the following six classes in the phylum Ascomycota: Dothideomycetes, Eurotiomycetes, Lecanoromycetes, Leotiomycetes, Pezizomycetes and Sordariomycetes. For the first time we report the presence of subphylum Mortierellomycotina that may belong to an undescribed order in endophytic fungi. Taken together, our results imply that lichens and bryophytes provide similar niches and harbour a selection of these fungi, indicating generalists within the framework of evolutionary adaptation.

Biodegradation of Chlorpyrifos, Malathion, and Dimethoate by Three Strains of Bacteria Isolated from Pesticide-Polluted Soils in Sudan.

This study was done to identify pesticide-biodegrading microorganisms and to characterize degradation rates. Bacillus safensis strain FO-36bT, Bacillus subtilis subsp. inaquosorum strain KCTC13429T, and Bacillus cereus strain ATCC14579T were isolated from pesticide-polluted soil in Sudan, separately incubated with each pesticide with periodic samples drawn for GC and GC-MS. Pesticide biodegradation followed a biphasic model. α and ß half-lives (days) of chlorpyrifos, malathion, and dimethoate in B. safensis culture were 2.13, 4.76; 2.59, 5.66; and 9.5, 11.0, respectively. Values in B. subtilis and B. cereus cultures were 4.09, 9.45 and 4.33, 9.99 for chlorpyrifos; 2.99, 5.36 and 2.43, 4.71 for malathion; and 9.53, 15.11 and 4.16, 9.27 for dimethoate. No metabolite was detected in B. subtilis cultures, whereas a few were detected from B. safensis and B. cereus cultures. Bacterial efficiency can be ordered as B. safensis > B. subtilis > B. cereus for chlorpyrifos and B. cereus > B. subtilis > B. safensis for malathion and dimethoate.

A chemogenomic approach to understand the antifungal action of Lichen-derived vulpinic acid.

AIM: To determine uncovered antifungal activity of lichen-derived compound, vulpinic acid, by using chemical-genetic analyses. METHODS AND RESULTS: Haploinsufficiency and homozygous-profiling assays were performed, revealing that strains lacking GLC7, MET4, RFC2, YAE1 and PRP18 were sensitive to three concentrations (12·5, 25 and 50% of inhibitory concentration) of vulpinic acid and independently validated. To verify inhibition of those genes, cell cycle analysis using flow cytometry was performed and relative expressions were measured. Under vulpinic acid-treated condition, cell cycle was arrested in S and G2/M phases and sensitive strains' relative expressions were significantly lower than the wild type yeast. CONCLUSIONS: Vulpinic acid mainly affects cell cycle, glycogen metabolism, transcription and translation to fungi. SIGNIFICANCE AND IMPACT OF THE STUDY: Although lichen-derived compounds are commercially valuable, few studies have determined their modes of action. This study used a chemogenomic approach to gain insight into the mechanisms of one of well-known lichen-derived compound, vulpinic acid.

Disruption of effective connectivity from the dorsolateral prefrontal cortex to the orbitofrontal cortex by negative emotional distraction in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) has been associated with abnormal cognitive and emotional functions and these dysfunctions may be dependent on the disruption of dynamic interactions within neuronal circuits associated with emotion regulation. Although several studies have shown the aberrant cognitive-affective processing in OCD patients, little is known about how to characterize effective connectivity of the disrupted neural interactions. In the present study, we applied effective connectivity analysis using dynamic causal modeling to explore the disturbed neural interactions in OCD patients. METHOD: A total of 20 patients and 21 matched healthy controls performed a delayed-response working memory task under emotional or non-emotional distraction while undergoing functional magnetic resonance imaging. RESULTS: During the delay interval under negative emotional distraction, both groups showed similar patterns of activations in the amygdala. However, under negative emotional distraction, the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC) exhibited significant differences between groups. Bayesian model averaging indicated that the connection from the DLPFC to the OFC was negatively modulated by negative emotional distraction in patients, when compared with healthy controls (p < 0.05, Bonferroni-corrected). CONCLUSIONS: Exaggerated recruitment of the DLPFC may induce the reduction of top-down prefrontal control input over the OFC, leading to abnormal cortico-cortical interaction. This disrupted cortico-cortical interaction under negative emotional distraction may be responsible for dysfunctions of cognitive and emotional processing in OCD patients and may be a component of the pathophysiology associated with OCD.

Dynamic 4D MRI for Characterization of Parathyroid Adenomas: Multiparametric Analysis.

BACKGROUND AND PURPOSE: The hypervascular nature of parathyroid adenomas can be explored by proper dynamic imaging to narrow the target lesions for surgical exploration. The purpose of this study was to establish MR perfusion characteristics of parathyroid adenomas to differentiate them from their mimics, such as subjacent thyroid tissue and cervical lymph nodes. MATERIALS AND METHODS: Preoperative high-spatial and -temporal resolution dynamic 4D contrast-enhanced MR imaging in 30 patients with surgically proved parathyroid adenomas was evaluated retrospectively. Using coregistered images, we placed ROIs over the parathyroid adenoma, thyroid gland, and a cervical lymph node (jugulodigastric) to obtain peak enhancement, time-to-peak, wash-in, and washout in each patient. Data were analyzed by logistic regression and analysis of variance. Receiver operating characteristic analysis was performed to determine the optimal parameters for determination of parathyroid adenomas versus thyroid tissue and cervical lymph nodes. RESULTS: Parathyroid adenomas showed significantly (P < .05) faster time-to-peak, higher wash-in, and higher washout compared with cervical lymph nodes and significantly (P < .05) higher peak enhancement, faster time-to-peak, higher wash-in, and higher washout compared with thyroid tissue. Logistic regression analysis indicated significant contribution from time-to-peak (P = .02), wash-in (P = .03), and washout (P = .008) for differentiation of parathyroid adenomas from thyroid and cervical lymph nodes. Using receiver operating characteristic analysis, we obtained the best diagnostic accuracy from a combination of time-to-peak/wash-in/washout in the differentiation of parathyroid adenomas versus lymph nodes (area under the curve, 0.96; sensitivity/specificity, 88%/90%) and in distinguishing parathyroid adenomas versus thyroid tissue (area under the curve, 0.96; sensitivity/specificity, 91%/95%). CONCLUSIONS: Dynamic 4D contrast-enhanced MR imaging can be used to exploit the hypervascular nature of parathyroid adenomas. Multiparametric MR perfusion can distinguish parathyroid adenomas from subjacent thyroid tissue or lymph nodes with diagnostic accuracies of 96%.

Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease.

Amylin, a pancreatic peptide, and amyloid-beta peptides (Aß), a major component of Alzheimer's disease (AD) brain, share similar ß-sheet secondary structures, but it is not known whether pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aß in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aß1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aß in the serum, the magnitude of which is proportionate to the amount of Aß in brain tissue. One intracerebroventricular injection of amylin induces a more significant surge in serum Aß than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aß1-42 as well as Aß1-40 is found only in patients with AD or amnestic mild cognitive impairment. As amylin readily crosses the blood-brain barrier, our study demonstrates that peripheral amylin's action on the central nervous system results in translocation of Aß from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aß in blood. As naturally occurring amylin may play a role in regulating Aß in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD.

Integrated systems pharmacology analysis of clinical drug-induced peripheral neuropathy.

A systems pharmacology approach was undertaken to define and identify the proteins/genes significantly associated with clinical incidence and severity of drug-induced peripheral neuropathy (DIPN). Pharmacological networks of 234 DIPN drugs, their known targets (both intended and unintended), and the intermediator proteins/genes interacting with these drugs via their known targets were examined. A permutation test identified 230 DIPN-associated intermediators that were enriched with apoptosis and stress response genes. Neuropathy incidence and severity were curated from drug labels and literature and were used to build a predictive model of DIPN using a regression tree algorithm, based on the drug targets and their intermediators. DIPN drugs whose targets interacted with both v-myc avian myelocytomatosis viral oncogene homolog (MYC) and proliferating cell nuclear antigen-associated factor (PAF15) were associated with a neuropathy incidence of 38.1%, whereas drugs interacting only with MYC had an incidence of 2.9%. These results warrant further investigation in order to develop a predictive tool for the DIPN potential of a new drug.

Chest CT findings of toxocariasis: correlation with laboratory results.

AIM: To assess the relationship between chest computed tomography (CT) findings of patients with toxocariasis and levels of serological markers. MATERIALS AND METHODS: A total of 38 cases of patients diagnosed with toxocariasis by enzyme-linked immunosorbent assay (ELISA), CT, and serological markers were retrospectively reviewed. The presence of nodule with or without ground-glass opacity (GGO) halo, consolidation, focal GGO, pleural effusion, and lymphadenopathy at chest CT were evaluated. Statistical analysis was performed with the Fisher's exact test. RESULTS: The most common chest CT findings were nodule (n = 12, 31.6%) and focal GGO (n = 12, 31.6%). In patients with normal eosinophil levels, focal GGO (n = 9, 37.5%) was the most common finding. In contrast, nodule with a GGO halo (n = 7, 50%) was the most common finding in the eosinophilia group. Nodule with a GGO halo was more common in the eosinophilia group, with a statistically significant difference (p = 0.017). Nodule was more common in the eosinophilia group, and focal GGO was more common in the normal eosinophil group. CONCLUSION: The most common chest CT findings in toxocariasis were nodule with or without GGO halo, and focal GGO. In the eosinophilia group, nodule with a GGO halo was significantly more frequent. Other CT findings did not show a statistically significant relationship with serological markers.

Chloride channel 4 is required for nerve growth factor-induced TrkA signaling and neurite outgrowth in PC12 cells and cortical neurons.

We have previously shown that chloride ion flux plays an important role in receptor tyrosine kinase A (TrkA)-mediated signaling pathway during nerve growth factor (NGF)-induced differentiation in pheochromocytoma (PC12) cells. Here we found out that chloride channel 4 (CLC-4) is responsible for the NGF-induced neurite outgrowth in neuronal cells. Using a patch-clamp technique, we found that NGF treatment increased anionic conductance in PC12 cells, an effect which was blocked by transfection of siRNA of CLC-4. Also, the NGF-induced TrkA phosphorylation and subsequent Akt/moesin phosphorylation was suppressed in the CLC-4 knock down cells. Moreover, CLC-4 knock down also suppressed the neurite outgrowth in response to long-term treatment of NGF in PC12 cells and in primary cortical neurons. In summary, our results suggest that CLC-4 is an important mediator of the TrkA-mediated signaling pathway and thus, the NGF-induced differentiation of neuronal cells.

Higher levels of small dense low-density lipoprotein (LDL) are associated with cardiac autonomic neuropathy in patients with type 2 diabetes.

AIM: To investigate the relationship between small dense LDL cholesterol and cardiac autonomic neuropathy among patients with Type 2 diabetes. METHODS: A total of 175 patients who had not taken lipid-lowering agents previously were enrolled consecutively in this study. Small dense LDL cholesterol level was measured using polyacrylamide tube gel electrophoresis, which fractionates LDL cholesterol into seven components according to particle size and charge. We analysed the mean LDL cholesterol particle size and the proportion of small dense LDL cholesterol. RESULTS: The mean (± sd) patient age was 56 (± 14) years, the mean (± sd) duration of diabetes was 10.3 (± 8.3) years, the mean (± sd) proportion of small dense LDL cholesterol was 21.3 (± 17.6)% and the mean (± sd) LDL cholesterol size was 26.33 (± 0.8) nm. Men with cardiac autonomic neuropathy had a longer duration of diabetes compared with those without cardiac autonomic neuropathy. Women with cardiac autonomic neuropathy had a larger waist circumference, higher plasma triglyceride levels, smaller mean (± sd) LDL cholesterol size [26.8 (± 4.3) nm vs 26.4 (± 6.9) nm; P < 0.01] and larger mean (± sd) proportion of small dense LDL cholesterol [10.1 (± 9.9)% vs 19.1 (± 16.8)%; P < 0.01] compared with those without cardiac autonomic neuropathy. After adjusting for other confounding risk factors, the triglyceride/ HDL cholesterol ratio (odds ratio = 1.698, 95% CI: 1.07-2.69; P = 0.025) and mean LDL cholesterol size (odds ratio = 0.873, 95% CI: 0.77-0.99; P = 0.038) remained as independent risk factors for cardiac autonomic neuropathy in women. CONCLUSIONS: A more atherogenic lipid profile such as the triglyceride: HDL cholesterol ratio and a smaller mean LDL cholesterol particle size were related to the prevalence of cardiac autonomic neuropathy in women with Type 2 diabetes.

The protective effects of oxyresveratrol imine derivative against hydrogen peroxide-induced cell death in PC12 cells.

Oxyresveratrol (2',3,4',5-tetrahydroxystilbene) is a naturally occurring ingredient found in mulberries that shows potential as an antioxidant, anti-inflammatory, and neuroprotective agent. This study was performed to identify materials similar to oxyresveratrol that may have more effective antioxidant properties. We synthesized a stilbene analog referred to as Compound 1 (2',3,4',5-tetramethoxystilbene); a benzamide analog referred to as Compound 2 ((2,4-dimethoxyphenyl)-3,5-dimethoxybenzamide); and three imine analogs referred to as Compound 3 (3,5-dimethoxybenzylidene)-(2,4-dimethoxyphenylamine), Compound 4 ((4-methoxybenzylidene)-(3-methoxyphenyl)amine), and Compound 5 ((4-methoxybenzylidene)phenylamine). The cytoprotective effects of these compounds were subsequently evaluated using hydrogen peroxide-treated PC12 cells. The cytoprotective effects of the imine analogs were greater than the effects of oxyresveratrol and the other analogs at concentrations of 200 µM. The Compound 3, which is the most effective imine analog of oxyresveratrol, exhibited these cytoprotective effects against hydrogen peroxide-induced oxidative stress through the regulation of heme oxygenase-1 (HO-1) expression and the translocation of nuclear factor E2-related factor 2 (Nrf2). Our results suggest that imine analogs of oxyresveratrol may be useful agents in reducing neuronal oxidative damage.

Association between urine cotinine levels, continuous performance test variables, and attention deficit hyperactivity disorder and learning disability symptoms in school-aged children.

BACKGROUND: We examined the cross-sectional relationship between environmental tobacco smoke exposure, continuous performance test (CPT) measures, and attention deficit hyperactivity disorder (ADHD) or learning disability symptoms in school-aged children. METHOD: In total, 989 children (526 boys, mean age 9.1 ± 0.7 years), recruited from five South Korean cities participated in this study. We used urine cotinine as a biomarker for environmental tobacco smoke exposure, and obtained the children's scores on a CPT. Parents completed the Korean versions of the ADHD rating scale-IV (ADHD-RS) and learning disability evaluation scale (LDES). Using generalized linear mixed model (GLMM), we assessed the associations between urine cotinine concentrations, neuropsychological variables, and symptoms of ADHD and learning disabilities. Additionally, we conducted structural equation models to explore the effects' pathways. RESULTS: After adjusting for a range of relevant covariates, GLMM showed urinary cotinine levels were significantly and positively associated with CPT scores on omission errors, commission errors, response time, and response time variability, and with parent- and teacher-rated ADHD-RS scores. In addition, urine cotinine levels were negatively associated with LDES scores on spelling and mathematical calculations. The structural equation model revealed that CPT variables mediated the association between urine cotinine levels and parental reports of symptoms of ADHD and learning disabilities. CONCLUSIONS: Our data indicate that environmental exposure to tobacco smoke is associated with ADHD and learning disabilities in children, and that impairments in attention and inhibitory control probably mediate the effect.

Central nervous system endoplasmic reticulum stress in a murine model of type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with complications in the central nervous system (CNS), including learning and memory, and an increased risk for neurodegenerative diseases. The mechanism underlying this association is not understood. The aim of this study was to gain greater insight into the possible mechanisms of diabetes-induced cognitive decline. METHODS: We used microarray technology to identify and examine changes in gene expression in the hippocampus of a murine model of type 2 diabetes, the db/db mouse. Bioinformatics approaches were then used to investigate the biological significance of these genes. To validate the biological significance we evaluated mRNA and protein levels. RESULTS: At 8 and 24 weeks, 256 and 822 genes, respectively, were differentially expressed in the db/db mice. The most significantly enriched biological functions were related to mitochondria, heat shock proteins, or the endoplasmic reticulum (ER), the majority of which were downregulated. The ER-enriched cluster was one of the clusters that contained the highest number of differentially expressed genes. Several of the downregulated genes that were differentially expressed at 24 but not at 8 weeks are directly involved in the unfolded protein response (UPR) pathway and include two heat shock proteins (encoded by Hspa5 and Hsp90b1), a transcriptional factor (x-box binding protein 1, encoded by Xbp1), and an apoptotic mediator (DNA-damage inducible transcript 3, encoded by Ddit3). CONCLUSIONS/INTERPRETATION: The changes that we observed in the UPR pathway due to ER stress may play a role in the pathogenesis of CNS complications in diabetes. The results of this study are a foundation for the development of pharmacological targets to reduce ER stress in diabetic hippocampi.

Relationship between the expression of fibulin-3 and anterior vaginal wall prolapse.

Anterior vaginal wall prolapse is the most common type of pelvic organ prolapse. Vaginal wall samples were obtained from women with (n =12) and without (n =12) anterior vaginal wall prolapse. No reports have been published on the content of fibulin-3 in the vaginal walls of patients with prolapse; thus, we compared the expression of fibulin-3 in the vaginal walls of women with and without anterior vaginal wall prolapse. RT-PCR was performed to measure mRNA expression and the expression of protein was assessed by immunohistochemistry. Statistical analysis was performed to determine differences between the two groups of women. Age, parity and menopausal status did not differ between women with and without prolapse. The expressions of fibulin-3 mRNA and protein were not different between the prolapse and no prolapse groups. It is unlikely that abnormal expression of fibulin-3 has a major role in the pathogenesis of anterior vaginal wall prolapse.

Use of parenteral colistin for the treatment of multiresistant Gram-negative organisms in major burn patients in South Korea.

PURPOSE: To assess the therapeutic effect and toxicity of intravenous colistin in the treatment of multidrug-resistant (MDR) Gram-negative bacteria in patients with severe burns. METHODS: The medical records of 930 patients admitted to the Burn Intensive Care Unit (ICU) at Hallym University Hangang Sacred Heart Hospital, Seoul, South Korea between April 2007 and December 2009 were retrospectively reviewed. Of these, the 104 patients who had received intravenous colistin treatments (104 courses) during this period were enrolled in the study. Changes in creatinine level were analyzed in three groups: all patients receiving colistin (n = 104), patients with undergoing continuous renal replacement therapy (CRRT group; n = 38), and patients not undergoing CRRT (non-CRRT group; n = 66). RESULTS: Among these patients, the burnt body surface area ranged from 5 to 96% (mean 49.7%). Thirty-five patients (33.7%) suffered inhalation injury, and CRRT was administered to 38 patients. The mean duration of colistin treatment was 14.7 (range 4-71) days. The total dose of colistin was 3,045.7 mg (range 100-13,800). The length of ICU stay was 48.9 (range 7-154) days. Forty patients (38.5%) died. The mean pre-colistin creatinine level of all patients was 1.04 mg/dL, and the mean post-colistin level was 1.34 mg/dL. The mean pre-colistin creatinine level of the CRRT group and non-CRRT group was 1.68 and 0.66 mg/dL, and the mean post-colistin level was 1.68 and 1.14 mg/dL, respectively. CONCLUSIONS: Colistin appears to be a relatively safe and effective treatment for major burn patients with infections caused by MDR Gram-negative bacteria when no other drug is available. Additionally, we found no statistically significant impairment of creatinine levels.