bluuebunny/crossref_metadata_2025 huggingface dataset:
Host response transcriptional profiling reveals extracellular components and ABC (ATP-binding cassette) transporters gene enrichment in typhoid fever-infected Nigerian children
Authors: Khoo Sok Kean , Petillo David , Parida Mrutyunjaya , Tan Aik Choon , Resau James H , Obaro Stephen K
Published: September 2011

Background

Salmonella enterica serovar Typhi (S. Typhi) is a human-specific pathogen that causes typhoid fever, and remains a global health problem especially in developing countries. Its pathogenesis is complex and host response is poorly understood. In Africa, typhoid fever can be a major cause of morbidity in young infected children. The onset of the illness is insidious and clinical diagnosis is often unreliable. Gold standard blood culture diagnostic services are limited, thus rapid, sensitive, and affordable diagnostic test is essential in poor-resourced clinical settings. Routine typhoid fever vaccination is highly recommended but currently licensed vaccines provide only 55-75% protection. Recent epidemiological studies also show the rapid emergence of multi-drug resistant S. Typhi strains. High-throughput molecular technologies, such as microarrays, can dissect the molecular mechanisms of host responses which are S. Typhi-specific to provide a comprehensive genomic component of immunological responses and suggest new insights for diagnosis and treatment.

Methods

Global transcriptional profiles of S. Typhi-infected young Nigerian children were obtained from their peripheral blood and compared with that of other bacteremic infections using Agilent gene expression microarrays. The host-response profiles of the same patients in acute vs. convalescent phases were also determined. The top 96-100 differentially-expressed genes were identified and four genes were validated by quantitative real-time PCR. Gene clusters were obtained and functional pathways were predicted by DAVID (Database for Annotation, Visualization and Integrated Discovery).

Results

Transcriptional profiles from S. Typhi-infected children could be distinguished from those of other bacteremic infections. Enriched gene clusters included genes associated with extracellular peptides/components such as lipocalin (LCN2) and systemic immune response which is atypical in bacterial invasion. Distinct gene expression profiles can also be obtained from acute vs. convalescent phase during typhoid fever infection. We found novel down-regulation of ABC (ATP-binding cassette) transporters genes such as ABCA7, ABCC5, and ABCD4 and ATPase activity as the highest enriched pathway.

Conclusions

We identified unique extracellular components and ABC transporters gene enrichments in typhoid fever-infected Nigerian children, which have never been reported. These enriched gene clusters may represent novel targeted pathways to improve diagnostic, prognostic, therapeutic and next-generation vaccine strategies for typhoid fever in Africa.
In vitro characterization of cells derived from chordoma cell line U-CH1 following treatment with X-rays, heavy ions and chemotherapeutic drugs
Authors: Kato Takamitsu A , Tsuda Akihisa , Uesaka Mitsuru , Fujimori Akira , Kamada Tadashi , Tsujii Hirohiko , Okayasu Ryuichi
Published: September 2011

Background

Chordoma, a rare cancer, is usually treated with surgery and/or radiation. However, very limited characterizations of chordoma cells are available due to a minimal availability (only two lines validated by now) and the extremely long doubling time. In order to overcome this situation, we successfully derived a cell line with a shorter doubling time from the first validated chordoma line U-CH1 and obtained invaluable cell biological data.

Method

After isolating a subpopulation of U-CH1 cells with a short doubling time (U-CH1-N), cell growth, cell cycle distribution, DNA content, chromosome number, p53 status, and cell survival were examined after exposure to X-rays, heavy ions, camptothecin, mitomycin C, cisplatin and bleocin. These data were compared with those of HeLa (cervical cancer) and U87-MG (glioblastoma) cells.

Results

The cell doubling times for HeLa, U87-MG and U-CH1-N were approximately 18 h, 24 h and 3 days respectively. Heavy ion irradiation resulted in more efficient cell killing than x-rays in all three cell lines. Relative biological effectiveness (RBE) at 10% survival for U-CH1-N was about 2.45 for 70 keV/μm carbon and 3.86 for 200 keV/μm iron ions. Of the four chemicals, bleocin showed the most marked cytotoxic effect on U-CH1-N.

Conclusion

Our data provide the first comprehensive cellular characterization using cells of chordoma origin and furnish the biological basis for successful clinical results of chordoma treatment by heavy ions.
Validation of the relevant outcome scale for Alzheimer's disease: a novel multidomain assessment for daily medical practice
Authors: Holthoff Vjera A , Ferris Steven , Ihl Ralf , Robert Philippe , Winblad Bengt , Gauthier Serge , Sternberg Kati , Tennigkeit Frank
Published: September 2011

Introduction

The Relevant Outcome Scale for Alzheimer's Disease (ROSA) is a new observer rating instrument recently developed for routine medical practice. The validity and reliability of ROSA as well as sensitivity to changes due to intervention were examined in an open-label, single-arm, multicenter clinical study in patients with Alzheimer's disease (AD).

Methods

The study enrolled 471 patients with a diagnosis of AD consistent with the criteria of the National Institute of Neurological and Communicative Disease and Stroke/Alzheimer's Disease and Related Disorders Association or with the Diagnostic and Statistical Manual Disorders criteria for dementia of Alzheimer's type. Following assessments of the ROSA and other standard assessments (Alzheimer's Disease Assessment Scale - cognitive subscale, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia), patients were treated with memantine for 12 weeks. Factor analysis of the baseline ROSA total scores was performed based on the principal components method using the varimax orthogonal rotational procedure. The psychometric analyses of the ROSA included internal consistency, test-retest reliability, inter-rater reliability, construct validity, and responsiveness to changes over time.

Results

All items showed adequate factor loadings and were retained in the final ROSA as Factor 1 (all items related to cognition, communication, function, quality of life and caregiver burden) and Factor 2 (all behavior items). The ROSA demonstrated high internal consistency (Cronbach's α = 0.93), test-retest reliability (intraclass correlation coefficient = 0.93), and inter-rater reliability (intraclass correlation coefficient = 0.91). The correlation coefficients between the ROSA and each of the validated scales ranged between 0.4 and 0.7, confirming the ROSA construct validity. Nonsubstantial floor and ceiling effects were found in middle and late disease stages, whereas a small ceiling effect was observed in the early stage. The ROSA responsiveness to change was high (responsiveness index ≥0.8) for all severity stages.

Conclusions

The ROSA is a valid and reliable instrument to aid medical practitioners in sensitively assessing AD-relevant symptoms over time in their clinical practice.
The gene expression profile of preclinical autoimmune arthritis and its modulation by a tolerogenic disease-protective antigenic challenge
Authors: Yu Hua , Lu Changwan , Tan Ming T , Moudgil Kamal D
Published: September 2011

Introduction

Autoimmune inflammation is a characteristic feature of rheumatoid arthritis (RA) and other autoimmune diseases. In the natural course of human autoimmune diseases, it is rather difficult to pinpoint the precise timing of the initial event that triggers the cascade of pathogenic events that later culminate into clinically overt disease. Therefore, it is a challenge to examine the early preclinical events in these disorders. Animal models are an invaluable resource in this regard. Furthermore, considering the complex nature of the pathogenic immune events in arthritis, microarray analysis offers a versatile tool to define the dynamic patterns of gene expression during the disease course.

Methods

In this study, we defined the profiles of gene expression at different phases of adjuvant arthritis (AA) in Lewis rats and compared them with those of antigen mycobacterial heat shock protein 65 (Bhsp65)-tolerized syngeneic rats. Purified total RNA (100 ng) extracted from the draining lymph node cells was used to generate biotin-labeled fragment cRNA, which was then hybridized with an oligonucleotide-based DNA microarray chip. Significance analysis of microarrays was used to compare gene expression levels between the two different groups by limiting the false discovery rate to < 5%. Some of the data were further analyzed using a fold change ≥2.0 as the cutoff. The gene expression of select genes was validated by quantitative real-time PCR.

Results

Intriguingly, the most dramatic changes in gene expression in the draining lymphoid tissue ex vivo were observed at the preclinical (incubation) phase of the disease. The affected genes represented many of the known proteins that participate in the cellular immune response. Interestingly, the preclinical gene expression profile was significantly altered by a disease-modulating, antigen-based tolerogenic regimen. The changes mostly included upregulation of several genes, suggesting that immune tolerance suppressed disease by activating disease-regulating pathways. We identified a molecular signature comprising at least 12 arthritis-related genes altered by Bhsp65-induced tolerance.

Conclusions

This is the first report of microarray analysis in the rat AA model. The results of this study not only advance our understanding of the early phase events in autoimmune arthritis but also help in identifying potential targets for the immunomodulation of RA.
Biomechanical signals and the C-type natriuretic peptide counteract catabolic activities induced by IL-1β in chondrocyte/agarose constructs
Authors: Ramachandran Manoj , Achan Prim , Salter Donald M , Bader Dan L , Chowdhury Tina T
Published: September 2011

Introduction

The present study examined the effect of C-type natriuretic peptide (CNP) on the anabolic and catabolic activities in chondrocyte/agarose constructs subjected to dynamic compression.

Methods

Constructs were cultured under free-swelling conditions or subjected to dynamic compression with low (0.1 to 100 pM) or high concentrations (1 to 1,000 nM) of CNP, interleukin-1β (IL-1β), and/or KT-5823 (inhibits cyclic GMP-dependent protein kinase II (PKGII)). Anabolic and catabolic activities were assessed as follows: nitric oxide (NO) and prostaglandin E2 (PGE2) release, and [3H]-thymidine and 35SO4 incorporation were quantified by using biochemical assays. Gene expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), aggrecan, and collagen type II were assessed with real-time quantitative PCR (qPCR). Two-way ANOVA and the post hoc Bonferroni-corrected t tests were used to examine data.

Results

CNP reduced NO and PGE2 release and partially restored [3H]-thymidine and 35SO4 incorporation in constructs cultured with IL-1β. The response was dependent on the concentration of CNP, such that 100 pM increased [3H]-thymidine incorporation (P < 0.001). This is in contrast to 35SO4 incorporation, which was enhanced with 100 or 1000 nM CNP in the presence and absence of IL-1β (P < 0.001). Stimulation by both dynamic compression and CNP and/or the PKGII inhibitor further reduced NO and PGE2 release and restored [3H]-thymidine and 35SO4 incorporation. In the presence and absence of IL-1β, the magnitude of stimulation for [3H]-thymidine and 35SO4 incorporation by dynamic compression was dependent on the concentration of CNP and the response was inhibited with the PKGII inhibitor. In addition, stimulation by CNP and/or dynamic compression reduced IL-1β-induced iNOS and COX-2 expression and restored aggrecan and collagen type II expression. The catabolic response was not further influenced with the PKGII inhibitor in IL-1β-treated constructs.

Conclusions

Treatment with CNP and dynamic compression increased anabolic activities and blocked catabolic effects induced by IL-1β. The anabolic response was PKGII mediated and raises important questions about the molecular mechanisms of CNP with mechanical signals in cartilage. Therapeutic agents like CNP could be administered in conjunction with controlled exercise therapy to slow the OA disease progression and to repair damaged cartilage. The findings from this research provide the potential for developing novel agents to slow the pathophysiologic mechanisms and to treat OA in the young and old.
Prostaglandin E2 receptor type 2-selective agonist prevents the degeneration of articular cartilage in rabbit knees with traumatic instability
Authors: Mitsui Hiroto , Aoyama Tomoki , Furu Moritoshi , Ito Kinya , Jin Yonghui , Maruyama Takayuki , Kanaji Toshiya , Fujimura Shinsei , Sugihara Hikaru , Nishiura Akio , Otsuka Takanobu , Nakamura Takashi , Toguchida Junya
Published: September 2011

Introduction

Osteoarthritis (OA) is a common cause of disability in older adults. We have previously reported that an agonist for subtypes EP2 of the prostaglandin E2 receptor (an EP2 agonist) promotes the regeneration of chondral and osteochondral defects. The purpose of the current study is to analyze the effect of this agonist on articular cartilage in a model of traumatic degeneration.

Methods

The model of traumatic degeneration was established through transection of the anterior cruciate ligament and partial resection of the medial meniscus of the rabbits. Rabbits were divided into 5 groups; G-S (sham operation), G-C (no further treatment), G-0, G-80, and G-400 (single intra-articular administration of gelatin hydrogel containing 0, 80, and 400 μg of the specific EP2 agonist, ONO-8815Ly, respectively). Degeneration of the articular cartilage was evaluated at 2 or 12 weeks after the operation.

Results

ONO-8815Ly prevented cartilage degeneration at 2 weeks, which was associated with the inhibition of matrix metalloproteinase-13 (MMP-13) expression. The effect of ONO-8815Ly failed to last, and no effects were observed at 12 weeks after the operation.

Conclusions

Stimulation of prostaglandin E2 (PGE2) via EP2 prevents degeneration of the articular cartilage during the early stages. With a system to deliver it long term, the EP2 agonist could be a new therapeutic tool for OA.
A new category of autoinflammatory disease associated with NOD2 gene mutations
Authors: Yao Qingping , Zhou Lan , Cusumano Philip , Bose Nilanjana , Piliang Melissa , Jayakar Bijal , Su Le-Chu , Shen Bo
Published: September 2011

Introduction

Autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high titers of autoantibodies or antigen-specific T cells, and derive from genetic variants of the innate immune system. This study characterized a cohort of patients with similar phenotypes and nucleotide oligomerization domain 2 (NOD2) gene mutations.

Methods

Diagnostically challenging patients with the following clinical and genetic characteristics were prospectively studied between January 2009 and April 2011: periodic fever, dermatitis, polyarthritis, serositis, negative serum autoantibodies and additional positive NOD2 IVS8+158 gene mutation. Genetic testing for gene mutations of NOD2, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) and familial Mediterranean fever (FMF) was performed.

Results

All seven patients with the disease were Caucasians, with four being male. The mean age at disease onset was 40.7 years and disease duration was 3.2 years. These patients characteristically presented with periodic fever, dermatitis and inflammatory polyarthritis. There were gastrointestinal symptoms in three patients, granulomas of the skin and gut in two, and recurrent chest pain in two, with one having pleuritis and pericarditis. Three patients had sicca-like symptoms. Five patients had increased acute phase reactants. All seven patients had negative tests for autoantibodies but carried the NOD2 gene mutation IVS8+158 with four having concurrent R702W mutation.

Conclusions

Our cohort may represent a new disease category of autoinflammatory disease with characteristic clinical phenotypes and genotypes. It may somewhat resemble pediatric Blau's syndrome.
Persistent upregulation of U6:SNORD44 small RNA ratio in the serum of breast cancer patients
Authors: Appaiah Hitesh N , Goswami Chirayu P , Mina Lida A , Badve Sunil , Sledge George W , Liu Yunlong , Nakshatri Harikrishna
Published: September 2011

Introduction

Serum microRNAs have the potential to be valuable biomarkers of cancer. This investigation addresses two issues that impact their utility: a) appropriate normalization controls and b) whether their altered levels persist in patients who are clinically free of the disease.

Methods

Sera from 40 age-matched healthy women and 39 breast cancer patients without clinical disease at the time of serum collection were analyzed for microRNAs let-7f, miR-16, miR-21 and miR-155 using quantitative real-time PCR. U6 and 5S, which are transcribed by RNA polymerase III (RNAP-III) and the small nucleolar RNU44 (SNORD44), were also analyzed for normalization. Significant results from the initial study were verified using a second set of sera from 15 healthy patients, 15 breast cancer patients without clinical disease and 15 with metastatic disease, and a third set of 12 healthy and 18 patients with metastatic disease. U6 was further verified in the extended second cohort of 75 healthy and 68 breast cancer patients without clinical disease.

Results

U6:SNORD44 ratio was consistently higher in breast cancer patients with or without active disease (fold change range 1.5-6.6, p value range 0.0003 to 0.05). This increase in U6:SNORD44 ratio was observed in the sera of both estrogen receptor-positive (ER+) and ER-negative breast cancer patients. MiR-16 and 5S, which are often used as normalization controls for microRNAs, showed remarkable experimental variability and thus are not ideal for normalization.

Conclusions

Elevated serum U6 levels in breast cancer patients irrespective of disease activity at the time of serum collection suggest a new paradigm in cancer; persistent systemic changes during cancer progression, which result in elevated activity of RNAP-III and/or the stability/release pathways of U6 in non-cancer tissues. Additionally, these results highlight the need for developing standards for normalization between samples in microRNA-related studies for healthy versus cancer and for inter-laboratory reproducibility. Our studies rule out the utility of miR-16, U6 and 5S RNAs for this purpose.
Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study
Authors: Sihto Harri , Lundin Johan , Lundin Mikael , Lehtimäki Tiina , Ristimäki Ari , Holli Kaija , Sailas Liisa , Kataja Vesa , Turpeenniemi-Hujanen Taina , Isola Jorma , Heikkilä Päivi , Joensuu Heikki
Published: September 2011

Introduction

Some molecular subtypes of breast cancer have preferential sites of distant relapse. The protein expression pattern of the primary tumor may influence the first distant metastasis site.

Methods

We identified from the files of the Finnish Cancer Registry patients diagnosed with breast cancer in five geographical regions Finland in 1991-1992, reviewed the hospital case records, and collected primary tumor tissue. Out of the 2,032 cases identified, 234 developed distant metastases after a median follow-up time of 2.7 years and had the first metastatic site documented (a total of 321 sites). Primary tumor microarray (TMA) cores were analyzed for 17 proteins using immunohistochemistry and for erbB2 using chromogenic in situ hybridization, and their associations with the first metastasis site were examined. The cancers were classified into luminal A, luminal B, HER2+ enriched, basal-like or non-expressor subtypes.

Results

A total of 3,886 TMA cores were analyzed. Luminal A cancers had a propensity to give rise first to bone metastases, HER2-enriched cancers to liver and lung metastases, and basal type cancers to liver and brain metastases. Primary tumors that gave first rise to bone metastases expressed frequently estrogen receptor (ER) and SNAI1 (SNAIL) and rarely COX2 and HER2, tumors with first metastases in the liver expressed infrequently SNAI1, those with lung metastases expressed frequently the epidermal growth factor receptor (EGFR), cytokeratin-5 (CK5) and HER2, and infrequently progesterone receptor (PgR), tumors with early skin metastases expressed infrequently E-cadherin, and breast tumors with first metastases in the brain expressed nestin, prominin-1 and CK5 and infrequently ER and PgR.

Conclusions

Breast tumor biological subtypes have a tendency to give rise to first distant metastases at certain body sites. Several primary tumor proteins were associated with homing of breast cancer cells.
Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams
Authors: Gonçalves-Pereira Joao , Póvoa Pedro
Published: September 2011

Introduction

Several reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers.

Methods

We performed a full review of published studies addressing the PK of intravenous β-lactam antibiotics given to infected ICU patients. Study selection comprised a comprehensive bibliographic search of the PubMed database and bibliographic references in relevant reviews from January 1966 to December 2010. We selected only English-language articles reporting studies addressing β-lactam antibiotics that had been described in at least five previously published studies. Studies of the PK of patients undergoing renal replacement therapy were excluded.

Results

A total of 57 studies addressing six different β-lactam antibiotics (meropenem, imipenem, piperacillin, cefpirome, cefepime and ceftazidime) were selected. Significant PK heterogeneity was noted, with a broad, more than twofold variation both of volume of distribution and of drug clearance (Cl). The correlation of antibiotic Cl with creatinine clearance was usually reported. Consequently, in ICU patients, β-lactam antibiotic half-life and T > MIC were virtually unpredictable, especially in those patients with normal renal function. A better PD profile was usually obtained by prolonged or even continuous infusion. Tissue penetration was also found to be compromised in critically ill patients with septic shock.

Conclusions

The PK of β-lactam antibiotics are heterogeneous and largely unpredictable in ICU patients. Consequently, the dosing of antibiotics should be supported by PK concepts, including data derived from studies of the PK of ICU patients and therapeutic drug monitoring.
Prehospital intubation of the moderately injured patient: a cause of morbidity? A matched-pairs analysis of 1,200 patients from the DGU Trauma Registry
Authors: Hussmann Bjoern , Lefering Rolf , Waydhas Christian , Ruchholtz Steffen , Wafaisade Arasch , Kauther Max Daniel , Lendemans Sven
Published: September 2011

Introduction

Hypoxia and hypoxemia can lead to an unfavorable outcome after severe trauma, by both direct and delayed mechanisms. Prehospital intubation is meant to ensure pulmonary gas exchange. Limited evidence exists regarding indications for intubation after trauma. The aim of this study was to analyze prehospital intubation as an independent risk factor for the posttraumatic course of moderately injured patients. Therefore, only patients who, in retrospect, would not have required intubation were included in the matched-pairs analysis to evaluate the risks related to intubation.

Methods

The data of 42,248 patients taken from the trauma registry of the German Association for Trauma Surgery (Deutsche Gesellschaft für Unfallchirurgie (DGU)) were analyzed. Patients who met the following criteria were included: primary admission to a hospital; Glasgow Coma Scale (GCS) of 13 to 15; age 16 years or older; maximum injury severity per body region (AIS) ≤ 3; no administration of packed red blood cell units in the emergency trauma room; admission between 2005 and 2008; and documented data regarding intubation. The intubated patients were then matched with not-intubated patients.

Results

The study population included 600 matched pairs that met the inclusion criteria. The results indicated that prehospital intubation was associated with a prolonged rescue time (not intubated, 64.8 minutes; intubated, 82.3 minutes; P ≤ 0.001) and a higher volume replacement (not intubated, 911.3 ml; intubated, 1,573.8 ml; P ≤ 0.001). In the intubated patients, coagulation parameters, such as the prothrombin time ratio (PT) and platelet count, declined, as did the hemoglobin value (PT not intubated: 92.3%; intubated, 85.7%; P ≤ 0.001; hemoglobin not intubated, 13.4 mg/dl; intubated, 12.2 mg/dl; P ≤ 0.001). Intubation at the scene resulted in an elevated sepsis rate (not intubated, 1.5%; intubated, 3.7%; P ≤ 0.02) and an elevated prevalence of multiorgan failure (MOF) and organ failure (OF) (OF not intubated, 9.1%; intubated, 23.4%; P ≤ 0.001).

Conclusions

Prehospital intubation in trauma patients is associated with a number of risks and should be critically weighed, except in cases with clear indicators, such as posttraumatic apnea.
Community-acquired polymicrobial pneumonia in the intensive care unit: aetiology and prognosis
Authors: Cillóniz Catia , Ewig Santiago , Ferrer Miquel , Polverino Eva , Gabarrús Albert , Puig de la Bellacasa Jorge , Mensa Josep , Torres Antoni
Published: September 2011

Introduction

The frequency and clinical significance of polymicrobial aetiology in community-acquired pneumonia (CAP) patients admitted to the ICU have been poorly studied. The aim of the present study was to describe the prevalence, clinical characteristics and outcomes of severe CAP of polymicrobial aetiology in patients admitted to the ICU.

Methods

The prospective observational study included 362 consecutive adult patients with CAP admitted to the ICU within 24 hours of presentation; 196 (54%) patients had an established aetiology.

Results

Polymicrobial infection was present in 39 (11%) cases (20% of those with defined aetiology): 33 cases with two pathogens, and six cases with three pathogens. The most frequently identified pathogens in polymicrobial infections were Streptococcus pneumoniae (n = 28, 72%), respiratory viruses (n = 15, 39%) and Pseudomonas aeruginosa (n = 8, 21%). Chronic respiratory disease and acute respiratory distress syndrome criteria were independent predictors of polymicrobial aetiology. Inappropriate initial antimicrobial treatment was more frequent in the polymicrobial aetiology group compared with the monomicrobial aetiology group (39% vs. 10%, P < 0.001), and was an independent predictor of hospital mortality (adjusted odds ratio = 10.79, 95% confidence interval = 3.97 to 29.30; P < 0.001). The trend for higher hospital mortality of the polymicrobial aetiology group compared with the monomicrobial aetiology group (n = 8, 21% versus n = 17, 11%), however, was not significantly different (P = 0.10).

Conclusions

Polymicrobial pneumonia occurs frequently in patients admitted to the ICU. This is a risk factor for inappropriate initial antimicrobial treatment, which in turn independently predicts hospital mortality.
Colonization with antibiotic-susceptible strains protects against methicillin-resistant Staphylococcus aureus but not vancomycin-resistant enterococci acquisition: a nested case-control study
Authors: Huang Susan S , Datta Rupak , Rifas-Shiman Sheryl , Kleinman Ken , Placzek Hilary , Lankiewicz Julie D , Platt Richard
Published: September 2011

Introduction

Harboring sensitive strains may prevent acquisition of resistant pathogens by competing for colonization of ecological niches. Competition may be relevant to decolonization strategies that eliminate sensitive strains and may predispose to acquiring resistant strains in high-endemic settings. We evaluated the impact of colonization with methicillin-sensitive Staphylococcus aureus (MSSA) and vancomycin-sensitive enterococci (VSE) on acquisition of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), respectively, when controlling for other risk factors.

Methods

We conducted a nested case-control study of patients admitted to eight ICUs performing admission and weekly bilateral nares and rectal screening for MRSA and VRE, respectively. Analyses were identical for both pathogens. For MRSA, patients were identified who had a negative nares screen and no prior history of MRSA. We evaluated predictors of MRSA acquisition, defined as a subsequent MRSA-positive clinical or screening culture, compared to those with a subsequent MRSA-negative nares screen within the same hospitalization. Medical records were reviewed for the presence of MSSA on the initial MRSA-negative nares screen, demographic and comorbidity information, medical devices, procedures, antibiotic utilization, and daily exposure to MRSA-positive patients in the same ward. Generalized linear mixed models were used to assess predictors of acquisition.

Results

In multivariate models, MSSA carriage protected against subsequent MRSA acquisition (OR = 0.52, CI: 0.29, 0.95), even when controlling for other risk factors. MRSA predictors included intubation (OR = 4.65, CI: 1.77, 12.26), fluoroquinolone exposure (OR = 1.91, CI: 1.20, 3.04), and increased time from ICU admission to initial negative swab (OR = 15.59, CI: 8.40, 28.94). In contrast, VSE carriage did not protect against VRE acquisition (OR = 1.37, CI: 0.54, 3.48), whereas hemodialysis (OR = 2.60, CI: 1.19, 5.70), low albumin (OR = 2.07, CI: 1.12, 3.83), fluoroquinolones (OR = 1.90, CI: 1.14, 3.17), third-generation cephalosporins (OR = 1.89, CI: 1.15, 3.10), and increased time from ICU admission to initial negative swab (OR = 15.13, CI: 7.86, 29.14) were predictive.

Conclusions

MSSA carriage reduced the odds of MRSA acquisition by 50% in ICUs. In contrast, VSE colonization was not protective against VRE acquisition. Studies are needed to evaluate whether decolonization of MSSA ICU carriers increases the risk of acquiring MRSA when discharging patients to high-endemic MRSA healthcare settings. This may be particularly important for populations in whom MRSA infection may be more frequent and severe than MSSA infections, such as ICU patients.
Implication of Low Level Inflammation in the Insulin Resistance of Adipose Tissue at Late Pregnancy
Authors: de Castro J. , Sevillano J. , Marciniak J. , Rodriguez R. , González-Martín C. , Viana M. , Eun-suk O. H. , de Mouzon S. Hauguel , Herrera E. , Ramos M. P.
Published: September 2011

Insulin resistance is a characteristic of late pregnancy, and adipose tissue is one of the tissues that most actively contributes to the reduced maternal insulin sensitivity. There is evidence that pregnancy is a condition of moderate inflammation, although the physiological role of this low-grade inflammation remains unclear. The present study was designed to validate whether low-grade inflammation plays a role in the development of insulin resistance in adipose tissue during late pregnancy. To this end, we analyzed proinflammatory adipokines and kinases in lumbar adipose tissue of nonpregnant and late pregnant rats at d 18 and 20 of gestation. We found that circulating and tissue levels of adipokines, such as IL-1β, plasminogen activator inhibitor-1, and TNF-α, were increased at late pregnancy, which correlated with insulin resistance. The observed increase in adipokines coincided with an enhanced activation of p38 MAPK in adipose tissue. Treatment of pregnant rats with the p38 MAPK inhibitor SB 202190 increased insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and IR substrate-1 in adipose tissue, which was paralleled by a reduction of IR substrate-1 serine phosphorylation and an enhancement of the metabolic actions of insulin. These results indicate that activation of p38 MAPK in adipose tissue contributes to adipose tissue insulin resistance at late pregnancy. Furthermore, the results of the present study support the hypothesis that physiological low-grade inflammation in the maternal organism is relevant to the development of pregnancy-associated insulin resistance.
Regulation of NKB Pathways and Their Roles in the Control of Kiss1 Neurons in the Arcuate Nucleus of the Male Mouse
Authors: Navarro V. M. , Gottsch M. L. , Wu M. , García-Galiano D. , Hobbs S. J. , Bosch M. A. , Pinilla L. , Clifton D. K. , Dearth A. , Ronnekleiv O. K. , Braun R. E. , Palmiter R. D. , Tena-Sempere M. , Alreja M. , Steiner R. A.
Published: September 2011

Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus (ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male.
Immediate-Early Transcriptional Response to Angiotensin II in Human Adrenocortical Cells
Authors: Thiel Gerald , Rössler Oliver G.
Published: September 2011

Angiotensin II binds to the angiotensin II receptors type 1 (AT1 receptors) in adrenocortical cells and triggers an intracellular signaling cascade leading to changes in the gene expression pattern. Here, we show that stimulation with angiotensin II induces the expression of biologically active early growth response (Egr)-1, a zinc finger transcription factor, in human H295R adrenocortical cells. Expression of a dominant-negative mutant of the ternary complex factor Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, prevented Egr-1 expression in angiotensin II-stimulated H295R cells, indicating that Ets-like protein-1 (Elk-1) or related ternary complex factors connect the intracellular signaling cascade elicited by activation of AT1 receptors with transcription of the Egr-1 gene. These data were corroborated by the fact that angiotensin II stimulation increased the transcription activation potential of Elk-1. In addition, activator protein-1 transcriptional activity was significantly elevated in angiotensin II-treated H295R cells. Expression of c-Jun and c-Fos was increased as well as the transcription activation potential of c-Fos. Expression of a dominant-negative mutant of Elk-1 reduced c-Fos expression in angiotensin II-stimulated adrenocortical cells, suggesting that the serum response element within the c-Fos promoter functions as an angiotensin II-response element. Expression of a dominant-negative mutant of c-Jun reduced activator protein-1 activity in angiotensin II-stimulated adrenocortical cells and reduced the up-regulation of c-Jun after angiotensin II stimulation. Thus, c-Jun regulates its own expression in adrenocortical cells. Together, the data show that angiotensin II stimulation activates the transcription factors Egr-1, Elk-1, c-Jun, and c-Fos in adrenocortical cells, leading to stimulus-dependent changes in the gene expression pattern.
Neuropeptide Y Cells Represent a Distinct Glucose-Sensing Population in the Lateral Hypothalamus
Authors: Marston Oliver J. , Hurst Paul , Evans Mark L. , Burdakov Denis I. , Heisler Lora K.
Published: September 2011

The maintenance of appropriate glucose levels is necessary for survival. Within the brain, specialized neurons detect glucose fluctuations and alter their electrical activity. These glucose-sensing cells include hypothalamic arcuate nucleus neurons expressing neuropeptide Y (NPY) and lateral hypothalamic area (LHA) neurons expressing orexin/hypocretins (ORX) or melanin-concentrating hormone (MCH). Within the LHA, a population of NPY-expressing cells exists; however, their ability to monitor energy status is unknown. We investigated whether NPY neurons located in the LHA, a classic hunger center, detect and respond to fluctuations in glucose availability and compared these responses with those of known LHA glucose sensors expressing ORX or MCH. Using mice expressing green fluorescent protein under the control of NPY regulatory elements, we identified LHA NPY cells and explored their anatomical distribution, neurochemical and electrical properties, in vivo responses to fasting and insulin-induced hypoglycemia, and in situ electrical responses to extracellular glucose. We report that NPY, ORX, and MCH are expressed in nonoverlapping populations within the LHA. Subpopulations of LHA NPY neurons were activated in vivo by both a 6-h fast and insulin-induced hypoglycemia. Likewise, increased extracellular glucose suppressed the electrical activity of approximately 70% of LHA NPY neurons in situ, eliciting hyperpolarization and activating background K+ currents. Furthermore, we report that the glucose sensitivity of LHA NPY neurons is significantly different from neighboring ORX and MCH neurons. These data suggest that NPY-expressing cells in the LHA are a novel population of glucose-sensing neurons that represent a new player in the brain circuitry integrating information about glucose homeostasis.
Shoulder dystocia: analysis from a risk management perspective
Authors: Barrett Niamh , Ryan Helen , Corcoran Siobhan , Burke Naomi , McMillan Helen , Geary Michael
Published: September 2011

We sought to audit the documentation of shoulder dystocia in our institution and re-audit following the introduction of a structured proforma. All cases of shoulder dystocia were identified and studied retrospectively from January 1st 2005 to December 31st 2006. A standardized proforma was introduced and cases of shoulder dystocia were prospectively identified over a 6 month period in 2008. The incidence of shouder dystocia was 0.79% in the initial study and 1.36% in the subsequent audit. Documentation improved with the introduction of the proforma. There was also a significant improvement in neonatal APGARs in the re-audit (35% vs 11.5% APGARs <7 at 1 minute), suggesting improved management of cases of shoulder dystocia. The introduction of a proforma significantly improved the documentation of cases of shoulder dystocia. We would encourage other units to introduce a similar proforma to improve documentation of shoulder dystocia.
Is home delivery safe for all involved? A new arrival breaks grandma's heart. Literally
Authors: Doolub Gemina , Daniels Matthew J , Ormerod Oliver
Published: September 2011

Home birth is becoming increasingly popular. Labour in the privacy and comfort of a familiar environment has clear appeal. Home birth is usually as safe for low-risk women with appropriate prenatal care. Yet events during delivery can be unpredictable and may be stressful for unprepared family members. Here we report a case of Tako-tsubo cardiomyopathy, also known as broken-heart syndrome, in a relative attending an impromptu home delivery. Thus, while home delivery is generally safe for the mother we ask: is it safe for everyone involved?
Causes of mortality associated with HIV/AIDS in health-care facilities in Togo: a six-month prospective study
Authors: Balogou A A K , Saka B , Kombaté D , Kombaté K , Mouhari-Toure A , Akakpo S , Singo A , Pitché P
Published: September 2011

In order to determine the rate and the different causes of mortality associated with HIV/AIDS in health-care facilities we conducted a prospective study between 1 April and 30 September 2010 in the six health regions of Togo. We rationalized the choice of the healthcare facilities in order to cover the entire national territory. During the study period, 24,054 patients were hospitalized. HIV serology was positive in 1065 (18.2%) of the 5865 tested patients. Of the 24,054 patients, we recorded 2551 deaths (10.6%), including 309 HIV-infected patients (5.2%). The mortality rate associated with HIV/AIDS was 1.3% of the total number of inpatients and 5.3% of the number of patients tested for HIV. The mortality rate among HIV-infected patients was 29%. The causes of death in patients infected with HIV/AIDS were mainly anaemia and cerebral toxoplasmosis. This study shows that mortality associated with HIV/AIDS in health-care facilities in Togo remains relatively high.
Incidence of Hospitalized Rhabdomyolysis with Statin and Fibrate Use in an Insured US Population
Authors: Amend Kandace L , Landon Joan , Thyagarajan Veena , Niemcryk Steve , McAfee Andrew
Published: September 2011

Background:

The incidence of hospitalized rhabdomyolysis is not well characterized among patients taking statin-fibrate combination therapies.

Objective:

To estimate and compare the rates of hospitalized rhabdomyolysis during periods of exposure to different statins and fibrates.

Methods:

We retrospectively identified a cohort patients who initiated a statin or fibrate between January 1, 1998, and December 31, 2007, using a database of a large US hearth insurer. Patients were followed for the occurrence of hospitalized rhabdomyolysis, determined by clinical review of medical records. Exposure status during the study period was determined by electronic records of statin and fibrate dispensing. Incidence rates (IRs) and incidence rate ratios (IRRs) for various combinations of fibrate and statin exposure were modeled, using Poisson regression.

Results:

There were 1,116,805 patients who initiated statin and/or fibrate therapy, with 2.4 million person-years of observation. Seventy cases of hospitalized rhabdomyolysis were confirmed. Adjusted analyses showed a persistent increased risk of rhabdomyolysis with combination therapy, while statin and fibrate therapy alone showed similar, nonsignificant increases in risk. The adjusted IRR for a statin and fenofibrate was 3.26 (95% CI 1.21 to 8.60), while the adjusted IRR for a statin and gemfibrozil was 11.93 (95% CI 3.96 to 35.93) versus statin therapy alone. The individual IRs for statin monotherapy ranged from 0.00 to 3.34 per 100,000 person-years. The number needed to harm was tower for combination statin-gemfibrozil therapy (2753) compared with that for statin therapy atone (454,545).

Conclusions:

The incidence of hospitalized rhabdomyolysis is rare, but higher in patients with concomitant statin-fibrate treatment than in patients on statin therapy atone. The rate found in this study is consistent with the known profile of the statin-fibrate treatment option for mixed dyslipidemia.
Estradiol Valerate/Dienogest: A Novel Oral Contraceptive
Authors: Whalen Karen L , Rose Renee
Published: September 2011

Objective:

To review the pharmacology, pharmacokinetics, efficacy, and safety of the new oral contraceptive estradiol valerate/dienogest.

Data Sources:

Searches of PubMed (1966-July 2011) and International Pharmaceutical Abstracts (1970-July 2011) were conducted using the key words estradiol valerate, dienogest, Natazia, and Olaira. Bibliographies of retrieved articles were reviewed to identify additional références.

Study Selection and Data Extraction:

All identified studies published in English and involving efficacy and safety of estradiol valerate/dienogest as an oral contraceptive were reviewed.

Data Synthesis:

Estradiol valerate/dienogest is a 4-phasic oral contraceptive approved for the prevention of pregnancy. The 4-phasic design allows for acceptable cycle control with this hormonal combination. In efficacy trials of estradiol valerate/dienogest in women aged 18–35 years, the Pearl Index ranged from 0.40 to 1.64, a range comparable to that of other combination oral contraceptives. The safety profile was also similar to that of other oral contraceptives, with headache, metrorrhagia, breast tenderness, nausea or vomiting, acne, and weight gain reported as the most common adverse effects. Menstrual bleeding patterns and cycle control with estradiol valerate/dienogest were comparable to those of a monophasic oral contraceptive containing ethinyl estradiol/levonorgestrel. Estradiol valerate/dienogest differs from other oral contraceptives in that il necessitates more stringent dosing guidelines for maximum contraceptive efficacy. New starts should be on the first day of menses only, and a back-up method of contraception is required for the first 9 days, as compared to 7 days with other oral contraceptives. Back-up contraception is usually required for any pill taken more than 12 hours later than scheduled.

Conclusions:

Estradiol valerate/dienogest is an effective oral contraceptive. Because it has more stringent start times and requires a longer duration of back-up contraception and stricter adherence, estradiol valerate/dienogest should be reserved for patients who are intolerant of other combination oral contraceptives.
Developing New-to-the-Firm Products: The Role of Micropolitical Strategies
Authors: Sethi Rajesh , Iqbal Zafar , Sethi Anju
Published: September 2011

This research addresses three questions: (1) To what extent do new-to-the-firm products (with market and technology newness) face resistance in winning approval for development during the review process? (2) To what degree does product development teams’ use of micropolitical strategies help reduce resistance and get approval with minimum compromise in the product? (3) To what extent do some of these micropolitical strategies harm the new product's performance? The findings suggest that products with both market and technology newness encounter resistance in getting approval for development. If the product development team wants to reduce resistance to products with market newness, it needs to build a coalition of supporters that can help it during the review process. Similarly, if the team seeks to minimize resistance to products with technology newness, it should frame the product in terms of the firms’ existing products, strategies, and competitive thrusts. However, such framing increases resistance to market newness. If products continue to be resisted, they must be compromised (i.e., modified as a concession) to win approval. If the team wants to reduce the degree of compromise, it should initially develop the product in hiding. Products that are compromised perform poorly in the marketplace.