bluuebunny/crossref_metadata_2025 huggingface dataset:
Capacity building permitting comprehensive monitoring of a severe case of Lassa hemorrhagic fever in Sierra Leone with a positive outcome: Case Report
Authors: Grove Jessica N , Branco Luis M , Boisen Matt L , Muncy Ivana J , Henderson Lee A , Schieffellin John S , Robinson James E , Bangura James J , Fonnie Mbalu , Schoepp Randal J , Hensley Lisa E , Seisay Alhassan , Fair Joseph N , Garry Robert F
Published: June 2011

Lassa fever is a neglected tropical disease with a significant impact on the health care system of endemic West African nations. To date, case reports of Lassa fever have focused on laboratory characterisation of serological, biochemical and molecular aspects of the disease imported by infected individuals from Western Africa to the United States, Canada, Europe, Japan and Israel. Our report presents the first comprehensive real time diagnosis and characterization of a severe, hemorrhagic Lassa fever case in a Sierra Leonean individual admitted to the Kenema Government Hospital Lassa Fever Ward. Fever, malaise, unresponsiveness to anti-malarial and antibiotic drugs, followed by worsening symptoms and onset of haemorrhaging prompted medical officials to suspect Lassa fever. A recombinant Lassa virus protein based diagnostic was employed in diagnosing Lassa fever upon admission. This patient experienced a severe case of Lassa hemorrhagic fever with dysregulation of overall homeostasis, significant liver and renal system involvement, the interplay of pro- and anti-inflammatory cytokines during the course of hospitalization and an eventual successful outcome. These studies provide new insights into the pathophysiology and management of this viral illness and outline the improved infrastructure, research and real-time diagnostic capabilities within LASV endemic areas.
Zingiber officinale acts as a nutraceutical agent against liver fibrosis
Authors: Motawi Tarek K , Hamed Manal A , Shabana Manal H , Hashem Reem M , Aboul Naser Asmaa F
Published: June 2011

Background/objective

Zingiber officinale Roscoe (ginger) (Zingiberaceae) has been cultivated for thousands of years both as a spice and for medicinal purposes. Ginger rhizomes successive extracts (petroleum ether, chloroform and ethanol) were examined against liver fibrosis induced by carbon tetrachloride in rats.

Results

The evaluation was done through measuring antioxidant parameters; glutathione (GSH), total superoxide dismutase (SOD) and malondialdehyde (MDA). Liver marker enzymes; succinate and lactate dehydrogenases (SDH and LDH), glucose-6-phosphatase (G-6-Pase), acid phosphatase (AP), 5'- nucleotidase (5'NT) and liver function enzymes; aspartate and alanine aminotransferases (AST and ALT) as well as cholestatic markers; alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin were estimated. Liver histopathological analysis and collagen content were also evaluated. Treatments with the selected extracts significantly increased GSH, SOD, SDH, LDH, G-6-Pase, AP and 5'NT. However, MDA, AST, ALT ALP, GGT and total bilirubin were significantly decreased.

Conclusions

Extracts of ginger, particularly the ethanol one resulted in an attractive candidate for the treatment of liver fibrosis induced by CCl4. Further studies are required in order to identify the molecules responsible of the pharmacological activity.
Prevention of: self harm in British South Asian women: study protocol of an exploratory RCT of culturally adapted manual assisted Problem Solving Training (C- MAP)
Authors: Husain Nusrat , Chaudhry Nasim , Durairaj Steevart V , Chaudhry Imran , Khan Sarah , Husain Meher , Nagaraj Diwaker , Naeem Farooq , Waheed Waquas
Published: June 2011

Background

Suicide is a major public health problem worldwide. In the UK suicide is the second most common cause of death in people aged 15-24 years. Self harm is one of the commonest reasons for medical admission in the UK. In the year following a suicide attempt the risk of a repeat attempt or death by suicide may be up to 100 times greater than in people who have never attempted suicide.

Research evidence shows increased risk of suicide and attempted suicide among British South Asian women. There are concerns about the current service provision and its appropriateness for this community due to the low numbers that get involved with the services. Both problem solving and interpersonal forms of psychotherapy are beneficial in the treatment of patients who self harm and could potentially be helpful in this ethnic group.

The paper describes the trial protocol of adapting and evaluating a culturally appropriate psychological treatment for the adult British South Asian women who self harm.

Methods

We plan to test a culturally adapted Problem Solving Therapy (C- MAP) in British South Asian women who self harm. Eight sessions of problem solving each lasting approximately 50 minutes will be delivered over 3 months. The intervention will be assessed using a prospective rater blind randomized controlled design comparing with treatment as usual (TAU). Outcome assessments will be carried out at 3 and 6 months. A sub group of the participants will be invited for qualitative interviews.

Discussion

This study will test the feasibility and acceptability of the C- MAP in British South Asian women. We will be informed on whether a culturally adapted brief psychological intervention compared with treatment as usual for self-harm results in decreased hopelessness and suicidal ideation. This will also enable us to collect necessary information on recruitment, effect size, the optimal delivery method and acceptability of the intervention in preparation for a definitive RCT using repetition of self harm and cost effectiveness as primary outcome measures.

Trial Registration

Current Controlled Trials 08/H1013/6
Aortic valve tear with severe aortic regurgitation following blunt chest trauma
Authors: Li Weidong , Ni Yiming , chen Xin , Ma Liang
Published: June 2011

An aortic valve tear associated with aortic regurgitation following blunt chest trauma is seldom seen. In this case, a 55-year-old man sustained a non-penetrating chest injury caused by a sudden fall from 10 meters. This led to a sizable tear in the left coronary cusp associated with severe aortic insufficiency. The case was treated successfully by surgical replacement of the aortic valve with a mechanical prosthesis.
Bronchogenic cyst associated with pericardial defect: Case report and review of the literature
Authors: Imperatori Andrea , Rotolo Nicola , Nardecchia Elisa , Mariscalco Giovanni , Spagnoletti Marco , Dominioni Lorenzo
Published: June 2011

Partial defect of the pericardium combined with bronchogenic cyst is a very rare congenital anomaly. We describe the case of a 32-year-old man with a partial defect of the left pericardium and a bronchogenic cyst arising from the border of the pericardial defect. The cyst was successfully resected with the harmonic scalpel by three-port videothoracoscopic approach.
Temporal-spatial changes in Sonic Hedgehog expression and signaling reveal different potentials of ventral mesencephalic progenitors to populate distinct ventral midbrain nuclei
Authors: Blaess Sandra , Bodea Gabriela O , Kabanova Anna , Chanet Soline , Mugniery Emilie , Derouiche Amin , Stephen Daniel , Joyner Alexandra L
Published: June 2011

Background

The ventral midbrain contains a diverse array of neurons, including dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN) and neurons of the red nucleus (RN). Dopaminergic and RN neurons have been shown to arise from ventral mesencephalic precursors that express Sonic Hedgehog (Shh). However, Shh expression, which is initially confined to the mesencephalic ventral midline, expands laterally and is then downregulated in the ventral midline. In contrast, expression of the Hedgehog target gene Gli1 initiates in the ventral midline prior to Shh expression, but after the onset of Shh expression it is expressed in precursors lateral to Shh-positive cells. Given these dynamic gene expression patterns, Shh and Gli1 expression could delineate different progenitor populations at distinct embryonic time points.

Results

We employed genetic inducible fate mapping (GIFM) to investigate whether precursors that express Shh (Shh-GIFM) or transduce Shh signaling (Gli1-GIFM) at different time points give rise to different ventral midbrain cell types. We find that precursors restricted to the ventral midline are labeled at embryonic day (E)7.5 with Gli1-GIFM, and with Shh-GIFM at E8.5. These precursors give rise to all subtypes of midbrain dopaminergic neurons and the anterior RN. A broader domain of progenitors that includes the ventral midline is marked with Gli1-GIFM at E8.5 and with Shh-GIFM at E9.5; these fate-mapped cells also contribute to all midbrain dopaminergic subtypes and to the entire RN. In contrast, a lateral progenitor domain that is labeled with Gli1-GIFM at E9.5 and with Shh-GIFM at E11.5 has a markedly reduced potential to give rise to the RN and to SN dopaminergic neurons, and preferentially gives rise to the ventral-medial VTA. In addition, cells derived from Shh- and Gli1-expressing progenitors located outside of the ventral midline give rise to astrocytes.

Conclusions

We define a ventral midbrain precursor map based on the timing of Gli1 and Shh expression, and suggest that the diversity of midbrain dopaminergic neurons is at least partially determined during their precursor stage when their medial-lateral position, differential gene expression and the time when they leave the ventricular zone influence their fate decisions.
Influence of dietary iodine deficiency on the thyroid gland in Slc26a4-null mutant mice
Authors: Iwata Tomoyuki , Yoshida Tadao , Teranishi Masaaki , Murata Yoshiharu , Hayashi Yoshitaka , Kanou Yasuhiko , Griffith Andrew J , Nakashima Tsutomu
Published: June 2011

Background

Pendred syndrome (PDS) is an autosomal recessive disorder characterized by sensorineural hearing impairment and variable degree of goitrous enlargement of the thyroid gland with a partial defect in iodine organification. The thyroid function phenotype can range from normal function to overt hypothyroidism. It is caused by loss-of-function mutations in the SLC26A4 (PDS) gene. The severity of the goiter has been postulated to depend on the amount of dietary iodine intake. However, direct evidence has not been shown to support this hypothesis. Because Slc26a4-null mice have deafness but do not develop goiter, we fed the mutant mice a control diet or an iodine-deficient diet to evaluate whether iodine deficiency is a causative environmental factor for goiter development in PDS.

Methods

We evaluated the thyroid volume in histological sections with the use of three-dimensional reconstitution software, we measured serum levels of total tri-iodothyronine (TT3) and total thyroxine (TT4) levels, and we studied the thyroid gland morphology by transmission electron microscopy.

Results

TT4 levels became low but TT3 levels did not change significantly after eight weeks of an iodine-deficient diet compared to levels in the control diet animals. Even in Slc26a4-null mice fed an iodine-deficient diet, the volume of the thyroid gland did not increase although the size of each epithelial cell increased with a concomitant decrease of thyroid colloidal area.

Conclusions

An iodine-deficient diet did not induce goiter in Slc26a4-null mice, suggesting that other environmental, epigenetic or genetic factors are involved in goiter development in PDS.
The impact of socio‐economic disadvantage on rates of hospital separations for diabetes‐related foot disease in Victoria, Australia
Authors: Bergin Shan M , Brand Caroline A , Colman Peter G , Campbell Don A
Published: June 2011

Background

Information describing variation in health outcomes for individuals with diabetes related foot disease, across socioeconomic strata is lacking. The aim of this study was to investigate variation in rates of hospital separations for diabetes related foot disease and the relationship with levels of social advantage and disadvantage.

Methods

Using the Index of Relative Socioeconomic Disadvantage (IRSD) each local government area (LGA) across Victoria was ranked from most to least disadvantaged. Those LGAs ranked at the lowest end of the scale and therefore at greater disadvantage (Group D) were compared with those at the highest end of the scale (Group A), in terms of total and per capita hospital separations for peripheral neuropathy, peripheral vascular disease, foot ulceration, cellulitis and osteomyelitis and amputation. Hospital separations data were compiled from the Victorian Admitted Episodes Database.

Results

Total and per capita separations were 2,268 (75.3/1,000 with diabetes) and 2,734 (62.3/1,000 with diabetes) for Group D and Group A respectively. Most notable variation was for foot ulceration (Group D, 18.1/1,000 versus Group A, 12.7/1,000, rate ratio 1.4, 95% CI 1.3, 1.6) and below knee amputation (Group D 7.4/1,000 versus Group A 4.1/1,000, rate ratio 1.8, 95% CI 1.5, 2.2). Males recorded a greater overall number of hospital separations across both socioeconomic strata with 66.2% of all separations for Group D and 81.0% of all separations for Group A recorded by males. However, when comparing mean age, males from Group D tended to be younger compared with males from Group A (mean age; 53.0 years versus 68.7 years).

Conclusion

Variation appears to exist for hospital separations for diabetes related foot disease across socioeconomic strata. Specific strategies should be incorporated into health policy and planning to combat disparities between health outcomes and social status.
Concurrency revisited: increasing and compelling epidemiological evidence
Authors: Mah Timothy L , Shelton James D
Published: June 2011

Multiple sexual partnerships must necessarily lie at the root of a sexually transmitted epidemic. However, that overlapping or concurrent partnerships have played a pivotal role in the generalized epidemics of sub‐Saharan Africa has been challenged. Much of the original proposition that concurrent partnerships play such a role focused on modelling, self‐reported sexual behaviour data and ethnographic data. While each of these has definite merit, each also has had methodological limitations. Actually, more recent cross‐national sexual behaviour data and improved modelling have strengthened these lines of evidence. However, heretofore the epidemiologic evidence has not been systematically brought to bear. Though assessing the epidemiologic evidence regarding concurrency has its challenges, a careful examination, especially of those studies that have assessed HIV incidence, clearly indicates a key role for concurrency.

Such evidence includes: 1) the early and dramatic rise of HIV infection in generalized epidemics that can only arise from transmission through rapid sequential acute infections and thereby concurrency; 2) clear evidence from incidence studies that a major portion of transmission in the population occurs via concurrency both for concordant negative and discordant couples; 3) elevation in risk associated with partner's multiple partnering; 4) declines in HIV associated with declines in concurrency; 5) bursts and clustering of incident infections that indicate concurrency and acute infection play a key role in the propagation of epidemics; and 6) a lack of other plausible explanations, including serial monogamy and non‐sexual transmission. While other factors, such as sexually transmitted infections, other infectious diseases, biological factors and HIV sub‐type, likely play a role in enhancing transmission, it appears most plausible that these would amplify the role of concurrency rather than alter it. Additionally, critics of concurrency have not proposed plausible alternative explanations for why the explosive generalized epidemics occurred. Specific behaviour change messaging bringing the concepts of multiple partnering and concurrency together appears salient and valid in promoting safer individual behaviour and positive social norms.
Computer-aided diagnosis of renal obstruction: utility of log-linear modeling versus standard ROC and kappa analysis
Authors: Manatunga Amita K , G Binongo José Nilo , Taylor Andrew T
Published: June 2011

Background

The accuracy of computer-aided diagnosis (CAD) software is best evaluated by comparison to a gold standard which represents the true status of disease. In many settings, however, knowledge of the true status of disease is not possible and accuracy is evaluated against the interpretations of an expert panel. Common statistical approaches to evaluate accuracy include receiver operating characteristic (ROC) and kappa analysis but both of these methods have significant limitations and cannot answer the question of equivalence: Is the CAD performance equivalent to that of an expert? The goal of this study is to show the strength of log-linear analysis over standard ROC and kappa statistics in evaluating the accuracy of computer-aided diagnosis of renal obstruction compared to the diagnosis provided by expert readers.

Methods

Log-linear modeling was utilized to analyze a previously published database that used ROC and kappa statistics to compare diuresis renography scan interpretations (non-obstructed, equivocal, or obstructed) generated by a renal expert system (RENEX) in 185 kidneys (95 patients) with the independent and consensus scan interpretations of three experts who were blinded to clinical information and prospectively and independently graded each kidney as obstructed, equivocal, or non-obstructed.

Results

Log-linear modeling showed that RENEX and the expert consensus had beyond-chance agreement in both non-obstructed and obstructed readings (both p < 0.0001). Moreover, pairwise agreement between experts and pairwise agreement between each expert and RENEX were not significantly different (p = 0.41, 0.95, 0.81 for the non-obstructed, equivocal, and obstructed categories, respectively). Similarly, the three-way agreement of the three experts and three-way agreement of two experts and RENEX was not significantly different for non-obstructed (p = 0.79) and obstructed (p = 0.49) categories.

Conclusion

Log-linear modeling showed that RENEX was equivalent to any expert in rating kidneys, particularly in the obstructed and non-obstructed categories. This conclusion, which could not be derived from the original ROC and kappa analysis, emphasizes and illustrates the role and importance of log-linear modeling in the absence of a gold standard. The log-linear analysis also provides additional evidence that RENEX has the potential to assist in the interpretation of diuresis renography studies.
Evaluation of 18F-nifene binding to α4β2 nicotinic receptors in the rat brain using microPET imaging
Authors: Kant Ritu , Constantinescu Cristian C , Parekh Puja , Pandey Suresh K , Pan Min-Liang , Easwaramoorthy Balu , Mukherjee Jogeshwar
Published: June 2011

MicroPET imaging studies using 18F-nifene, a new positron emission tomography (PET) radiotracer for nicotinic acetylcholinergic receptors (nAChR) α4β2 receptors in rats, have been carried out. Rats were imaged for 90 min after intravenous injection of 18F-nifene (0.8 to 1 mCi), and binding potential (BPND) was measured. 18F-Nifene binding to thalamic and extrathalamic brain regions was consistent with the α4β2 nAChR distribution in the rat brain. Using the cerebellum as a reference, the values for the thalamus varied less than 5% (BPND = 1.30, n = 3), confirming reproducibility of 18F-nifene binding. 18F-Nifene microPET imaging was also used to evaluate effects of nicotine in a group of Sprague-Dawley rats under isoflurane anesthesia. Nicotine challenge postadministration of 18F-nifene demonstrated reversibility of 18F-nifene binding in vivo. For α4β2 nAChR receptor occupancy (nAChROCC), various doses of nicotine (0, 0.02, 0.1, 0.25, and 0.50 mg/kg nicotine free base) 15 min prior to 18F-nifene were administered. Low-dose nicotine (0.02 mg) reached > 80% nAChROCC while at higher doses (0.25 mg) > 90% nAChROCC was measured. The small amount of 18F-nifene binding with reference to the cerebellum affects an accurate evaluation of nAChROCC. Efforts are underway to identify alternate reference regions for 18F-nifene microPET studies in rodents.
Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease
Authors: Ferris Steven H , Schmitt Frederick A , Saxton Judith , Richardson Sharon , Mackell Joan , Sun Yijun , Xu Yikang
Published: June 2011

Introduction

Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function.

Methods

In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity-plus caregiver input/Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated.

Results

At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores.

Conclusions

Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.

ClinicalTrials.gov identifier: NCT00478205
Platelet-derived growth factor receptor-β and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study
Authors: Overbeek Maria J , Boonstra Anco , Voskuyl Alexandre E , Vonk Madelon C , Vonk-Noordegraaf Anton , van Berkel Maria PA , Mooi Wolter J , Dijkmans Ben AC , Hondema Laurens S , Smit Egbert F , Grünberg Katrien
Published: June 2011

Introduction

Systemic sclerosis (SSc) complicated by pulmonary arterial hypertension (PAH) carries a poor prognosis, despite pulmonary vascular dilating therapy. Platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR) are potential therapeutic targets for PAH because of their proliferative effects on vessel remodelling. To explore their role in SScPAH, we compared PDGFR- and EGFR-mmunoreactivity in lung tissue specimens from SScPAH. We compared staining patterns with idiopathic PAH (IPAH) and pulmonary veno-occlusive disease (PVOD), as SScPAH vasculopathy differs from IPAH and sometimes displays features of PVOD. Immunoreactivity patterns of phosphorylated PDGFR-β (pPDGFR-β) and the ligand PDGF-B were evaluated to provide more insight into the patterns of PDGFR-b activation.

Methods

Lung tissue specimens from five SScPAH, nine IPAH, six PVOD patients and five controls were examined. Immunoreactivity was scored for presence, distribution and intensity.

Results

All SScPAH and three of nine IPAH cases (P = 0.03) showed PDGFR-β-immunoreactivity in small vessels (arterioles/venules); of five SScPAH vs. two of nine IPAH cases (P = 0.02) showed venous immunoreactivity. In small vessels, intensity was stronger in SScPAH vs. IPAH. No differences were found between SScPAH and PVOD. One of five normal controls demonstrated focally mild immunoreactivity. There were no differences in PDGF-ligand and pPDGFR-b-immunoreactivity between patient groups; however, pPDGFR-b-immunoreactivity tended to be more prevalent in SScPAH small vasculature compared to IPAH. Vascular EGFR-immunoreactivity was limited to arterial and arteriolar walls, without differences between groups. No immunoreactivity was observed in vasculature of normals.

Conclusions

PDGFR-β-immunoreactivity in SScPAH is more common and intense in small- and post-capillary vessels than in IPAH and does not differ from PVOD, fitting in with histomorphological distribution of vasculopathy. PDGFR-β immunoreactivity pattern is not paralleled by pPDGFR-β or PDGF-B patterns. PDGFR-β- and EGFR-immunoreactivity of pulmonary vessels distinguishes PAH patients from controls.
Combined treatment with dexamethasone and raloxifene totally abrogates osteoporosis and joint destruction in experimental postmenopausal arthritis
Authors: Islander Ulrika , Jochems Caroline , Stubelius Alexandra , Andersson Annica , Lagerquist Marie K , Ohlsson Claes , Carlsten Hans
Published: June 2011

Introduction

Postmenopausal patients with rheumatoid arthritis (RA) are often treated with corticosteroids. Loss of estrogen, the inflammatory disease and exposure to corticosteroids all contribute to the development of osteoporosis. Therefore, our aim was to investigate if addition of the selective estrogen receptor modulator raloxifene, or estradiol, could prevent loss of bone mineral density in ovariectomized and dexamethasone treated mice with collagen-induced arthritis (CIA).

Methods

Female DBA/1-mice were ovariectomized or sham-operated, and CIA was induced. Treatment with dexamethasone (Dex) (125 μg/d), estradiol (E2) (1 μg/d) or raloxifene (Ral) (120 μg/day) alone, or the combination of Dex + E2 or Dex + Ral, was started after disease onset, and continued until termination of the experiments. Arthritic paws were collected for histology and one of the femoral bones was used for measurement of bone mineral density.

Results

Dex-treatment alone protected against arthritis and joint destruction, but had no effect on osteoporosis in CIA. However, additional treatment with either Ral or E2 resulted in completely preserved bone mineral density.

Conclusions

Addition of raloxifene or estradiol to dexamethasone-treatment in experimental postmenopausal polyarthritis prevents generalized bone loss.
Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis
Authors: Sutherland Allison , Thomas Mervyn , Brandon Roslyn A , Brandon Richard B , Lipman Jeffrey , Tang Benjamin , McLean Anthony , Pascoe Ranald , Price Gareth , Nguyen Thu , Stone Glenn , Venter Deon
Published: June 2011

Introduction

Sepsis is a complex immunological response to infection characterized by early hyper-inflammation followed by severe and protracted immunosuppression, suggesting that a multi-marker approach has the greatest clinical utility for early detection, within a clinical environment focused on Systemic Inflammatory Response Syndrome (SIRS) differentiation. Pre-clinical research using an equine sepsis model identified a panel of gene expression biomarkers that define the early aberrant immune activation. Thus, the primary objective was to apply these gene expression biomarkers to distinguish patients with sepsis from those who had undergone major open surgery and had clinical outcomes consistent with systemic inflammation due to physical trauma and wound healing.

Methods

This was a multi-centre, prospective clinical trial conducted across four tertiary critical care settings in Australia. Sepsis patients were recruited if they met the 1992 Consensus Statement criteria and had clinical evidence of systemic infection based on microbiology diagnoses (n = 27). Participants in the post-surgical (PS) group were recruited pre-operatively and blood samples collected within 24 hours following surgery (n = 38). Healthy controls (HC) included hospital staff with no known concurrent illnesses (n = 20). Each participant had minimally 5 ml of PAXgene blood collected for leucocyte RNA isolation and gene expression analyses. Affymetrix array and multiplex tandem (MT)-PCR studies were conducted to evaluate transcriptional profiles in circulating white blood cells applying a set of 42 molecular markers that had been identified a priori. A LogitBoost algorithm was used to create a machine learning diagnostic rule to predict sepsis outcomes.

Results

Based on preliminary microarray analyses comparing HC and sepsis groups, a panel of 42-gene expression markers were identified that represented key innate and adaptive immune function, cell cycling, WBC differentiation, extracellular remodelling and immune modulation pathways. Comparisons against GEO data confirmed the definitive separation of the sepsis cohort. Quantitative PCR results suggest the capacity for this test to differentiate severe systemic inflammation from HC is 92%. The area under the curve (AUC) receiver operator characteristics (ROC) curve findings demonstrated sepsis prediction within a mixed inflammatory population, was between 86 and 92%.

Conclusions

This novel molecular biomarker test has a clinically relevant sensitivity and specificity profile, and has the capacity for early detection of sepsis via the monitoring of critical care patients.
5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells
Authors: Stroud Hume , Feng Suhua , Morey Kinney Shannon , Pradhan Sriharsa , Jacobsen Steven E
Published: June 2011

Background

5-Hydroxymethylcytosine (5hmC) was recently found to be abundantly present in certain cell types, including embryonic stem cells. There is growing evidence that TET proteins, which convert 5-methylcytosine (5mC) to 5hmC, play important biological roles. To further understand the function of 5hmC, an analysis of the genome-wide localization of this mark is required.

Results

Here, we have generated a genome-wide map of 5hmC in human embryonic stem cells by hmeDIP-seq, in which hydroxymethyl-DNA immunoprecipitation is followed by massively parallel sequencing. We found that 5hmC is enriched in enhancers as well as in gene bodies, suggesting a potential role for 5hmC in gene regulation. Consistent with localization of 5hmC at enhancers, 5hmC was significantly enriched in histone modifications associated with enhancers, such as H3K4me1 and H3K27ac. 5hmC was also enriched in other protein-DNA interaction sites, such as OCT4 and NANOG binding sites. Furthermore, we found that 5hmC regions tend to have an excess of G over C on one strand of DNA.

Conclusions

Our findings suggest that 5hmC may be targeted to certain genomic regions based both on gene expression and sequence composition.
Randomized Multicenter Trial of the Effects of Melanoma-Associated Helper Peptides and Cyclophosphamide on the Immunogenicity of a Multipeptide Melanoma Vaccine
Authors: Slingluff Craig L. , Petroni Gina R. , Chianese-Bullock Kimberly A. , Smolkin Mark E. , Ross Merrick I. , Haas Naomi B. , von Mehren Margaret , Grosh William W.
Published: June 2011

Purpose

This multicenter randomized trial was designed to test whether melanoma-associated helper peptides augment CD8+T-cell responses to a melanoma vaccine and whether cyclophosphamide (CY) pretreatment augments CD4+or CD8+T-cell responses to that vaccine.

Patients and Methods

In all, 167 eligible patients with resected stage IIB to IV melanoma were randomly assigned to four vaccination study arms. Patients were vaccinated with 12 class I major histocompatibility complex–restricted melanoma peptides (12MP) to stimulate CD8+T cells and were randomly assigned to receive a tetanus helper peptide or a mixture of six melanoma-associated helper peptides (6MHP) to stimulate CD4+T cells. Before vaccination, patients were also randomly assigned to receive CY pretreatment or not. T-cell responses were assessed by an ex vivo interferon gamma ELISpot assay. Clinical outcomes and toxicities were recorded.

Results

Vaccination with 12MP plus tetanus induced CD8+T-cell responses in 78% of patients and CD4+T-cell responses to tetanus peptide in 93% of patients. Vaccination with 12MP plus 6MHP induced CD8+responses in 19% of patients and CD4+responses to 6MHP in 48% of patients. CY had no significant effect on T-cell responses. Overall 3-year survival was 79% (95% CI, 71% to 86%), with no significant differences (at this point) by study arm.

Conclusion

Melanoma-associated helper peptides paradoxically decreased CD8+T-cell responses to a melanoma vaccine (P < .001), and CY pretreatment had no immunologic or clinical effect. Prior work showed immunologic and clinical activity of 6MHP alone. Possible explanations for negative effects on CD8 responses include modulation of homing receptor expression or induction of antigen-specific regulatory T cells.
Chronic Immune Stimulation Might Act As a Trigger for the Development of Acute Myeloid Leukemia or Myelodysplastic Syndromes
Authors: Kristinsson Sigurdur Y. , Björkholm Magnus , Hultcrantz Malin , Derolf Åsa R. , Landgren Ola , Goldin Lynn R.
Published: June 2011

Purpose

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections, but there are little data to assess whether a personal history of selected infections may act as pathogenic triggers. To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases.

Patients and Methods

By using population-based central registries in Sweden, we included 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls. We used logistic regression to calculate odds ratios (ORs) and 95% CIs for the association of AML or MDS with infectious and/or autoimmune diseases.

Results

Overall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1-fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS.

Conclusion

Our novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions.
Faces with given directions in anisotropic Poisson hyperplane mosaics
Authors: Hug Daniel , Schneider Rolf
Published: June 2011

For stationary Poisson hyperplane tessellations in d-dimensional Euclidean space and a dimension k ∈ {1, …, d}, we investigate the typical k-face and the weighted typical k-face (weighted by k-dimensional volume), without isotropy assumptions on the tessellation. The case k = d concerns the previously studied typical cell and zero cell, respectively. For k < d, we first find the conditional distribution of the typical k-face or weighted typical k-face, given its direction. Then we investigate how the shapes of the faces are influenced by assumptions of different types: either via containment of convex bodies of given volume (including a new result for k = d), or, for weighted typical k-faces, in the spirit of D. G. Kendall's asymptotic problem, suitably generalized. In all these results on typical or weighted typical k-faces with given direction space L, the Blaschke body of the section process of the underlying hyperplane process with L plays a crucial role.
Probabilistic results for a mobile service scenario
Authors: Møller Jesper , Yiu Man Lung
Published: June 2011

We consider the following stochastic model for a mobile service scenario. Consider a stationary Poisson process in Rd, with its points radially ordered with respect to the origin (the anchor); if d = 2, the points may correspond to locations of, e.g. restaurants. A user, with a location different from the origin, asks for the location of the first Poisson point and keeps asking for the location of the next Poisson point until the first time that he/she can be completely certain that he/she knows which Poisson point is his/her nearest neighbour. This waiting time is the communication cost, while the inferred privacy region is a random set obtained by an adversary who only knows the anchor and the points received from the server, where the adversary ‘does the best’ to infer the possible locations of the user. Probabilistic results related to the communication cost and the inferred privacy region are established for any dimension d ≥ 1. Furthermore, special results when d = 1 and particularly when d = 2 are derived.
Bounding basic characteristics of spatial epidemics with a new percolation model
Authors: Meester Ronald , Trapman Pieter
Published: June 2011

We introduce a new 1-dependent percolation model to describe and analyze the spread of an epidemic on a general directed and locally finite graph. We assign a two-dimensional random weight vector to each vertex of the graph in such a way that the weights of different vertices are independent and identically distributed, but the two entries of the vector assigned to a vertex need not be independent. The probability for an edge to be open depends on the weights of its end vertices, but, conditionally on the weights, the states of the edges are independent of each other. In an epidemiological setting, the vertices of a graph represent the individuals in a (social) network and the edges represent the connections in the network. The weights assigned to an individual denote its (random) infectivity and susceptibility, respectively. We show that one can bound the percolation probability and the expected size of the cluster of vertices that can be reached by an open path starting at a given vertex from above by the corresponding quantities for independent bond percolation with a certain density; this generalizes a result of Kuulasmaa (1982). Many models in the literature are special cases of our general model.
Phenotypic diversity and population growth in a fluctuating environment
Authors: Dombry Clément , Mazza Christian , Bansaye Vincent
Published: June 2011

Organisms adapt to fluctuating environments by regulating their dynamics, and by adjusting their phenotypes to environmental changes. We model population growth using multitype branching processes in random environments, where the offspring distribution of some organism having trait t ∈ in environment e ∈ ε is given by some (fixed) distribution ϒt,e on ℕ. Then, the phenotypes are attributed using a distribution (strategy) πt,e on the trait space . We look for the optimal strategy πt,e, t ∈ , e ∈ ε, maximizing the net growth rate or Lyapounov exponent, and characterize the set of optimal strategies. This is considered for various models of interest in biology: hereditary versus nonhereditary strategies and strategies involving or not involving a sensing mechanism. Our main results are obtained in the setting of nonhereditary strategies: thanks to a reduction to simple branching processes in a random environment, we derive an exact expression for the net growth rate and a characterization of optimal strategies. We also focus on typical genealogies, that is, we consider the problem of finding the typical lineage of a randomly chosen organism.
Asymptotic normality for the number of records from general distributions
Authors: Gouet Raul , López F. Javier , Sanz Gerardo
Published: June 2011

We provide necessary and sufficient conditions for the asymptotic normality of Nn, the number of records among the first n observations from a sequence of independent and identically distributed random variables, with general distribution F. In the case of normality we identify the centering and scaling sequences. Also, we characterize distributions for which the limit is not normal in terms of their discrete and continuous components.
Duality and intertwining for discrete Markov kernels: relations and examples
Authors: Huillet Thierry , Martinez Servet
Published: June 2011

We supply some relations that establish intertwining from duality and give a probabilistic interpretation. This is carried out in the context of discrete Markov chains, fixing up the background of previous relations established for monotone chains and their Siegmund duals. We revisit the duality for birth-and-death chains and the nonneutral Moran model, and we also explore the duality relations in an ultrametric-type dual that extends the Siegmund kernel. Finally, we discuss the sharp dual, following closely the Diaconis-Fill study.
Exact Monte Carlo simulation for fork-join networks
Authors: Dai Hongsheng
Published: June 2011

In a fork-join network each incoming job is split into K tasks and the K tasks are simultaneously assigned to K parallel service stations for processing. For the distributions of response times and queue lengths of fork-join networks, no explicit formulae are available. Existing methods provide only analytic approximations for the response time and the queue length distributions. The accuracy of such approximations may be difficult to justify for some complicated fork-join networks. In this paper we propose a perfect simulation method based on coupling from the past to generate exact realisations from the equilibrium of fork-join networks. Using the simulated realisations, Monte Carlo estimates for the distributions of response times and queue lengths of fork-join networks are obtained. Comparisons of Monte Carlo estimates and theoretical approximations are also provided. The efficiency of the sampling algorithm is shown theoretically and via simulation.
Analysis of swaps in radix selection
Authors: Elmasry Amr , Mahmoud Hosam
Published: June 2011

Radix Sort is a sorting algorithm based on analyzing digital data. We study the number of swaps made by Radix Select (a one-sided version of Radix Sort) to find an element with a randomly selected rank. This kind of grand average provides a smoothing over all individual distributions for specific fixed-order statistics. We give an exact analysis for the grand mean and an asymptotic analysis for the grand variance, obtained by poissonization, the Mellin transform, and depoissonization. The digital data model considered is the Bernoulli(p). The distributions involved in the swaps experience a phase change between the biased cases (p≠ ½) and the unbiased case (p= ½). In the biased cases, the grand distribution for the number of swaps (when suitably scaled) converges to that of a perpetuity built from a two-point distribution. The tool for this proof is contraction in the Wasserstein metric space, and identifying the limit as the fixed-point solution of a distributional equation. In the unbiased case the same scaling for the number of swaps gives a limiting constant in probability.
Large deviations for a feed-forward network
Authors: Setayeshgar Leila , Wang Hui
Published: June 2011

We consider a feed-forward network with a single-server station serving jobs with multiple levels of priority. The service discipline is preemptive in that the server always serves a job with the current highest level of priority. For this system with discontinuous dynamics, we establish the sample path large deviation principle using a weak convergence argument. In the special case where jobs have two different levels of priority, we also explicitly identify the exponential decay rate of the total population overflow probabilities by examining the geometry of the zero-level sets of the system Hamiltonians.
Optimal control of stochastic delay equations and time-advanced backward stochastic differential equations
Authors: Øksendal Bernt , Sulem Agnès , Zhang Tusheng
Published: June 2011

We study optimal control problems for (time-)delayed stochastic differential equations with jumps. We establish sufficient and necessary stochastic maximum principles for an optimal control of such systems. The associated adjoint processes are shown to satisfy a (time-)advanced backward stochastic differential equation (ABSDE). Several results on existence and uniqueness of such ABSDEs are shown. The results are illustrated by an application to optimal consumption from a cash flow with delay.
New Limiting Distributions for Bellman-Harris Processes
Authors: Angerer Wolfgang P.
Published: June 2011

We present a number of new solutions to an integral equation arising in the limiting theory of Bellman-Harris processes. The argument proceeds via straightforward analysis of Mellin transforms. We also derive a criterion for the analyticity of the Laplace transform of the limiting distribution on Re(u) ≥ -c for some c > 0.
Contact Process with Destruction of Cubes and Hyperplanes: Forest Fires Versus Tornadoes
Authors: Lanchier N.
Published: June 2011

Nonspatial stochastic models of populations subject to catastrophic events result in the common conclusion that the survival probability of the population is nondecreasing with respect to the random number of individuals removed at each catastrophe. The purpose of this paper is to prove that such a monotonic relationship is not true for simple spatial models based on Harris' contact processes, whose dynamics are described by hypergraph structures rather than traditional graph structures. More precisely, it is proved that, for a wide range of parameters, the destruction of (infinite) hyperplanes does not affect the existence of a nontrivial invariant measure, whereas the destruction of large (finite) cubes drives the population to extinction, a result that we depict by using the biological picture: forest fires are more devastating than tornadoes. This indicates that the geometry of the subsets struck by catastrophes is somewhat more important than their area, thus the need to consider spatial rather than nonspatial models in this context.
On the Markov Transition Kernels for First Passage Percolation on the Ladder
Authors: Schlemm Eckhard
Published: June 2011

We consider the first passage percolation problem on the random graph with vertex set N x {0, 1}, edges joining vertices at a Euclidean distance equal to unity, and independent exponential edge weights. We provide a central limit theorem for the first passage times ln between the vertices (0, 0) and (n, 0), thus extending earlier results about the almost-sure convergence of ln / n as n → ∞. We use generating function techniques to compute the n-step transition kernels of a closely related Markov chain which can be used to explicitly calculate the asymptotic variance in the central limit theorem.
Improved Fréchet Bounds and Model-Free Pricing of Multi-Asset Options
Authors: Tankov Peter
Published: June 2011

Improved bounds on the copula of a bivariate random vector are computed when partial information is available, such as the values of the copula on a given subset of [0, 1]2, or the value of a functional of the copula, monotone with respect to the concordance order. These results are then used to compute model-free bounds on the prices of two-asset options which make use of extra information about the dependence structure, such as the price of another two-asset option.