Background: Heat stress (HS) and related illnesses are a major concern in military, sports, and fire brigadiers. HS results in physiologic responses of increased temperature, heart rate and sweating. In heat stroke, inflammatory response plays an important role and it is evidenced that turpentine (T) induced circulating inflammatory cytokines reduced survival rate and duration at 42oC. Here we report the alteration in the protein expression in liver cells upon HS with and without T treatment using two dimensional gel electrophoresis (2-DE), tryptic in-gel digestion and MALDI-TOF-MS/MS approaches Results: The effects of HS and T treatments alone and a combined treatments (T+HS) was performed in Wistar rat models. Proteomic analysis of liver in the HS and T+HS groups were analyzed compared to liver profiles of resting control and T treated groups. The study revealed a total of 25 and 29 differentially expressed proteins in the HS and T+HS groups respectively compared to resting control group. Fourteen proteins showed altered expression upon T treatment compared to resting control group. Proteins that are involved in metabolic and signal transduction pathways, defense, redox regulation, and cytoskeletal restructuring functions were identified. The altered expression of proteins reflected in 2D gels were corroborated by quantitative real time RT-PCR analysis of 8 protein coding genes representing metabolic and regulatory pathways for their expression and normalized with the house keeping gene beta-actin Conclusions: The present study has identified a number of differentially expressed proteins in the liver cells of rats subjected to T, HS and T+HS treatments. Most of these proteins are implicated in cell metabolism, as well as adaptive response to incurred oxidative stress and tissue damage due to T+HS and HS effects.

Background: Inflammation-mediated hyperalgesia involves tissue acidosis and sensitization of nociceptors. Many studies have reported increased expression of acid-sensing ion channel 3 (ASIC3) in inflammation and enhanced ASIC3 channel activity with pro-inflammatory mediators. However, the role of ASIC3 in inflammation remains inconclusive because of conflicting results generated from studies of ASIC3 knockout (ASIC3-/-) or dominant-negative mutant mice, which have shown normal, decreased or increased hyperalgesia during inflammation. Results: Here, we tested whether ASIC3 plays an important role in inflammation of subcutaneous tissue of paw and muscle in ASIC3-/- mice induced by complete Freund's adjuvant (CFA) or carrageenan by investigating behavioral and pathological responses, as well as the expression profile of ion channels. Compared with the ASIC3+/+ controls, ASIC3-/- mice showed normal thermal and mechanical hyperalgesia with acute (4-h) intraplantar CFA- or carrageenan-induced inflammation, but the hyperalgesic effects in the sub-acute phase (1-2 days) were milder in all paradigms except for thermal hyperalgesia with CFA-induced inflammation. Interestingly, carrageenan-induced primary hyperalgesia was accompanied by an ASIC3-dependent Nav1.9 up-regulation and increase of tetrodotoxin (TTX)-resistant sodium currents. CFA-inflamed muscle did not evoke hyperalgesia in ASIC3-/- or ASIC3+/+ mice, whereas carrageenan-induced inflammation in muscle abolished mechanical hyperalgesia in ASIC3-/- mice, as previously described. However, ASIC3-/- mice showed attenuated pathological features such as less CFA-induced granulomas and milder carrageenan-evoked vasculitis as compared with ASIC3+/+ mice. Conclusion: We provide a novel finding that ASIC3 participates in the maintenance of sub-acute-phase primary hyperalgesia in subcutaneous inflammation and mediates the process of granuloma formation and vasculitis in intramuscular inflammation.

The Pool region of the Republic of Congo is an isolated, conflict-affected area with under-resourced and poorly functioning health care services. Despite significant AIDS-related mortality and morbidity in this area, and a national level commitment to universal HIV care, HIV has been largely neglected. In 2005 Medecins Sans Frontieres decided to introduce HIV care activities. However, in this setting of high basic health care needs, limited medical resources and competing medical priorities, a vertical HIV programme was not suitable. This paper describes the process of integrating HIV care and treatment into basic health services, the clinical outcomes of 222 patients started on antiretroviral treatment (ART), and the benefits to communities and health care systems. Key lessons learned include the use of multi-skilled human resources, the step-wise implementation of HIV activities, the initial engagement of an HIV experienced staff member, the use of simplified and adapted testing, clinical and monitoring protocols and drug regimens, the introduction of more complex monitoring tools to simplify clinical management decisions and intensive staff education regarding the benefits of HIV integration. This project in a rural and remote conflict-affected setting demonstrates that integrated HIV programs can save lives and play a key role in helping to achieve universal access to ART in Africa.

Background: To evaluate the effectiveness and safety of water aerobics during pregnancy. Methods: A randomized controlled trial carried out in 71 low-risk sedentary pregnant women, randomly allocated to water aerobics or no physical exercise. Maternal body composition and perinatal outcomes were evaluated. For statistical analysis Chi-square, Fisher's or Student's t-tests were applied. Risk ratios and their 95% CI were estimated for main outcomes. Body composition was evaluated across time using MANOVA or Friedman multiple analysis. Results: There were no significant differences between the groups regarding maternal weight gain, BMI or percentage of body fat during pregnancy. Incidence of preterm births (RR=0.84; 95%CI:0.28-2.53), vaginal births (RR=1.24; 95%CI:0.73-2.09), low birthweight (RR=1.30; 95%CI:0.61-2.79) and adequate weight for gestational age (RR=1.50; 95%CI:0.65-3.48) were also not significantly different between groups. There were no significant differences in systolic and diastolic blood pressure and heart rate between before and immediately after the water aerobics session measurements. Conclusion: Water aerobics for sedentary pregnant women proved to be safe and was not associated with any alteration in maternal body composition, type of delivery, preterm birth rate, neonatal well-being or weight.

Background: A 14 year old boy with a history and clinical examination suggestive of a medial meniscal tear is presented.Case presentationThe MRI findings suggested a horizontal cleavage tear so arthroscopy was carried out. No intra articular pathology was found at the time of surgery. Conclusions: The role of MRI in investigation of meniscal injuries in children is discussed and the limitations highlighted.

Background: Benzodiazepines are frequently prescribed to elderly patients' despite concerns about adverse effects leading to injurious falls. Previous studies have not investigated the extent to which patients with pre-existing risk factors for falls are prescribed benzodiazepines. The objective of this study is to assess if some of the risk factors for falls are associated with new benzodiazepine prescriptions in elderly persons. Methods: Using provincial administrative databases, elderly Quebec residents were screened in 1989 for benzodiazepine use and non-users were followed for up to 5 years. Logistic regression models were used to evaluate potential predictors of new benzodiazepine use among patient baseline characteristics. Results: In the 252,811 elderly patients who had no benzodiazepine prescription during the baseline year (1989), 174,444 (69%) never filled a benzodiazepine prescription and 78,367 (31%) filled at least one benzodiazepine prescription. In the adjusted analysis, several risk factors for falls were associated with statistically significant increases in the risk of receiving a new benzodiazepine prescription including the number of prescribing physicians seen at baseline (OR: 1.12; 95% CI 1.11-1.13), being female (OR: 1.20; 95% CI 1.18-1.22) or a diagnosis of arthritis (OR: 1.11; 95% CI 1.09-1.14), depression (OR: 1.42; 95% CI 1.35-1.49) or alcohol abuse (OR: 1.24; 95% CI 1.05-1.46). The strongest predictor for starting a benzodiazepine was the use of other medications, particularly anti-depressants (OR: 1.85; 95% CI 1.75-1.95). Conclusions: Patients with pre-existing conditions that increase the risk of injurious falls are significantly more likely to receive a new prescription for a benzodiazepine. The strength of the association between previous medication use and new benzodiazepine prescriptions highlights an important medication safety issue.

Although many secondary metabolites with diverse biological activities have been isolated from myxobacteria, most strains of these biotechnologically important gliding prokaryotes remain difficult to handle genetically. In this study we describe the new fast growing myxobacterial thermophilic isolate GT-2 as a heterologous host for the expression of natural product biosynthetic pathways isolated from other myxobacteria. According to the results of sequence analysis of the 16S rDNA, this moderately thermophilic isolate is closely related to Corallococcus macrosporus and was therefore named C. macrosporus GT-2. Fast growth of moderately thermophilic strains results in shorter fermentation and generation times, aspects which are of significant interest for molecular biological work as well as production of secondary metabolites. Development of a genetic manipulation system allowed the introduction of the complete myxochromide biosynthetic gene cluster, located on a transposable fragment, into the chromosome of GT-2. Genetic engineering of the biosynthetic gene cluster by promoter exchange leads to much higher production of myxochromides in the heterologous host C. macrosporus GT-2 in comparison to the original producer Stigmatella aurantiaca and to the previously described heterologous host Pseudomonas putida (600 mg/L versus 8 mg/L and 40 mg/L, respectively).

This review is intended to provide physicians with an overview of the benefits and risks associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of their patients with mild-to-moderate osteoarthritis (OA). New information on the inflammatory component of OA and the cardiovascular (CV) risk associated with cyclooxygenase (COX)-2-specific inhibitors has prompted efforts to revise the current recommendations for the use of NSAIDs in the treatment of patients with OA. Clinical studies have shown that naproxen and ibuprofen are significantly more effective at reducing OA pain than is acetaminophen, the traditional first-line therapy, which has no apparent anti-inflammatory activity in the joints. The theoretical advantage of COX-2-specific inhibitors in reducing gastrointestinal (GI) toxicity has been demonstrated by clinical studies. GI complications can be reduced by using lower NSAID doses for the shortest duration or with a concomitant proton-pump inhibitor. All prescription NSAIDs carry a black box warning regarding CV risks; these risks vary among the NSAIDs. While ibuprofen and diclofenac are associated with an increased CV risk, naproxen was associated with a neutral CV risk relative to placebo. Ibuprofen, but not naproxen, attenuates the antiplatelet effects of aspirin. An understanding of the risks and benefits is important when choosing an NSAID. An exhaustive search of the medical literature since 1990 was conducted using the words "ibuprofen," "naproxen," "COX-2-specific NSAIDs," "nonspecific NSAIDs," "low-dose aspirin," and "nonprescription dosage." Databases searched included MEDLINE, EMBASE, and SCISEARCH. This article provides primary care physicians with the information needed to assist them in making more informed decisions in managing patients experiencing mild-to-moderate OA pain.

Background: Even though two prophylactic vaccines against HPV are currently licensed, infections by the virus continue to be a major health problem mainly in developing countries. The cost of the vaccines limits wide-scale application in poor countries. A promising strategy for producing affordable and efficient vaccines involves the expression of recombinant immunogens in plants. Several HPV genes have been expressed in plants, including L1, which can self-assemble into virus-like particles. A plant-based, dual prophylactic/therapeutic vaccine remains an attractive possibility. Results: We sought to express in tomato plants chimeric HPV 16 VLPs containing L1 fused to a string of epitopes from HPV 16 E6 and E7 proteins. The L1 employed had been modified to eliminate a strong inhibitory region at the 5' end of the molecule to increase expression levels. Several tomato lines were obtained expressing either L1 alone or L1-E6/E7 from 0.05% to 0.1% of total soluble protein. Stable integration of the transgenes was verified by Southern blot. Northern and western blot revealed successful expression of the transgenes at the mRNA and protein level. The chimeric VLPs were able to assemble adequately in tomato cells. Intraperitoneal administration in mice was able to elicit both neutralizing antibodies against the viral particle and cytotoxic T-lymphocytes activity against the epitopes. Conclusion: In this work, we report for the first time the expression in plants of a chimeric particle containing the HPV 16 L1 sequence and a string of T-cell epitopes from HPV 16 E6 and E7 fused to the C-terminus. The particles were able to induce a significant antibody and cytotoxic T-lymphocytes response. Experiments in vivo are in progress to determine whether the chimeric particles are able to induce regression of disease and resolution of viral infection in mice. Chimeric particles of the type described in this work may potentially be the basis for developing prophylactic/therapeutic vaccines. The fact that they are produced in plants, may lower production costs considerably.

Background: Data from the National Health Interview Survey (NHIS) show a larger-than-expected increase in mean BMI between 1996 and 1997. Proxy-reports of height and weight were discontinued as part of the 1997 NHIS redesign, suggesting that the sharp increase between 1996 and 1997 may be artifactual. Methods: We merged NHIS data from 1976-2002 into a single database consisting of approximately 1.7 million adults aged 18 and over. The analysis consisted of two parts: First, we estimated the magnitude of BMI differences by reporting status (i.e., self-reported versus proxy-reported height and weight). Second, we developed a procedure to correct biases in BMI introduced by reporting status. Results: Our analyses confirmed that proxy-reports of weight tended to be biased downward, with the degree of bias varying by race, sex, and other characteristics. We developed a correction procedure to minimize BMI underestimation associated with proxy-reporting, substantially reducing the larger-than-expected increase found in NHIS data between 1996 and 1997. Conclusions: It is imperative that researchers who use reported estimates of height and weight think carefully about flaws in their data and how existing correction procedures might fail to account for them. The development of this particular correction procedure represents an important step toward improving the quality of BMI estimates in a widely used source of epidemiologic data.

IntroductionMucosa associated lymphoid tissue (MALT) lymphoma is the third most common non-Hodgkin's lymphoma subtype. Clinical presentation is often insidious as a low-grade lesion and disease tends to remain localised for a long period of time. Ileal involvement is rare and presentation within an area of focal anti-mesenteric ileal wall dilation simulating a large diverticulum has not been reported.Case presentationA 59-year-old man of Caucasian origin presented to a general surgical outpatients clinic with an 18-month history of intermittent upper abdominal pain following meals. Following normal gastroscopy and abdominal ultrasound, a focally dilated segment of ileum was seen on computed tomography and further clarified by barium investigation. Histology of this segment demonstrated MALT lymphoma of the small bowel. Conclusion: A solitary focally dilated segment of ileal wall may be neoplastic in nature and surgical resection needs to be considered.

Purpose To study the efficacy of whole brain radiotherapy (WBRT) with radiosensitizer in comparison with WBRT alone for patients with brain metastases in terms of overall survival, disease progression, response to treatment and adverse effects of treatment. Materials and Methods A meta-analysis of randomized controlled trials (RCT) was performed in order to compare WBRT with radiosensitizer for brain metastases and WBRT alone. The MEDLINE, EMBASE, LILACS, and Cochrane Library databases, in addition to Trial registers, bibliographic databases, and recent issues of relevant journals were researched. Significant reports were reviewed by two reviewers independently. Results: A total of 8 RCTs, yielding 2317 patients were analyzed. Pooled results from this 8 RCTs of WBRT with radiosensitizer have not shown a meaningful improvement on overall survival compared to WBRT alone OR= 1.03 (95% CI0.84 -1.25, p=0.77). Also, there was no difference in local brain tumor response OR=0.8(95% CI 0.5 - 1.03) and brain tumor progression (OR=1.11, 95% CI 0.9 - 1.3) when the two arms were compared. Conclusion: Our data show that WBRT with the following radiosentizers (ionidamine, metronidazole, misonodazole, motexafin gadolinium, BUdr, efaproxiral, thalidomide), have not improved significatively the overall survival, local control and tumor response compared to WBRT alone for brain metastases. However, 2 of them, motexafin- gadolinium and efaproxiral have been shown in recent publications (lung and breast) to have positive action in lung and breast carcinoma brain metastases in association with WBRT.

Background: Patient complexity is not incorporated into quality of care comparisons for glycemic control. We developed a method to adjust hemoglobin A1c levels for patient characteristics that reflect complexity, and examined the effect of using adjusted A1c values on quality comparisons. Methods: This cross-sectional observational study used 1999 national VA (US Department of Veterans Affairs) pharmacy, inpatient and outpatient utilization, and laboratory data on diabetic veterans. We adjusted individual A1c levels for available domains of complexity: age, social support (marital status), comorbid illnesses, and severity of disease (insulin use). We used adjusted A1c values to generate VA medical center level performance measures, and compared medical center ranks using adjusted versus unadjusted A1c levels across several thresholds of A1c (8.0%, 8.5%, 9.0%, and 9.5%). Results: The adjustment model had R2 = 8.3% with stable parameter estimates on thirty random 50% resamples. Adjustment for patient complexity resulted in the greatest rank differences in the best and worst performing deciles, with similar patterns across all tested thresholds. Conclusions: Adjustment for complexity resulted in large differences in identified best and worst performers at all tested thresholds. Current performance measures of glycemic control may not be reliably identifying quality problems, and tying reimbursements to such measures may compromise the care of complex patients.

Background: The amyloid beta-peptide is a ubiquitous peptide, which is prone to aggregate forming soluble toxic oligomers and insoluble less-toxic aggregates. The intrinsic and external/environmental factors that determine Abeta aggregation in vivo are poorly understood, as well as the cellular meaning of this process itself. Genetic data as well as cell biological and biochemical evidence strongly support the hypothesis that Abeta is a major player in the onset and development of Alzheimer's disease. In addition, it is also known that Abeta is involved in Inclusion Body Myositis, a common myopathy of the elderly in which the peptide accumulates intracellularly. Results: In the present work, we found that intracellular Abeta aggregation in muscle cells of Caenorhabditis elegans overexpressing Abeta peptide is affected by two single amino acid substitutions, E22G (Arctic) and V18A (NIC). Both variations show decrease intracellular amyloidogenesis compared to wild type Abeta. We show that intracellular amyloid aggregation of wild type Abeta is accelerated by Cu2+ and diminished by copper chelators. Moreover, we demonstrate through toxicity and behavioral assays that Abeta-transgenic worms display a higher tolerance to Cu2+ toxic effects and that this resistance may be linked to the formation of amyloid aggregates. Conclusions: Our data show that intracellular Abeta amyloid aggregates may trap excess of free Cu2+ buffering its cytotoxic effects and that accelerated intracellular Abeta aggregation may be part of a cell protective mechanism.

Background: We investigate automated and generic alphabet reduction techniques for protein structure prediction datasets. Reducing alphabet cardinality without losing key biochemical information opens the door to potentially faster machine learning, data mining and optimization applications in structural bioinformatics. Furthermore, reduced but informative alphabets often result in, e.g., more compact and human-friendly classification/clustering rules. In this paper we propose a robust and sophisticated alphabet reduction protocol based on mutual information and state-of-the-art optimization techniques. Results: We applied this protocol to the prediction of two protein structural features: contact number and relative solvent accessibility. For both features we generated alphabets of two, three, four and five letters. The five-letter alphabets gave prediction accuracies statistically similar to that obtained using the full amino acid alphabet. Moreover, the automatically designed alphabets were compared against other reduced alphabets taken from the literature or human-designed, outperforming them. The differences between our alphabets and the alphabets taken from the literature were quantitatively analyzed. All the above process had been performed using a primary sequence representation of proteins. As a final experiment, we extrapolated the obtained five-letter alphabet to reduce a, much richer, protein representation based on evolutionary information for the prediction of the same two features. Again, the performance gap between the full representation and the reduced representation was small, showing that the results of our automated alphabet reduction protocol, even if they were obtained using a simple representation, are also able to capture the crucial information needed for state-of-the-art protein representations. Conclusions: Our automated alphabet reduction protocol generates competent reduced alphabets tailored specifically for a variety of protein datasets. This process is done without any domain knowledge, using information theory metrics instead. The reduced alphabets contain some unexpected (but sound) groups of amino acids, thus suggesting new ways of interpreting the data.

Background: Natural selection is a potent evolutionary force that shapes phenotypic variation to match ecological conditions. However, we know little about the year-to-year consistency of selection, or how inter-annual variation in ecology shapes adaptive landscapes and ultimately adaptive radiations. Methods: Here we combine remote sensing data, field experiments, and a four-year study of natural selection to show that changes in vegetation structure associated with a severe drought altered both habitat use and natural selection in the brown anole, Anolis sagrei. Results: In natural populations, lizards increased their use of vegetation in wet years and this was correlated with selection on limb length but not body size. By contrast, a die-back of vegetation caused by drought was followed by reduced arboreality, selection on body size, and relaxed selection on limb length. With the return of the rains and recovery of vegetation, selection reverted back to pre-drought pattern of selection acting on limb length but not body size. To test for the impact of vegetation loss on natural selection during the drought, we experimentally removed vegetation on a separate study island in a naturally wet year. The experiment revealed similar inter-annual changes in selection on body size but not limb length. Conclusion: Our results illustrate the dynamic nature of ecology driving natural selection on Anolis morphology and emphasize the importance of inter-annual environmental variation in shaping adaptive variation. In addition, results illustrate the utility of using remote sensing data to examine ecology's role in driving natural selection.

Carcinosarcoma of the breast, often referred to as metaplastic carcinoma of the breast, is a rare malignancy with two distinct cell lines described as a breast carcinoma of ductal type with a sarcoma-like component. The two cases we describe exemplify the aggressive nature of carcinosarcoma of the breast and support the findings that this tumor type does not express the common receptors found in other breast carcinomas. These case reports also emphasize the need for investigating the role for blockade of the HER-1/EGFR receptor with targeted therapies when found to be over-expressed in the primary tumor.

Background: Unexplained somatic symptoms are common among trauma survivors. The relationship between trauma and somatization appears to be mediated by posttraumatic stress disorder (PTSD). However, only few studies have focused on what other psychological risk factors may predispose a trauma victim towards developing somatoform symptoms. Methods: The present paper examines the predictive value of PTSD severity, social support, dissociation, negative affectivity, depression, anxiety, and feeling incompetent on somatization in a Danish sample of 169 adult men and women who were affected by a series of explosions in a firework factory settled in a residential area. Results: Negative affectivity and feelings of incompetence significantly predicted somatization, explaining 42% of the variance. PTSD was significant until negative affectivity was controlled for. Conclusions: Negative affectivity and feelings of incompetence significantly predicted degree of somatization in the trauma sample whereas dissociation, social support, depression, and anxiety were not associated with degree of somatization. PTSD as a risk factor was mediated by negative affectivity.

Background: Fourmidable is an infrastructure to curate and share the emerging genetic, molecular, and functional genomic data and protocols for ants. Description The Fourmidable assembly pipeline groups nucleotide sequences into clusters before independently assembling each cluster. Subsequently, assembled sequences are annotated via Interproscan and BLAST against general and insect-specific databases. Gene-specific information can be retrieved using gene identifiers, searching for similar sequences or browsing through inferred Gene Ontology annotations. The database will readily scale as ultra-high throughput sequence data and sequences from additional species become available. Conclusions: Fourmidable currently houses EST data from two ant species and microarray gene expression data for one of these. Fourmidable is publicly available at http://fourmidable.unil.ch

Background: Inferior vena cava (IVC) leiomyosarcoma is a rare tumor of smooth muscle origin. It is often large by the time of diagnosis and may involve adjacent organs. A margin-free resection may be curative, but the resection must involve the tumor en bloc with the affected segment of vena cava and locally involved organs. IVC resection often requires vascular reconstruction, which can be done with prosthetic graft. Case presentationWe describe a 39-year-old man with an IVC leiomyosarcoma that involved the adrenal gland, distal pancreas, and blood supply to the spleen and left kidney. Tumor excision involved en bloc resection of all involved organs with reimplantation of the right renal vein and reconstruction of the IVC with a polytetrafluoroethylene graft. The patient recovered without renal insufficiency, graft infection, or other complications. Follow-up abdominal imaging at 1 year showed a patent IVC graft and no locally recurrent tumor. Prosthetic graft provides a sufficient diameter and length for replacement conduit in extensive resection of IVC leiomyosarcoma. Conclusions: To our knowledge, this is the first case of resection of an IVC sarcoma with prosthetic graft reconstruction in combination with pancreatic resection. Aggressive surgical resection including vascular reconstruction is warranted for select IVC tumors to achieve a potentially curative outcome.

Background: Biomedical scientists need to access figures to validate research facts and to formulate or to test novel research hypotheses. However, figures are difficult to comprehend without associated text (e.g., figure legend and other reference text). We are developing automated systems to extract the relevant explanatory information along with figures extracted from full text articles. Such systems could be very useful in improving figure retrieval and in reducing the workload of biomedical scientists, who otherwise have to retrieve and read the entire full-text journal article to determine which figures are relevant to their research. As a crucial step, we studied the importance of associated text in biomedical figure comprehension. Methods: Twenty subjects evaluated three figure-text combinations: figure+legend, figure+legend+title+abstract, and figure+full-text. Using a Likert scale, each subject scored each figure+text according to the extent to which the subject thought he/she understood the meaning of the figure and the confidence in providing the assigned score. Additionally, each subject entered a free text summary for each figure-text. We identified missing information using indicator words present within the text summaries. Both the Likert scores and the missing information were statistically analyzed for differences among the figure-text types. We also evaluated the quality of text summaries with the text-summarization evaluation method the ROUGE score. Results: Using figure+legend category as a baseline, the comprehension and confidence scores entered by biomedical scientists increased 27% and 7% when title+abstract were added, and 40% and 11% when full-text was available. Figure comprehension on the basis of missing information analysis increased 25-128% when title+abstract were added, and 49-169% when full-text was available. The ROUGE score also followed the same trend, increasing 25%-30% when title+abstract were added, and 33-155% when full-text was available. The differences in figure comprehension at different levels of associated text were in most cases statistically significant. Conclusion: We conclude that the texts that appear in full-text biomedical articles are useful for understanding the meaning of a figure, and an effective figure-mining system needs to unlock the information beyond figure legend. Our work provides important guidance to the figure mining systems that extract information only from figure and figure legend.

Background: Salmonella enterica serovar Typhimurium (Typhimurium) is an important pathogen that infects a broad range of hosts. In humans, Typhimurium causes a gastroenteritis characterized by vomiting, diarrhea, and abdominal pains. Typhimurium infection occurs mainly through the ingestion of contaminated food including poultry, pork, eggs, and milk. Chickens that are asymptomatic carriers of Typhimurium constitute a potential reservoir for infection. The type three secretion systems encoded by Salmonella pathogenicity islands (SPI) 1 and 2 are major virulence factors of Salmonella. However,only a few studies have investigated their role during the infection of chickens. Results: We have taken a mixed infection approach to study the contribution of SPI1 and SPI2 to the colonization of the chicken by Typhimurium. We found that SPI1 contributes to colonization of both the cecum and spleen in the chicken. In contrast, SPI2 contributes to colonization of the spleen but not the cecum and, in the absence of SPI1, inhibits cecal colonization. Additionally, we show that the contribution of SPI1 in the spleen is greater than that of SPI2. These results are different from those observed during the infection of the mouse by Typhimurium where SPI2 is the major player during systemic colonization. Conclusions: The co-infection model we used provides a sensitive assay that confirms the role of SPI1 and clarifies the role of SPI2 in the colonization of the chicken by Typhimurium.

Background: System analyses of incidents that occur in the process of health care delivery are rare. A case study of a series of incidents that one of the authors experienced after routine urologic surgery is presented. We interpret the sequence of events as a case of cascading incidents that resulted in outcomes that were suboptimal, although fortunately not fatal. Methods: A system dynamics approach was employed to develop illustrative models (flow diagrams) of the dynamics of the patient's interaction with surgery and emergency departments. The flow diagrams were constructed based upon the experience of the patient, chart review, discussion with the involved physicians as well as several physician colleagues, comparison of our diagrams with those developed by the hospital of interest for internal planning purposes, and an iterative process with one of the co-authors who is a system dynamics expert. A dynamic hypothesis was developed using insights gained by building the flow diagrams. Results: The incidents originated in design flaws and many small innocuous system changes that have occurred incrementally over time, which by themselves may have no consequence but in conjunction with some system randomness can have serious consequences. In the patient's case, the incidents that occurred in preoperative assessment and surgery originated in communication and procedural failures. System delays, communication failures, and capacity issues contributed largely to the subsequent incidents. Some of these issues were controllable by the physicians and staff of the institution, whereas others were less controllable. To the system's credit, some of the more controllable issues were addressed, but systemic problems like overcrowding are unlikely to be addressed in the near future. Conclusions: This is first instance that we are aware of in the literature where a system dynamics approach has been used to analyze a patient safety experience. The qualitative system dynamics analysis was useful in understanding the system, and contributed to learning on the part of some components of the system. We suggest that further data collection and quantitative analysis would be highly informative for identification of system changes to improve quality and safety.

Background: In the United States, social burdens including war casualties are often distributed unequally across groups of individuals, communities, and states. The purpose of this report was to examine the association between war deaths and per capita income in the 50 states and District of Columbia during the Vietnam and Iraq wars. Methods: The numbers of deaths by the home state of record for each conflict were obtained from Department of Defense records on the Internet as were key variables including age at death, gender, race, branch of service, rank, circumstances of death, home state of record and the ratio of wounded to dead. In addition, we obtained state per capita income and state population for the relevant times. Results: Characteristics of decedents in the 2 conflicts were very similar with young, white enlisted men accounting for the majority of deaths. However, in the Iraq war, women accounted for a 2.4% of casualties. Also of note was the higher ratio of wounded to dead in Iraq. At the level of the state, the correlation between the ratio of deaths per 100,000 and per capita income was -0.51 (p

Background: In high throughput screening, such as differential gene expression screening, drug sensitivity screening, and genome-wide RNAi screening, tens of thousands of tests need to be conducted simultaneously. However, the number of replicate measurements per test is extremely small, rarely exceeding 3. Several current approaches demonstrate that test statistics with shrinking variance estimates have more power over the traditional t statistic. Results: We propose a Bayesian hierarchical model to incorporate the shrinkage concept by introducing a mixture structure on variance components. The estimates from the Bayesian model are further implemented in the optimal discovery procedure (ODP) proposed by Storey in 2007, which was shown to have optimal performance in multiple significance tests. We compared the Bayesian ODP with several competing test statistics. Conclusion: We have conducted simulation studies with 2 to 6 replicates per gene. We have also included test results from two real datasets. The Bayesian ODP outperforms the other methods in our study, including the original ODP. The advantage of the Bayesian ODP becomes more significant when there are few replicates per test. The improvement over the original ODP is based on the fact that Bayesian model borrows strength across genes in estimating unknown parameters. The proposed approach is efficient in computation due to the conjugate structure of the Bayesian model. The R code (see Additional file 1) to calculate the Bayesian ODP is provided.

IntroductionThe risk of developing schizophrenia is higher among persons with an affected sibling compared to the general population. Beliefs about aetiology influence presentation, management and treatment outcomes. There are no reports on multiple occurrences of this disorder in a family in this part of the world. In this case series we also highlight how cultural beliefs hamper and shape management.Case presentationWe report a case series of schizophrenia spectrum disorders affecting four women in a Nigerian family of Ibo tribal origin who responded marginally to pharmacological interventions and required insight oriented psychotherapy and family therapy in resolving psychosocial problems. Conclusion: While western taught disease models might explain these presentations, it is not usually accepted by lay persons from developing cultures. Limitations in contemporary treatment approaches necessitate the development of culturally relevant psychotherapeutic interventions.

Background: In recent years, apart from antibacterial properties, doxycycline is reported to have cytotoxic and anti-proliferative actions in various cancers including colorectal cancer. Colorectal cancer constitutes one of the most common cancers in the western population. Apart from surgery, chemotherapy plays crucial role in the treatment of colorectal cancer. Cisplatin and oxaliplatin are most commonly used platinum compounds for the cancer chemotherapy. This study has looked for any impact of doxycycline on the cytotoxic effects of platinum compounds in colorectal cancer including its mechanisms of actions. Methods: HT 29 colorectal cancer cells were used for this study. These cells were treated with cisplatin and oxaliplatin with or without doxycycline treatment. The caspase 3 gene expression was quantitated by gel electrophoresis and qualitated by real time polymerase chain reactions. The caspase 3 activity was assessed in HT 29 cells with fluorescence kit. Results: The results revealed increased caspase 3 gene expressions and activities in HT 29 cells treated with cisplatin, oxaliplatin and doxycycline; however the combination of doxycycline with cisplatin and oxaliplatin did not report increased caspase 3 gene expressions and activity compared to cisplatin and oxaliplatin alone. Conclusions: We concluded that doxycycline has role in apoptosis induction in the colorectal cancer. However, it did not show any synergy with platinum compounds in the colorectal cancer cells. This study also pointed towards possible caspase-independent actions of doxycycline with cisplatin and oxaliplatin. However, further work is required to underpin the mechanisms of actions of doxycycline.

Background: Quantitative data from gene expression experiments are often normalized by transcription levels of reference or housekeeping genes. An inherent assumption for their use is that the expression of these genes is highly uniform in living organisms during various phases of development, in different cell types and under diverse environmental conditions. To date, the validation of reference genes in plants has received very little attention and suitable reference genes have not been defined for a great number of crop species including Coffea arabica. The aim of the research reported herein was to compare the relative expression of a set of potential reference genes across different types of tissue/organ samples of coffee. We also validated the expression profiles of the selected reference genes at various stages of development and under a specific biotic stress. Results: The expression levels of five frequently used housekeeping genes (reference genes), namely alcohol dehydrogenase (adh), 14-3-3, polyubiquitin (poly), beta-actin (actin) and glyceraldehyde-3-phosphate dehydrogenase (gapdh) was assessed by quantitative real-time RT-PCR over a set of five tissue/organ samples (root, stem, leaf, flower, and fruits) of Coffea arabica plants. In addition to these commonly used internal controls, three other genes encoding a cysteine proteinase (cys), a caffeine synthase (ccs) and the 60S ribosomal protein L7 (rpl7) were also tested. Their stability and suitability as reference genes were validated by geNorm, NormFinder and BestKeeper programs. The obtained results revealed significantly variable expression levels of all reference genes analyzed, with the exception of gapdh, which showed no significant changes in expression among the investigated experimental conditions. Conclusions: Our data suggests that the expression of housekeeping genes is not completely stable in coffee. Based on our results, gapdh, followed by 14-3-3 and rpl7 were found to be homogeneously expressed and are therefore adequate for normalization purposes, showing equivalent transcript levels in different tissue/organ samples. Gapdh is therefore the recommended reference gene for measuring gene expression in Coffea arabica. Its use will enable more accurate and reliable normalization of tissue/organ-specific gene expression studies in this important cherry crop plant.

Background: The purpose of this study was to examine the effect of a pre-exercise high energy drink on reaction time and anaerobic power in competitive strength/power athletes. In addition, the effect of the pre-exercise drink on subjective feelings of energy, fatigue, alertness and focus was also explored. Methods: Twelve male strength/power athletes (21.1 +/- 1.3y; 179.8 +/- 7.1 cm; 88.6 +/- 12.1 kg; 17.6 +/- 3.3% body fat) underwent two testing sessions administered in a randomized and double-blind fashion. During each session, subjects reported to the Human Performance Laboratory and were provided with either 120 ml of a high energy drink (SUP), commercially marketed as Redline Extreme(R) or 120 ml of a placebo (PL) that was similar in taste and appearance but contained no active ingredients. Following consumption of the supplement or placebo subjects rested quietly for 10-minutes prior to completing a survey and commencing exercise. The survey consisted of 4 questions asking each subject to describe their feelings of energy, fatigue, alertness and focus for that moment. Following the completion of the questionnaire subjects performed a 2-minute quickness and reaction test on the Makoto testing device (Makoto USA, Centennial CO) and a 20-second Wingate Anaerobic Power test. Following a 10-minute rest subjects repeated the testing sequence and after a similar rest period a third and final testing sequence was performed. The Makoto testing device consisted of subjects reacting to both a visual and auditory stimulus and striking one out of 30 potential targets on three towers. Results: Significant difference in reaction performance was seen between SUP and PL in both average number of targets struck (55.8 +/- 7.4 versus 51.9 +/- 7.4, respectively) and percent of targets struck (71.9 +/- 10.5% versus 66.8 +/- 10.9%, respectively). No significant differences between trials were seen in any anaerobic power measure. Subjective feelings of energy (3.5 +/- 0.5 versus 3.1 +/- 0.5) and focus (3.8 +/- 0.5 versus 3.3 +/- 0.7) were significantly higher during SUP compared to PL, respectively. In addition, a trend towards an increase in average alertness (p = 0.06) was seen in SUP compared to P. Conclusion: Results indicate a significant increase in reaction performance, with no effect on anaerobic power performance. In addition, ingestion of this supplement significantly improves subjective feelings of focus and energy in male strength/power athletes.

Background: The purpose of this study was to examine the acute effects of a weight loss supplement on resting oxygen uptake (VO2), respiratory quotient (RQ), caloric expenditure (kcal), heart rate (HR), and blood pressure (BP) in healthy and physically active individuals. Methods: Ten subjects (5 male, 5 female; 20.2 +/- 1.2y; 172.2 +/- 8.9 cm; 71.5 +/- 17.2 kg; 17.3 +/- 2.6% body fat) underwent two testing sessions administered in a randomized and double-blind fashion. During each session, subjects reported to the Human Performance Laboratory after at least 3-h post-absorptive state and were provided either 3 capsules of the weight loss supplement (SUP), commercially marketed as Meltdown(R) or 3 capsules of a placebo (P). Subjects then rested in a semi-recumbent position for three hours. VO2 and HR were determined every 5 min during the first 30 min and every 10 min during the next 150 min. BP was determined every 15 min during the first 30 min and every 30 min thereafter. The profile of mood states was assessed every 30 min. Results: Area under the curve analysis revealed a significant 28.9% difference in VO2 between SUP and P for the three hour study period. In addition, a significant difference in energy expenditure was also seen between S (1.28 +/- 0.33 kcalmin-1) and P (1.00 +/- 0.32 kcalmin-1). A trend (p = 0.06) towards a greater utilization of stored fat as an energy source was also demonstrated (0.78 +/- 0.23 kcalmin-1 and 0.50 +/- 0.38 kcalmin-1 in P and SUP, respectively). Significant elevations in HR were seen during hours two and three of the study, and significantly higher average systolic BP was observed between SUP (118.0 +/- 7.3 mmHg) and P (111.4 +/- 8.2 mmHg). No significant differences were seen in diastolic blood pressure at any time point. Significant increases in tension and confusion were seen in SUP. Conclusion: Results indicate a significant increase in energy expenditure in young, healthy individuals following an acute ingestion of a weight loss supplement. In addition, ingestion of this supplement appears modify mood and elevate HR and systolic BP following ingestion.

Background: Activation of the liver X receptors (LXRs) by exogenous ligands stimulates the degradation of beta-amyloid 1-42 (Abeta42), a peptide that plays a central role in the pathogenesis of Alzheimer's disease (AD). The oxidized cholesterol products (oxysterols), 24-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), are endogenous activators of LXRs. However, the mechanisms by which these oxysterols may modulate Abeta42 levels are not well known. Results: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells. We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide. Increased Abeta42 levels with 27-OHC are associated with increased levels of beta-amyloid precursor protein (APP) as well as beta-secretase (BACE1), the enzyme that cleaves APP to yield Abeta. Unchanged Abeta42 levels with 24-OHC are associated with increased levels of sAPPalpha, suggesting that 24-OHC favors the processing of APP to the non-amyloidogenic pathway. Interestingly, 24-OHC, but not 27-OHC, increases levels of the ATP-binding cassette transporters, ABCA1 and ABCG1, which regulate cholesterol transport within and between cells. Conclusion: These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance the production of Abeta42 peptide by upregulating levels of APP and BACE1. Regulation of 24-OHC: 27-OHC ratio could be an important strategy in controlling Abeta42 levels in AD.

IntroductionGuillain-Barre syndrome is an acute demyelinating disorder of the peripheral nervous system that results from an aberrant immune response directed at peripheral nerves. Autonomic abnormalities in Guillain-Barre syndrome are usually transient and reversible. We present a case of Guillain-Barre syndrome requiring a permanent pacemaker in view of persistent symptomatic bradyarrhythmia. Case Presentation An 18-year-old Caucasian female presented with bilateral lower limb paraesthesias followed by bilateral progressive leg weakness and difficulty in walking. She reported an episode of an upper respiratory tract infection 3 weeks prior to the onset of her neurological symptoms. Diagnosis of Guillain-Barre syndrome was considered and a lumbar puncture was performed. Cerebrospinal fluid revealed albuminocytologic dissociation (increased protein but normal white blood cell count) suggestive of Guillain-Barre syndrome and hence an intravenous immunoglobulin G infusion was started. Within 48 hours, she progressed to complete flaccid quadriparesis with involvement of respiratory muscles requiring mechanical ventilatory support. While in the intensive care unit, she developed multiple episodes of bradycardia and asystole requiring a temporary pacemaker. In view of the persistent requirement for the temporary pacemaker for more than 5 days, she received a permanent pacemaker. She returned for follow-up three months after discharge with an intermittent need for ventricular pacing. Conclusion: Guillain-Barre syndrome can result in permanent damage to the cardiac conduction system. Patients with multiple episodes of bradycardia and asystole in the setting of Guillain-Barre syndrome should be evaluated and considered as potential candidates for permanent pacemaker implantation.

A 29-year-old woman presented with a breast tumor with a primary diagnosis of MALT lymphoma. A repeat biopsy revealed a hematological neoplasm with diffuse, Indian file, and targetoid patterns. The cells were intermediate size with eosinophilic granules; the immunophenotyping showed monocytic differentiation, and no lymphoepithelial lesion was observed. The diagnosis was granulocytic sarcoma. Three different bone marrow biopsies were negative for neoplastic infiltration. After treatment, she developed secondary pancytopenia which contributed to her death 16 months after primary diagnosis. Granulocytic sarcoma of the breast is uncommon. A complete panel of immunohistochemistry is necessary to perform this diagnosis.

Background: Regeneration of neurons and fibers in the mammalian spinal cord has not been plausible, even though extensive studies have been made to understand the restrictive factors involved. New experimental models and strategies are necessary to determine how new nerve cells are generated and how fibers regrow and connect with their targets in adult animals. Non-vertebrate deuterostomes might provide some answers to these questions. Echinoderms, with their amazing regenerative capacities could serve as model systems; however, very few studies have been done to study the regeneration of their nervous system. Results: We have studied nerve cord regeneration in the echinoderm Holothuria glaberrima. These are sea cucumbers or holothurians members of the class Holothuroidea. One radial nerve cord, part of the echinoderm CNS, was completely transected using a scalpel blade. Animals were allowed to heal for up to four weeks (2, 6, 12, 20, and 28 days post-injury) before sacrificed. Tissues were sectioned in a cryostat and changes in the radial nerve cord were analyzed using classical dyes and immmuohistochemistry. In addition, the temporal and spatial distribution of cell proliferation and apoptosis was assayed using BrdU incorporation and the TUNEL assay, respectively. We found that H. glaberrima can regenerate its radial nerve cord within a month following transection. The regenerated cord looks amazingly similar in overall morphology and cellular composition to the uninjured cord. The cellular events associated to radial cord regeneration include: (1) outgrowth of nerve fibers from the injured radial cord stumps, (2) intense cellular division in the cord stumps and in the regenerating radial nerve cords, (3) high levels of apoptosis in the RNC adjacent to the injury and within the regenerating cord and (4) an increase in the number of spherule-containing cells. These events are similar to those that occur in other body wall tissues during wound healing and during regeneration of the intestine. Conclusions: Our data indicate that holothurians are capable of rapid and complete regeneration of the main component of their CNS. Regeneration involves both the outgrowth of nerve fibers and the formation of neurons. Moreover, the cellular events employed during regeneration are similar to those involved in other regenerative processes, namely wound healing and intestinal regeneration. Thus, holothurians should be viewed as an alternative model where many of the questions regarding nervous system regeneration in deuterostomes could be answered.

Background: There is no safe, effective human vaccine against brucellosis. Live attenuated Brucella strains are widely used to vaccinate animals. However these live Brucella vaccines can cause disease and are unsafe for humans. Killed Brucella or subunit vaccines are not effective in eliciting long term protection. In this study, we evaluate an approach using a live, non-pathogenic bacteria (E. coli) genetically engineered to mimic the Brucella pathway of infection and present antigens for an appropriate cytolitic T cell response. Methods: E. coli was modified to express invasin of Yersinia and listerialysin O (LLO) of Listeria to impart the necessary infectivity and antigen releasing traits of the intracellular pathogen, Brucella. This modified E. coli was considered our vaccine delivery system and was engineered to express Green Fluorescent Protein (GFP) or Brucella antigens for in vitro and in vivo immunological studies including cytokine profiling and cytotoxicity assays. Results: The E. coli vaccine vector was able to infect all cells tested and efficiently deliver therapeutics to the host cell. Using GFP as antigen, we demonstrate that the E. coli vaccine vector elicits a Th1 cytokine profile in both primary and secondary immune responses. Additionally, using this vector to deliver a Brucella antigen, we demonstrate the ability of the E. coli vaccine vector to induce specific Cytotoxic T Lymphocytes (CTLs). Conclusion: Protection against most intracellular bacterial pathogens can only be obtained through cell mediated immunity. Data presented here suggest modified E. coli can be used as a vaccine vector for delivery of antigens and therapeutics mimicking the infection of the pathogen and inducing cell mediated immunity to that pathogen.

Background: Chronic hypoxia in utero (CHU) is one of the most common insults to fetal development and may be associated with poor cardiac recovery from ischaemia-reperfusion injury, yet the effects on normal cardiac mechanical performance are poorly understood. Methods: Pregnant female wistar rats were exposed to hypoxia (12% oxygen, balance nitrogen) for days 10-20 of pregnancy. Pups were born into normal room air and weaned normally. At 10 weeks of age, hearts were excised under anaesthesia and underwent retrograde 'Langendorff' perfusion. Mechanical performance was measured at constant filling pressure (100cm H2O) with intraventricular balloon. Left ventricular free wall was dissected away and capillary density estimated following alkaline phosphatase staining. Expression of SERCA2a and Nitric Oxide Synthases (NOS) proteins were estimated by immunoblotting. Results: CHU significantly increased body mass (P

Background: Cutaneous leishmaniasis can be caused by several Leishmania species and is transmitted to human beings and animals by sand flies, Down syndrome is known to cause immunodeficiency that might lead to increase the susceptibility to infection with Leishmania. Up to our knowledge this is the first case of isolated facial cutaneous leshmaniasis in association with Down syndrome. Case presentationA 2 month old Saudi Arabian male infant was admitted in the pediatric ward of maternity and children's hospital, Buraidah, Kingdom of Saudi Arabia for the management of multiple ulcers on his face, two ulcers were big and were surrounded by edema, causing severe disfigurement. This disfigurement caused difficulty in recognizing the facial feature of Down syndrome. The presence of hypotonia, microcephaly, low set ears, bilateral simian creases and wide separation between big toe and other toes directed us to request karyotyping. The result of karyotyping confirmed the diagnosis of Down syndrome. Conclusion: Children with Down syndrome are immunodeficient, they have been reported to have a complex of immunological alterations which might lead to increased susceptibility to infection.

Background: Under natural circumstances, attention plays an important role in extracting relevant auditory signals from simultaneously present, irrelevant noises. Excitatory and inhibitory neural activity, enhanced by attentional processes, seems to sharpen frequency tuning, contributing to improved auditory performance especially in noisy environments. In the present study, we investigated auditory magnetic fields in humans that were evoked by pure tones embedded in band-eliminated noises during two different stimulus sequencing conditions (constant vs. random) under auditory focused attention by means of magnetoencephalography (MEG). Results: In total, we used identical auditory stimuli between conditions, but presented them in a different order, thereby manipulating the neural processing and the auditory performance of the listeners. Constant stimulus sequencing blocks were characterized by the simultaneous presentation of pure tones of identical frequency with band-eliminated noises, whereas random sequencing blocks were characterized by the simultaneous presentation of pure tones of random frequencies and band-eliminated noises. We demonstrated that auditory evoked neural responses were larger in the constant sequencing compared to the random sequencing condition, particularly when the simultaneously presented noises contained narrow stop-bands. Conclusions: The present study confirmed that population-level frequency tuning in human auditory cortex can be sharpened in a frequency-specific manner. This frequency-specific sharpening may contribute to improved auditory performance during detection and processing of relevant sound inputs characterized by specific frequency distributions in noisy environments.

Background: The oxidation of fatty acids in mitochondria plays an important role in energy metabolism and genetic disorders of this pathway may cause metabolic diseases. Enzyme deficiencies can block the metabolism at defined reactions in the mitochondrion and lead to accumulation of specific substrates causing severe clinical manifestations. Ten of the disorders directly affecting mitochondrial fatty acid oxidation have been well-defined, implicating episodic hypoketotic hypoglycemia provoked by catabolic stress, multiple organ failure, muscle weakness, or hypertrophic cardiomyopathy. Additionally, syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by fatty acid oxidation deficiencies. However, little is known about fatty acids kinetics, especially during fasting or exercise when the demand for fatty acid oxidation is increased (catabolic stress). Results: A computational kinetic network of 64 reactions with 91 compounds and 301 parameters was constructed to study dynamic properties of mitochondrial fatty acid beta-oxidation. Various deficiencies of acyl-CoA dehydrogenase were simulated and verified with measured concentrations of indicative metabolites of screened newborns in Middle Europe and South Australia. The simulated accumulation of specific acyl-CoAs according to the investigated enzyme deficiencies are in agreement with experimental data and findings in literature. Investigation of the dynamic properties of the fatty acid beta-oxidation reveals that the formation of acetyl-CoA - substrate for energy production - is highly impaired within the first hours of fasting corresponding to the rapid progress to coma within 1-2 hours. LCAD deficiency exhibits the highest accumulation of fatty acids along with marked increase of these substrates during catabolic stress and the lowest production rate of acetyl-CoA. These findings might confirm gestational loss to be the explanation that no human cases of LCAD deficiency have been described. Conclusions: In summary, this work provides a detailed kinetic model of mitochondrial metabolism with specific focus on fatty acid beta-oxidation to simulate and predict the dynamic response of that metabolic network in the context of human disease. Our findings offer insight into the disease process (e.g. rapid progress to coma) and might confirm new explanations (no human cases of LCAD deficiency), which can hardly be obtained from experimental data alone.

IntroductionExtramammary Paget's disease is a rare cutaneous, slow growing, intraepithelial adenocarcinoma developing in the apocrine gland-bearing areas. Isolated Paget's disease of the penis is extremely rare. Case presentationWe describe the case of an 87-year-old Caucasian male who presented with a non-healing erythematous plaque on the shaft of the penis previously misdiagnosed as Bowen's disease. The diagnosis was made histologically on the excised specimen and was supported by immunohistochemical staining. Conclusion: Extramammary Paget's disease is a rare disease which can mimic various types of dermatosis. A high index of suspicion is required, combined with biopsy and immunohistochemical staining in order to make the correct diagnosis. Long-term follow-up is mandatory in these patients in order to identify and treat any subsequent recurrence or concurrent malignancy.

Background: Pancreatic islets of Langerhans originate from endocrine progenitors within the pancreatic ductal epithelium. Concomitant with differentiation of these progenitors into hormone-producing cells such cells delaminate, aggregate and migrate away from the ductal epithelium. The cellular and molecular mechanisms regulating islet cell delamination and cell migration are poorly understood. Extensive biochemical and cell biological studies using cultured cells demonstrated that Rac1, a member of the Rho family of small GTPases, acts as a key regulator of cell migration. Results: To address the functional role of Rac1 in islet morphogenesis, we generated transgenic mice expressing dominant negative Rac1 under regulation of the Rat Insulin Promoter. Blocking Rac1 function in beta cells inhibited their migration away from the ductal epithelium in vivo. Consistently, transgenic islet cell spreading was compromised in vitro. We also show that the EGF-receptor ligand betacellulin induced actin remodelling and cell spreading in wild-type islets, but not in transgenic islets. Finally, we demonstrate that cell-cell contact E-cadherin increased as a consequence of blocking Rac1 activity. Conclusions: Our data support a model where Rac1 signalling controls islet cell migration by modulating E-cadherin-mediated cell-cell adhesion. Furthermore, in vitro experiments show that betacellulin stimulated islet cell spreading and actin remodelling is compromised in transgenic islets, suggesting that betacellulin may act as a regulator of Rac1 activity and islet migration in vivo. Our results further emphasize Rac1 as a key regulator of cell migration and cell adhesion during tissue and organ morphogenesis.

Background: In mass spectrometry (MS) based proteomic data analysis, peak detection is an essential step for subsequent analysis. Recently, there has been significant progress in the development of various peak detection algorithms. However, neither a comprehensive survey nor an experimental comparison of these algorithms is yet available. The main objective of this paper is to provide such a survey and to compare the performance of single spectrum based peak detection methods. Results: In general, we can decompose a peak detection procedure into three consequent parts: smoothing, baseline correction and peak finding. We first categorize existing peak detection algorithms according to the techniques used in different phases. Such a categorization reveals the differences and similarities among existing peak detection algorithms. Then, we choose five typical peak detection algorithms to conduct a comprehensive experimental study using both simulation data and real MALDI MS data. Conclusions: The results of comparison show that the continuous wavelet-based algorithm provides the best average performance.

Background: Fibronectin 1 (FN1), a glycoprotein component of the extracellular matrix, exerts different functions during reproductive processes such as fertilisation, gastrulation and implantation. FN1 expression has been described to increase significantly from the morula towards the early blastocyst stage, suggesting that FN1 may also be involved in early blastocyst formation. By alternative splicing at 3 defined regions, different FN1 isoforms are generated, each with a unique biological function. The analysis of the alternative FN1 splicing on the one hand and the search for candidate FN1 receptors on the other hand during early bovine embryo development may reveal more about its function during bovine preimplantation embryo development. Results: RT-qPCR quantification of the FN1 splice isoforms in oocytes, embryos, cumulus cells and adult tissue samples revealed a large variation in overall FN1 expression and in splice variant expression. Moreover, two new FN1 transcript variants were identified, the first one expressed in bovine preimplantation embryos and the second one expressed in cumulus cells. In the search for candidate receptors for the new embryo specific FN1 isoform, RNA expression analysis identified 5 alpha integrin subunits (ITGA2B, ITGA3, ITGA5, ITGA8, ITGAV) and 2 beta integrin subunits (ITGB1 and ITGB3) with a similar or overlapping RNA expression pattern as compared to FN1. But double immunofluorescent stainings could not confirm complete co-localisation between FN1 and one out of 3 selected integrins alpha subunits (ITGA3, ITGA5, ITGAV). Conclusions: The existence of a new FN1 transcript variant, specifically expressed in morulae and blastocysts strengthens the idea that FN1 is involved in the process of compaction and blastocyst formation. Analysis of the integrin expression could not identify the binding partner for the embryo specific FN1 transcript variant making further steps necessary for the identification of the FN1 receptor and the downstream effects of FN1-receptor binding.

IntroductionA case of Lactococcus lactis cremoris causing cholangitis is described. This Gram-positive organism is not routinely considered to be pathogenic in immunocompetent individuals. To our knowledge, this is the thirteenth report of invasive infection and the first of cholangitis to be reported in association with this organism. Case presentationA 72-year-old patient presented with Charcot's triad and was demonstrated to have cholangitis with Lactococcus lactis cremoris bacteraemia. Biliary drainage was achieved through endoscopic retrograde cholangiography. Antibiotic therapy with multiple agents was necessary. Conclusions: This report provides corroboration of evidence that Lactococcus lactis cremoris is a potential pathogen in immunocompetent adults. There remains a debate about the most appropriate empirical antibiotic therapy in this condition. In the light of this case, it is important to keep an open mind to potential pathogens.

Background: Recent studies have revealed expansion by an array of Filarioid nematodes' into the northern boreal region of Finland. The vector-borne nematode, Setaria tundra, caused a serious disease outbreak in the Finnish reindeer population in 2003-05. The main aim of this study was to understand the outbreak dynamics and the rapid expansion of S. tundra in the sub arctic. We describe the vectors of S. tundra, and its development in vectors, for the first time. Finally we discuss the results in the context of the host-parasite ecology of S. tundra in Finland Results: Development of S. tundra to the infective stage occurs in mosquitoes, (genera Aedes and Anopheles). We consider Aedes spp. the most important vectors. The prevalence of S. tundra naturally infected mosquitoes from Finland varied from 0.5 to 2.5%. The rate of development in mosquitoes was temperature-dependent. Infective larvae were present approximately 14 days after a blood meal in mosquitoes maintained at room temperature (mean 21 C), but did not develop in mosquitoes maintained outside for 22 days at a mean temperature of 14.1 C. The third-stage (infective) larvae were elongated (mean length 1411 mum (SD 207), and width 28 mum (SD 2)). The anterior end was blunt, and bore two liplike structures, the posterior end slight tapering with a prominent terminal papilla. Infective larvae were distributed anteriorly in the insect's body, the highest abundance being 70 larvae in one mosquito. A questionnaire survey revealed that the peak activity of Culicidae in the reindeer herding areas of Finland was from the middle of June to the end of July and that warm summer weather was associated with reindeer flocking behaviour on mosquito-rich wetlands. Conclusions: In the present work, S. tundra vectors and larval development were identified and described for the first time. Aedes spp. mosquitoes likely serve as the most important and competent vectors for S. tundra in Finland. Warm summers apparently promote transmission and genesis of disease outbreaks by favouring the development of S. tundra in its mosquito vectors, by improving the development and longevity of mosquitoes, and finally by forcing the reindeer to flock on mosquito rich wetlands. Thus we predict that global climate change has the potential to promote the further emergence of Filarioid nematodes and the disease caused by them in subarctic regions.

Background: Complications of acute myocardial infarction (AMI) with mechanical defects are associated with poor prognosis. Surgical intervention is indicated for a majority of patients. The goal of surgical intervention is to improve the systolic cardiac function and to achieve a hemodynamic stability. In this present study we reviewed the outcome of patients with post infarction ventricular septal defect (PVSD) who underwent cardiac surgery. Methods: We analysed retrospectively the hospital records of 41 patients, whose ages range from 48 to 81, and underwent a surgical treatment between 1990 and 2005 because of PVSD. Results: In 22 patients concomitant coronary artery bypass grafting (CAGB) was performed. In 15 patients a residual shunt was found, this required re-op in seven of them. The time interval from infarct to rupture was 8.7 days and from rupture to surgery was 23.1 days. Hospital mortality in PVSD group was 32%. The mortality of urgent repair within 3 days of intractable cardiogenic shock was 100%. The mortality of patients with an anterior VSD and a posterior VSD was 29.6% vs 42.8%, respectively. All patients who underwent the surgical repair later than day 36 survived. Conclusions: Surgical intervention is indicated for a majority of patients with mechanical complications. Cardiogenic shock remains the most important factor that affects the early results. The surgical repair of PVSD should be performed 4-5 weeks after AMI. To improve surgical outcome and hemodynamics the choice of surgical technique and surgical timing as well as preoperative management should be tailored for each patient individually.

Background: Although uncommon, anaphylaxis due to a colloid plasma expander can occur peri-operatively.Case presentationWe present a case of an intra-operative cardiac arrest in a 72 year old Caucasian male patient who underwent prophylactic intramedullary nailing for a proximal femoral metastasis from prostate cancer. The patient was resuscitated successfully and the procedure was completed uneventfully. Elevated serum tryptase levels confirmed the diagnosis of an anaphylactic reaction and positive allergy skin prick testing identified gelofusine as the causative agent. Conclusion: A high index of suspicion, prompt diagnosis and rapid institution of treatment are essential for a safe outcome following such reactions. To our knowledge, this is the first published report of such a severe reaction to gelofusine infusion that occurs during an orthopaedic procedure.

Background: Dengue virus type 1 (DENV-1) have been mostly circulating silently with dominant serotypes DENV-2 and DENV-3 in India. However recent times have marked an increase in DENV-1 circulation in yearly outbreaks. Many studies have not been carried out on this virus type, leaving a lacunae pertaining to the circulating genotypes, since its earliest report in India. In the present study, we sequenced CprM gene junction of 13 DENV-1 isolated from Delhi and Gwalior (North India) between 2001-2007 and one 1956 Vellore isolate as reference. For comparison, we retrieved 11 other Indian and 70 global reference sequences from NCBI database, making sure that Indian and global isolates from all decades are available for comparative analysis. Results: The region was found to be AT rich with no insertion or deletion. Majority of the nucleotide substitutions were silent, except 3 non-conservative amino acid changes (I->T, A->T and L->S at amino acid positions 59,114 and 155 respectively) in the Indian DENV-1 sequences, sequenced in this study. Except two 1997-98 Delhi isolates, which group in genotype I; all other Indian isolates group in genotype III. All Indian genotype III DENV-1 exhibited diversity among them, giving rise to at least 4 distinct lineages (India 1-4) showing proximity to isolates from diverse geographic locations. Conclusion: The extensive phylogenetic analysis revealed consistent existence of multiple lineages of DENV-1 genotype III during the last 5 decades in India.

Background: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. Methods: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis (MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. Results: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. Conclusions: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed.

IntroductionIsolated cases of epicarditis are rare. Thus far, all have occurred with constrictive physiology as most cases involve both parietal and visceral pericardium. We report the first case of asymptomatic epicarditis that involved only the visceral pericardium presenting without constrictive physiology.Case presentationA 71-year-old male with a history of atrial fibrillation, coronary artery disease, pericardial effusion, type-2 diabetes and hypothyroidism presented with 5 weeks of fatigue and 1 day of dizziness. Physical examination was significant for pallor and tachycardia. Laboratory analysis revealed a hemoglobin count of 7.2g/dl and iron deficiency anemia. The patient was transfused and evaluated by endoscopic ultrasound. A polypoid mass in the gastric cardia was found and later diagnosed as gastric adenocarcinoma (staged as T1N0M0). The pericardial effusion was evaluated with transthoracic echocardiography which showed a 2.0 x 2.7cm mass associated with the right atrium. Transesophageal echocardiography confirmed the mass but did not reveal constrictive physiology. Whole-body contrast computed tomography failed to demonstrate metastatic disease. Biopsy of the cardiac mass revealed epicarditis without parietal pericardium involvement. Partial gastrectomy was performed to remove the gastric adenocarcinoma. Conclusions: This is the first reported case of asymptomatic epicarditis. Our case was especially unusual because the epicarditis presented as an incidental cardiac mass. The clinical picture was complicated due to the concomitant presence of gastric adenocarcinoma and chronic pericardial effusion. This case demonstrates that epicarditis should be considered in the differential diagnosis of cardiac masses.