bluuebunny/crossref_metadata_2025 huggingface dataset:
Long term expression of bicistronic vector driven by the FGF-1 IRES in mouse muscle
Authors: Allera-Moreau Camille , Delluc-Clavières Aurélie , Castano Caroline , Van den Berghe Loïc , Golzio Muriel , Moreau Marc , Teissié Justin , Arnal Jean-François , Prats Anne-Catherine
Published: October 2007

Background

Electrotransfer of plasmid DNA into skeletal muscle is a promising strategy for the delivery of therapeutic molecules targeting various muscular diseases, cancer and lower-limb ischemia. Internal Ribosome Entry Sites (IRESs) allow co-expression of proteins of interest from a single transcriptional unit. IRESs are RNA elements that have been found in viral RNAs as well as a variety of cellular mRNAs with long 5' untranslated regions. While the encephalomyocarditis virus (EMCV) IRES is often used in expression vectors, we have shown that the FGF-1 IRES is equally active to drive short term transgene expression in mouse muscle. To compare the ability of the FGF-1 IRES to drive long term expression against the EMCV and FGF-2 IRESs, we performed analyses of expression kinetics using bicistronic vectors that express the bioluminescent renilla and firefly luciferase reporter genes. Long term expression of bicistronic vectors was also compared to that of monocistronic vectors. Bioluminescence was quantified ex vivo using a luminometer and in vivo using a CCD camera that monitors luminescence within live animals.

Results

Our data demonstrate that the efficiency of the FGF-1 IRES is comparable to that of the EMCV IRES for long term expression of bicistronic transgenes in mouse muscle, whereas the FGF-2 IRES has a very poor activity. Interestingly, we show that despite the global decrease of vector expression over time, the ratio of firefly to renilla luciferase remains stable with bicistronic vectors containing the FGF-1 or FGF-2 IRES and is slightly affected with the EMCV IRES, whereas it is clearly unstable for mixed monocistronic vectors. In addition, long term expression more drastically decreases with monocistronic vectors, and is different for single or mixed vector injection.

Conclusion

These data validate the use of bicistronic vectors rather than mixed monocistronic vectors for long term expression, and support the use of the FGF-1 IRES. The use of a cellular IRES over one of viral origin is of particular interest in the goal of eliminating viral sequences from transgenic vectors. In addition, the FGF-1 IRES, compared to the EMCV IRES, has a more stable activity, is shorter in length and more flexible in terms of downstream cloning of second cistrons. Finally, the FGF-1 IRES is very attractive to develop multicistronic expression cassettes for gene transfer in mouse muscle.
A web-based laboratory information system to improve quality of care of tuberculosis patients in Peru: functional requirements, implementation and usage statistics
Authors: Blaya Joaquin A , Shin Sonya S , Yagui Martin JA , Yale Gloria , Suarez Carmen Z , Asencios Luis L , Cegielski J Peter , Fraser Hamish SF
Published: October 2007

Background

Multi-drug resistant tuberculosis patients in resource-poor settings experience large delays in starting appropriate treatment and may not be monitored appropriately due to an overburdened laboratory system, delays in communication of results, and missing or error-prone laboratory data. The objective of this paper is to describe an electronic laboratory information system implemented to alleviate these problems and its expanding use by the Peruvian public sector, as well as examine the broader issues of implementing such systems in resource-poor settings.

Methods

A web-based laboratory information system "e-Chasqui" has been designed and implemented in Peru to improve the timeliness and quality of laboratory data. It was deployed in the national TB laboratory, two regional laboratories and twelve pilot health centres. Using needs assessment and workflow analysis tools, e-Chasqui was designed to provide for improved patient care, increased quality control, and more efficient laboratory monitoring and reporting.

Results

Since its full implementation in March 2006, 29,944 smear microscopy, 31,797 culture and 7,675 drug susceptibility test results have been entered. Over 99% of these results have been viewed online by the health centres. High user satisfaction and heavy use have led to the expansion of e-Chasqui to additional institutions. In total, e-Chasqui will serve a network of institutions providing medical care for over 3.1 million people. The cost to maintain this system is approximately US$0.53 per sample or 1% of the National Peruvian TB program's 2006 budget.

Conclusion

Electronic laboratory information systems have a large potential to improve patient care and public health monitoring in resource-poor settings. Some of the challenges faced in these settings, such as lack of trained personnel, limited transportation, and large coverage areas, are obstacles that a well-designed system can overcome. e-Chasqui has the potential to provide a national TB laboratory network in Peru. Furthermore, the core functionality of e-Chasqui as been implemented in the open source medical record system OpenMRS http://www.openmrs.org for other countries to use.
Measuring global health inequity
Authors: Reidpath Daniel D , Allotey Pascale
Published: October 2007

Background

Notions of equity are fundamental to, and drive much of the current thinking about global health. Health inequity, however, is usually measured using health inequality as a proxy – implicitly conflating equity and equality. Unfortunately measures of global health inequality do not take account of the health inequity associated with the additional, and unfair, encumbrances that poor health status confers on economically deprived populations.

Method

Using global health data from the World Health Organization's 14 mortality sub-regions, a measure of global health inequality (based on a decomposition of the Pietra Ratio) is contrasted with a new measure of global health inequity. The inequity measure weights the inequality data by regional economic capacity (GNP per capita).

Results

The least healthy global sub-region is shown to be around four times worse off under a health inequity analysis than would be revealed under a straight health inequality analysis. In contrast the healthiest sub-region is shown to be about four times better off. The inequity of poor health experienced by poorer regions around the world is significantly worse than a simple analysis of health inequality reveals.

Conclusion

By measuring the inequity and not simply the inequality, the magnitude of the disparity can be factored into future economic and health policy decision making.
Impact of reduced vancomycin susceptibility on the therapeutic outcome of MRSA bloodstream infections
Authors: Neoh Hui-min , Hori Satoshi , Komatsu Mitsutaka , Oguri Toyoko , Takeuchi Fumihiko , Cui Longzhu , Hiramatsu Keiichi
Published: October 2007

Background

The aim of this study was to determine whether clinical outcome of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia was correlated with vancomycin susceptibility of the corresponding strains.

Methods

A retrospective study on MRSA bacteraemia was performed at a teaching hospital between January 1998 and October 2005 by linking vancomycin susceptibility profiles of patients' isolates with hospitalization data.

Results

A total of 20 out of 209 MRSA bacteraemia patients were treated with vancomycin for at least 5 days with adequate trough levels, and fulfilled the study's inclusion and exclusion criteria. Twenty-two S. aureus isolates from these patients' blood cultures were identified as MRSA, including two hetero-VISA from separate patients and two VISA with vancomycin MIC of 4 mg/L from one patient. Between patients who showed 'good' vancomycin response and patients who did not, there was a significant difference (p < 0.01) in their corresponding MRSAs' vancomycin susceptibility expressed by 'area under curve' (AUC) of population analysis. Significant correlations were found between AUC and initial vancomycin therapeutic response parameters of 'days till afebrile' (r = 0.828, p < 0.01) and 'days till CRP ≦ 30% of maximum' (r = 0.627, p < 0.01)

Conclusion

Our study results caution healthcare personnel that early consideration should be given to cases with a poor vancomycin treatment response that could signify the involvement of MRSA with reduced susceptibility to vancomycin.
Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma
Authors: Tsou Jeffrey A , Galler Janice S , Siegmund Kimberly D , Laird Peter W , Turla Sally , Cozen Wendy , Hagen Jeffrey A , Koss Michael N , Laird-Offringa Ite A
Published: October 2007

Background

Lung cancer is the number one cancer killer of both men and women in the United States. Three quarters of lung cancer patients are diagnosed with regionally or distantly disseminated disease; their 5-year survival is only 15%. DNA hypermethylation at promoter CpG islands shows great promise as a cancer-specific marker that would complement visual lung cancer screening tools such as spiral CT, improving early detection. In lung cancer patients, such hypermethylation is detectable in a variety of samples ranging from tumor material to blood and sputum. To date the penetrance of DNA methylation at any single locus has been too low to provide great clinical sensitivity. We used the real-time PCR-based method MethyLight to examine DNA methylation quantitatively at twenty-eight loci in 51 primary human lung adenocarcinomas, 38 adjacent non-tumor lung samples, and 11 lung samples from non-lung cancer patients.

Results

We identified thirteen loci showing significant differential DNA methylation levels between tumor and non-tumor lung; eight of these show highly significant hypermethylation in adenocarcinoma: CDH13, CDKN2A EX2, CDX2, HOXA1, OPCML, RASSF1, SFPR1, and TWIST1 (p-value << 0.0001). Using the current tissue collection and 5-fold cross validation, the four most significant loci (CDKN2A EX2, CDX2, HOXA1 and OPCML) individually distinguish lung adenocarcinoma from non-cancer lung with a sensitivity of 67–86% and specificity of 74–82%. DNA methylation of these loci did not differ significantly based on gender, race, age or tumor stage, indicating their wide applicability as potential lung adenocarcinoma markers. We applied random forests to determine a good classifier based on a subset of our loci and determined that combined use of the same four top markers allows identification of lung cancer tissue from non-lung cancer tissue with 94% sensitivity and 90% specificity.

Conclusion

The identification of eight CpG island loci showing highly significant hypermethylation in lung adenocarcinoma provides strong candidates for evaluation in patient remote media such as plasma and sputum. The four most highly ranked loci, CDKN2A EX2, CDX2, HOXA1 and OPCML, which show significant DNA methylation even in stage IA tumor samples, merit further investigation as some of the most promising lung adenocarcinoma markers identified to date.
Study of molecular mechanisms of pro-apoptotic activity of NCX 4040, a novel nitric oxide-releasing aspirin, in colon cancer cell lines
Authors: Tesei Anna , Rosetti Marco , Ulivi Paola , Fabbri Francesco , Medri Laura , Vannini Ivan , Bolla Manlio , Amadori Dino , Zoli Wainer
Published: October 2007

Background

Despite numerous studies aimed at verifying the antitumor activity of nitric oxide-releasing nonsteroidal antiflammatory drugs (NO-NSAIDs), little is known about the molecular targets responsible for their antineoplastic properties. In the present study, we investigated the mechanisms underlying the cytotoxicity of NCX 4040, a novel NO-aspirin with promising antineoplastic action, inin vitrohuman colon cancer models.

Methods

The effect on tumor growth was evaluated in four human colon cancer cell lines (LoVo, LRWZ, WiDr and LoVo Dx) by sulforhodamine B assay, oxidative stress by immunohistochemistry, apoptosis by laddering assay, mitochondrial membrane potential (ΔΨm) by flow cytometry, and apoptosis- and chemoresistance-related markers by western-blot and real-time method, respectively. Prostaglandin E2levels were determined by ELISA.

Results

NCX 4040 produced a higher cytotoxic effect in all the cell lines than that produced by other NO donors tested. In particular, in LoVo and LRWZ cells, NCX 4040 induced a cytocidal effect and apoptosis through p53 and NAG-1 expression, an early ΔΨmcollapse, and a sequential release of cytoplasmatic cytochrome c and caspase -9 and -3 active forms. 8-hydroxyguanine lesions, indicative of oxidative stress, were also observed. Conversely, in WiDr line, the drug caused a cytocidal effect, albeit not through apoptosis, and a concomitant increase in COX-2 activity. In LoVo Dx line, characterized by high levels drug resistance and DNA repair-related markers, only a cytostatic effect was observed, again in concomitance with the increase in COX-2 enzyme activity.

Conclusion

This study highlights the multiplicity of mechanisms involved in sensitivity or resistance to NCX 4040 and could provide useful indications for tailored therapy by identifying potentially drug-responsive tumors.
Optimal ex vivo expansion of neutrophils from PBSC CD34+ cells by a combination of SCF, Flt3-L and G-CSF and its inhibition by further addition of TPO
Authors: Tura Olga , Barclay G Robin , Roddie Huw , Davies John , Turner Marc L
Published: October 2007

Background

Autologous mobilised peripheral blood stem cell (PBSC) transplantation is now a standard approach in the treatment of haematological diseases to reconstitute haematopoiesis following myeloablative chemotherapy. However, there remains a period of severe neutropenia and thrombocytopenia before haematopoietic reconstitution is achieved. Ex vivo expanded PBSC have been employed as an adjunct to unmanipulated HSC transplantation, but have tended to be produced using complex cytokine mixtures aimed at multilineage (neutrophil and megakaryocyte) progenitor expansion. These have been reported to reduce or abrogate neutropenia but have little major effect on thrombocytopenia. Selective megakaryocyte expansion has been to date ineffective in reducing thrombocytopenia. This study was implemented to evaluate neutrophil specific rather than multilineage ex vivo expansion of PBSC for specifically focusing on reduction or abrogation of neutropenia.

Methods

CD34+ cells (PBSC) were enriched from peripheral blood mononuclear cells following G-CSF-mobilisation and cultured with different permutations of cytokines to determine optimal cytokine combinations and doses for expansion and functional differentiation and maturation of neutrophils and their progenitors. Results were assessed by cell number, morphology, phenotype and function.

Results

A simple cytokine combination, SCF + Flt3-L + G-CSF, synergised to optimally expand and mature neutrophil progenitors assessed by cell number, phenotype, morphology and function (superoxide respiratory burst measured by chemiluminescence). G-CSF appears mandatory for functional maturation. Addition of other commonly employed cytokines, IL-3 and IL-6, had no demonstrable additive effect on numbers or function compared to this optimal combination. Addition of TPO, commonly included in multilineage progenitor expansion for development of megakaryocytes, reduced the maturation of neutrophil progenitors as assessed by number, morphology and function (respiratory burst activity).

Conclusion

Given that platelet transfusion support is available for autologous PBSC transplantation but granulocyte transfusion is generally lacking, and that multilineage expanded PBSC do not reduce thrombocytopenia, we suggest that instead of multilineage expansion selective neutrophil expansion based on this relatively simple cytokine combination might be prioritized for development for clinical use as an adjunct to unmanipulated PBSC transplantation to reduce or abrogate post-transplant neutropenia.
The E5 protein of the human papillomavirus type 16 down-regulates HLA-I surface expression in calnexin-expressing but not in calnexin-deficient cells
Authors: Gruener Myriam , Bravo Ignacio G , Momburg Frank , Alonso Angel , Tomakidi Pascal
Published: October 2007

The human papillomavirus type 16 E5 protein (HPV16 E5) down-regulates surface expression of HLA-I molecules. The molecular mechanisms underlying this effect are so far unknown. Here we show that HPV16 E5 down-regulates HLA-I surface expression in calnexin-containing but not in calnexin-deficient cells. Immunoprecipitation experiments reveal that calnexin and HPV16E5 can be co-precipitated and that this association depends on the presence of a wild-type first hydrophobic region of E5. When an E5 mutant (M1) in which the first putative transmembrane helix had been disrupted was used for the transfections calnexin-E5 co-precipitation was strongly impaired. In addition, we show that the M1 mutant is only able to marginally down-regulate HLA-I surface expression compared to the wild-type protein. Besides, we demonstrate that E5 forms a ternary complex with calnexin and the heavy chain of HLA-I, which is mediated by the first hydrophobic region of the E5 protein. On the basis of our results we conclude that formation of this complex is responsible for retention of HLA-I molecules in the ER of the cells.
Neurokinin-1 (NK-1) Receptor and Brain-Derived Neurotrophic Factor (BDNF) Gene Expression is Differentially Modulated in the Rat Spinal Dorsal Horn and Hippocampus During Inflammatory Pain
Authors: Duric Vanja , McCarson Kenneth E
Published: October 2007

Persistent pain produces complex alterations in sensory pathways of the central nervous system (CNS) through activation of various nociceptive mechanisms. However, the effects of pain on higher brain centers, particularly the influence of the stressful component of pain on the limbic system, are poorly understood. Neurokinin-1 (NK-1) receptors and brain-derived neurotrophic factor (BDNF), known neuromediators of hyperalgesia and spinal central sensitization, have also been implicated in the plasticity and neurodegeneration occurring in the hippocampal formation during exposures to various stressors. Results of this study showed that injections of complete Freund's adjuvant (CFA) into the hind paw increased NK-1 receptor and BDNF mRNA levels in the ipsilateral dorsal horn, supporting an important role for these nociceptive mediators in the amplification of ascending pain signaling. An opposite effect was observed in the hippocampus, where CFA down-regulated NK-1 receptor and BDNF gene expression, phenomena previously observed in immobilization models of stress and depression. Western blot analyses demonstrated that in the spinal cord, CFA also increased levels of phosphorylated cAMP response element-binding protein (CREB), while in the hippocampus the activation of this transcription factor was significantly reduced, further suggesting that tissue specific transcription of either NK-1 or BDNF genes may be partially regulated by common intracellular transduction mechanisms mediated through activation of CREB. These findings suggest that persistent nociception induces differential regional regulation of NK-1 receptor and BDNF gene expression and CREB activation in the CNS, potentially reflecting varied roles of these neuromodulators in the spinal cord during persistent sensory activation vs. modulation of the higher brain structures such as the hippocampus.
Depression and anxiety in epilepsy: the association with demographic and seizure-related variables
Authors: Kimiskidis Vasilios K , Triantafyllou Nikolaos I , Kararizou Eleni , Gatzonis Stergios-Stylianos , Fountoulakis Konstantinos N , Siatouni Anna , Loucaidis Panagiotis , Pseftogianni Dimitra , Vlaikidis Nikolaos , Kaprinis George S
Published: October 2007

Background

Depression and anxiety are common psychiatric symptoms in patients with epilepsy, exerting a profound negative effect on health-related quality of life. Several issues, however, pertaining to their association with psychosocial, seizure-related and medication factors, remain controversial. Accordingly, the present study was designed to investigate the association of interictal mood disorders with various demographic and seizure-related variables in patients with newly-diagnosed and chronic epilepsy.

Methods

We investigated 201 patients with epilepsy (51.2% males, mean age 33.2 ± 10.0 years, range 16–60) with a mean disease duration of 13.9 ± 9.5 years. Depression and anxiety were assessed in the interictal state with the Beck Depression Inventory, 21-item version (BDI-21) and the state and trait subscales of the State-Trait Anxiety Inventory (STAI-S and STAI-T), respectively. The association of mood disorders with various variables was investigated with simple and multiple linear regression analyses.

Results

High seizure frequency and symptomatic focal epilepsy (SFE) were independent determinants of depression, together accounting for 12.4% of the variation of the BDI-21. The STAI-S index was significantly associated with the type of epilepsy syndrome (SFE). Finally, high seizure frequency, SFE and female gender were independent determinants of trait anxiety accounting for 14.7% of the variation of the STAI-T.

Conclusion

Our results confirm the prevailing view that depression and anxiety are common psychological disorders in epileptics. It is additionally concluded that female gender, high seizure frequency and a symptomatic epilepsy syndrome are independent risk factors for the development of anxiety and/or depression.
Factors that help injecting drug users to access and benefit from services: A qualitative study
Authors: Neale Joanne , sheard Laura , Tompkins Charlotte NE
Published: October 2007

Background

International research shows that injecting drug users (IDUs) can encounter many barriers when they try to access drug treatment and other services. However, the existing literature is mostly quantitative and does not consider the kinds of factors that injectors themselves identify as enabling them to access and benefit from services. Responding to this gap in knowledge, our paper explores IDUs' own suggestions for improving service engagement and their reports of other factors enabling them to seek help.

Methods

Semi-structured qualitative interviews were conducted with 75 current illicit drug injectors in three geographically diverse areas of West Yorkshire, England. Recruitment was through needle exchange programmes, with additional snowball sampling to ensure inclusivity of gender, ethnicity and primary drug injected. Transcribed data were analysed thematically using Framework.

Results

Although participants were often satisfied with current access to services, they made three broad suggestions for improving engagement. These were: providing more services (more providers and more forms of support); better operation of existing services (including better communication systems and more flexibility around individual needs); and staffing-related improvements (particularly, less judgemental and more understanding staff attitudes). Other factors identified as important enablers of help seeking were: having supporting relationships (particularly with family members); personal circumstances/life events (especially becoming a parent); and an injector's state of mind (such as feeling motivated and positive).

Conclusion

A range of practical suggestions for improving IDUs' access to drug treatment and other services are identified.
Unilateral pedicle screws asymmetric tethering: an innovative method to create idiopathic deformity
Authors: Zhang Yonggang , Wang Yan , Zheng Guoquan , Zhang Xuesong , Zhang Ruyi , Zhang Wei
Published: October 2007

Objective

To evaluate the feasibility of the method that unilateral pedicle screws asymmetric tethering in concave side in combination with convex rib resection for creating idiopathic deformity.

Summary of background data

Various methods are performed to create idiopathic deformity. Among these methods, posterior asmmetric tethering of the spine shows satisfying result, but some drawbacks related to the current posterior asymmetric tether were still evident.

Materials and methods

Unilateral pedicle screws asymmetric tethering was performed to 14 female goats (age: 5–8 week-old, weight: 6–8 kg) in concave side in combination with convex rib resection. Dorsoventral and lateral plain radiographs were taken of each thoracic spine in the frontal and sagittal planes right after the surgery and later every 4 weeks.

Results

All animals ambulated freely after surgery. For technical reasons, 2 goats were excluded (one animal died for anesthetic during the surgery, and one animal was lost for instrumental fail due to postoperative infection). Radiography showed that 11 goats exhibited scoliosis with convex toward to the right side, and as the curve increased with time, only 1 goat showed nonprogressive. The initial scoliosis generated in the progressors after the procedures measured 29.0° on average (range 23.0°–38.5°) and increased to 43.0° on average (range 36.0°–58.0°) over 8 to 10 weeks. The average progression of 14.0° was measured. The curvature immediately after tethering surgery (the initial Cobb angle) did have a highly significant correlation with the final curvature (p < 0.001). The progressive goats showed an idiopathic-like deformity not only by radiography, but in general appearance.

Conclusion

Unilateral pedicle screws asymmetric tethering is a practical method to create experimental scoliosis, especially for those who would like to study the correction of this deformity.
Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism
Authors: Bron Romke , Vermeren Matthieu , Kokot Natalie , Andrews William , Little Graham E , Mitchell Kevin J , Cohen James
Published: October 2007

Background

In developing neurons, somal migration and initiation of axon outgrowth often occur simultaneously and are regulated in part by similar classes of molecules. When neurons reach their final destinations, however, somal translocation and axon extension are uncoupled. Insights into the mechanisms underlying this process of disengagement came from our study of the behaviour of embryonic spinal motor neurons following ablation of boundary cap cells. These are neural crest derivatives that transiently reside at motor exit points, central nervous system (CNS):peripheral nervous system (PNS) interfaces where motor axons leave the CNS. In the absence of boundary cap cells, motor neuron cell bodies migrate along their axons into the periphery, suggesting that repellent signals from boundary cap cells regulate the selective gating of somal migration and axon outgrowth at the motor exit point. Here we used RNA interference in the chick embryo together with analysis of null mutant mice to identify possible boundary cap cell ligands, their receptors on motor neurons and cytoplasmic signalling molecules that control this process.

Results

We demonstrate that targeted knock down in motor neurons of Neuropilin-2 (Npn-2), a high affinity receptor for class 3 semaphorins, causes their somata to migrate to ectopic positions in ventral nerve roots. This finding was corroborated in Npn-2 null mice, in which we identified motor neuron cell bodies in ectopic positions in the PNS. Our RNA interference studies further revealed a role for Plexin-A2, but not Plexin-A1 or Plexin-A4. We show that chick and mouse boundary cap cells express Sema3B and 3G, secreted semaphorins, and Sema6A, a transmembrane semaphorin. However, no increased numbers of ectopic motor neurons are found in Sema3B null mouse embryos. In contrast, Sema6A null mice display an ectopic motor neuron phenotype. Finally, knockdown of MICAL3, a downstream semaphorin/Plexin-A signalling molecule, in chick motor neurons led to their ectopic positioning in the PNS.

Conclusion

We conclude that semaphorin-mediated repellent interactions between boundary cap cells and immature spinal motor neurons regulates somal positioning by countering the drag exerted on motor neuron cell bodies by their axons as they emerge from the CNS at motor exit points. Our data support a model in which BC cell semaphorins signal through Npn-2 and/or Plexin-A2 receptors on motor neurons via a cytoplasmic effector, MICAL3, to trigger cytoskeletal reorganisation. This leads to the disengagement of somal migration from axon extension and the confinement of motor neuron cell bodies to the spinal cord.
Community-acquired Klebsiella pneumoniae meningitis in an alcoholic patient with an infected pancreatic pseudocyst; a case report and review of literature
Authors: Orzechowska Adriana , Lacey Sandra , Soosay Geraldine , Melzer Mark
Published: October 2007

We report a case of a 49-year-old male with a history of chronic alcoholism and evidence of a pancreatic pseudocyst on CT scanning. He presented with a 3-days history of fever, loss of appetite and upper abdominal pain. Blood cultures grew Klebsiella pneumoniae and he improved clinically with a seven-day course of intravenous co-amoxiclav and metronidazole. Two weeks later he was readmitted to hospital with impaired consciousness and septic shock, and died three days later in intensive care. Post mortem examination revealed bacterial meningitis and an infected pancreatic pseudocyst. Klebsiella pneumoniae was isolated from the pancreas and meninges.
Atypical haemolytic uraemic syndrome presenting initially as suspected meningococcal disease: a case report
Authors: Sivamurthy Siddharthan , Mooney John D , Kenny Tom D
Published: October 2007

Background

Haemolytic uraemic syndrome (HUS) is the most common cause of acute renal failure in children and is usually linked with Escherichia coli O157 infection. With a fatality rate of around 5%, some reports have associated antibiotic treatment with a worsening prognosis.

Case Presentation

We describe a female infant patient, initially treated for suspected meningococcal septicaemia, who went on to develop renal complications and thrombocytopenia characteristic of HUS. A subsequent positive stool sample for E. coli O157 confirmed HUS as an appropriate diagnosis, although there was no evidence of diarrhoea or vomiting throughout the course of her management.

Conclusion

The urgency of early recognition and treatment for suspected meningococcal disease in very young children while entirely appropriate can initially divert attention from other serious conditions. Evidence of infection with E. coli O157 infection in this case also highlights what can be a blurred distinction between atypical (non-diarrhoeal) HUS from classical HUS of infective origin.
Analysis of C4 and the C4 binding protein in the MRL/lpr mouse
Authors: Wenderfer Scott E , Soimo Kipruto , Wetsel Rick A , Braun Michael C
Published: October 2007

Systemic lupus erythematosus is a complement-mediated autoimmune disease. While genetic deficiencies of classical pathway components lead to an increased risk of developing systemic lupus erythematosus, end organ damage is associated with complement activation and immune complex deposition. The role of classical pathway regulators in systemic lupus erythematosus is unknown. C4 binding protein (C4bp) is a major negative regulator of the classical pathway. In order to study the role of C4bp deficiency in an established murine model of lupus nephritis, mice with a targeted deletion in the gene encoding C4bp were backcrossed into the MRL/lpr genetic background. Compared with control MRL/lpr mice, C4bp knockout MLR/lpr mice had similar mortality and similar degrees of lymphoproliferation. There were no differences in the extent of proteinuria or renal inflammation. Staining for complement proteins and immunoglobulins in the kidneys of diseased mice revealed no significant strain differences. Moreover, there was no difference in autoantibody production or in levels of circulating immune complexes. In comparison with C57BL/6 mice, MRL/lpr mice had depressed C4 levels as early as 3 weeks of age. The absence of C4bp did not impact serum C4 levels or alter classical pathway hemolytic activity. Given that immune complex renal injury in the MRL/lpr mouse is independent of Fc receptors as well as the major negative regulator of the classical pathway, new mechanisms for immune-complex-mediated renal injury need to be considered.
Cellular turnover and expression of hypoxic-inducible factor in acute acalculous and calculous cholecystitis
Authors: Vakkala Merja , Laurila Jouko J , Saarnio Juha , Koivukangas Vesa , Syrjälä Hannu , Karttunen Tuomo , Soini Ylermi , Ala-Kokko Tero I
Published: October 2007

Introduction

Epithelial corrective and destructive mechanisms have not been studied in inflammatory gallbladder disease.

Methods

Epithelial apoptosis, cell proliferation and expression of hypoxia-inducible factor (HIF)-1α were compared in gallbladders from patients with acute acalculous cholecystitis (AAC; n = 30) and acute calculous cholecystitis (ACC; n = 21), and from patients undergoing surgery for other reasons (normal gallbladders; n = 9), which were removed during open cholecystectomy. The immunohistochemical stains included antibodies to Ki-67 (proliferation), M30 (apoptosis) and HIF-1α. Proliferation and apoptosis were expressed as percentages of positive cells. HIF-1α expression was expressed as absent, weak, or strong.

Results

Apoptosis (median [25th to 75th percentile]) was significantly increased in AAC (1.31% [0.75% to 1.8%], P < 0.001) and ACC (1.10% [0.63% to 1.64%], P = 0.001), compared with control samples (0.20% [0.07% to 0.45%]. The proliferation rate was significantly increased in AAC (8.0% [4.0% to 17.0%], P < 0.001) and ACC (14% [7.5% to 26.5%], P = 0.001) compared with control samples (1.0% [1.0% to 3.0%]). Strong HIF-1α staining was observed in 57% of AAC, in 100% of ACC and in 44% of control specimens (P < 0.001). Intense HIF-1α expression was associated with increased cell proliferation (P = 0.002).

Conclusion

Cell proliferation and apoptosis were increased in AAC and ACC, as compared with normal gallbladders. Expression of HIF-1α was lower in AAC than in ACC.
Cortisol and post-traumatic stress disorder in adults
Authors: Meewisse Marie-Louise , Reitsma Johannes B. , De Vries Giel-Jan , Gersons Berthold P. R. , Olff Miranda
Published: October 2007

Background

Post-traumatic stress disorder (PTSD) has inconsistently been associated with lower levels of cortisol.

Aims

To compare basal cortisol levels in adults with current PTSD and in people without psychiatric disorder.

Method

Systematic review and meta-analysis. Standardised mean differences (SMD) in basal cortisol levels were calculated and random-effects models using inverse variance weighting were applied.

Results

Across 37 studies, 828 people with PTSD and 800 controls did not differ in cortisol levels (pooled SMD = −0.12, 95% C1= −0.32 to 0.080). Subgroup analyses revealed that studies assessing plasma or serum showed significantly lower levels in people with PTSD than in controls not exposed to trauma. Lower levels were also found in people with PTSD when females were included, in studies on physical or sexual abuse, and in afternoon samples.

Conclusions

Low cortisol levels in PTSD are only found under certain conditions. Future research should elucidate whether low cortisol is related to gender or abuse and depends on the measurement methods used.
Effects of treating postnatal depression on mother-infant interaction and child development
Authors: Poobalan Amudha S. , Aucott Lorna S. , Ross Louise , Smith W. Cairns. S. , Helms Peter J. , Williams Justin H. G.
Published: October 2007

Background

Postnatal depression has detrimental effects on the child's cognitive and emotional development.

Aims

To assess the benefits of treating postnatal depression for mother–infant interaction and child development.

Method

A systematic search was made of 12 electronic bibliographic databases for randomised controlled trials and controlled clinical trials on treatment of mothers with postnatal depression, where outcomes were assessed in children; findings were assessed.

Results

Only eighttrials met the inclusion criteria. Of those included, interventions varied widely but all involved therapies directed at the mother–infant relationship. One study with intensive and prolonged therapy showed cognitive improvement, whereas two others with briefer interventions improved maternal–infant relationships but did not affect the child's cognitive or behavioural development. All five studies assessing only mother–infant relationships showed improvements.

Conclusions

Cognitive development in children of depressed mothers, along with better mother–infant relationships, might be improved with sustained interventions. Trials assessing treatments for postnatal depression would benefit from looking more closely at benefits for children as well as mothers, using validated objective measures.
Structured patient–clinician communication and 1-year outcome in community mental healthcare
Authors: Priebe Stefan , McCabe Rosemarie , Bullenkamp Jens , Hansson Lars , Lauber Christoph , Martinez-Leal Rafael , Rössler Wulf , Salize Hans , Svensson Bengt , Torres-Gonzales Francisco , Van Den Brink Rob , Wiersma Durk , Wright Donna J.
Published: October 2007

Background

Patient–clinician communication is central to mental healthcare but neglected in research.

Aims

To test a new computer-mediated intervention structuring patient–clinician dialogue (DIALOG) focusing on patients' quality of life and needs for care.

Method

In a cluster randomised controlled trial, 134 keyworkers in six countries were allocated to DIALOG or treatment as usual; 507 people with schizophrenia or related disorders were included. Every 2 months for 1 year, clinicians asked patients to rate satisfaction with quality of life and treatment, and request additional or different support. Responses were fed back immediately in screen displays, compared with previous ratings and discussed. Primary outcome was subjective quality of life, and secondary outcomes were unmet needs and treatment satisfaction.

Results

Of 507 patients, 56 were lost to follow-up and 451 were included in intention-to-treat analyses. Patients receiving the DIALOG intervention had better subjective quality of life, fewer unmet needs and higher treatment satisfaction after 12 months.

Conclusions

Structuring patient–clinician dialogue to focus on patients' views positively influenced quality of life, needs for care and treatment satisfaction.
Foundation programme assessment tools in psychiatry
Authors: Naeem Asim , Kent Andrew , Vijayakrishnan Ajay
Published: October 2007

In line with Modernising Medical Careers (Department of Health, 2003), the foundation year programme aims to bridge the gap between undergraduate and specialist training. Psychiatry posts have been incorporated into the second year of this programme, with satisfactory progress of doctors being monitored via a range of workplace-based assessment tools. Learning that occurs in the context of the daily workplace is more likely to be relevant and reinforced, leading to better practice (Davis et al, 1995).
Oxygen, Hypoxia, and Stress
Authors: TAYLOR CORMAC T. , POUYSSEGUR JACQUES
Published: October 2007

Abstract:  Since cyanobacteria began to photosynthesize and introduce the colorless and odorless gas oxygen into the earth's atmosphere some 2.5 billion years ago, human evolution has been intrinsically linked to this critical molecule. Initially, the electrophilic chemical properties of oxygen rendered it a formidable toxic challenge to organisms; however, eukaryotic cells, following the incorporation of bacterial‐derived mitochondria, evolved to make beneficial use of the chemical properties of molecular oxygen as the final electron acceptor in the highly efficient production of cellular energy supplies in the form of adenosine triphosphate. Because of both its necessity for eukaryotic life and its reactive chemical nature, however, a delicate balance exists between the supply of oxygen to a cell/tissue/organism and the beneficial or harmful outcome. In this minireview, we shall discuss the role of oxygen in metabolism with a particular emphasis on outcomes when oxygen supply is significantly altered. Furthermore, we will describe endogenous mechanisms that have evolved to protect cells and tissues during such adverse conditions and may prove useful as novel therapeutic targets in a range of disease states where oxygen‐related stress occurs.
Heat Shock Factors at a Crossroad between Stress and Development
Authors: ÅKERFELT MALIN , TROUILLET DIANE , MEZGER VALÉRIE , SISTONEN LEA
Published: October 2007

Abstract:  Organisms must be able to sense and respond rapidly to changes in their environment in order to maintain homeostasis and survive. Induction of heat shock proteins (Hsps) is a common cellular defense mechanism for promoting survival in response to various stress stimuli. Heat shock factors (HSFs) are transcriptional regulators of Hsps, which function as molecular chaperones in protecting cells against proteotoxic damage. Mammals have three different HSFs that have been considered functionally distinct: HSF1 is essential for the heat shock response and is also required for developmental processes, whereas HSF2 and HSF4 are important for differentiation and development. Specifically, HSF2 is involved in corticogenesis and spermatogenesis, and HSF4 is needed for maintenance of sensory organs, such as the lens and the olfactory epithelium. Recent evidence, however, suggests a functional interplay between HSF1 and HSF2 in the regulation of Hsp expression under stress conditions. In lens formation, HSF1 and HSF4 have been shown to have opposite effects on gene expression. In this chapter, we present the different roles of the mammalian HSFs as regulators of cellular stress and developmental processes. We highlight the interaction between different HSFs and discuss the discoveries of novel target genes in addition to the classical Hsps.
Chronic Stress and Social Changes
Authors: KOPP MÁRIA S. , SKRABSKI ÁRPÁD , SZÉKELY ANDRÁS , STAUDER ADRIENNE , WILLIAMS REDFORD
Published: October 2007

Abstract:  In the last decades in the transforming societies of Central and Eastern Europe, premature mortality increased dramatically, especially among men. Increasing disparities in socioeconomic conditions have been accompanied by a widening socioeconomic gradient in mortality among men. Social cohesion and meaning in life may help to counterbalance the widening gap in material circumstances. Not the difficult social situation in itself, but the subjective experience of relative disadvantage, the prolonged negative emotional state, that is, chronic stress seems to be the most important risk factor. The health consequences of a low socioeconomic situation among men might be mostly explained by chronic stress caused by work and close‐partner–related factors, and the toxic components of this interaction are depression and hopelessness. In the case of women, the broader personal and family relations are the most important health‐related factors. Weekend workload, low social support at work and low control at work accounted for a large part of variation in male premature cardiovascular mortality rates, whereas job insecurity, high weekend workload, and low control at work contribute most markedly to variations in premature cardiovascular mortality rates among women. There are two general approaches that scientists and practitioners might take: train individuals and groups to use skills that will enable them to cope better with the stressful conditions that are damaging their health; and lobby governments to adopt policies that will result in decreased chronic stress on the societal level.
Endoplasmic Reticulum Stress
Authors: BÁNHEGYI GÁBOR , BAUMEISTER PETER , BENEDETTI ANGELO , DONG DEZHENG , FU YONG , LEE AMY S. , LI JIANZE , MAO CHANGHUI , MARGITTAI ÉVA , NI MIN , PASCHEN WULF , PICCIRELLA SIMONA , SENESI SILVIA , SITIA ROBERTO , WANG MIAO , YANG WEI
Published: October 2007

Abstract:  Stress is the imbalance of homeostasis, which can be sensed even at the subcellular level. The stress‐sensing capability of various organelles including the endoplasmic reticulum (ER) has been described. It has become evident that acute or prolonged ER stress plays an important role in many human diseases; especially those involving organs/tissues specialized in protein secretion. This article summarizes the emerging role of ER stress in diverse human pathophysiological conditions such as carcinogenesis and tumor progression, cerebral ischemia, plasma cell maturation and apoptosis, obesity, insulin resistance, and type 2 diabetes. Certain components of the ER stress response machinery are identified as biomarkers of the diseases or as possible targets for therapeutic intervention.
Heavy Metal Ions in Normal Physiology, Toxic Stress, and Cytoprotection
Authors: LYNES MICHAEL A. , KANG Y. JAMES , SENSI STEFANO L. , PERDRIZET GEORGE A. , HIGHTOWER LAWRENCE E.
Published: October 2007

Abstract:  As a group, heavy metals include both those essential for normal biological functioning (e.g., Cu and Zn), and nonessential metals (e.g., Cd, Hg, and Pb). Both essential and nonessential metals can be present at concentrations that disturb normal biological functions, and which evoke cellular stress responses. The cellular targets for metal toxicity include tissues of the kidney, liver, heart, and the immune response and nervous systems. Intriguingly, manipulations of specific metals, their reservoirs, and the cellular stress response can have therapeutic effects on certain diseases. In this minireview, we will consider both the biological responses to stressful levels of heavy metal cations, and experimental and clinical manipulations of these cations as a means to improve human health parameters.
Drugging the Cancer Chaperone HSP90
Authors: WORKMAN PAUL , BURROWS FRANCIS , NECKERS LEN , ROSEN NEAL
Published: October 2007

Abstract:  The molecular chaperone HSP90 has emerged as an exciting target for cancer treatment. We review the potential advantages of HSP90 inhibitors, particularly the simultaneous combinatorial depletion of multiple oncogenic “client” proteins, leading to blockade of many cancer‐causing pathways and the antagonism of all of the hallmark pathological traits of malignancy. Cancer selectivity is achieved by exploiting cancer “dependencies,” including oncogene addiction and the stressed state of malignant cells. The multiple downstream effects of HSP90 inhibitors should make the development of resistance more difficult than with agents having more restricted effects. We review the various classes of HSP90 inhibitor that have been developed, including the natural products geldanamycin and radicicol and also the purine scaffold and pyrazole/isoxazole class of synthetic small molecule inhibitors. A first‐in‐class HSP90 drug, the geldanamycin analog 17‐AAG, has provided proof of concept for HSP90 inhibition in patients at well tolerated doses and therapeutic activity has been seen. Other inhibitors show promise in preclinical and clinical development. Opportunities and challenges for HSP90 inhibitors are discussed, including use in combination with other agents. Most of the current HSP90 inhibitors act by blocking the essential nucleotide binding and ATPase activity required for chaperone function. Potential new approaches are discussed, for example, interference with cochaperone binding and function in the superchaperone complex. Biomarkers for use with HSP90 inhibitors are described. We stress how basic and translational research has been mutually beneficial and indicate future directions to enhance our understanding of molecular chaperones and their exploitation in cancer and other diseases.