bluuebunny/crossref_metadata_2025 huggingface dataset:
Rationale and design of The Delphi Trial – I(RCT)2: international randomized clinical trial of rheumatoid craniocervical treatment, an intervention-prognostic trial comparing 'early' surgery with conservative treatment [ISRCTN65076841]
Authors: Wolfs Jasper FC , Peul Wilco C , Boers Maarten , van Tulder Maurits W , Brand Ronald , van Houwelingen Hans JC , Thomeer Raph TWM
Published: February 2006

Background

Rheumatoid arthritis is a chronic inflammatory disease, which affects 1% of the population. Hands and feet are most commonly involved followed by the cervical spine. The spinal column consists of vertebrae stabilized by an intricate network of ligaments. Especially in the upper cervical spine, rheumatoid arthritis can cause degeneration of these ligaments, causing laxity, instability and subluxation of the vertebral bodies. Subsequent compression of the spinal cord and medulla oblongata can cause severe neurological deficits and even sudden death. Once neurological deficits occur, progression is inevitable although the rapidity of progression is highly variable. The first signs and symptoms are pain at the back of the head caused by compression of the major occipital nerve, followed by loss of strength of arms and legs. The severity of the subluxation can be observed with radiological investigations (MRI, CT) with a high sensitivity.

The authors have sent a Delphi Questionnaire about the current treatment strategies of craniocervical involvement by rheumatoid arthritis to an international forum of expert rheumatologists and surgeons. The timing of surgery in patients with radiographic instability without evidence of neurological deficit is an area of considerable controversy. If signs and symptoms of myelopathy are present there is little chance of recovery to normal levels after surgery.

Design

In this international multicenter randomized clinical trial, early surgical atlantoaxial fixation in patients with rheumatoid arthritis and radiological abnormalities without neurological deficits will be compared with prolonged conservative treatment. The main research question is whether early surgery can prevent radiological and neurological progression. A cost-effectivity analysis will be performed. 250 patients are needed to answer the research question.

Discussion

Early surgery could prevent serious neurological deficits, but may have peri-operative morbidity and loss of rotation of the head and neck. The objective of this study is to identify the best timing of surgery for patients at risk for the development of neurological signs and symptoms.
Idiopathic sclerosing encapsulating peritonitis (or abdominal cocoon)
Authors: Serafimidis Costas , Katsarolis Ioannis , Vernadakis Spyros , Rallis George , Giannopoulos George , Legakis Nikolaos , Peros George
Published: February 2006

Background

Idiopathic sclerosing encapsulating peritonitis (or abdominal cocoon) is a rare cause of small bowel obstruction, especially in adult population. Diagnosis is usually incidental at laparotomy. We discuss one such rare case, outlining the fact that an intra-operative surprise diagnosis could have been facilitated by previous investigations.

Case presentation

A 56 year-old man presented in A&E department with small bowel ileus. He had a history of 6 similar episodes of small bowel obstruction in the past 4 years, which resolved with conservative treatment. Pre-operative work-up did not reveal any specific etiology. At laparotomy, a fibrous capsule was revealed, in which small bowel loops were encased, with the presence of interloop adhesions. A diagnosis of abdominal cocoon was established and extensive adhesiolysis was performed. The patient had an uneventful recovery and follow-up.

Conclusion

Idiopathic sclerosing encapsulating peritonitis, although rare, may be the cause of a common surgical emergency such as small bowel ileus, especially in cases with attacks of non-strangulating obstruction in the same individual. A high index of clinical suspicion may be generated by the recurrent character of small bowel ileus combined with relevant imaging findings and lack of other plausible etiologies. Clinicians must rigorously pursue a preoperative diagnosis, as it may prevent a "surprise" upon laparotomy and result in proper management.
Comparison between two methods of working length determination and its effect on radiographic extent of root canal filling: a clinical study [ISRCTN71486641]
Authors: Smadi L
Published: February 2006

Background

Obtaining a correct working length is critical to the success of endodontic therapy. Different methods have been used to identify this crucial measurement. The Aim of this clinical study was to compare the effect of working length determination using apex locator alone or in combination with working length radiograph on the apical extent of root canal filling.

Methods

A total number of 66 patients, 151 canals were randomized into two groups, In group (I) working length was determined by apex locator alone, while in group (II) working length was determined by apex locator confirmed by working length radiograph, length of obturation was assessed, and the total number of radiographs was recorded. The data were analyzed using SAS system and T. tests were carried out. Statistical significance was considered to be P ≤ 0.05.

Results

Sixty seven canals in group I were treated with a mean distance from the tip of root canal filling to radiographic apex -0.5 mm ± 0.5 and a mean of a total number of radiographs of 2.0, while in group II eighty four canals were treated with a mean distance from the tip of root canal filling to radiographic apex -0.4 mm ± 0.5 and a mean of a total number of radiographs of 3.2. There was no statistically significant difference in the mean distance from the tip of root filling to radiographic apex between group I and group II (P > 0.05).

Conclusion

The practice of using electronic apex locator in the determination of working length is useful and reliable with no statistical difference of the radiographic extent of root canal filling when using apex locator alone or in combination with working length radiograph. Under the clinical conditions of this study, it is suggested that the correct use of an apex locator alone could prevent the need for further diagnostic radiographs for determination of working length. This method can be useful in patients who need not to be exposed to repeated radiation because of mental, medical or oral conditions.
The pattern of symptoms in patients receiving home based care in Bangwe, Malawi : a descriptive study
Authors: Bowie Cameron , Kalilane Linda , Cleary Paul , Bowie Claire
Published: February 2006

Background

Home based care of HIV/AIDS patients is a health need recommended but not often available in Africa. Population based assessment helps to identify unmet health needs to plan services. Careful assessment and follow up of patients receiving home based care in a defined population of Bangwe, Malawi provides details of the frequency and severity of common symptoms.

Methods

Mortality and the incidence, duration and severity of common symptoms of patients in a defined population receiving home based care were measured over an eighteen month period.

Results

358 patients, of whom 199 died, were studied. A third of patients died within 4 months of being first seen. About half the patients were unable to care for themselves on first assessment. Half were malnourished with a Body Mass Index (BMI) < 18.5 kg/m2. Most patients had a mixture of symptoms at presentation. These symptoms responded to treatment usually within a fortnight. However a small proportion (5%) of patients suffered repeated episodes often as many as 6–9 times a year. Incidence rates are estimated.

Conclusion

Symptoms which are alleviated by simple treatments are common. The patients in whom symptoms recur need a responsive home based care service. Population based estimates of incidence and duration of disease and the visit work load allow an assessment of home based care needs in an urban setting in Africa.
Using Ontario's "Telehealth" health telephone helpline as an early-warning system: a study protocol
Authors: Rolland Elizabeth , Moore Kieran M , Robinson Victoria A , McGuinness Don
Published: February 2006

Background

The science of syndromic surveillance is still very much in its infancy. While a number of syndromic surveillance systems are being evaluated in the US, very few have had success thus far in predicting an infectious disease event. Furthermore, to date, the majority of syndromic surveillance systems have been based primarily in emergency department settings, with varying levels of enhancement from other data sources. While research has been done on the value of telephone helplines on health care use and patient satisfaction, very few projects have looked at using a telephone helpline as a source of data for syndromic surveillance, and none have been attempted in Canada. The notable exception to this statement has been in the UK where research using the national NHS Direct system as a syndromic surveillance tool has been conducted.

Methods/design

The purpose of our proposed study is to evaluate the effectiveness of Ontario's telephone nursing helpline system as a real-time syndromic surveillance system, and how its implementation, if successful, would have an impact on outbreak event detection in Ontario. Using data collected retrospectively, all "reasons for call" and assigned algorithms will be linked to a syndrome category. Using different analytic methods, normal thresholds for the different syndromes will be ascertained. This will allow for the evaluation of the system's sensitivity, specificity and positive predictive value. The next step will include the prospective monitoring of syndromic activity, both temporally and spatially.

Discussion

As this is a study protocol, there are currently no results to report. However, this study has been granted ethical approval, and is now being implemented. It is our hope that this syndromic surveillance system will display high sensitivity and specificity in detecting true outbreaks within Ontario, before they are detected by conventional surveillance systems. Future results will be published in peer-reviewed journals so as to contribute to the growing body of evidence on syndromic surveillance, while also providing an non US-centric perspective.
Cancer: looking for simplicity and finding complexity
Authors: Grizzi Fabio , Chiriva-Internati Maurizio
Published: February 2006

Cancer is one of the most complex dynamic human disease. Despite rapid advances in the fields of molecular and cell biology, it is still widely debated as to how neoplastic cells progress through carcinogenesis and acquire their metastatic ability. The need to find a new way of observing anatomical entities and their underlying processes, and measuring the changes they undergo, prompted us to investigate theTheory of Complexity, and to apply its principles to human cancer. Viewing a neoplasm as a system that is complex intimeandspaceit is likely to reveal more about its behavioral characteristics, and this manner of thinking may help to clarify concepts, interpret experimental data, indicate specific experiments and categorize the rich body of knowledge on the basis of the similarities and/or shared behaviors of very different tumors.
Landscape determinants and remote sensing of anopheline mosquito larval habitats in the western Kenya highlands
Authors: Mushinzimana Emmanuel , Munga Stephen , Minakawa Noboru , Li Li , Feng Chen-chieh , Bian Ling , Kitron Uriel , Schmidt Cindy , Beck Louisa , Zhou Guofa , Githeko Andrew K , Yan Guiyun
Published: February 2006

Background

In the past two decades the east African highlands have experienced several major malaria epidemics. Currently there is a renewed interest in exploring the possibility of anopheline larval control through environmental management or larvicide as an additional means of reducing malaria transmission in Africa. This study examined the landscape determinants of anopheline mosquito larval habitats and usefulness of remote sensing in identifying these habitats in western Kenya highlands.

Methods

Panchromatic aerial photos, Ikonos and Landsat Thematic Mapper 7 satellite images were acquired for a study area in Kakamega, western Kenya. Supervised classification of land-use and land-cover and visual identification of aquatic habitats were conducted. Ground survey of all aquatic habitats was conducted in the dry and rainy seasons in 2003. All habitats positive for anopheline larvae were identified. The retrieved data from the remote sensors were compared to the ground results on aquatic habitats and land-use. The probability of finding aquatic habitats and habitats with Anopheles larvae were modelled based on the digital elevation model and land-use types.

Results

The misclassification rate of land-cover types was 10.8% based on Ikonos imagery, 22.6% for panchromatic aerial photos and 39.2% for Landsat TM 7 imagery. The Ikonos image identified 40.6% of aquatic habitats, aerial photos identified 10.6%, and Landsate TM 7 image identified 0%. Computer models based on topographic features and land-cover information obtained from the Ikonos image yielded a misclassification rate of 20.3–22.7% for aquatic habitats, and 18.1–25.1% for anopheline-positive larval habitats.

Conclusion

One-metre spatial resolution Ikonos images combined with computer modelling based on topographic land-cover features are useful tools for identification of anopheline larval habitats, and they can be used to assist to malaria vector control in western Kenya highlands.
Occupation, smoking, and chronic obstructive respiratory disorders: a cross sectional study in an industrial area of Catalonia, Spain
Authors: Jaén Ángeles , Zock Jan Paul , Kogevinas Manolis , Ferrer Antonio , Marín Albert
Published: February 2006

Background

Few studies have investigated the independent effects of occupational exposures and smoking on chronic bronchitis and airflow obstruction. We assessed the association between lifetime occupational exposures and airflow obstruction in a cross-sectional survey in an urban-industrial area of Catalonia, Spain.

Methods

We interviewed 576 subjects of both sexes aged 20–70 years (response rate 80%) randomly selected from census rolls, using the ATS questionnaire. Forced spirometry was performed by 497 subjects according to ATS normative.

Results

Lifetime occupational exposure to dust, gases or fumes was reported by 52% of the subjects (63% in men, 41% in women). Textile industry was the most frequently reported job in relation to these exposures (39%). Chronic cough, expectoration and wheeze were more prevalent in exposed subjects with odds ratios ranging from 1.7 to 2.0 being highest among never-smokers (2.1 to 4.3). Lung function differences between exposed and unexposed subjects were dependent on duration of exposure, but not on smoking habits. Subjects exposed more than 15 years to dusts, gases or fumes had lower lung function values (FEV1-80 ml, 95% confidence interval (CI) -186 to 26; MMEF -163 ml, CI -397 to 71; FEV1/FVC ratio -1.7%, CI -3.3 to -0.2) than non-exposed.

Conclusion

Chronic bronchitis symptoms and airflow obstruction are associated with occupational exposures in a population with a high employment in the textile industry. Lung function impairment was related to the duration of occupational exposure, being independent of the effect of smoking.
Aluminum sulfate significantly reduces the skin test response to common allergens in sensitized patients
Authors: Smith C Steven , Smith Scott A , Grier Thomas J , Justus David E
Published: February 2006

Background

Avoidance of allergens is still recommended as the first and best way to prevent allergic illnesses and their comorbid diseases. Despite a variety of attempts there has been very limited success in the area of environmental control of allergic disease. Our objective was to identify a non-invasive, non-pharmacological method to reduce indoor allergen loads in atopic persons' homes and public environments. We employed a novel in vivo approach to examine the possibility of using aluminum sulfate to control environmental allergens.

Methods

Fifty skin test reactive patients were simultaneously skin tested with conventional test materials and the actions of the protein/glycoprotein modifier, aluminum sulfate. Common allergens, dog, cat, dust mite, Alternaria, and cockroach were used in the study.

Results

Skin test reactivity was significantly reduced by the modifier aluminum sulfate. Our studies demonstrate that the effects of histamine were not affected by the presence of aluminum sulfate. In fact, skin test reactivity was reduced independent of whether aluminum sulfate was present in the allergen test material or removed prior to testing, indicating that the allergens had in some way been inactivated.

Conclusion

Aluminum sulfate was found to reduce the in vivo allergic reaction cascade induced by skin testing with common allergens. The exact mechanism is not clear but appears to involve the alteration of IgE-binding epitopes on the allergen. Our results indicate that it may be possible to diminish the allergenicity of an environment by application of the active agent aluminum sulfate, thus producing environmental control without complete removal of the allergen.
The thrombopoietin receptor, c-Mpl, is a selective surface marker for human hematopoietic stem cells
Authors: Ninos John M , Jefferies Leigh C , Cogle Christopher R , Kerr William G
Published: February 2006

Background

Thrombopoietin (TPO), the primary cytokine regulating megakaryocyte proliferation and differentiation, exerts significant influence on other hematopoietic lineages as well, including erythroid, granulocytic and lymphoid lineages. We previously demonstrated that the receptor for TPO, c-mpl, is expressed by a subset of human adult bone marrow hematopoietic stem/progenitor cells (HSC/PC) that are enriched for long-term multilineage repopulating ability in the SCID-hu Bonein vivomodel of human hematopoiesis.

Methods

Here, we employ flow cytometry and an anti-c-mpl monoclonal antibody to comprehensively define the surface expression pattern of c-mpl in four differentiation stages of human CD34+HSC/PC (I:CD34+38--,II:CD34+38dim,III:CD34+38+,IV:CD34dim38+) for the major sources of human HSC: fetal liver (FL), umbilical cord blood (UCB), adult bone marrow (ABM), and cytokine-mobilized peripheral blood stem cells (mPBSC). We use a surrogatein vivomodel of human thymopoiesis, SCID-hu Thy/Liv, to compare the capacity of c-mpl+vs. c-mpl--CD34+38--/dimHSC/PC for thymocyte reconstitution.

Results

For all tissue sources, the percentage of c-mpl+cells was significantly highest in stageIHSC/PC (FL 72 ± 10%, UCB 67 ± 19%, ABM 82 ± 16%, mPBSC 71 ± 15%), and decreased significantly through stagesII,III, andIV((FL 3 ± 3%, UCB 8 ± 13%, ABM 0.6 ± 0.6%, mPBSC 0.2 ± 0.1%) [ANOVA: P < 0.0001]. The relative median fluorescence intensity of c-mpl expression was similarly highest in stageI, decreasing through stageIV[ANOVA: P < 0.0001]. No significant differences between tissue sources were observed for either % c-mpl+cells [P = 0.89] or intensity of c-mpl expression [P = 0.21]. Primary Thy/Liv grafts injected with CD34+38--/dimc-mpl+cells showed slightly higher levels of donor HLA+thymocyte reconstitution vs. CD34+38--/dimc-mpl---injected grafts and non-injected controls (c-mpl+vs. c-mpl--: CD2+6.8 ± 4.5% vs. 2.8 ± 3.3%, CD4+8--54 ± 35% vs. 31 ± 29%, CD4--8+29 ± 19% vs. 18 ± 14%).

Conclusion

These findings support the hypothesis that the TPO receptor, c-mpl, participates in the regulation of primitive human HSC from mid-fetal through adult life. This study extends our previous work documenting human B-lineage, myeloid and CD34+cell repopulation by c-mpl+progenitors to show that c-mpl+HSC/PC are also capable of significant T-lineage reconstitutionin vivo. These results suggest that c-mpl merits consideration as a selective surface marker for the identification and isolation of human HSC in both basic research and clinical settings.
Sepsis progression and outcome: a dynamical model
Authors: Zuev Sergey M , Kingsmore Stephen F , Gessler Damian DG
Published: February 2006

Background

Sepsis (bloodstream infection) is the leading cause of death in non-surgical intensive care units. It is diagnosed in 750,000 US patients per annum, and has high mortality. Current understanding of sepsis is predominately observational and correlational, with only a partial and incomplete understanding of the physiological dynamics underlying the syndrome. There exists a need for dynamical models of sepsis progression, based upon basic physiologic principles, which could eventually guide hourly treatment decisions.

Results

We present an initial mathematical model of sepsis, based on metabolic rate theory that links basic vascular and immunological dynamics. The model includes the rate of vascular circulation, a surrogate for the metabolic rate that is mechanistically associated with disease progression. We use the mass-specific rate of blood circulation (SRBC), a correlate of the body mass index, to build a differential equation model of circulation, infection, organ damage, and recovery. This introduces a vascular component into an infectious disease model that describes the interaction between a pathogen and the adaptive immune system.

Conclusion

The model predicts that deviations from normal SRBC correlate with disease progression and adverse outcome. We compare the predictions with population mortality data from cardiovascular disease and cancer and show that deviations from normal SRBC correlate with higher mortality rates.
Intracellular assembly and budding of the Murine Leukemia Virus in infected cells
Authors: Houzet Laurent , Gay Bernard , Morichaud Zakia , Briant Laurence , Mougel Marylène
Published: February 2006

Background

Murine Leukemia Virus (MLV) assembly has been long thought to occur exclusively at the plasma membrane. Current models of retroviral particle assembly describe the recruitment of the host vacuolar protein sorting machinery to the cell surface to induce the budding of new particles. Previous fluorescence microscopy study reported the vesicular traffic of the MLV components (Gag, Env and RNA). Here, electron microscopy (EM) associated with immunolabeling approaches were used to go deeply into the assembly of the "prototypic" MLV in chronically infected NIH3T3 cells.

Results

Beside the virus budding events seen at the cell surface of infected cells, we observed that intracellular budding events could also occur inside the intracellular vacuoles in which many VLPs accumulated. EM in situ hybridization and immunolabeling analyses confirmed that these latter were MLV particles. Similar intracellular particles were detected in cells expressing MLV Gag alone. Compartments containing the MLV particles were identified as late endosomes using Lamp1 endosomal/lysosomal marker and BSA-gold pulse-chase experiments. In addition, infectious activity was detected in lysates of infected cells.

Conclusion

Altogether, our results showed that assembly of MLV could occur in part in intracellular compartments of infected murine cells and participate in the production of infectious viruses. These observations suggested that MLV budding could present similarities with the particular intracellular budding of HIV in infected macrophages.
Coordinate enhancement of transgene transcription and translation in a lentiviral vector
Authors: Yilmaz Alper , Fernandez Soledad , Lairmore Michael D , Boris-Lawrie Kathleen
Published: February 2006

Background

Coordinate enhancement of transgene transcription and translation would be a potent approach to significantly improve protein output in a broad array of viral vectors and nonviral expression systems. Many vector transgenes are complementary DNA (cDNA). The lack of splicing can significantly reduce the efficiency of their translation. Some retroviruses contain a 5' terminal post-transcriptional control element (PCE) that facilitates translation of unspliced mRNA. Here we evaluated the potential for spleen necrosis virus PCE to stimulate protein production from HIV-1 based lentiviral vector by: 1) improving translation of the internal transgene transcript; and 2) functionally synergizing with a transcriptional enhancer to achieve coordinate increases in RNA synthesis and translation.

Results

Derivatives of HIV-1 SIN self-inactivating lentiviral vector were created that contain PCE and cytomegalovirus immediate early enhancer (CMV IE). Results from transfected cells and four different transduced cell types indicate that: 1) PCE enhanced transgene protein synthesis; 2) transcription from the internal promoter is enhanced by CMV IE; 3) PCE and CMV IE functioned synergistically to significantly increase transgene protein yield; 4) the magnitude of translation enhancement by PCE was similar in transfected and transduced cells; 5) differences were observed in steady state level of PCE vector RNA in transfected and transduced cells; 6) the lower steady state was not attributable to reduced RNA stability, but to lower cytoplasmic accumulation in transduced cells.

Conclusion

PCE is a useful tool to improve post-transcriptional expression of lentiviral vector transgene. Coordinate enhancement of transcription and translation is conferred by the combination of PCE with CMV IE transcriptional enhancer and increased protein yield up to 11 to 17-fold in transfected cells. The incorporation of the vector provirus into chromatin correlated with reduced cytoplasmic accumulation of PCE transgene RNA. We speculate that epigenetic modulation of promoter activity altered cotranscriptional recruitment of RNA processing factors and reduced the availability of fully processed transcript or the efficiency of export from the nucleus. Our results provide an example of the dynamic interplay between the transcription and post-transcription steps of gene expression and document that introduction of heterologous gene expression signals can yield disparate effects in transfected versus transduced cells.
Higher transactivation activity associated with LTR and Tat elements from HIV-1 BF intersubtype recombinant variants
Authors: Turk Gabriela , Carobene Mauricio , Monczor Ana , Rubio Andrea Elena , Gómez-Carrillo Manuel , Salomón Horacio
Published: February 2006

Background

HIV-1 is characterized by its rapid genetic evolution and high diversity as a consequence of its error-prone reverse transcriptase and genetic recombination. This latter mechanism is responsible for the creation of circulating recombinant forms (CRFs) found in nature. Previous studies from our lab group have shown that the epidemic in Argentina is characterized by one highly prevalent circulating recombinant form, CRF12_BF, and many related BF recombinant forms. Since transcriptional transactivation of the HIV-1 long terminal repeat (LTR) promoter element requires the essential viral Tat protein, since these genetic structures underwent recombination in variants widely spread in South America, the aim of this work was to study transcriptional activity associated with the recombinant LTR and Tat elements.

Results

Differential transcriptional activity was measured for the BF recombinant LTR/Tat complex that is present in widely spread viral variants was demonstrated. This analysis demonstrated a higher activity for the BF complex when compared to its B subtype counterpart.

Conclusion

This study indicates structural and functional consequences of recombination events within the LTR promoter and Tat transactivator protein of a naturally occurring HIV-1 recombinant form.
Identification of collagen-induced arthritis loci in aged multiparous female mice
Authors: Liljander Maria , Sällström Mary-Ann , Andersson Sara , Andersson Åsa , Holmdahl Rikard , Mattsson Ragnar
Published: February 2006

Collagen-induced arthritis in mice is one of the most commonly used autoimmune experimental models, with many similarities to rheumatoid arthritis. Since collagen-induced arthritis is a complex polygenic disease there is a need for identification of several major disease-controlling genes. Because rheumatoid arthritis particularly affects aged women, we have in the present study identified new genetic regions critical for collagen-induced arthritis by studying aged female mice of a cross between NFR/N and B10.Q (H-2q haplotype). The mice in the present study had different reproductive histories, which did not significantly affect the onset, incidence or severity of the disease. A total of 200 female mice were used in a total genome-wide screening with 125 microsatellite markers. We found one new significant quantitative trait locus affecting the arthritis incidence, severity and day of onset on chromosome 11 (denoted Cia40), which colocalizes with a locus controlling pregnancy failure. Furthermore, a quantitative trait locus of suggestive significance associated with the incidence, severity and day of onset was identified on chromosome 1. Finally, a suggestively significant quantitative trait locus associated with collagen type II antibody titers was identified on chromosome 13. This study indicates that several gene loci control arthritis in aged multiparous females, and that at least one of these loci coincides with pregnancy failure.
Analysis of cancer risk and BRCA1 and BRCA2mutation prevalence in the kConFab familial breast cancer resource
Authors: Mann Graham J , Thorne Heather , Balleine Rosemary L , Butow Phyllis N , Clarke Christine L , Edkins Edward , Evans Gerda M , Fereday Sián , Haan Eric , Gattas Michael , Giles Graham G , Goldblatt Jack , Hopper John L , Kirk Judy , Leary Jennifer A , Lindeman Geoffrey , Niedermayr Eveline , Phillips Kelly-Anne , Picken Sandra , Pupo Gulietta M , Saunders Christobel , Scott Clare L , Spurdle Amanda B , Suthers Graeme , Tucker Kathy , Chenevix-Trench Georgia ,   The Kathleen Cuningham Consortium for Research in Familial Breast Cancer
Published: February 2006

Introduction

The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives.

Methods

Epidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study.

Results

Of kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFab's fresh tissue bank includes 253 specimens of breast or ovarian tissue – both normal and malignant – including 126 from carriers of BRCA1 or BRCA2 mutations.

Conclusion

These kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected.
Continuous infusion of ceftazidime in critically ill patients undergoing continuous venovenous haemodiafiltration: pharmacokinetic evaluation and dose recommendation
Authors: Mariat Christophe , Venet Christophe , Jehl François , Mwewa Sandrine , Lazarevic Vesna , Diconne Eric , Fonsale Nathalie , Carricajo Anne , Guyomarc'h Stéphane , Vermesch Régine , Aubert Gérald , Bidault Roselyne , Bertrand Jean-Claude , Zeni Fabrice
Published: February 2006

Introduction

In seriously infected patients with acute renal failure and who require continuous renal replacement therapy, data on continuous infusion of ceftazidime are lacking. Here we analyzed the pharmacokinetics of ceftazidime administered by continuous infusion in critically ill patients during continuous venovenous haemodiafiltration (CVVHDF) in order to identify the optimal dosage in this setting.

Method

Seven critically ill patients were prospectively enrolled in the study. CVVHDF was performed using a 0.6 m2 AN69 high-flux membrane and with blood, dialysate and ultrafiltration flow rates of 150 ml/min, 1 l/hour and 1.5 l/hour, respectively. Based on a predicted haemodiafiltration clearance of 32.5 ml/min, all patients received a 2 g loading dose of ceftazidime, followed by a 3 g/day continuous infusion for 72 hours. Serum samples were collected at 0, 3, 15 and 30 minutes and at 1, 2, 4, 6, 8, 12, 24, 36, 48 and 72 hours; dialysate/ultrafiltrate samples were taken at 2, 8, 12, 24, 36 and 48 hours. Ceftazidime concentrations in serum and dialysate/ultrafiltrate were measured using high-performance liquid chromatography.

Results

The mean (± standard deviation) elimination half-life, volume of distribution, area under the concentration-time curve from time 0 to 72 hours, and total clearance of ceftazidime were 4 ± 1 hours, 19 ± 6 l, 2514 ± 212 mg/h per l, and 62 ± 5 ml/min, respectively. The mean serum ceftazidime steady-state concentration was 33.5 mg/l (range 28.8–36.3 mg/l). CVVHDF effectively removed continuously infused ceftazidime, with a sieving coefficient and haemodiafiltration clearance of 0.81 ± 0.11 and 33.6 ± 4 mg/l, respectively.

Conclusion

We conclude that a dosing regimen of 3 g/day ceftazidime, by continuous infusion, following a 2 g loading dose, results in serum concentrations more than four times the minimum inhibitory concentration for all susceptible pathogens, and we recommend this regimen in critically ill patients undergoing CVVHDF.
Effects of coagulation factor XIII on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation in experimental endotoxemia
Authors: Birnbaum Jürgen , Hein Ortrud Vargas , Lührs Carsten , Rückbeil Oskar , Spies Claudia , Ziemer Sabine , Gründling Matthias , Usichenko Taras , Meissner Konrad , Pavlovic Dragan , Kox Wolfgang J , Lehmann Christian
Published: February 2006

Introduction

The objective of this study was to determine the effects of the administration of the coagulation factor XIII (F XIII) on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation during experimental endotoxemia.

Methods

In a prospective, randomized, controlled animal study 42 male Wistar rats were divided into three groups. Group 1 served as the control group. Groups 2 (lipopolysaccharide (LPS) group) and 3 (F XIII group) received endotoxin infusions (2.5 mg/kg/h for 2 hours). In group 3, 50 U/kg body weight F XIII was continuously administered during the first 30 minutes of endotoxemia. F XIII levels were measured in all animals. One half of the animals of each group were studied for intestinal functional capillary density (FCD) and leukocyte adherence on venular endothelium by intravital fluorescence microscopy (IVM). In the other half of each group, mesenteric plasma extravasation (FITC-albumin) was determined by IVM.

Results

The F XIII level was significantly increased in the F XIII treatment group. In the LPS group, endotoxemia led to a significant reduction of mucosal FCD (-18.5%; p < 0.01 versus control group). F XIII administration in the F XIII group attenuated the decrease in mucosal FCD (-3.7% compared to control; p < 0.05 versus LPS group). During endotoxemia, a significant increase of leukocyte adherence at the endothelium could be noted in the LPS group compared to the control group. Leukocyte adherence at the endothelium and plasma extravasation in the F XIII group did not differ significantly from the LPS group.

Conclusion

Factor XIII protected mucosal capillary perfusion against endotoxin-induced impairment in an experimental sepsis model in rats, whereas leukocyte adherence and plasma extravasation remained unchanged.
Toxicity of polymyxins: a systematic review of the evidence from old and recent studies
Authors: Falagas Matthew E , Kasiakou Sofia K
Published: February 2006

Background

The increasing problem of multidrug-resistant Gram-negative bacteria causing severe infections and the shortage of new antibiotics to combat them has led to the re-evaluation of polymyxins. These antibiotics were discovered from different species of Bacillus polymyxa in 1947; only two of them, polymyxin B and E (colistin), have been used in clinical practice. Their effectiveness in the treatment of infections due to susceptible Gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii, has not been generally questioned. However, their use was abandoned, except in patients with cystic fibrosis, because of concerns related to toxicity.

Methods

We reviewed old and recent evidence regarding polymyxin-induced toxicity by searching Pubmed (from 1950 until May 2005).

Results

It was reported in the old literature that the use of polymyxins was associated with considerable toxicity, mainly nephrotoxicity and neurotoxicity, including neuromuscular blockade. However, recent studies showed that the incidence of nephrotoxicity is less common and severe compared to the old studies. In addition, neurotoxic effects of polymyxins are usually mild and resolve after prompt discontinuation of the antibiotics. Furthermore, cases of neuromuscular blockade and apnea have not been reported in the recent literature.

Conclusion

New evidence shows that polymyxins have less toxicity than previously reported. The avoidance of concurrent administration of nephrotoxic and/or neurotoxic drugs, careful dosing, as well as more meticulous management of fluid and electrolyte abnormalities and use of critical care services may be some of the reasons for the discrepancy between data reported in the old and recent literature.
Process monitoring in intensive care with the use of cumulative expected minus observed mortality and risk-adjusted p charts
Authors: Cockings Jerome GL , Cook David A , Iqbal Rehana K
Published: February 2006

Introduction

A health care system is a complex adaptive system. The effect of a single intervention, incorporated into a complex clinical environment, may be different from that expected. A national database such as the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme in the UK represents a centralised monitoring, surveillance and reporting system for retrospective quality and comparative audit. This can be supplemented with real-time process monitoring at a local level for continuous process improvement, allowing early detection of the impact of both unplanned and deliberately imposed changes in the clinical environment.

Methods

Demographic and UK Acute Physiology and Chronic Health Evaluation II (APACHE II) data were prospectively collected on all patients admitted to a UK regional hospital between 1 January 2003 and 30 June 2004 in accordance with the ICNARC Case Mix Programme. We present a cumulative expected minus observed (E-O) plot and the risk-adjusted p chart as methods of continuous process monitoring. We describe the construction and interpretation of these charts and show how they can be used to detect planned or unplanned organisational process changes affecting mortality outcomes.

Results

Five hundred and eighty-nine adult patients were included. The overall death rate was 0.78 of predicted. Calibration showed excess survival in ranges above 30% risk of death. The E-O plot confirmed a survival above that predicted. Small transient variations were seen in the slope that could represent random effects, or real but transient changes in the quality of care. The risk-adjusted p chart showed several observations below the 2 SD control limits of the expected mortality rate. These plots provide rapid analysis of risk-adjusted performance suitable for local application and interpretation. The E-O chart provided rapid easily visible feedback of changes in risk-adjusted mortality, while the risk-adjusted p chart allowed statistical evaluation.

Conclusion

Local analysis of risk-adjusted mortality data with an E-O plot and a risk-adjusted p chart is feasible and allows the rapid detection of changes in risk-adjusted outcome of intensive care patients. This complements the centralised national database, which is more archival and comparative in nature.
Reproductive Experience Reduces Circulating 17β-Estradiol and Prolactin Levels during Proestrus and Alters Estrogen Sensitivity in Female Rats
Authors: Bridges Robert S. , Byrnes Elizabeth M.
Published: February 2006

The reproductive experiences of pregnancy, parturition, and lactation affect a range of neural and endocrine processes after the end of lactation. In women, previous parity results in reduced circulating prolactin (PRL) and androgen levels years after giving birth. Reductions in PRL secretion also occur in reproductively experienced, female rats. In the present study we examined the status and regulation of estradiol (E2) and PRL during the reproductive cycle after reproductive experience. These hormones regulate one another and have been implicated in a number of disease and aging processes. Using a rat model, the patterns of E2 and PRL secretion, pituitary PRL content, and estrogen receptor α expression were characterized from 1200–1800 h on proestrus in age-matched, primiparous and nulliparous animals. The possible effect of parity on estrogen sensitivity was then examined by challenging nonlactating, ovariectomized, age-matched, multiparous and nulliparous rats with estradiol benzoate (EB; 0, 1, 5, 25, and 125 μg/kg) and measuring PRL responses 24 and 48 h later. Previous parity resulted in modest, yet significant, reductions in E2 and PRL levels on proestrus, a limited increase in pituitary estrogen receptor α expression, and a significant shift in estrogen sensitivity, as measured by EB-induced PRL secretion. Nulliparous animals were more sensitive than multiparous rats to the two lower doses of EB, whereas multiparous animals were more responsive to the highest EB dose. These unique parity-induced alterations in the female’s endocrine state that persist beyond lactation may impact a multitude of estrogen-mediated processes over the female’s adult life span.
Progesterone Signaling in Human Myometrium through Two Novel Membrane G Protein-Coupled Receptors: Potential Role in Functional Progesterone Withdrawal at Term
Authors: Karteris Emmanouil , Zervou Sevasti , Pang Yefei , Dong Jing , Hillhouse Edward W. , Randeva Harpal S. , Thomas Peter
Published: February 2006

Progestin withdrawal is a crucial event for the onset of labor in many mammalian species. However, in humans the mechanism of a functional progestin withdrawal is unclear, because progestin concentrations do not drop in maternal plasma preceding labor. We report the presence of two novel functional membrane progestin receptors (mPRs), mPRα and mPRβ, in human myometrium that are differentially modulated during labor and by steroids in vitro. The mPRs are coupled to inhibitory G proteins, resulting in a decline in cAMP levels and increased phosphorylation of myosin light chain, both of which facilitate myometrial contraction. Activation of mPRs leads to transactivation of PR-B, the first evidence for cross-talk between membrane and nuclear PRs. Progesterone activation of the mPRs leads also to a decrease of the steroid receptor coactivator 2. Our data indicate the presence of a novel signaling pathway mediated by mPRs that may result in a functional progestin withdrawal, shifting the balance from a quiescent state to one of contraction.
Microsurgical Cervical Nerve Root Decompression by Anterolateral Approach
Authors: Bruneau Michaël , Cornelius Jan Frédérick , George Bernard
Published: February 2006

OBJECTIVE:

Cervical radiculopathy caused by a posterolateral soft disc herniation or spondylosis is a common pathology.

METHODS:

Decompression of a stressed cervical nerve root is a routine neurosurgical procedure. Most of the time it is achieved through an anterior approach and, less frequently, through a posterior approach in specific indications.

RESULTS:

According to the principles that an anterolateral compression must directly be reached and that working in the vicinity of the vertebral artery is safe under visual control, we developed the anterolateral approach to the cervical intervertebral foramen and the nerve root using a minimally invasive technique to remove the offending process.

CONCLUSION:

Microsurgical cervical nerve root decompression by anterolateral approach is a minimally invasive technique, permitting one to remove the offending process staightforwardly. The disc and bone resections are minimal. This method avoids osteoarthrodesis or arthroplasty with disc prosthesis. This technique is efficient with good results and low morbidity.
Intraorbital Arteriovenous Fistulae Of The Ophthalmic Veins Treated By Transvenous Endovascular Occlusion:Technical Case Report
Authors: Caragine Louis P. , Halbach Van V. , Dowd Chris F. , Higashida Randall T.
Published: February 2006

OBJECTIVE AND IMPORTANCE

Intraorbital arteriovenous fistulas (AVF) of the ophthalmic veins are an extremely rare phenomenon. This article describes two such cases treated solely by transvenous occlusion and not hitherto described in the literature.

METHODS AND RESULTS:

Two women, aged 51 and 63 years old, presented with proptosis and chemosis mimicking a carotid-cavernous fistula. In both cases, cerebral angiography revealed an intraorbital dural AVF of the superior and inferior ophthalmic vein, respectively. Both patients underwent transvenous ablation of the dural AVF retrograde via the facial vein and subsequently had complete resolution of the presenting symptoms.

METHODS:

Ophthalmic vein fistulas are a rare form of AVF with presenting symptoms mimicking those of carotid cavernous fistulae. This report describes two cases of ophthalmic vein fistulas successfully treated and angiographically obliterated via transvenous embolization with resolution of the patient's presenting symptoms.