Altered collecting duct adenylyl cyclase content in collecting duct endothelin-1 knockout mice

<p>Abstract</p> <p>Background</p> <p>Endothelin-1 (ET-1) inhibition of vasopressin (AVP)-stimulated water reabsorption by the inner medullary collecting duct (IMCD) is associated with reduced cAMP accumulation. To determine the effect of ET-1 deficiency, AVP-stimulated cAMP responsiveness was assessed in IMCD from mice with collecting duct-specific deletion of ET-1 (CD ET-1 KO) and from control animals.</p> <p>Methods</p> <p>Cyclic AMP production, adenylyl cyclase (AC) mRNA, and AC protein were measured in acutely isolated IMCD.</p> <p>Results</p> <p>CD ET-1 KO IMCD had enhanced AVP-stimulated cAMP accumulation. Inhibition of calcium-stimulated AC using BAPTA did not prevent enhanced AVP responsiveness in CD ET-1 KO IMCD. Factors known to be modified by ET-1, including nitric oxide, cyclooxygenase metabolites, and superoxide did not affect the increased AVP responsiveness of CD ET-1 KO IMCD. Differential V2 receptor or G-protein activity was not involved since CD ET-1 KO IMCD had increased cAMP accumulation in response to forskolin and/or cholera toxin. CD ET-1 KO did not affect mRNA or protein levels of AC3, one of the major known collecting duct AC isoforms. However, the other known major collecting duct AC isoform (AC5/6) did have increased protein levels in CD ET-1 KO IMCD, although AC5 (weak signal) and 6 mRNA levels were unchanged.</p> <p>Conclusion</p> <p>ET-1 deficiency increases IMCD AC5/6 content, an effect that may synergize with acute ET-1 inhibition of AVP-stimulated cAMP accumulation.</p

The relationship between hip abductor muscle strength and iliotibial band tightness in individuals with low back pain

<p>Abstract</p> <p>Background</p> <p>Shortening of the iliotibial band (ITB) has been considered to be associated with low back pain (LBP). It is theorized that ITB tightness in individuals with LBP is a compensatory mechanism following hip abductor muscle weakness. However, no study has clinically examined this theory. The purpose of this study was to investigate the muscle imbalance of hip abductor muscle weakness and ITB tightness in subjects with LBP.</p> <p>Methods</p> <p>A total of 300 subjects with and without LBP between the ages of 20 and 60 participated in this cross-sectional study. Subjects were categorized in three groups: LBP with ITB tightness (n = 100), LBP without ITB tightness (n = 100) and no LBP (n = 100). Hip abductor muscle strength was measured in all subjects.</p> <p>Results</p> <p>Analysis of Covariance (ANCOVA) with the body mass index (BMI) as the covariate revealed significant difference in hip abductor strength between three groups (P < 0.001). Post hoc analysis showed no significant difference in hip abductor muscle strength between the LBP subjects with and without ITB tightness (P = 0.59). However, subjects with no LBP had significantly stronger hip abductor muscle strength compared to subjects with LBP with ITB tightness (P < 0.001) and those with LBP without ITB tightness (P < 0.001).</p> <p>Conclusion</p> <p>The relationship between ITB tightness and hip abductor weakness in patients with LBP is not supported as assumed in theory. More clinical studies are needed to assess the theory of muscle imbalance of hip abductor weakness and ITB tightness in LBP.</p

Gram Negative Bacteria Are Associated with the Early Stages of Necrotizing Enterocolitis

Introduction: Necrotizing enterocolitis (NEC) affects 5–10 % of infants born weighing less than 1500 g. Most models of NEC recapitulate late-stage disease with gut necrosis and elevated inflammatory mediators. Evaluation of NEC at earlier, less lethal stages of disease will allow investigation of initial disease triggers and may advance our understanding of temporal relationships between factors implicated in NEC pathogenesis. In this manuscript, we describe our investigation of early NEC and test the hypothesis that bacteria and inflammatory mediators differ between animals with early NEC and disease fre

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

Drug waste minimisation and cost-containment in Medical Oncology: Two-year results of a feasibility study

<p>Abstract</p> <p>Background</p> <p>Cost-containment strategies are required to face the challenge of rising drug expenditures in Oncology. Drug wastage leads to economic loss, but little is known about the size of the problem in this field.</p> <p>Methods</p> <p>Starting January 2005 we introduced a day-to-day monitoring of drug wastage and an accurate assessment of its costs. An internal protocol for waste minimisation was developed, consisting of four corrective measures: 1. A rational, per pathology distribution of chemotherapy sessions over the week. 2. The use of multi-dose vials. 3. A reasonable rounding of drug dosages. 4. The selection of the most convenient vial size, depending on drug unit pricing.</p> <p>Results</p> <p>Baseline analysis focused on 29 drugs over one year. Considering their unit price and waste amount, a major impact on expense was found to be attributable to six drugs: cetuximab, docetaxel, gemcitabine, oxaliplatin, pemetrexed and trastuzumab. The economic loss due to their waste equaled 4.8% of the annual drug expenditure. After the study protocol was started, the expense due to unused drugs showed a meaningful 45% reduction throughout 2006.</p> <p>Conclusion</p> <p>Our experience confirms the economic relevance of waste minimisation and may represent a feasible model in addressing this issue.</p> <p>A centralised unit of drug processing, the availability of a computerised physician order entry system and an active involvement of the staff play a key role in allowing waste reduction and a consequent, substantial cost-saving.</p

Characterization of Parameters Required for Effective Use of Tamoxifen-Regulated Recombination

Conditional gene targeting using the Cre-loxp system is a well established technique in numerous in vitro and in vivo systems. Ligand regulated forms of Cre have been increasingly used in these applications in order to gain temporal and spatial control over conditional targeting. The tamoxifen-regulated Cre variant mer-Cre-mer (mCrem) is widely utilized because of its reputation for tight regulation in the absence of its tamoxifen ligand. In the DT40 chicken B cell line, we generated an mCrem-based reversible switch for conditional regulation of a transgene, and in contrast with previous work, observed significant constitutive activity of mCrem. This prompted us to use our system for analysis of the parameters governing tamoxifen-regulated mCrem recombination of a genomic target. We find that robust mCrem expression correlates with a high level of tamoxifen-independent Cre activity, while clones expressing mCrem at the limit of western blot detection exhibit extremely tight regulation. We also observe time and dose-dependent effects on mCrem activity which suggest limitations on the use of conditional targeting approaches for applications which require tight temporal coordination of Cre action within a cell population

Hawk Eyes II: Diurnal Raptors Differ in Head Movement Strategies When Scanning from Perches

Background Relatively little is known about the degree of inter-specific variability in visual scanning strategies in species with laterally placed eyes (e.g., birds). This is relevant because many species detect prey while perching; therefore, head movement behavior may be an indicator of prey detection rate, a central parameter in foraging models. We studied head movement strategies in three diurnal raptors belonging to the Accipitridae and Falconidae families. Methodology/Principal Findings We used behavioral recording of individuals under field and captive conditions to calculate the rate of two types of head movements and the interval between consecutive head movements. Cooper\u27s Hawks had the highest rate of regular head movements, which can facilitate tracking prey items in the visually cluttered environment they inhabit (e.g., forested habitats). On the other hand, Red-tailed Hawks showed long intervals between consecutive head movements, which is consistent with prey searching in less visually obstructed environments (e.g., open habitats) and with detecting prey movement from a distance with their central foveae. Finally, American Kestrels have the highest rates of translational head movements (vertical or frontal displacements of the head keeping the bill in the same direction), which have been associated with depth perception through motion parallax. Higher translational head movement rates may be a strategy to compensate for the reduced degree of eye movement of this species. Conclusions Cooper\u27s Hawks, Red-tailed Hawks, and American Kestrels use both regular and translational head movements, but to different extents. We conclude that these diurnal raptors have species-specific strategies to gather visual information while perching. These strategies may optimize prey search and detection with different visual systems in habitat types with different degrees of visual obstruction

Overdiagnosis and overtreatment of early detected prostate cancer

Early detection of prostate cancer is associated with the diagnosis of a considerable proportion of cancers that are indolent, and that will hardly ever become symptomatic during lifetime. Such overdiagnosis should be avoided in all forms of screening because of potential adverse psychological and somatic side effects. The main threat of overdiagnosis is overtreatment of indolent disease. Men with prostate cancer that is likely to be indolent may be offered active surveillance. Evaluation of active surveillance studies and validation of new biological parameters for risk assessment are expected

The Tuberculin Skin Test (TST) Is Affected by Recent BCG Vaccination but Not by Exposure to Non-Tuberculosis Mycobacteria (NTM) during Early Life

The tuberculin skin test (TST) is widely used in TB clinics to aid Mycobacterium tuberculosis (M.tb) diagnosis, but the definition and the significance of a positive test in very young children is still unclear. This study compared the TST in Gambian children at 4½ months of age who either received BCG vaccination at birth (Group 1) or were BCG naïve (Group 2) in order to examine the role of BCG vaccination and/or exposure to environmental mycobacteria in TST reactivity at this age. Nearly half of the BCG vaccinated children had a positive TST (≥5 mm) whereas all the BCG naïve children were non-reactive, confirming that recent BCG vaccination affects TST reactivity. The BCG naïve children demonstrated in vitro PPD responses in peripheral blood in the absence of TST reactivity, supporting exposure to and priming by environmental mycobacterial antigens. Group 2 were then vaccinated at 4½ months of age and a repeat TST was performed at 20–28 months of age. Positive reactivity (≥5 mm) was evident in 11.1% and 12.5% infants from Group 1 and Group 2 respectively suggesting that the timing of BCG vaccination had little effect by this age. We further assessed for immune correlates in peripheral blood at 4½ months of age. Mycobacterial specific IFNγ responses were greater in TST responders than in non-responders, although the size of induration did not correlate with IFNγ. However the IFNγ: IL-10 ratio positively correlated with TST induration suggesting that the relationship between PPD induced IFNγ and IL-10 in the peripheral blood may be important in controlling TST reactivity. Collectively these data provide further insights into how the TST is regulated in early life, and how a positive response might be interpreted