Generation and Export of Red Blood Cell ATP in Health and Disease.

Metabolic homeostasis in animals depends critically on evolved mechanisms by which red blood cell (RBC) hemoglobin (Hb) senses oxygen (O) need and responds accordingly. The entwined regulation of ATP production and antioxidant systems within the RBC also exploits Hb-based O-sensitivity to respond to various physiologic and pathophysiologic stresses. O offloading, for example, promotes glycolysis in order to generate both 2,3-DPG (a negative allosteric effector of Hb O binding) and ATP.

Twist1 in podocytes ameliorates podocyte injury and proteinuria by limiting CCL2-dependent macrophage infiltration.

The transcription factor Twist1 regulates several processes that could impact kidney disease progression, including epithelial cell differentiation and inflammatory cytokine induction. Podocytes are specialized epithelia that exhibit features of immune cells and could therefore mediate unique effects of Twist1 on glomerular disease. To study Twist1 functions in podocytes during proteinuric kidney disease, we employed a conditional mutant mouse in which Twist1 was selectively ablated in podocytes (Twist1-PKO).

The Importance of Tumor Length in Needle Biopsies of the Prostate.

Objectives: To form a composite predictor variable that combines the effects of tumor length, serum prostate-specific antigen (PSA), and International Society of Urologic Pathologists (ISUP) grade on the observation of adverse prostatectomy pathology.

Methods: Logistic regression analysis was used to demonstrate how tumor length, serum PSA, and ISUP grade related to adverse prostatectomy results and to derive weighting factors for a composite variable, cx.

Results: The composite variable, cx, relates closely to adverse prostatectomy results as well as to observed PSA failure.

Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis Matrix Metallopeptidase 13-Mediated Matrix Degradation.

Background: Following an acute insult, macrophages regulate renal fibrogenesis through the release of various factors that either encourage the synthesis of extracellular matrix synthesis or the degradation of matrix endocytosis, proteolysis, or both. However, the roles of infiltrating versus resident myeloid cells in these opposing processes require elucidation. The transcription factor Twist1 controls diverse essential cellular functions through induction of several downstream targets, including matrix metalloproteinases (MMPs).

The Calculus of Serum PSA.

Objectives: To review the mathematics of kinetic changes in serum prostate-specific antigen (PSA) and to use a compartmental model to derive a new kinetic measure, alpha.

Methods: The calculus of kinetic measures of PSA changes with time is presented, and a compartmental model is then used to derive alpha of serum PSA. Alpha is then tested for prognostic importance in 119 men who underwent prostatectomy.

A review of the incidence of adenocarcinoma detected during surveillance for Barrett's esophagus.

The objective of this study is to provide an up-to-date estimate of the incidence of adenocarcinoma detected during surveillance of Barrett's esophagus. Fifty-five longitudinal studies involving approximately 61 000 patients were reviewed. A general linear model analyses with Poisson link function was used to study how the number of cancer cases detected depended on study details.

Serum Prostate-Specific Antigen (PSA) Concentration, PSA Mass, and Obesity: A Mathematical Analysis.

Objectives: To provide a mathematical background for understanding the phenomenon of analyte hemodilution using a kinetic analysis.

Methods: The first assumption for this analysis is that change in concentration of any analyte, such as prostate-specific antigen (PSA), is due to the flux of the analyte from an organ into the blood minus its flux from the blood. What results is a relatively simple differential equation that emphasizes the importance of plasma volume, organ mass, and two rate constants.

Defining Papillary Carcinoma of the Thyroid: A Short Review and Analysis.

Objectives: To review how changes in the pathologic definitions for papillary tumors of the thyroid during recent decades have affected outcomes for patients with these tumors.

Methods: Forty-nine previous reports or studies involving collectively 53,606 patients were reviewed, and new analyses were performed on the data to include analyses of agreement, incidence, survival, and diagnostic categories.

Results: The past emphasis on cytologic features to define papillary tumors has not resulted in ideal pairwise agreement between pathologists and has produced incidence and survival data suggesting overdetection and overdiagnosis.

Characterization and Functional Phenotyping of Renal Immune Cells via Flow Cytometry.

A variety of immune cell subsets contribute to the pathogenesis of hypertension and associated kidney damage following inappropriate activation of the renin-angiotensin system (RAS). These immune cell subsets often express common surface markers, which complicates their separation and characterization in vivo. Accordingly, flow cytometry has become an invaluable tool for parsing immune cell populations because this technique permits the simultaneous detection of up to 18 markers on a single cell.

Gleason Grading, Biochemical Failure, and Prostate Cancer-Specific Death.

Objectives: To examine the relationship between the recently defined Gleason grade groups and prostate cancer-specific mortality.

Methods: If the probability of prostate cancer-specific death is symbolized as P(PSD), the probability of biochemical failure is symbolized as P(BF), and the probability of prostate cancer-specific death after biochemical failure is symbolized as P(PSD | BF), then the rules of probability provide a way to estimate P(PSD) as P(PSD) = P(PSD | BF) * P(BF) Using this model and data from the literature for P(PSD | BF) and P(BF), I estimate here values of P(PSD) for the five newly described Gleason grade groups.

Results: The expected probability of prostate cancer- specific death is closely related to the new Gleason grade groups and ranges from a low of 0.

The role of chemokines in hypertension and consequent target organ damage.

Immune cells infiltrate the kidney, vasculature, and central nervous system during hypertension, consequently amplifying tissue damage and/or blood pressure elevation. Mononuclear cell motility depends partly on chemokines, which are small cytokines that guide cells through an increasing concentration gradient via ligation of their receptors. Tissue expression of several chemokines is elevated in clinical and experimental hypertension.

Systemic HMGB1 Neutralization Prevents Postoperative Neurocognitive Dysfunction in Aged Rats.

Postoperative neurocognitive disorders are common complications in elderly patients following surgery or critical illness. High mobility group box 1 protein (HMGB1) is rapidly released after tissue trauma and critically involved in response to sterile injury. Herein, we assessed the role of HMGB1 after liver surgery in aged rats and explored the therapeutic potential of a neutralizing anti-HMGB1 monoclonal antibody in a clinically relevant model of postoperative neurocognitive disorders.

Pyrrolidine Dithiocarbamate Prevents Neuroinflammation and Cognitive Dysfunction after Endotoxemia in Rats.

Systemic inflammation, for example as a result of infection, often contributes to long-term complications. Neuroinflammation and cognitive decline are key hallmarks of several neurological conditions, including advance age. The contribution of systemic inflammation to the central nervous system (CNS) remains not fully understood.

A Review of Outcomes for Stage Ta Bladder Tumors.

Objectives: Using data from former reports, this study reviews and analyzes the outcomes of tumor recurrence, tumor progression, and tumor-specific survival of patients with stage Ta bladder tumors.

Methods: Data were collected from 19 longitudinal studies of outcomes after the first diagnosis of tumor and collected as individual patient results, that is, as failure times from the first tumor to any of the three outcomes. Altogether, there were 14,252 patients, including 4,050 for the outcome of tumor recurrence, 2,937 for the outcome of tumor progression, and 11,595 for the outcome of disease-specific survival (some patients were available for more than one outcome).

Probabilistic issues with sentinel lymph nodes in malignant melanoma.

Objectives: To address issues of probability for sentinel lymph node results in melanoma and provide details about the probabilistic nature of the numbers of sentinel nodes as well as to address how these issues relate to tumor thickness and patient outcomes.

Methods: Analysis of the probability of observing sentinel node metastases uses the discrete exponential probability distribution to address the number of observed positive sentinel nodes. In addition, mathematical functions derived from survival analysis are used.

Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion.

Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice.

Sensitivity and specificity of polysomnographic criteria for defining insomnia.

Study Objectives: In recent years, polysomnography-based eligibility criteria have been increasingly used to identify candidates for insomnia research, and this has been particularly true of studies evaluating pharmacologic therapy for primary insomnia. However, the sensitivity and specificity of PSG for identifying individuals with insomnia is unknown, and there is no consensus on the criteria sets which should be used for participant selection. In the current study, an archival data set was used to test the sensitivity and specificity of PSG measures for identifying individuals with primary insomnia in both home and lab settings.

The dynamics of death in melanoma.

Background: Melanoma has been recently characterized as an over-diagnosed tumor, and some have suggested that the 'epidemic' in melanoma is spurious. Nevertheless, a fraction of melanoma patients continue to die of this tumor. For any tumor, the hazard function provides information about the timing and intensity of fatalities, and to examine the details of fatality in melanoma, herein the hazard functions for melanoma are derived and examined.

Pretherapy cognitive dispositions and treatment outcome in cognitive behavior therapy for insomnia.

This study consisted of secondary analyses of data from 2 randomized clinical trials to test whether pretherapy cognitions predict CBT outcomes. The sample consisted of 155 primary insomnia patients with sleep maintenance complaints. Of these, 98 were randomized to CBT, 23 were assigned to progressive muscle relaxation training (PMR), and 34 were assigned to a control (sham therapy or wait-list) condition (CON).

Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia.

Several parameters may predict disease severity and overall survival in chronic lymphocytic leukemia (CLL). The purpose of our study of 190 CLL patients was to compare immunoglobulin heavy chain variable region (IgV(H)) mutation status, cytogenetic abnormalities, and leukemia cell CD38 and Zap-70 to older, traditional parameters. We also wanted to construct a simple, inexpensive prognosis score that would significantly predict TTT and survival in patients at the time of diagnosis and help practicing clinicians.

Nitric oxide synthase and cyclooxygenase interactions in cartilage and meniscus: relationships to joint physiology, arthritis, and tissue repair.

Rheumatoid arthritis and osteoarthritis are painful and debilitating diseases with complex pathophysiology. There is growing evidence that pro-inflammatory cytokines (e.g.

Engineered zinc finger-activating vascular endothelial growth factor transcription factor plasmid DNA induces therapeutic angiogenesis in rabbits with hindlimb ischemia.

Background: Therapeutic angiogenesis seeks to promote blood vessel growth to improve tissue perfusion. Vascular endothelial growth factor (VEGF) exists in multiple isoforms. We investigated an engineered zinc finger-containing transcription factor plasmid designed to activate the endogenous VEGF gene (ZFP-VEGF).