A cell stress signaling model of fetal hemoglobin induction: what doesn't kill red blood cells may make them stronger

A major goal of hemoglobinopathy research is to develop treatments that correct the underlying molecular defects responsible for sickle cell disease and beta-thalassemia. One approach to achieving this goal is the pharmacologic induction of fetal hemoglobin (HbF). This strategy is capable of inhibiting the polymerization of sickle hemoglobin and correcting the globin chain imbalance of beta-thalassemia. Despite this promise, none of the currently available HbF-inducing agents exhibit the combination of efficacy, safety, and convenience of use that would make them applicable to most patients. The recent success of targeted drug therapies for malignant diseases suggests that this approach could be effective for developing optimal HbF-inducing agents. A first step in applying this approach is the identification of specific molecular targets. However, while >70 HbF-inducing agents have been described, neither molecular mechanisms nor target molecules have been definitively verified for any of these compounds. To help focus investigation in this area, we have reviewed known HbF-inducing agents and their proposed mechanisms of action. We find that in many cases, current models inadequately explain key experimental results. By integrating features of the erythropoietic stress model of HbF induction with data from recent intracellular signaling experiments, we have developed a new model that has the potential to explain several findings that are inconsistent with previous models and to unify most HbF-inducing agents under a common mechanism: cell stress signaling. If correct, this or related models could lead to new opportunities for development of targeted therapies for the beta-hemoglobinopathies.     

Intracellular actin-based transport: how far you go depends on how often you switch

Intracellular molecular motor-driven transport is essential for such diverse processes as mitosis, neuronal function, and mitochondrial transport. Whereas there have been in vitro studies of how motors function at the single-molecule level, and in vivo studies of the structure of filamentary networks, studies of how the motors effectively use the networks for transportation have been lacking. We investigate how the combined system of myosin-V motors plus actin filaments is used to transport pigment granules in Xenopus melanophores. Experimentally, we characterize both the actin filament network, and how this transport is altered in response to external signals. We then develop a theoretical formalism to explain these changes. We show that cells regulate transport by controlling how often granules switch from one filament to another, rather than by altering individual motor activity at the single-molecule level, or by relying on structural changes in the network.     

A prolonged gestational intrahepatic cholestasis: a case report.

Gestational intrahepatic cholestasis, characterized by generalized pruritus and biochemical changes of cholestasis, usually occurs in the third trimester of pregnancy, persists until delivery and resolves spontaneously within the initial four weeks of the puerperium. The incidence is dependent on genetic basis, environmental factors and geographical location. We report the case of a patient with gestational intrahepatic cholestasis with an extraordinary clinical course that extended to the 82nd week postpartum.     

Decreasing daily blood work in hospitals: What works and what doesn't

Recurrent, inappropriate laboratory testing is a costly and wasteful use of healthcare resources. Recognizing this problem, the American Board of Internal Medicine, Canadian Society of Internal Medicine, and the Canadian Association of Pathologist all supported the Choosing Wisely campaign to reduce laboratory investigations in patients who demonstrate clinical and laboratory stability. In this narrative, we review studies looking at a variety of approaches to reduce excessive testing including education, audit and feedback, computerized physician order entry system changes, and forcing functions. Each type of intervention has its own unique advantages and disadvantages, varying in complexity, disruptiveness, effectiveness, and sustainability. Before implementing any quality improvement project, it is important to analyze the local context to identify the root causes for the practice behavior and aim to use the minimal amount of intervention to achieve the desired result. Change is often incremental and will seldom occur with a single intervention or Plan‐Do‐Study‐Act cycle. Garnering the support of opinion leaders and a quality improvement team will help make the process and intervention a success.     

“What makes you think you have special privileges because you are a police officer?” A qualitative exploration of police's role in the risk environment of female sex workers

Worldwide, female sex workers (FSWs) have high rates of HIV. Many factors that escalate their risk lay outside of their control, primarily in the environments in which they practice sex. An understudied yet powerful risk environment is that of police. We qualitatively explored sex workers' interactions with police in their personal and professional lives. Thirty-five FSWs were purposively sampled in Baltimore, MD, in 2012. Women discussed experiences of police verbal harassment, sexual exploitation, extortion, and a lack of police responsiveness to 911 calls in emergencies, largely partner violence. Women's mistrust of police was often developed at an early age and further reinforced by interactions in their personal and professional lives. The study underscores the need for targeting police in reducing sex workers' HIV and other risks. The case for police's role in generating risk is evident, which could be addressed through structural interventions targeting both police practices and policies.     

Treatment of DVT: how long is enough and how do you predict recurrence

Abstract Currently available anticoagulants are effective in reducing the recurrence rate of venous thromboembolism (VTE). However, anticoagulant treatment is associated with an increased risk for bleeding complications. Thus, anticoagulation has to be discontinued when benefit of treatment no longer clearly outweigh its risks. The duration of anticoagulant treatment is currently framed based on the estimated individual risk for recurrent VTE. The incidence of recurrent VTE can be estimated through a two-step decision algorithm. Firstly, the features of the patient (gender), of the initial event (proximal or distal deep vein thrombosis or pulmonary embolism), and the associated conditions (cancer, surgery, etc) provide essential information on the risk for recurrence after anticoagulant treatment discontinuation. Secondly, at time of anticoagulant treatment discontinuation, d-dimer levels and residual thrombosis have been indicated as predictors of recurrent VTE. Current evidence suggests that the risk of recurrence after stopping therapy is largely determined by whether the acute episode of VTE has been effectively treated and by the patient’s intrinsic risk of having a new episode of VTE. All patients with acute VTE should receive oral anticoagulant treatment for three months. At the end of this treatment period, physicians should decide for withdrawal or indefinite anticoagulation. Based on intrinsic patient’s risk for recurrent VTE and for bleeding complications and on patient preference, selected patients could be allocated to indefinite treatment with VKA with scheduled periodic re-assessment of the benefit from extending anticoagulation. Alternative strategies for secondary prevention of VTE to be used after conventional anticoagulation are currently under evaluation. Cancer patients should receive low molecular-weight heparin over warfarin in the long-term treatment of VTE. These patients should be considered for extended anticoagulation at least until resolution of underlying disease. Abbreviated abstract The risk for recurrent venous thromboembolism can be estimated through a two-step algorithm. Firstly, the features of the patient (gender), of the initial event (proximal or distal deep vein thrombosis or pulmonary embolism), and the associated conditions (cancer, surgery, etc) are essential to estimate the risk for recurrence after anticoagulant treatment discontinuation. Secondly, a correlation has been shown between d-dimer levels and residual thrombosis at time of anticoagulant treatment discontinuation and the risk of recurrence. Currently available anticoagulants are effective in reducing the incidence of recurrent venous thromboembolism, but they are associated with an increased risk for bleeding complications. All patients with acute venous thromboembolism should receive oral anticoagulant treatment for three months. At the end of this treatment period physicians should decide for definitive withdrawal or indefinite anticoagulation with scheduled periodic re-assessment of the benefit from extending anticoagulation.     

Severe asthma: What makes it so hard to manage?

Severe asthma presents significant management challenges. Patients can be difficult to control despite use of current standard-of-care therapy, including inhaled corticosteroids and long-acting β-agonists. Alternative diagnoses, noncompliance, and comorbidities all can influence asthma control, future risk, and response to currently available therapy. Definitions of severe asthma evaluate and address these confounding variables, and yet patients are still symptomatic despite aggressive, appropriate therapy. Severe asthma has a distinct pathophysiology including airway remodeling that contributes to the decreased effectiveness of standard therapy. Multiple phenotypes exist within severe asthma that likely require distinct therapeutic approaches to achieve control and improve long-term health outcomes. New therapeutic approaches to these distinct phenotypes will improve our understanding and treatment of this difficult-to-manage disease.