Paracatalytic induction: Subverting specificity in hedgehog protein autoprocessing with small molecules.

Paracatalytic inducers are antagonists that shift the specificity of biological catalysts, resulting in non-native transformations. In this Chapter we describe methods to discover paracatalytic inducers of Hedgehog (Hh) protein autoprocessing. Native autoprocessing uses cholesterol as a substrate nucleophile to assist in cleaving an internal peptide bond within a precursor form of Hh.

A cell-based bioluminescence reporter assay of human Sonic Hedgehog protein autoprocessing to identify inhibitors and activators.

The Sonic Hedgehog (SHh) precursor protein undergoes biosynthetic autoprocessing to cleave off and covalently attach cholesterol to the SHh signaling ligand, a vital morphogen and oncogenic effector protein. Autoprocessing is self-catalyzed by SHhC, the SHh precursor's C-terminal enzymatic domain. A method to screen for small molecule regulators of this process may be of therapeutic value.

Barriers to Enrollment in Post-Stroke Brain Stimulation in a Racially and Ethnically Diverse Population.

Background And Purpose: Brain stimulation is an adjuvant strategy to promote rehabilitation after stroke. Here, we evaluated the influence of inclusion/exclusion criteria on enrollment in a transcranial direct current stimulation (tDCS) trial in the context of a racially/ethnically diverse acute stroke service at University of Texas Southwestern (UTSW).

Methods: 3124 (59.

Nanomolar, Noncovalent Antagonism of Hedgehog Cholesterolysis: Exception to the "Irreversibility Rule" for Protein Autoprocessing Inhibition.

Hedgehog (Hh) signaling ligands undergo carboxy terminal sterylation through specialized autoprocessing, called cholesterolysis. Sterylation is brought about intramolecularly in a single turnover by an adjacent enzymatic domain, called HhC, which is found in precursor Hh proteins only. Previous attempts to identify antagonists of the intramolecular activity of HhC have yielded inhibitors that bind HhC irreversibly through covalent mechanisms, as is common for protein autoprocessing inhibitors.

Outcomes Associated with Dronedarone Use in Patients with Atrial Fibrillation.

The antiarrhythmic drug dronedarone was designed to reduce the extra-cardiac adverse effects associated with amiodarone use in treatment of patients with atrial fibrillation / atrial flutter (AF/AFL). This epidemiological study used a retrospective cohort design to compare risk of cardiovascular-related hospitalizations and death in AF/AFL patients treated with dronedarone versus other antiarrhythmic drugs (AADs). AF/AFL patients with incident dronedarone fills were matched by propensity score (PS) to incident users of other AADs.

Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.

Hedgehog proteins, a family of vital cell signaling factors, are expressed in precursor form, which requires specialized autoprocessing, called cholesterolysis, for full biological activity. Cholesterolysis occurs through the action of the precursor's C-terminal enzymatic domain, HhC. In this work, we describe HhC activator compounds (HACs), a novel class of noncovalent modulators that induce autoprocessing infidelity, diminishing native cholesterolysis in favor of precursor autoproteolysis, an otherwise minor and apparently nonphysiological side reaction.

Sterol A-ring plasticity in hedgehog protein cholesterolysis supports a primitive substrate selectivity mechanism.

Cholesterolysis of Hedgehog family proteins couples endoproteolysis to protein C-terminal sterylation. The transformation is self-catalyzed by HhC, a partially characterized enzymatic domain found in precursor forms of Hedgehog. Here we explore spatial ambiguity in sterol recognition by HhC, using a trio of derivatives where the sterol A-ring is contracted, fused, or distorted.

Long-term risk of hysterectomy and ectopic pregnancy among Vietnamese women using the quinacrine hydrochloride pellet system vs. intrauterine devices or tubal ligation for contraception.

Objectives: Determine the long-term risk of hysterectomy and ectopic pregnancy in women using the quinacrine hydrochloride pellet system of permanent contraception (QS) relative to the comparable risk in women using Copper T intrauterine device (IUD) or tubal ligation surgery (TL) for long-term or permanent contraception.

Methods: This was a retrospective cohort study, conducted in the Northern Vietnamese provinces of Ha Nam, Nam Dinh, Ninh Binh and Thai Binh. Women who had their first QS procedure, last IUD insertion or TL between 1989 and 1996 were interviewed regarding post-procedure health outcomes approximately 16 years post exposure.

Long-term risk of reproductive cancer among Vietnamese women using the quinacrine hydrochloride pellet system vs. intrauterine devices or tubal ligation for contraception.

Objectives: To determine the long-term risk of reproductive tract cancer in women using the quinacrine hydrochloride pellet system of permanent contraception (QS) relative to the comparable risk in women using Copper T intrauterine device (IUD) or tubal ligation surgery (TL) for long-term or permanent contraception.

Methods: This was a retrospective cohort study, conducted in the Northern Vietnamese provinces of Ha Nam, Nam Dinh, Ninh Binh and Thai Binh. Women who had their first QS procedure, last IUD insertion or TL between 1989 and 1996 were interviewed regarding post-procedure health outcomes, particularly reproductive tract cancers.

Efficacy of a novel formulation of L-Carnitine, creatine, and leucine on lean body mass and functional muscle strength in healthy older adults: a randomized, double-blind placebo-controlled study.

Background: Progressive decline in skeletal muscle mass and function are growing concerns in an aging population. Diet and physical activity are important for muscle maintenance but these requirements are not always met. This highlights the potential for nutritional supplementation.

Neonatal complications in vacuum-assisted vaginal delivery: are they associated with number of pulls, cup detachments, and duration of vacuum application?

Purpose: To explore whether the characteristics of vacuum delivery are associated with the occurrence of head injury and neonatal complications.

Methods: Retrospectively cohort study of vacuum-assisted attempted vaginal deliveries of singletons. We studied the association of total duration of vacuum application and number of pulls and cup dislodgement with (1) primary outcome: the occurrence of major (subgaleal hemorrhage, skull fracture, and intracranial hemorrhage) or minor (cephalohematoma, scalp laceration more extensive than simple abrasions) neonatal head injuries and (2) secondary outcome: the occurrence of neonatal complications, including 5-min Apgar score <7, umbilical artery pH < 7.

Effect of oxytocin during labor on neonatal acidemia.

Objective: To assess the factors affecting neonatal acidemia, including occurrence of tachysystole/hypertonus in fetuses exposed to oxytocin during labour and with continuously-monitored fetal heart rate (FHR) tracings.

Methods: Prospective observational study of all women with term pregnancies who received oxytocin for induction/augmentation of labour. FHR tracings were prospectively classified using ACOG classification.

The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans.

The renin-angiotensin-aldosterone (RAAS) and renal dopaminergic systems interact to maintain sodium balance. High NaCl intake increases renal synthesis of dopamine and dopaminergic receptor activity, decreasing epithelial sodium transport, whereas sodium deficit activates the RAAS, increasing epithelial sodium transport. We tested the hypothesis that attenuation of the natriuretic effect of dopamine D1-like receptors during salt restriction results in part from increased RAAS activity in seven salt-resistant normotensive adults using a double-blind placebo-controlled balanced crossover design.

Fetal hydronephrosis: natural history and risk factors for postnatal surgery.

Background: The objective of this study was to assess the ability of prenatal ultrasound to predict an unfavorable outcome and the need for postnatal surgery in cases of fetal hydronephrosis (HY).

Methods: Antenatal HY was classified according to the renal pelvis anteroposterior (AP) diameter in the third trimester. Postnatal outcome was considered favorable in the presence of spontaneous resolution or postnatal diagnosis of HY <20 mm, and unfavorable in the presence of postnatal diagnosis of >20 mm HY or urinary tract pathologies.

Defining risk groups to yellow fever vaccine-associated viscerotropic disease in the absence of denominator data.

Several risk groups are known for the rare but serious, frequently fatal, viscerotropic reactions following live yellow fever virus vaccine (YEL-AVD). Establishing additional risk groups is hampered by ignorance of the numbers of vaccinees in factor-specific risk groups thus preventing their use as denominators in odds ratios (ORs). Here, we use an equation to calculate ORs using the prevalence of the factor-specific risk group in the population who remain well.

Wolf Motor Function Test for characterizing moderate to severe hemiparesis in stroke patients.

Objective: To extend the applicability of the Wolf Motor Function Test (WMFT) to describe the residual functional abilities of moderate to severely affected stroke patients.

Design: Data were collected as part of 2 double-blind, sham-controlled, randomized interventional studies: the Transcranial Direct Current Stimulation (tDCS) in Chronic Stroke Recovery and the tDCS Enhanced Stroke Recovery and Cortical Reorganization. Stroke patients were evaluated with the upper extremity Fugl-Meyer (UFM) and the WMFT in the same setting before treatment.

How the 2008 stock market crash and seasons affect total and cardiac deaths in Los Angeles County.

Various stressors trigger cardiac death. The objective was to investigate a possible relation between a stock market crash and cardiac death in a large population within the United States. We obtained daily stock market data (Dow Jones Industrial Average Index), death certificate data for daily deaths in Los Angeles County (LA), and annual LA population estimates for 2005 through 2008.

Ghrelin agonist TZP-101/ulimorelin accelerates gastrointestinal recovery independently of opioid use and surgery type: covariate analysis of phase 2 data.

Background: Delayed recovery of gastrointestinal (GI) motility is a common complication following surgery. TZP-101/ulimorelin is a macrocyclic peptidomimetic ghrelin receptor agonist with GI promotility effects that significantly accelerates time to recovery of GI motility compared to placebo following partial colectomy. It is also well tolerated.

A phase I study of low-pressure hyperbaric oxygen therapy for blast-induced post-concussion syndrome and post-traumatic stress disorder.

This is a preliminary report on the safety and efficacy of 1.5 ATA hyperbaric oxygen therapy (HBOT) in military subjects with chronic blast-induced mild to moderate traumatic brain injury (TBI)/post-concussion syndrome (PCS) and post-traumatic stress disorder (PTSD). Sixteen military subjects received 40 1.

Variability in rate of cervical dilation in nulliparous women at term.

Background: Cervical dilatation is commonly documented on a partogram indicating the expected rate of progress of labor. Although deviations from such a line can be used to indicate abnormal progress, what constitutes the "normal" rate of cervical dilation is still largely unknown. The objectives of this study were to assess the variability of the rate of cervical dilation in nulliparous women and to determine whether the rate of labor was independent of dilation on admission.

Hospital length of stay--does 1% TBSA really equal 1 day?

Length of stay (LOS) continues to be a standard variable when evaluating progress and outcomes in burn care. Common wisdom would dictate that this measure is linearly related to TBSA. Is this truly the case? A retrospective review of the National Burn Repository was conducted to evaluate factors that affect hospital LOS.

Diet as prophylaxis and treatment for venous thromboembolism?

Background: Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S.

Epidemiology of bloodstream infections in burn-injured patients: a review of the national burn repository.

Bloodstream infections (BSIs) are a major cause of morbidity and mortality in thermally injured patients. However, these infections have not been well defined in this patient population. Therefore, the authors performed a retrospective case-control study to characterize the epidemiology, microbiology, and outcomes of burn-associated BSIs.