Synergistic efficacy of the combination of ST-246 with CMX001 against orthopoxviruses

The combination of ST-246 and hexadecyloxypropyl-cidofovir or CMX001 was evaluated for synergistic activity in vitro against vaccinia virus and cowpox virus (CV) and in vivo against CV. In cell culture the combination was highly synergistic against both viruses, and the results suggested that combined treatment with these agents might offer superior efficacy in vivo. For animal models, ST-246 was administered orally with or without CMX001 to mice lethally infected with CV. Treatments began 1, 3, or 6 days postinfection using lower dosages than previously used for single-drug treatment. ST-246 was given at 10, 3, or 1 mg/kg of body weight with or without CMX001 at 3, 1, or 0.3 mg/kg to evaluate potential synergistic interactions. Treatment beginning 6 days post-viral inoculation with ST-246 alone only increased the mean day to death at 10 or 3 mg/kg but had no effect on survival. CMX001 alone also had no effect on survival. When the combination of the two drugs was begun 6 days after viral infection using various dosages of the two, a synergistic reduction in mortality was observed. No evidence of increased toxicity was noted with the combination either in vitro or in vivo. These results indicate that combinations of ST-246 and CMX001 are synergistic both in vitro and in vivo and suggest that combination therapy using ST-246 and CMX001 for treatment of orthopoxvirus disease in humans or animals may provide an additional benefit over the use of the two drugs by themselves.     

Magnetic resonance imaging and characterization of spontaneous lesions in a transgenic mouse model of tuberous sclerosis as a model for endothelial cell-based transgene delivery

Tuberous sclerosis (TSC) is an autosomal dominant genetic disorder characterized by abnormalities in cellular migration, proliferation, and differentiation in many tissues. Benign hamartomas develop in multiple organs, believed to be caused by somatic mutation in addition to germ line mutation to cause loss of both alleles of either the TSC1 or TSC2 tumor suppressor gene, with resultant dysregulated growth due to loss of hamartin or tuberin function, respectively. This study focuses on detecting spontaneous lesions in a knockout mouse model of TSC2 by magnetic resonance imaging (MRI) and exploring the efficiency of introducing gene products into lesions, using transduced endothelial cells as gene vehicles. MRI was shown to be effective in detecting spontaneous lesions in multiple tissues as a means of assessing the prevalence of tumors. Tsc(2+/) heterozygous mice were screened at 12-24 months of age. MRI detected 100% of the renal lesions (cystadenomas, renal cell carcinomas) and 75% of the hepatic lesions (hemangiosarcomas), later identified by histology. Cell-mediated gene delivery was evaluated by immunohistochemical analysis of renal, hepatic, and lung lesions after intravenous delivery of MS1 mouse endothelial cells, transduced to express an enhanced form of green fluorescent protein (EGFP). Preliminary immunohistochemical analysis, using a polyclonal antibody to EGFP and a horseradish peroxidase-diaminobenzidine detection system, revealed these cells throughout liver, kidney, and lung sections from injected animals, organs that are frequently affected in TSC2 patients, as well as within the lesions themselves.     

Characteristics of volunteers responding to emergencies in the Public Access Defibrillation Trial

OBJECTIVES: To evaluate the characteristics of volunteers responding to emergencies in the North American Public Access Defibrillation (PAD) Trial. METHODS: The PAD Trial was a prospective evaluation of cardiac arrest survival in community facilities randomized to cardiopulmonary resuscitation (CPR) or to CPR with automated external defibrillators (AEDs). The PAD volunteers' characteristics were analyzed using Poisson regression clustered on the facility and offset by the number of emergency episodes to which volunteers were exposed. RESULTS: A total of 19,320 volunteers in 1260 facilities were trained to provide emergency care. Of these, 8169 volunteers were participating actively at their facility during a time when one or more emergency episodes occurred. There were 1971 emergency episodes responded to by 1245 volunteers. The treatment arm (CPR-only versus CPR+AED) was not associated with the likelihood of volunteer participation in an episode. Likewise, the volunteers' age or sex did not affect response. Volunteers more likely to respond were supervisory/management or security personnel, non-minority participants, volunteers with previous CPR training, volunteers with previous experience in emergency care and those who passed the PAD CPR skills follow-up test. Volunteers who had a formal education beyond a high school level were less likely to respond. CONCLUSIONS: Volunteers with previous emergency training and positions of responsibility in their facility had a greater likelihood of participation in medical emergencies in the PAD Trial.     

Elevated C-reactive protein in acute coronary syndrome presentation is an independent predictor of long-term mortality and heart failure

OBJECTIVES: To assess the ability of C-reactive protein (CRP) to predict long-term outcomes in a chest pain population. DESIGN AND METHODS: CRP was measured at presentation in 446 emergency department patients with acute coronary syndromes. All-cause mortality and hospital discharges for acute myocardial infarction (AMI) and congestive heart failure (CHF) were obtained for up to 8 years following the event. RESULTS: Kaplan-Meier analyses indicated that patients with CRP concentrations above the American Heart Association scientific statement cut-off had a higher rate for death and CHF admissions. After adjusting for troponin concentrations, in a Cox proportional hazard model, only CRP concentrations indicative of an acute phase response (i.e., >7.44 mg/L) were associated with a significant risk for death after 5 years and CHF readmission after 2 years. CONCLUSIONS: Patients presenting early with chest pain with elevated CRP concentrations have a greater long-term risk for death and heart failure.     

Nociceptive aspects of fibromyalgia

Although characterized by a variety of symptoms, chronic widespread pain is the primary complaint bringing most patients with fibromyalgia syndrome (FMS) into the clinic. The etiology of this painful condition is unknown, and any possible relationship between pain and the many other symptoms of FMS is unclear. This article focuses on the unique characteristics of nociception in patients with FMS. The intent is to present criteria that should be considered in the search for biological events that contribute to FMS pain. Based on this approach, examples are proposed of factors that fulfill some criteria and may, therefore, deserve further study for their possible role in pain associated with FMS.     

Screening for venous thromboembolism in traumatic brain injury: limitations of D-dimer assay

OBJECTIVES: To assess whether 2 different D-dimer fibrin degradation assays-a second-generation latex immunosorbent agglutination (LIA) and an enzyme-linked immunosorbent assay (ELISA)-are predictive for the development of deep venous thrombosis (DVT) at the currently accepted level of 500 microg/L of D-dimer assay during the first weeks after traumatic brain injury (TBI) and to correlate over 8 weeks the second-generation LIA assay with the ELISA assay after acute TBI. DESIGN: A case series of persons with TBI were screened for DVT at 2 weeks (+/-3d) using real-time, spectral Doppler ultrasound, as well as D-dimer fibrin split products. All persons were rescreened at 4, 6, and 8 weeks (+/-3d) after injury using D-dimer LIA and ELISA assays. SETTING: A university hospital with a directly connected comprehensive in- and outpatient rehabilitation center that are part of the Traumatic Brain Injury Model Systems. PARTICIPANTS: Over 3 years, 35 TBI subjects with a mean Glasgow Coma Scale score of 6.5 were consecutively enrolled into the trial while on acute care. Persons were at least 16 years of age with no history of treatment for DVT. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Data were analyzed for the levels of D-dimer and risk as established by a predictive value of 500 microg/L. Changes in D-dimer values over time and within subjects were assessed by analysis of variance (ANOVA) with repeated measures, and the methods were correlated. RESULTS: The mean LIA level at 2 weeks was 4.3mg/L and averaged 1.6 mg/L at 8 weeks from injury (P=.012, ANOVA), and the ELISA dropped from 4,748 microg/L to 1.695 microg/L (P=.0022, ANOVA). Except for 1 ELISA value in 1 patient, D-dimer levels were elevated beyond 500 microg/L at 2 weeks. There was a very good correlation between the LIA and the ELISA at 2, 4, 6, and 8 weeks after TBI (P<.0001). In individual cases, there were only occasional discrepancies between the LIA and ELISA methods. There were no positive DVTs at 2 weeks using ultrasound, so prediction of the sensitivity and the specificity of D-dimer with DVT was not possible. CONCLUSION: Using the currently recommended levels of D-dimer to predict DVT is not clinically useful in the acute TBI population.     

Central venous access and handwashing: variability in policies and practices

This study examined variability in handwashing policy between hospitals, variability in handwashing practices in nurses and how practice differed from policy in tertiary paediatric hospitals in Australia and New Zealand. Eight of the possible nine major paediatric hospitals provided a copy of their handwashing and/or central venous access device (CVAD) policies, and 67 nurses completed a survey on their handwashing practices associated with CVAD management. A high degree of variability was found in relation to all the questions posed in the study. There was little consistency between policies and little agreement between policies and clinical practice, with many nurses washing for longer than required by policy. Rigour of handwashing also varied according to the procedure undertaken and the type of CVAD with activities undertaken farther from the insertion site of the device more likely to be performed using a clean rather than an aseptic handwashing technique. As both patients and nursing staff move within and between hospitals, a uniform and evidence-based approach to handwashing is highly desirable.     

Paradoxical fall in proteinuria during pregnancy in an LCAT-deficient patient—A case report

A 29-year-old lady was diagnosed with lecithin:cholesterol acyltransferase (LCAT) deficiency having presented with bilateral corneal clouding, severely reduced high density lipoproteins cholesterol, and proteinuria. She is a compound heterozygote with two LCAT gene mutations, one of which is novel, c.321C>A in exon 3. Surprisingly, the level of proteinuria significantly improved during pregnancy, despite stopping the angiotensin-converting enzyme inhibitor. However, LCAT concentration and activity remained identical during pregnancy and postpartum. Her pregnancy was complicated by rising triglyceride levels from the second trimester requiring treatment with omega-3 fatty acid and fenofibrate. In the last trimester, a further complication arose when she became hypertensive and proteinuria worsened. She was diagnosed with pre-eclampsia and had an emergency cesarean section at 39 weeks delivering a healthy baby. This case adds to the knowledge of the pathophysiology of LCAT deficiency during pregnancy and will be useful in future patient management.     

Adaptive spectral strain estimators for elastography

In conventional elastography, internal tissue deformations, induced by external compression applied to the tissue surface, are estimated by cross-correlation analysis of echo signals obtained before and after compression. Conventionally, strains are estimated by computing the gradient of estimated displacement. However, gradient-based algorithms are highly susceptible to noise and decorrelation, which could limit their utility. We previously developed strain estimators based on a frequency-domain (spectral) formulation that were shown to be more robust but less precise compared to conventional strain estimators, In this paper, we introduce a novel spectral strain estimator that estimates local strain by maximizing the correlation between the spectra of pre- and postcompression echo signals using iterative frequency-scaling of the latter; we also discuss a variation of this algorithm that may be computationally more efficient but less precise. The adaptive spectral strain estimator combines the advantages of time- and frequency-domain methods and has outperformed conventional estimators in experiments and 2-D finite-element simulations.