Clinical review: Reappraising the concept of immediate defibrillatory attempts for out-of-hospital ventricular fibrillation

Despite well developed emergency medical services with rapid response advanced life support capabilities, survival rates following out-of-hospital ventricular fibrillation (VF) have remained bleak in many venues. Generally, these poor resuscitation rates are attributed to delays in the performance of basic cardiopulmonary resuscitation by bystanders or delays in defibrillation, but recent laboratory data suggest that the current standard of immediately providing a countershock as the first therapeutic intervention may be detrimental when VF is prolonged beyond several minutes. Several studies now suggest that when myocardial energy supplies begin to dwindle following more prolonged periods of VF, improvements in coronary artery perfusion must first be achieved in order to prime the heart for successful return of spontaneous circulation after defibrillation. Therefore, before countershocks, certain pharmacologic and/or mechanical interventions might take precedence during resuscitative efforts. This evolving concept has been substantiated recently by clinical studies, including a controlled clinical trial, demonstrating a significant improvement in survival when basic cardiopulmonary resuscitation is provided for several minutes before the initial countershock. Although this evolving concept differs from current standards and may pose a potential problem for automated defibrillator initiatives (e.g. public access defibrillation), successful defibrillation and return of spontaneous circulation have been rendered more predictable by evolving technologies that can score the VF waveform signal and differentiate between those who can be shocked immediately and those who should receive other interventions first.     

Copper and quaternary ammonium cations exert synergistic bactericidal and antibiofilm activity against Pseudomonas aeruginosa

Biofilms are slimy aggregates of microbes that are likely responsible for many chronic infections as well as for contamination of clinical and industrial environments. Pseudomonas aeruginosa is a prevalent hospital pathogen that is well known for its ability to form biofilms that are recalcitrant to many different antimicrobial treatments. We have devised a high-throughput method for testing combinations of antimicrobials for synergistic activity against biofilms, including those formed by P. aeruginosa. This approach was used to look for changes in biofilm susceptibility to various biocides when these agents were combined with metal ions. This process identified that Cu²⁺ works synergistically with quaternary ammonium compounds (QACs; specifically benzalkonium chloride, cetalkonium chloride, cetylpyridinium chloride, myristalkonium chloride, and Polycide) to kill P. aeruginosa biofilms. In some cases, adding Cu²⁺ to QACs resulted in a 128-fold decrease in the biofilm minimum bactericidal concentration compared to that for single-agent treatments. In combination, these agents retained broad-spectrum antimicrobial activity that also eradicated biofilms of Escherichia coli, Staphylococcus aureus, Salmonella enterica serovar Cholerasuis, and Pseudomonas fluorescens. To investigate the mechanism of action, isothermal titration calorimetry was used to show that Cu²⁺ and QACs do not interact in aqueous solutions, suggesting that each agent exerts microbiological toxicity through independent biochemical routes. Additionally, Cu²⁺ and QACs, both alone and in combination, reduced the activity of nitrate reductases, which are enzymes that are important for normal biofilm growth. Collectively, the results of this study indicate that Cu²⁺ and QACs are effective combinations of antimicrobials that may be used to kill bacterial biofilms.     

The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines

Type 1 neurofibromatosis (NF1) is a common autosomal dominant disorder that results in neuroectodermal tumors. The NF1 tumor-suppressor gene encodes neurofibromin, which includes a GTPase-activating domain for Ras inactivation. Affinity purification showed N-Ras to be the predominant activated isoform of Ras in two independent neurofibrosarcoma cell lines from NF1 patients (lines ST88-14 and NF90-8). These NF1 cells also demonstrated increased constitutive activity of the extracellular signal-regulated kinases 1 and 2 (ERK1,2) mitogen-activated protein (MAP) kinases compared with a sporadic malignant schwannoma cell line that maintains neurofibromin expression (STS-26T). Thus, MAP kinase kinase (MEK) inhibitors may be a rational approach to NF1 therapy. The MEK inhibitors PD98059 [2'-amino-3'-methoxyflavone], PD184352 (also called CI-1040) [2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide], and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] all produced concentration-dependent suppression of the proliferation of the three cell lines. Individual MEK inhibitors had similar effects in all three cell lines. However, only the antiproliferative effects of PD184352 correlated closely with the elimination of ERK1,2 MAP kinase activities. PD98059 was primarily cytostatic, whereas U0126 and PD184352 were cytotoxic. Only PD184352 induced apoptosis in all three lines, as indicated by morphology, activation of DEVDase, procaspase-3 cleavage, and the appearance of populations having sub-G(0)/G(1) DNA contents. The differential effects of the MEK inhibitors on cell survival were not dependent on p53 status or effects on the ERK5 pathway. PD184352 was also proapoptotic to primary rat Schwann cells. Hence, although PD184352 effectively killed neurofibrosarcoma cells, its effects on normal Schwann cells may limit its usefulness in the clinic.     

Biplanar Measurement of Thoracolumbar Curvature in Older Adults Using an Electromagnetic Tracking Device

Singh DK, Bailey M, Lee R. Biplanar measurement of thoracolumbar curvature in older adults using an electromagnetic tracking device.

Objectives

To develop a new biplanar method of thoracolumbar curvature measurement by using an electromagnetic tracking device and to study the effects of aging on the thoracolumbar curvature.

Design

Cross-sectional study.

Setting

Human movement laboratory.

Participants

Healthy (N=52, 26 younger and 26 older) volunteers.

Interventions

Not applicable.

Main Outcome Measures

An electromagnetic tracking device was used to trace the thoracolumbar curvature by recording the positions of the spinous processes of the spine. The coordinates of the curvature were fitted with polynomial equations, and the magnitudes of thoracic kyphosis, lumbar lordosis, and lateral thoracic and lumbar curves were determined.

Results

The present technique was shown to be highly reliable in measuring thoracolumbar curvature with an intraclass correlation coefficient of more than .90. The mean thoracic kyphosis (−46.95°±11.41°) in the older adults was significantly larger than that in the younger adults (−38.82°±9.86°) (P<.01). However, there were no significant differences in lumbar lordosis and lateral curvatures between the 2 subject groups.

Conclusions

The present study provided evidence of an increase in thoracic kyphosis in older adults. The method of measurement presented in this study was found to provide reliable biplanar data that will be useful in a clinical setting.     

Diagnosis and Treatment of Patients with Thyroid Cancer

Background

Thyroid cancer is the most common malignancy of the endocrine system, representing 3.8% of all new cancer cases in the United States and is the ninth most common cancer overall. The American Cancer Society estimates that 62,450 people in the United States will be diagnosed with thyroid cancer in 2015, and 1950 deaths will result from the disease.

Objective

To review the current approach to the diagnosis and treatment of patients with thyroid cancer.

Discussion

Over the past 3 decades, there has been a dramatic increase in the number of people diagnosed with thyroid cancer, which may be attributable to the wide use of imaging studies, including ultrasounds, computed tomography, magnetic resonance imaging, and positron emission tomography scans that incidentally detect thyroid nodules. Thyroid cancer is divided into several main types, with papillary thyroid cancer being the most common. The treatment options for patients with thyroid cancer include the surgical removal of the entire thyroid gland (total thyroidectomy), radioactive iodine therapy, and molecular-targeted therapies with tyrosine kinase inhibitors. This article summarizes the diagnosis and treatment of thyroid cancer, with recommendations from the American Thyroid Association regarding thyroid nodules and differentiated thyroid cancer. Recently approved drugs and treatment trends are also explored.

Conclusion

The prognosis and treatment of thyroid cancer depend on the tumor type and its stage at the time of diagnosis. Many thyroid cancers remain stable, microscopic, and indolent. The increasing treatment options for patients with thyroid cancer, including therapies that were recently approved by the US Food and Drug Administration, have kept the mortality rate from this malignancy low, despite the increase in its incidence. Early diagnosis and appropriate treatment can improve prognosis and reduce mortality.     

Elevated ARG1 expression in primary monocytes-derived macrophages as a predictor of radiation-induced acute skin toxicities in early breast cancer patients

Radiation therapy (RT) the front-line treatment after surgery for early breast cancer patients is associated with acute skin toxicities in at least 40% of treated patients. Monocyte-derived macrophages are polarized into functionally distinct (M1 or M2) activated phenotypes at injury sites by specific systemic cytokines known to play a key role in the transition between damage and repair in irradiated tissues. The role of M1 and M2 macrophages in RT-induced acute skin toxicities remains to be defined. We investigated the potential value of M1 and M2 macrophages as predictive factors of RT-induced skin toxicities in early breast cancer patients treated with adjuvant RT after lumpectomy. Blood samples collected from patients enrolled in a prospective clinical study (n = 49) were analyzed at baseline and after the first delivered 2Gy RT dose. We designed an ex vivo culture system to differentiate patient blood monocytes into macrophages and treated them with M1 or M2-inducing cytokines before quantitative analysis of their “M1/M2” activation markers, iNOS, Arg1, and TGFß1. Statistical analysis was performed to correlate experimental data to clinical assessment of acute skin toxicity using Common Toxicity Criteria (CTC) grade for objective evaluation of skin reactions. Increased ARG1 mRNA significantly correlated with higher grades of erythema, moist desquamation, and CTC grade. Multivariate analysis revealed that increased ARG1 expression in macrophages after a single RT dose was an independent prognostic factor of erythema (p = 0 .032), moist desquamation (p = 0 .027), and CTC grade (p = 0 .056). Interestingly, multivariate analysis of ARG1 mRNA expression in macrophages stimulated with IL-4 also revealed independent prognostic value for predicting acute RT-induced toxicity factors, erythema (p = 0 .069), moist desquamation (p = 0 .037), and CTC grade (p = 0 .046). To conclude, our findings underline for the first time the biological significance of increased ARG1 mRNA levels as an early independent predictive biomarker of RT-induced acute skin toxicities.