Acute effects of amiodarone on ultrastructure and electrical activity of isolated guinea pig hearts.

STUDY OBJECTIVE--The aim was to evaluate the effects of tissue concentration of amiodarone on ultrastructure and electrical activity in isolated spontaneously beating Langendorff perfused guinea pig hearts. DESIGN--Group 1: The influence of 10 microM amiodarone over a period of 1 h in a non-recirculated perfusate on conduction intervals, heart rate, creatine kinase concentration in the coronary effluent, coronary flow, and drug accumulation was determined. Group 2: Ultrastructural changes after 30 min and 60 min perfusion with amiodarone were examined. Group 3: Cardiac refractoriness was evaluated following 30 min and 60 min of perfusion with amiodarone. EXPERIMENTAL PREPARATIONS--Isolated hearts of guinea pigs (200-300 g) were used: group 1, n = 6 animals; group 2, n = 3 for each time span; and group 3, n = 6 for each time span. MEASUREMENTS AND MAIN RESULTS--A steady state for the effects of amiodarone on atrioventricular and intraventricular conduction [+31(SEM 5)%, p less than 0.01% +47(12)%, p less than 0.01, respectively] and on heart rate [-30(9)%, p less than 0.01] was reached after 15 min, and on His bundle conduction [+38(17)%, p less than 0.01] after 30 min. QT duration was not affected throughout the duration of the experiment. Cardiac refractoriness was significantly prolonged following 30 min perfusion with 10 microM amiodarone, and was further significantly increased following 60 min perfusion. Amiodarone tissue concentration increased to 365(39) nmol.g-1 wet weight, and this was accompanied by an increase in creatine kinase concentration in the coronary effluent. Coronary flow stayed constant throughout the whole experiment. At the end of the experiment electron microscopic examination of the myocardium of the left ventricle showed accumulation, fusion, and vacuolisation of mitochondria, and perinuclear oedema. CONCLUSIONS--These observations suggest that amiodarone, as well as exerting acute electrophysiological effects, creates ultrastructural changes which probably contribute to its effectiveness in arrhythmias caused by scarred myocardium.     

Rosuvastatin regulates vascular smooth muscle cell phenotypic modulation in vascular remodeling: role for the urokinase receptor

The urokinase (uPA)/urokinase receptor (uPAR) multifunctional system is an important mediator of migration and proliferation of vascular smooth muscle cells (VSMC). However, whether uPA/uPAR-directed mechanisms are involved in the beneficial effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on vascular remodeling remains unexplored. In this study, we have investigated the effect of the hydrophilic statin rosuvastatin on neointimal remodeling, and the role of uPAR. Using an ex vivo organ and in vitro cell culture models we demonstrate that rosuvastatin decreases injury-induced neointima formation and proliferation of medial VSMC in porcine coronary arteries, as well as migration and proliferation of human coronary VSMC. Studies on the underlying mechanisms show that rosuvastatin impairs VSMC transition from their physiological contractile to the pathophysiological synthetic phenotype. These effects are mediated, at least in part, via uPAR, as confirmed by means of rosuvastatin-directed uPAR expression and uPAR silencing in both models. Our findings provide evidence that rosuvastatin modulates VSMC phenotypic changes and subsequently their proliferation and migration, and indicate the important role for uPAR in these processes. This mechanism contributes to the beneficial non-lipid lowering effect of rosuvastatin on negative vascular remodeling.     

Life-threatening complications of extracorporeal treatment in patients with severe eosinophilia

We report three patients with massive eosinophilia of different etiology who developed bronchoconstriction, hypotension, and shock shortly after dialysis or leukapheresis had been begun. In two cases, ethylene oxide-free materials had been used ruling out an allergic reaction related to this compound. Degranulation of eosinophils with release of eosinophil peroxidase may have caused the observed adverse reactions, as suggested by in vitro experiments with blood from the three patients. Our observations draw attention to the fact that extracorporeal therapies may initiate life-threatening complications in patients with severe eosinophilia.     

MASSIVE LOWER GASTROINTESTINAL HAEMORRHAGE SECONDARY TO METASTATIC SQUAMOUS CELL CARCINOMA OF THE LUNG

SUMMARY Clinically significant symptoms due to gastrointestinal metastases from primary lung cancers is rare. A case of life-threatening lower gastrointestinal haemorrhage secondary to metastatic squamous cell carcinoma of the lung is reported. Previous reports of such metastases are reviewed, with reference to management and prognosis. After resection of colonic metastases from squamous cell lung cancer, survival is similar to that for primary disease. It is suggested that patients with known or suspected squamous cell lung cancer presenting with lower gastrointestinal symptoms be managed as aggressively as those with no previous history of disease.     

A systematic review of risk of HIV transmission through biting or spitting: implications for policy

Objectives

The perceived threat of HIV transmission through spitting and biting is evidenced by the increasing use of “spit hoods” by Police Forces in the UK. In addition, a draft parliamentary bill has called for increased penalties for assaults on emergency workers, citing the risk of communicable disease transmission as one justification. We aimed to review literature relating to the risk of HIV transmission through biting or spitting.

Methods

A systematic literature search was conducted using Medline, Embase and Northern Lights databases and conference websites using search terms relating to HIV, AIDS, bite, spit and saliva. Inclusion and exclusion criteria were applied to identified citations. We classified plausibility of HIV transmission as low, medium, high or confirmed based on pre‐specified criteria.

Results

A total of 742 abstracts were reviewed, yielding 32 articles for full‐text review and 13 case reports/series after inclusion and exclusion criteria had been applied. There were no reported cases of HIV transmission related to spitting and nine cases identified following a bite, in which the majority occurred between family (six of nine), in fights involving serious wounds (three of nine), or to untrained first‐aiders placing fingers in the mouth of someone having a seizure (two of nine). Only four cases were classified as highly plausible or confirmed transmission. None related to emergency workers and none were in the UK.

Conclusions

There is no risk of transmitting HIV through spitting, and the risk through biting is negligible. Post‐exposure prophylaxis is not indicated after a bite in all but exceptional circumstances. Policies to protect emergency workers should be developed with this evidence in mind.     

中西医结合治疗老年高脂血症

目的：探讨中西医结合治疗高脂血症的临床疗效。方法：符合高脂血症标准的老年患者120例，随机分为A、B2组各60例，A组采用益肾化淤、利湿化浊为主的中药及西药辛伐他汀片治疗；B组则单纯用辛伐他汀片治疗。治疗前及治疗4周后2组均行全套血脂水平测定。结果：与B组比较，A组血清总胆固醇（TC）及甘油三酯（TG）均明显下降，HDL明显上升（均P〈0．05）；A组临床控制率明显高于B组（P〈0．05）；治疗后A组患者未见肝功能损害，B组转氨酶及转肽酶轻度异常，2例。停药3个月后，A组复发率低于B组（2．2％、8．8％，P〈0．05）。结论：中西医结合治疗老年高脂血症的临床效果明显优于单一的一种治疗方法，值得临床进一步推广应用。     

Folding and ligand recognition of the TPP riboswitch aptamer at single-molecule resolution

Thiamine pyrophosphate (TPP)-sensitive mRNA domains are the most prevalent riboswitches known. Despite intensive investigation, the complex ligand recognition and concomitant folding processes in the TPP riboswitch that culminate in the regulation of gene expression remain elusive. Here, we used single-molecule fluorescence resonance energy transfer imaging to probe the folding landscape of the TPP aptamer domain in the absence and presence of magnesium and TPP. To do so, distinct labeling patterns were used to sense the dynamics of the switch helix (P1) and the two sensor arms (P2/P3 and P4/P5) of the aptamer domain. The latter structural elements make interdomain tertiary contacts (L5/P3) that span a region immediately adjacent to the ligand-binding site. In each instance, conformational dynamics of the TPP riboswitch were influenced by ligand binding. The P1 switch helix, formed by the 5′ and 3′ ends of the aptamer domain, adopts a predominantly folded structure in the presence of Mg²⁺ alone. However, even at saturating concentrations of Mg²⁺ and TPP, the P1 helix, as well as distal regions surrounding the TPP-binding site, exhibit an unexpected degree of residual dynamics and disperse kinetic behaviors. Such plasticity results in a persistent exchange of the P3/P5 forearms between open and closed configurations that is likely to facilitate entry and exit of the TPP ligand. Correspondingly, we posit that such features of the TPP aptamer domain contribute directly to the mechanism of riboswitch-mediated translational regulation.     

A Test of Adolescent Internalizing and Externalizing Symptoms as Prospective Predictors of Type of Trauma Exposure and Posttraumatic Stress Disorder

The present study utilized longitudinal data from a high‐risk community sample (N = 377; 166 trauma‐exposed; 202 males; 175 females; 73% non‐Hispanic Caucasian) to test pretrauma measures of adolescent internalizing and externalizing symptoms as unique prospective predictors of type of trauma exposure and PTSD over and above the influence of correlated family adversity (a composite of family conflict, stress, and parental psychopathology). Data were analyzed with logistic and multinomial logistic regressions. Results indicated that females, but not males, with higher levels of internalizing (OR = 2.91) and externalizing (OR = 2.37) symptoms during adolescence were significantly more likely to be exposed to assaultive violence (over and above family adversity). In fact, males with higher levels of internalizing symptoms were significantly less likely to be exposed to assaultive violence (OR = 0.54). Neither internalizing nor externalizing symptoms uniquely predicted exposure to traumatic events that did not involve assaultive violence. Among trauma‐exposed participants, the unique association between internalizing symptoms and later PTSD yielded an odds ratio of 1.79 (p = .07) over and above the influences of family adversity, type of trauma exposure, and gender. Assaultive violence exposure fully mediated the association between females’ externalizing symptoms and future PTSD. Findings may help inform the prevention of both assaultive violence exposure and PTSD.     

Biologic basis for interleukin-1 in disease

To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in disease, investigators have studied how production of the different members of the IL-1 family is controlled, the various biologic activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family, and the complexity of intracellular signaling. Mice deficient in IL-1Beta, IL-1Beta converting enzyme, and IL-1R type I have also been studied. Humans have been injected with IL- 1 (either IL-1alpha or IL-1beta) for enhancing bone marrow recovery and for cancer treatment. The IL-1-specific receptor antagonist (IL-1Ra) has also been tested in clinical trials. The topics discussed in this review include production and activities of IL-1 and IL-1Ra molecules, the effects of IL-1 on gene expression, functions of cell-bound and soluble IL-1 receptors, the importance of the IL-1R accessory protein, newly discovered signal transduction pathways, naturally occurring cytokines limiting IL-1 production or activity, the effects of blocking cyclooxygenase and nitric oxide, and the outcomes of IL-1 and IL-1 Ra in human trials. Special attention is paid to IL-1beta converting enzyme and programmed cell death. The roles of IL-1 in hematopoiesis, leukemia, atherosclerosis, and growth of solid tumors are also discussed. This is a lengthy review, with 586 citations chosen to illustrate specific areas of interest rather than a compendium of references. At the end of each section, a short commentary summarizes what the author considers established or controversial topics linking the biology of IL-1 to mechanisms of disease.