Biologic therapy for psoriasis: an update on the tumor necrosis factor inhibitors infliximab, etanercept, and adalimumab, and the T-cell-targeted therapies efalizumab and alefacept

Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European population. Over the last several years, one of the major focuses in psoriasis research has been the development of biologic therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention with fewer side effects than traditional therapies. The goal of this article is to update the progress of the tumor necrosis inhibitors which are available, or under investigation, for clinical use in psoriasis: infliximab, etanercept, and adalimumab, as well as the T-cell-targeted therapies efalizumab and alefacept (Table 1).     

Imbalance between matrix metalloproteinases (MMP-9 and MMP-2) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in acute respiratory distress syndrome patients

OBJECTIVE: Matrix metalloproteinases (MMPs) are known to be involved in degradation of extracellular matrix. We aimed to assess the role of MMPs and their natural inhibitors (TIMPs) in the genesis and the evolution of acute respiratory distress syndrome (ARDS). DESIGN: Prospective, clinical study. SETTING: Intensive care unit of a university hospital. PATIENTS: Twenty-one patients were assigned to three different groups: Group 1 patients developed ARDS that rapidly resolved in <4 days; Group 2 patients developed ARDS lasting >8 days; Group 3 (control group) patients had clinical criteria for hospital-acquired pneumonia without ARDS. INTERVENTION: Bronchoalveolar lavages were performed on day 0 of the onset of ARDS and on days 4, 8, and 12 for unresolving ARDS. For group 3, the bronchoalveolar lavages were performed on day 0 of the pneumonia. On these bronchoalveolar lavage fluids, we measured the amount of MMP-9 and -2 and their inhibitors TIMP-1 and -2. MEASUREMENTS AND MAIN RESULTS: The amount of MMP-9 measured by enzyme-linked immunosorbent assay was significantly lower in the bronchoalveolar lavages from patients with ARDS (group 1 and group 2) compared with the control group (p <.01) throughout the study. The ratio MMP-9/TIMP-1 was also significantly smaller and was less than one in the two ARDS groups (p <.05) compared with the control group (group 3), where this ratio was greater than one. In the second bronchoalveolar lavages, this ratio was greater than one only in the ARDS group that rapidly resolved (group 1), whereas it stayed less than one when the ARDS was lasting (group 2). Concerning the quantity of MMP-2 and the ratio MMP-2/TIMP-2, there was no statistical difference between the three groups throughout the study. Using zymography, there was no significant difference in the amounts of active and latent MMP-9 between the three groups. Moreover, no significant difference in the quantity of latent and active MMP-2 in the three groups was noted. CONCLUSION: These results suggest that the MMP-9 level and MMP-9/TIMP-1 ratio play a role in the pathogenesis of ARDS and, namely, the imbalance between MMP-9 and TIMP-1 would participate in airway remodeling leading to either short- or long-course ARDS. The ratio MMP-9/TIMP-1 could be a predictive factor of the ARDS evolution.     

Euthanasia and assisted suicide in the Netherlands: Clarifying the practice and the nurse's role

Many people believe that euthanasia and assisted suicide are condoned carte blanche in the Netherlands. Not true. Both are formally forbidden by criminal law and can be administered only when certain procedures and criteria have been followed. Below, a look at the policies and practices regarding euthanasia and assisted suicide in The Netherlands and the role of nurses in this area.     

Evaluation of a needle-free delivery platform for prime-boost immunization with DNA and modified vaccinia virus ankara vectors expressing herpes simplex virus 2 glycoprotein D

A previous report described a prime-boost immunization strategy using plasmid and modified vaccinia virus Ankara (MVA) vectors expressing herpes simplex virus 2 glycoprotein D (gD). Enhanced humoral and cellular immune responses were elicited by the prime-boost combination compared to plasmid DNA immunization alone. Surprisingly, a more diverse antibody isotype response, and a greater antibody and cellular immune response, was obtained if the gD MVA vector was used as the priming immunization rather than the gD plasmid vector. The present report evaluates the use of a needle-free delivery platform (Biojector) for delivery of plasmid and MVA gD-expressing vectors in a prime-boost immunization strategy. Needle-free delivery of both plasmid and MVA gD expression vectors was efficient, reproducible, and elicited a strong immune response in immunized mice. Biojector delivery of plasmid DNA was able to evoke a broader isotype response and cellular immune response than that obtained by gene gun delivered plasmid DNA. Further, DNA priming by Biojector delivery as part of a prime-boost procedure with MVA-gD2 resulted in a diverse antibody isotype distribution and enhanced cellular immune responses, similar to the responses obtained when MVA-gD2 was used as the priming immunization. Thus, needle-free delivery of plasmid DNA may provide additional flexibility and options for effective prime-boost vaccination.     

Deep brain stimulation for psychiatric disease: contributions and validity of animal models

During treatment with deep brain stimulation (DBS), electrical current is delivered into the brain parenchyma through implanted electrodes. Although this technique is routinely used in the treatment of Parkinson's disease, essential tremor, and dystonia, a growing number of neuropsychiatric applications for DBS are being investigated. Investigators can use animal models of these diseases to study the mechanisms through which DBS exerts its effects, to explore new applications of this therapy, and to identify and characterize alternative stimulation targets. Here, we discuss preclinical DBS research that provides insight into the mechanisms underlying cognitive and psychiatric applications of this technique, emphasizing the predictive validity of animal models and their potential use in translational research.     

Symptomatic peripheral arterial disease: the value of a validated questionnaire and a clinical decision rule

BACKGROUND: If a validated questionnaire, when applied to patients reporting with symptoms of intermittent claudication, could adequately discriminate between those with and without peripheral arterial disease, GPs could avoid the diagnostic measurement of the ankle brachial index. AIM: To investigate the Edinburgh Claudication Questionnaire (ECQ) in general practice and to develop a clinical decision rule based on risk factors to enable GPs to easily assess the likelihood of peripheral arterial disease. DESIGN OF STUDY: An observational study. SETTING: General practice in The Netherlands. METHOD: This observational study included patients of > or =55 years visiting their GP for symptoms suggestive of intermittent claudication or with one risk factor. The ECQ and the ankle brachial index were performed. The prevalence of peripheral arterial disease, defined as an ankle brachial index <0.9, was related to risk factors using logistic regression analyses, on which a clinical decision rule was developed and related to the presence of peripheral arterial disease. RESULTS: Of the 4790 included patients visiting their GP with symptoms suggestive of intermittent claudication, 4527 were eligible for analyses. The prevalence of peripheral arterial disease in this group was 48.3%. The sensitivity of the ECQ was only 56.2%. The prevalence of peripheral arterial disease in a clinical decision rule that included age, male sex, smoking, hypertension, hypercholesterolemia, and a positive ECQ, increased from 14% in the lowest to 76% in the highest category. CONCLUSION: This study indicates that the ECQ alone has an inadequate diagnostic value in detecting patients with peripheral arterial disease. The ankle brachial index should be performed to diagnose peripheral arterial disease in patients with complaints suggestive of intermittent claudication, although our clinical decision rule could help to differentiate between extremely high and lower prevalence of peripheral arterial disease.     

Expression of nectin-1 in normal and herpes simplex virus type 1-infected murine brain.

Nectin-1 is an adherens junction protein that serves as an entry receptor for neurotropic herpes simplex virus (HSV). The expression of nectin-1 in the central nervous system (CNS) has not been well defined. Furthermore, it is not known whether HSV infection has an effect on nectin-1 expression in the brain. To better understand nectin-1 expression in normal and HSV-infected brain, the authors used immunohistochemistry to characterize the expression of nectin-1 in brain tissue of uninfected adult mice and mice infected with HSV-1. In the CNS of untreated and mock-infected mice, virtually all neurons, ependymal cells, choroid plexus epithelial cells, meningothelial cells, and vascular endothelial cells expressed nectin-1. Many oligodendrocytes, astrocytes, and vascular smooth muscle cells also demonstrated nectin-1 expression, but a minority of these cells did not stain for nectin-1. Brain tissue derived from mice euthanized 5 to 8 days after intracerebral inoculation of HSV-1 showed inflammation and widespread expression of HSV-1 proteins in neurons. In HSV-1-infected brains, many inflammatory cells showed nectin-1 expression and neuronal nectin-1 staining showed a wider variation in signal strength than that detected in uninfected tissues. Many neurons showing nuclear fragmentation consistent with the morphologic appearance of apoptosis showed little or no evidence of nectin-1 expression, whereas occasional neurons stained more intensely positive for nectin-1 than those in uninfected brain tissue. These findings confirm and extend previous observations of nectin-1 expression in the nervous system and suggest that HSV-1 infection leads to changes in nectin-1 expression in the CNS, which may contribute to HSV-induced pathology and dissemination.     

Local frequency dependence in transcranial ultrasound transmission

The development of large-aperture multiple-source transducer arrays for ultrasound transmission through the human skull has demonstrated the possibility of controlled and substantial acoustic energy delivery into the brain parenchyma without the necessitation of a craniotomy. The individual control of acoustic parameters from each ultrasound source allows for the correction of distortions arising from transmission through the skull bone and also opens up the possibility for electronic steering of the acoustic focus within the brain. In addition, the capability to adjust the frequency of insonation at different locations on the skull can have an effect on ultrasound transmission. To determine the efficacy and applicability of a multiple-frequency approach with such a device, this study examined the frequency dependence of ultrasound transmission in the range of 0.6-1.4 MHz through a series of 17 points on four ex vivo human skulls. Effects beyond those that are characteristic of frequency-dependent attenuation were examined. Using broadband pulses, it was shown that the reflected spectra from the skull revealed information regarding ultrasound transmission at specific frequencies. A multiple-frequency insonation with optimized frequencies over the entirety of five skull specimens was found to yield on average a temporally brief 230% increase in the transmitted intensity with an 88% decrease in time-averaged intensity transmission within the focal volume. This finding demonstrates a potential applicability of a multiple-frequency approach in transcranial ultrasound transmission.