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Directors and officers (D&O) insurance policies are part of the insurance portfolio of many telecommunications companies. This statement holds true with NTCA members. Considering the majority of the membership are [...]

No doubt you or someone you work with has received or seen phishing emails. A review of my own work email account discovered 167 attempts made against my address in [...]

As we enter the summer and fall months, it is easy to envision a tornado or hurricane or some other weather-related incident potentially striking a telecommunications company and destroying a [...]

In today's electronic world, identity and credit theft have become very common occurrences. Sometimes, it is a single case of thievery. Other times, it is part of a much broader [...]

Who hasn't heard or even spoken to their fellow employees: 'the customer is always right,' 'we need to do more with less,' 'never say no to a customer,' and 'find [...]

If you have ever set out to read your insurance policies, you know it can be a daunting task. The binders are thicker than 'War and Peace' but lack a [...]

What do insurance and telecommunications companies have in common? This is a loaded question; at the root of both types of businesses exist many of the same foundations and principals. [...]

Some say success breeds success. Using college basketball as an example (down to the Final Four of the NCAA tournament as this is being written), it is easy to see [...]

It is not often that the word 'interesting' is used to describe anything that has to do with insurance. But two recent Supreme Court decisions in Ohio regarding coverage under [...]

Your customers want more and more from you. Does that sound familiar? As daunting as the thought of entering into new areas of service may be to deal with, the [...]

WHAT DO ARCHITECTURAL DOOR AND hardware businesses share in common with insurance consulting operations? If your answer is 'absolutely nothing', you would be wrong because at the root both types [...]

Are you a director, officer or manager of a rural telecom? If so, understanding your protection under your insurance policies is important to you. In the world of insurance, management [...]

The past year, 2008, was a challenging one for our nation. The economic turmoil touched almost every American and virtually all industries, including door & hardware distributors, and insurance. It [...]

What do architectural door and hardware businesses share in common with insurance consulting operations? If your answer is 'absolutely nothing,' you would be wrong because at the root both types [...]

The technology industry in the last decade has seen its share of business flameouts, including the widely publicized failures of dot-com and technology-related companies. Reuters reported in 2002 that one [...]

The Americans with Disabilities Act (ADA) is a federal antidiscrimination statute. The intended goal of the act is to remove barriers that would prevent qualified people with disabilities from experiencing [...]

It is a fact--sex sells. You don't have to look any further than the print and entertainment media to verify that statement. It also is tree that many jokes and [...]

What keeps you up at night? It is an age old question, and one that is overused and misused by many people. However, in the insurance industry, when a risk [...]

IT IS A PRETTY SAFE BET THAT by the time this article and magazine hit the press that our country's economy will still be challenged. Even if I am completely [...]

Corticosteroids are widely used for the suppression of cell-mediated cytotoxicity. This process is mediated by natural killer cells and cytotoxic T lymphocytes, and their activation can be monitored by levels of the chemokines CXCL9 and CXCL10, the degranulation product granzymes A and B, and by levels of secretory phospholipase A2. The current study aimed to determine the effects of increasing doses of prednisolone on the release of these mediators in healthy humans exposed to LPS. Therefore, 32 healthy men received prednisolone orally at doses of 0, 3, 10, or 30 mg (n = 8 per group) at2h before intravenous injection of Escherichia coliLPS (4 ng/kg). Prednisolone dose-dependently attenuated the LPS-induced rises in the plasma concentrations of the chemokines CXCL9 and CXCL10, as well as of granzymes A and B levels. CXCL10 and granzyme B release were most sensitive to prednisolone, with a significant inhibition already achieved at the lowest prednisolone dose (3 mg). The levels of secretory phospholipase A2 were increased after LPS administration but were not significantly affected by prednisolone. This study demonstrates that prednisolone differentially inhibits the systemic release of mediators involved in cell-mediated cytotoxicity in humans in vivo.

Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor—related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor κB (NF-κB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis. (Blood. 2003;102:303-310)

Secondary brain injury due to ischemia includes the infiltration of leukocytes into the brain parenchyma mediated by activation of nuclear factor-κB (NF-κB), which is activated by proteasome degradation. Neuroprotection with the proteasome inhibitor MLN519 has previously been reported to decrease ischemic brain injury in rats. The authors used higher doses of MLN519 to evaluate the neuroprotection therapeutic window after 24 hours of brain injury in rats as correlated to proteasome levels, activated NF-κB immunoreactivity, and leukocyte infiltration. Male Sprague-Dawley rats were subjected to 2-hour middle cerebral artery occlusion (MCAO) and recovery. MLN519 or vehicle was administered after injury with a single injection given in delayed increments of 2 hours (i.e., 4, 6, or 8 hours after MCAO). Treatment with MLN519 up to 6 hours after MCAO (4 hours after reperfusion) effectively reduced neuronal and astrocytic degeneration, decreased cortical infarct volume, and increased neurologic recovery. These effects were related to >80% reductions in blood proteasome levels, reduced neutrophil infiltration, and a decrease in activated NF-κB immunoreactivity. This improved neuroprotection profile and antiinflammatory effect of MLN519 provides an exciting avenue for potential treatment of focal ischemic brain injury in humans.

Ischemia-reperfusion brain injury initiates an inflammatory response involving the expression of adhesion molecules and cytokines, some of which are regulated by the nuclear transcription factor NF-κB. In this study the authors examined mRNA expression levels for several important genes associated with inflammation at five time points (3, 6, 12, 24, and 72 hours) after transient middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. A sensitive and quantitative technique (TaqMan real-time QRT-PCR) was used to simultaneously measure mRNA levels for key cell adhesion molecules and inflammatory cytokines. Gene expression increased significantly in the injured hemisphere for interleukin (IL)-1β (12-fold increase at 24 hours), IL-6 (25-fold increase at 6 hours) and ICAM-1 (4-fold increase at 24 hours), and the in-terhemispheric differences for these genes were significant for every time point examined (P< 0.05 for all values). Tumor necrosis factor-α mRNA was upregulated in the injured versus uninjured hemisphere from 3 to 24 hours (5-fold increase at 6 hours), while E-selectin showed a significant increase in mRNA levels from 6 to 24 hours after MCAO (10-fold increase at 6 hours) (P< 0.05 for all values). VCAM-1 mRNA levels did not respond differentially to injury at any time point between the two brain hemispheres. At all time points examined, activated NF-κB immunoreactivity was observed in cells throughout the infarct-damaged tissue. These results are consistent with the proinflammatory properties of the induced molecules, which are involved in the initiation of the inflammatory cascade, and may thus contribute to secondary cellular responses that lead to further brain damage.

PLP139–151-induced relapsing experimental autoimmune encephalomyelitis (R-EAE) in SJL mice is a Th1-mediated autoimmune demyelinating disease model for multiple sclerosis (MS) in which the primary disease relapse is mediated by T cells specific for the endogenous PLP178-191 epitope. This complex inflammatory process requires the co-ordinated expression of a wide variety of immune-related genes active at a variety of stages of the autoimmune process which are regulated, in part, by the transcription factor nuclear factor (NF)-κB which is activated via the ubiquitin-proteasome pathway. We asked if in vivoadministration of a selective inhibitor of the ubiquitin-proteasome pathway, PS-519, which downregulates activation of NF-κB, could downregulate ongoing R-EAE. Administration of PS-519 during the remission phase, following acute clinical disease was effective in significantly reducing the incidence of clinical relapses, CNS histopathology, and T cell responses to both the initiating and relapse-associated PLP epitopes. The inhibition of clinical disease was dependent upon continuous administration of PS-519 in that recovery of T cell function and onset of disease relapses developed within 10–14 days of drug withdrawal. The data suggest that targeting the ubiquitin proteasome pathway, in particular NF-κB, may offer a novel and efficacious approach for the treatment of progressive autoimmune diseases, including MS.

The effect and mechanism of the blood–brain barrier-permeabilizing agent, RMP-7, was investigated in a series of studies employing a rat RG2 glioma model. Changes in uptake of carboplatin into brain tumor and various nontumor brain tissue regions was determined using a sophisticated image analysis system. This system permitted quantitative autoradiography to be analyzed simultaneously with overlayed histological images from the same coronal brain section. A wide range of intracarotid doses of RMP-7 (0.01 to 9.0 μg/kg) was shown to significantly increase the permeability of carboplatin into tumor tissue and surrounding brain tissue (up to twofold) in a dose-dependent manner. Additionally, substantially greater permeability effects were seen in the tumor compared to healthy brain. Moreover, a clear topographic profile was observed in nontumor brain tissue, with progressively less uptake observed with increasing distance from the tumor. The fact that RMP-7 increased the uptake of carboplatin into ipsilateral brain tissue outside the tumor mass has potential implications for treating human glioma patients, for it is commonly recognized that tumor cells typically migrate from the tumor mass into surrounding brain tissue thereby escaping conventional attempts to destroy the malignant cells. To help elucidate the mechanism of RMP-7's permeability effects, the uptake of carboplatin was also determined under conditions where either the bradykinin B2receptor antagonist, HOE140, or the B1antagonist, [des-Arg10]HOE140, was coadministered with RMP-7. Results indicate that RMP-7's effects are mediated specifically through bradykinin B2receptors. Furthermore, neither bradykinin antagonist alone affected the uptake of carboplatin into the leaky tumor region, suggesting that abnormal elevations in endogenous bradykinin activity are not likely responsible for the characteristic leaky nature of the tumor vascular barrier. The combined results from these studies therefore offer new insight into the characteristics of the vascular barriers in normal and tumor brain tissue and further elucidate the novel permeability effects of RMP-7. Together, they support its potential use as an adjunctive therapy for the selective delivery of chemotherapeutic drugs to brain tumors and possibly other neurodegenerative conditions.

The involvement of neutrophils in the pathogenesis of cerebral ischemic injury in two rat models of focal ischemia was investigated. In Experiment I, a model of focal ischemia with partial reperfusion was used. Although significant and discrete ischemic damage within the neocortex was nearly maximal at 12 h postocclusion, no elevation in neutrophils was seen at this time point. Even after 21 h postocclusion, only a subtle increase in neutrophils within the ischemic tissue was observed. To further investigate the possible role of neutrophils in cerebral ischemia, the effect of cyclophosphamide-induced neutropenia was investigated (Experiment II). While a marked reduction (>98%) in systemic neutrophils was achieved in advance of and during the ischemic challenge, no reduction in the volume of ischemic damage was observed. In Experiment III, variations in the rat model of focal ischemia were made to produce a larger area of ischemic damage, as well as to permit complete reperfusion of blood to the affected cortex. While more neutrophils were seen in this variation of the model, very few were observed (<1 per field) prior to the time that maximal ischemic damage had already occurred. Together, these experiments revealed that substantial brain necrosis occurred prior to the appearance of neutrophils, under conditions of partial, as well as complete, reperfusion. Moreover, at the time points when elevations in neutrophils were observed, no further increase in volume of ischemic damage was noted. Finally, pharmacologic removal of neutrophils prior to ischemia did not alter the size of the ischemic region. These data therefore fail to support the hypothesis that neutrophils play a general and essential role in infarct formation following focal brain ischemia and argue that further studies are required to more clearly elucidate the conditions under which neutrophils might participate in ischemic pathogenesis.

Experiments were conducted to determine whether a potent, reversible calpain inhibitor could reduce the cortical ischemic brain damage associated with focal ischemia in the rat. AK275 (Z-Leu–Abu–CONH–CH2CH3), the active isomer of the diastereomeric mixture, CX275, was employed in conjunction with a novel method of perfusing drug directly onto the infarcted cortical surface. This protocol reduced or eliminated numerous, nonspecific pharmacokinetic, hemodynamic, and other potentially confounding variables that might complicate interpretation of any drug effect. Focal ischemia was induced using a variation of the middle cerebral artery occlusion method. These studies demonstrated a reliable and robust neuroprotective effect of AK275 over the concentration range of 10 to 200 μM(perfused supracortically at 4 μl/h for 21 h). Moreover, a 75% reduction in infarct volume was observed when initiation of drug treatment was delayed for 3 h postocclusion. Our data further support an important role of calpain in ischemia-induced neuropathology and suggest that calpain inhibitors may provide a unique and potentially powerful means of treating stroke and other ischemic brain incidents.