Relationship between the cardiovascular effects and both plasma and myocardial levels of clentiazem,a new benzothiazepine calcium antagonist,in anesthetized dogs

Summary We evaluated the relationship between the cardiovascular effects of clentiazem (TA-3090), a new 1,5-benzothiazepine calcium antagonist with high lipophilicity, and both its plasma and myocardial concentrations. Anesthetized, open-chest dogs, instrumented for hemodynamic data recording and blood sampling, were divided into three groups treated with 15, 50, or 200 g/kg of clentiazem, respectively, as an intravenous bolus. At the end of the protocol (240 minutes), myocardial samples were tested for clentiazem. The results indicated that the peripheral and coronary vasodilator effects of clentiazem were dose dependent and closely related to its plasma concentrations. It was also observed that the minimal effective plasma concentration was in the range of 15–20 ng/ml. Sustained negative chronotropic effects were recorded at the highest dose only and were best related to the amount of clentiazem detectable in the myocardium, suggesting that myocardial clentiazem retention is a major factor governing its depressant cardiac impact.     

Treatment to prevent recurrent genital herpes

PURPOSE OF REVIEW: Genital herpes is the leading cause of genital ulcer disease worldwide and is among the most common sexually transmitted diseases. Recurrent genital herpes is associated with major medical and psychosocial morbidities; therefore, suppressive therapy is required, especially in patients with frequent and/or severe episodes. RECENT FINDINGS: A recent meta-analysis evaluated prophylactic regimens in immunocompetent hosts, and proposed four alternatives with similar efficacies: three twice-daily regimens (i.e. acyclovir 400 mg, valaciclovir 250 mg and famciclovir 250 mg) and one once-daily regimen (valaciclovir 500 mg). Immunocompromised patients may have more prolonged, frequent and severe episodes of genital herpes. Valaciclovir 500 mg twice daily maintains the benefits of acyclovir treatment in terms of clinical efficacy and safety. Alternative therapies in case of clinical failure are discussed. Development of new strategies is moving in three directions: improvement in antiviral therapy or identification of new drug targets; local immune therapy; and vaccination. Many prophylactic and therapeutic vaccination approaches have been explored, but no effective vaccine is presently available. SUMMARY: In 2007 control of herpes recurrence remains an important goal because of the impact it has on the quality of life of millions of people and its relationship with transmission of other sexually transmitted diseases, especially HIV infection.     

Skull wounds linked with blunt trauma (hammer example). A report of two depressed skull fractures--elements of biomechanical explanation

The lesions of the skull following perforating traumas can create complex fractures. The blunt traumas can, according to the swiftness and the shape of the object used, create a depressed fracture. The authors describe through two clinical cases the lesional characteristic of the blunt traumas, perforating the skull using a hammer. In both cases the cranial lesions were very typical: they were geometrical, square shaped, of the same size than the tool (head and tip of the hammer). On the outer table of the skull, the edges of the wounds were sharp and regular. On the inner table, the edges of the wounds were beveled and irregular. The bony penetration in the depressed fracture results from a rupture of the outer table of the bone under tension, in periphery, by the bend of the bone to the impact (outbending) and then, from the inner table with comminuted bony fragmentation. Breeding on the fractures of the size and the shape of the blunt objects used is inconstant and differs, that it is the objects of flat surface or wide in opposition to those of small surface area. Fractures morphologies depend on one hand on these extrinsic factors and on the other hand, of intrinsic factors (structure of the bone). To identify them, we had previously conducted experimental work on cranial bone samples. The bone was submitted to a device for three-point bending. This work had shown properties of thickness and stiffness of the various areas of the vault. Our cases are consistent with these results and illustrate the variability of bone lesions according to region and mode of use of blunt weapons. Many studies have identified criteria for identification of the weapons and the assistance of digital and biomechanical models will be an invaluable contribution with this aim in the future.     

Indications for thrombolysis in ischemic stroke

Cerebral MRI with angio-MR are more effective than CT scan for selecting patients with ischemic stroke for thrombolysis. The use of cerebral MRI has to be available 24h a day and everyday as a standardized emergency procedure. Off-label criteria for thrombolysis after acute ischemic stroke are too restritive and have to be revised. In acute ischemic stroke, imaging that shows the collateral circulation within the hypoperfusion area has to be used to estimate the potential of therapeutic revascularization. When there are contraindications for intravenous thrombolysis, the endovascular approach must be argued individually by neurologists and neurointerventionalists together.     

CX3CL1 (fractalkine) and its receptor CX3CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin

Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX₃CL1 (fractalkine) and its unique receptor, CX₃CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX₃CR1-deficient mice and upon blocking CX₃CL1–CX₃CR1 interactions in wild-type mice. CX₃CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX₃CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX₃CL1 and CX₃CR1 regulate the pathology by controlling effector CD4⁺ T cell survival within inflamed tissues, adoptive transfer experiments established CX₃CR1 as a key regulator of CD4⁺ T cell retention in inflamed skin, indicating a new function for this chemokine receptor. Therefore, although CX₃CR1 and CX₃CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.Atopic dermatitis (AD) is a common, chronic inflammatory dermatosis that frequently occurs in individuals with a personal or family history of atopic diseases. AD pathophysiology is complex and results from skin barrier dysfunction and a dysregulated immune response, influenced by genetic and environmental factors (Guttman-Yassky et al., 2011a,b). Indeed, most patients with AD have increased serum IgE levels, with specific IgE directed against allergens or microbial proteins such as Staphylococcus aureus (Leung et al., 2004). Lesions in AD are characterized by increased epidermal thickness and a dermal inflammatory cell infiltrate, consisting of mast cells, eosinophils, and T lymphocytes. In acute AD lesions a preferential recruitment of Th2 cells occurs, whereas in the chronic lesions a Th1 profile is predominant (Grewe et al., 1998); allergic asthma or allergic rhinitis are more exclusively Th2-dominated diseases.Chemokines and their receptors play a key role in leukocyte recruitment to inflamed skin (Schall and Proudfoot, 2011). Eotaxins 1, 2, and 3 (CCL11, -24, and -26) bind to CCR3 and attract eosinophils, and CCL26 appears to be particularly involved in AD (Kagami et al., 2003; Owczarek et al., 2010). CCL27 together with CCR10 and CCR4 expression ensures T cell skin domiciliation (Reiss et al., 2001; Homey et al., 2002). More recently, CCR8 and CCL8 have been elegantly demonstrated to direct Th2 cell recruitment into allergen-inflamed skin and draining LNs in a murine model of AD (Islam et al., 2011).Besides chemoattraction, chemokine–chemokine receptor interactions also regulate other functions. Indeed, we have recently demonstrated that CX₃CR1, the receptor for CX₃CL1 (fractalkine [CX₃]), identified also as a receptor for CCL26 (Nakayama et al., 2010) in humans, controls the development of allergic asthma by providing a survival signal to the CD4⁺ effector T lymphocytes in the inflammatory airways (Mionnet et al., 2010; Julia, 2012). In AD patients, CX₃CL1 is up-regulated in both endothelial cells and skin lesions, and serum CX₃CL1 levels are positively associated with disease severity (Echigo et al., 2004). Another study reported that, although CX₃CR1 mRNA expression is consistently up-regulated in AD skin, CX₃CL1 mRNA levels are only increased in some patients with a significant correlation to the disease severity (Nakayama et al., 2010), a result likely to explain the earlier failure to detect CX₃CL1 in skin lesions (Fraticelli et al., 2001). Furthermore, two CX₃CR1 single nucleotide polymorphisms have been associated with asthma and atopy in French-Canadian populations (Tremblay et al., 2006) and German children (Depner et al., 2007).Thus, to functionally delineate the role of CX₃CL1–CX₃CR1 in AD, we used a mouse model of epicutaneous sensitization, by a protein antigen in the absence of adjuvant, faithfully mimicking features of human AD. Unexpectedly, we found that CX₃CL1–CX₃CR1 controlled AD to an even greater extent than allergic asthma through a new and distinct mechanism.