The protective effect of adenosine triphosphate-MgCl<Subscript>2</Subscript> on ischemia-reperfusion lung injury is leukocyte dependent

Adenosine triphosphate (ATP)-MgCl₂ attenuates ischemia-reperfusion (I-R)-induced lung injury in rats. A previous study indirectly suggests that Mg²⁺-dependent ecto-ATPases on the surface of leukocytes are responsible for the hydrolysis of ATP-MgCl₂ to adenosine, which then contributes to the protective effect of ATP-MgCl₂. This study investigated the role of leukocytes in I-R injury and the protective effect of ATP-MgCl₂ in our buffer-perfused isolated rat lung model. After isolating the lung blood flow of adult male Sprague-Dawley rats, the lungs were perfused through the pulmonary artery cannula with a physiologic salt solution containing human serum albumin. The protective effect of ATP-MgCl₂ pretreatment with or without leukocytes was investigated. Capillary permeability (K_fc), lung weight gain (LWG), lung wet weight/body weight ratio (LW/BW), lung lavage protein concentration (LPC) and pulmonary artery pressure (PAP) were measured. I-R produced a significant increase in K_fc, LWG, LW/BW, LPC, and PAP. The increases in these indices were significantly attenuated by pretreatment with ATP-MgCl₂ (1×10^–6 M) together with leukocytes (2.9×10⁶/ml in the perfusate) but not with ATP-MgCl₂ alone. Our data suggest that I-R-induced acute lung injury is not dependent on circulating leukocytes. Pretreatment with ATP-MgCl₂ plus leukocytes but not ATP-MgCl₂ alone had protective effects against I-R lung injury. Whether these findings occur in vivo could not be determined in this study. In our isolated lung red blood cell-free perfusate system, the protective effect of ATP-MgCl₂ requires the presence of leukocytes.     

αB-crystallin is a sensor for assembly intermediates and for the subunit topology of desmin intermediate filaments

Mutations in the small heat shock protein chaperone CRYAB (αB-crystallin/HSPB5) and the intermediate filament protein desmin, phenocopy each other causing cardiomyopathies. Whilst the binding sites for desmin on CRYAB have been determined, desmin epitopes responsible for CRYAB binding and also the parameters that determine CRYAB binding to desmin filaments are unknown. Using a combination of co-sedimentation centrifugation, viscometric assays and electron microscopy of negatively stained filaments to analyse the in vitro assembly of desmin filaments, we show that the binding of CRYAB to desmin is subject to its assembly status, to the subunit organization within filaments formed and to the integrity of the C-terminal tail domain of desmin. Our in vitro studies using a rapid assembly protocol, C-terminally truncated desmin and two disease-causing mutants (I451M and R454W) suggest that CRYAB is a sensor for the surface topology of the desmin filament. Our data also suggest that CRYAB performs an assembly chaperone role because the assembling filaments have different CRYAB-binding properties during the maturation process. We suggest that the capability of CRYAB to distinguish between filaments with different surface topologies due either to mutation (R454W) or assembly protocol is important to understanding the pathomechanism(s) of desmin-CRYAB myopathies.     

Involvement of phosphatidylinositol 3-kinase gamma in neutrophil apoptosis

Although phosphoinositide 3-kinases (PI3-K) are known to participate in anti-apoptotic pathways, their importance in modulating neutrophil apoptosis in vivo has not been examined. In these studies, we used neutrophils from mice lacking the PI3-Kgamma isoform (PI3-Kgamma-/-) to determine the role that PI3-Kgamma occupies in neutrophil apoptosis under in vivo conditions. We found that neutrophil apoptosis under basal and LPS-stimulated conditions was increased in PI3-Kgamma-/- mice compared to that present in control PI3-Kgamma+/+ animals. Neutrophils from PI3-Kgamma-/- mice demonstrated decreased amounts of active, serine 473 phosphorylated Akt, phosphorylated CREB, and diminished nuclear translocation of NF-kappaB. Levels of the CREB-dependent anti-apoptotic protein Mcl-1 and of the NF-kappaB-dependent anti-apoptotic mediator Bcl-x(L) were significantly decreased in PI3-Kgamma-/- neutrophils. In contrast, PI3-Kgamma-/- neutrophils contained diminished amounts of phosphorylated, inactive forms of the pro-apoptotic mediators, Bad, FKHR, and GSK-3beta. These results demonstrate that PI3-Kgamma directly participates in multiple in vivo pathways involved in regulating neutrophil apoptosis.     

Is the treatment of axillary osmidrosis with liposuction better than open surgery?

Axillary osmidrosis is an annoying, although not life-threatening, problem that includes unpleasant odor and the occasional staining of clothing. Suction-assisted lipectomy has been tested as a treatment for axillary osmidrosis with variable success. The authors retrospectively reviewed 134 patients who underwent superficial liposuction for bilateral axillary osmidrosis in their division between June of 1998 and June of 2002. The surgical complications and results were compared with those reported in their previous report of 343 patients (102 available for postoperative result evaluation) who received open surgical treatment with partial excision of axillary skin and subcutaneous tissue. The overall complication rate was 3.73 percent, significantly lower than the 11.08 percent complication rate seen with open surgical treatment. Of their 134 patients, 114 were available for long-term follow-up. Thirteen patients (11.40 percent) had very good results, 79 patients (69.30 percent) had good results, and 22 patients (19.30 percent) had poor results. Significant differences were found between those who underwent superficial liposuction and those who underwent open surgery. The number of patients with very good and good results decreased significantly from 91.18 percent (open surgery) to 80.70 percent (liposuction), and those with little or no improvement increased from 8.82 percent (open surgery) to 19.29 percent (liposuction). Compared with open surgery for the treatment of osmidrosis, liposuction produces significantly fewer complications but is less effective. Of the patients who underwent liposuction for osmidrosis, 80 percent were satisfied with the result. Further study is needed to determine whether liposuction for osmidrosis can be improved.     

Thalidomide reduces lipopolysaccharide/zymosan-induced acute lung injury in rats

Pharmacological therapies targeting fulminant lung inflammation in acute lung injury (ALI) need to be improved. We evaluated the effect of thalidomide, a chemical modulating both acute and chronic inflammation, on ALI induced by intravenous administration of lipopolysaccharide (LPS) and zymosan in male Sprague-Dawley rats. Injection of LPS and zymosan induced significant lung inflammation, as evidenced by increased neutrophil sequestration in lung tissue as well as enhanced nitric oxide metabolite (NO _x ^– ) production in the serum and bronchoalveolar lavage (BAL) fluid. Lactate dehydrogenase (LDH) activity and protein concentration in BAL fluid were significantly increased after administration of LPS and zymosan. Pulmonary microvascular permeability was determined using the Evans blue retention method, which showed a significant increase in microvascular permeability after LPS and zymosan administration, indicating the development of ALI. Animals that received thalidomide (100 mg/kg) 2 h prior to LPS injection had significantly reduced pulmonary NO _x ^– production, pulmonary microvascular permeability, and LDH activity and protein concentration in BAL fluid. We therefore conclude that thalidomide ameliorates lung inflammation and reduces ALI induced by combined LPS and zymosan administration in rats.     

Comparison of the small heat shock proteins αB-crystallin, MKBP, HSP25, HSP20, and cvHSP in heart and skeletal muscle

Seven members of the small heat shock protein (sHSP) family are exceptional with respect to their constitutive high abundance in muscle tissue. It has been suggested that sHSPs displaying chaperone-like properties may stabilize myofibrillar proteins during stress conditions and prevent them from loss of function. In the present study five sHSPs (B-crystallin, MKBP, HSP25, HSP20, and cvHSP) were investigated with respect to similarities and differences of their expression in heart and skeletal muscle under normal and ischemic conditions. In ischemic heart and skeletal muscle these five sHSPs translocated from cytosol to the Z-/I-area of myofibrils. Myofibrillar binding of all sHSPs was very tight and resisted for the most part extraction with 1 M NaSCN or 1 M urea. MKBP and HSP20 became extracted by 1 M NaSCN to a significant extent indicating that these two sHSPs may bind partially to actin-associated proteins which were completely extracted by this treatment. Ultrastructural localization of B-crystallin showed diffuse distribution of immunogold label throughout the entire I-band in skeletal muscle fibers whereas in cardiomyocytes B-crystallin was preferentially located at the N-line position of the I-band. These observations indicate different myofibrillar binding sites of B-crystallin in cardiomyocytes versus skeletal muscle fibers. Further differences of the properties of sHSPs could be observed regarding fiber type distribution of sHSPs. Thus sHSPs form a complex stress–response system in striated muscle tissue with some common as well as some distinct functions in different muscle types.     

An open-label, multicentre study of levocetirizine for the treatment of allergic rhinitis and urticaria in Taiwanese patients

Levocetirizine has been shown in observational studies in the west as an effective and satisfactory therapy for patients with allergic respiratory and skin disease. An open-label, multicentre observational study was conducted to investigate the patients' perception of levocetirizine in the treatment of allergic rhinitis (AR) and urticaria in Taiwanese patients. Three hundred and thirty-three patients (236 AR and 97 urticaria patients) attending out-patient clinics of medical centres across Taiwan were included in the study. Patients were treated with levocetirizine 5 mg once daily (AR patients for 2-4 weeks and urticaria patients for 2-6 weeks) and at the end of treatment, they evaluated for symptoms of disease, perception of change in symptoms, global efficacy and tolerability, global preference over previous antiallergic treatment, change in quality of sleep/daily activities, and safety and adverse events (AEs). Levocetirizine markedly improved the symptoms of AR and urticaria; with 70-75% of AR patients and 60-80% of urticaria patients reporting complete or marked improvements in individual symptoms. Asthma symptoms were completely or markedly improved in 44% of patients with AR and concomitant asthma. A majority of the patients was satisfied with levocetirizine therapy and 50-70% indicated preference for levocetirizine over previous therapy. Overall, 50-74% of all patients perceived improvements in quality of sleep/daily activities and 50-65% of the patients rated the onset of action for levocetirizine as very rapid or rapid. Somnolence was the most common AE, reported by 7.4% of AR and 7.0% of urticaria patients. The results of this study indicated that levocetirizine is an effective and satisfactory therapy for the management of allergic respiratory and skin disease in Taiwanese subjects.