Dynamic control of slow water transport by aquaporin 0: implications for hydration and junction stability in the eye lens

Aquaporin 0 (AQP0), the most abundant membrane protein in mammalian lens fiber cells, not only serves as the primary water channel in this tissue but also appears to mediate the formation of thin junctions between fiber cells. AQP0 is remarkably less water permeable than other aquaporins, but the structural basis and biological significance of this low permeability remain uncertain, as does the permeability of the protein in a reported junctional form. To address these issues, we performed molecular dynamics (MD) simulations of water transport through membrane-embedded AQP0 in both its (octameric) junctional and (tetrameric) nonjunctional forms. From our simulations, we measured an osmotic permeability for the nonjunctional form that agrees with experiment and found that the distinct dynamics of the conserved, lumen-protruding side chains of Tyr-23 and Tyr-149 modulate water passage, accounting for the slow permeation. The junctional and nonjunctional forms conducted water equivalently, in contrast to a previous suggestion based on static crystal structures that water conduction is lost on junction formation. Our analysis suggests that the low water permeability of AQP0 may help maintain the mechanical stability of the junction. We hypothesize that the structural features leading to low permeability may have evolved in part to allow AQP0 to form junctions that both conduct water and contribute to the organizational structure of the fiber cell tissue and microcirculation within it, as required to maintain transparency of the lens.     

Paranuclear microfilaments in multiple myeloma associated with the presence of free light chains

Two cases of multiple myeloma are reported showing striking arrays of paranuclear microfilaments confirming a previous single case report done on autopsy material. Both cases showed free light chains in the urine. In one case, free light chains were in the serum, and there was some evidence of polymer formation. Although this suggests that the microfilaments are polymerized light chains, amyloid strains were negative. Whatever their origin, the structures are clearly abnormal and may serve as a neoplastic marker.     

Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. recombinant Factor VIII Study Group

BACKGROUND. Current treatment of hemophilia A, a hereditary disorder affecting approximately 1 in 10,000 males, relies on plasma-derived factor VIII concentrates. We tested the safety and efficacy of a recombinant factor VIII preparation for the treatment of this disorder. METHODS. We conducted the investigation in three stages: comparing the pharmacokinetics of plasma-derived and recombinant factor VIII, assessing the efficacy of recombinant factor VIII for home therapy, and assessing its efficacy for major surgical procedures and hemorrhage. A total of 107 subjects with hemophilia, 20 of whom had not been treated previously, enrolled in the investigation. RESULTS. The in vivo recovery and elimination half-lives of recombinant factor VIII equaled or exceeded those of plasma-derived factor VIII. Seventy-six subjects participated in a home-treatment program, using recombinant factor VIII for 69 to 807 days (median, 618); home diaries of 56 subjects treated for 5 months were analyzed. Of 540 bleeding episodes, 399 (73.9 percent) required only one treatment with recombinant factor VIII. The projected annual consumption of recombinant factor VIII was similar to that of plasma-derived factor VIII concentrate. Twenty-six subjects received recombinant factor VIII for 22 surgical procedures and 10 serious hemorrhages; hemostasis was excellent in all cases. De novo formation of inhibitors occurred in only 1 of 85 previously treated subjects. Inhibitor antibodies also developed in 6 of 21 children, 20 of whom had not previously been treated; 5 had low levels (less than or equal to 7.5 Bethesda units) despite continued treatment with recombinant factor VIII. There was no evidence of new formation of antibody to foreign proteins, and recombinant factor VIII was well tolerated. CONCLUSIONS. Recombinant factor VIII has biologic activity comparable to that of plasma factor VIII and is safe and efficacious for the treatment of hemophilia A.     

THE UNSOLVED PROBLEMS OF PREVENTIVE MEDICINE

An inventory of the present status of the disease entities with which the modern sanitarian and clinician have to deal tempers the facile optimism of the unthinking. Whereas the infections transmitted by insects, the waterborn diseases, and certain diseases for which we possess methods of specific immunization have been well conquered, we are still unable to control the high mortality from degenerative diseases of the heart, bloodvessels and kidneys, from pneumonia and other acute respiratory infections, cancer and, to a less extent, tuberculosis. To map out the varied lines of attack upon these unsolved problems is the object of this paper.     

术前常规检查与选择性检查对白内障手术安全性的系统评价

目的系统评价术前常规检查与选择性检查对白内障手术的安全性。方法按Cochrane系统评价方法,计算机检索MEDLINE（1966—2008．10）、EMbase（1980～2008．10）、Cochrane协作网眼和视力组数据库（2008年3期）、中国生物医学文献数据库（1979～2008．10）,手工检索相关会议文献,纳入所有比较术前常规检查与选择性检查对白内障手术安全性的随机对照试验,并采用RevMan5．0软件进行Meta分析。结果共纳入4个随机对照试验,包括20490例患者。Meta分析结果显示,白内障手术患者,术前常规检查与选择性检查在术中全身并发症发生率[RR=1．05,95％CI（0．89,1．24）,P=0．59]、术后全身并发症发生率[RR=0．97,95％CI（0．80,1．18）,P=0．77]、术中眼部并发症发生率[RR=0．99,95％CI（0．74,1．33）,P=0．97]及术后眼部并发症发生率[RR=1．11,95％CI（0．76,1．60）,P=0．59]4方面,其差异均无统计学意义。结论术前常规检查与选择性检查相比,白内障手术患者术中、术后全身并发症发生率,以及术中、术后眼部并发症发生率差异均无统计学意义,但此结论对于危重病人的适用性有待于进一步研究。凶本系统评价纳入研究较少,上述结论有待更多设计严谨的大样本随机对照试验加以验证。关键词白内障;术前检查;安全性;随机对照试验     

Clearance of pediatric actinic prurigo with dupilumab

Actinic prurigo is a rare, idiopathic chronic photodermatosis of childhood characterized by excoriated papules, nodules, and plaques in sun-exposed areas. It is notoriously difficult to treat. The disorder involves a type IV hypersensitivity reaction driven by both Th1 and Th2 inflammatory pathways, the latter of which leads to secretion of IL-4, IL-5, IL-13, and production of B cells, IgE, and IgG4. Dupilumab, an IL-4 receptor antagonist, disrupts the Th2 pathway. We present a pediatric patient with severe, recalcitrant actinic prurigo who achieved rapid and sustained clearance with dupilumab.