Vaginal mucosal immunization for recurrent urinary tract infection: phase II clinical trial

PURPOSE: Decreased local immunity to uropathogenic bacteria may be a factor predisposing women to recurrent urinary tract infections. Our phase I study demonstrated the safety of a multi-strain vaccine administered as a vaginal suppository. A phase II study was conducted to determine vaccine efficacy. MATERIALS AND METHODS: A total of 91 women susceptible to recurrent urinary tract infections was entered into the study and the courses were analyzed in a randomized, double-blind, placebo controlled trial of vaginal mucosal immunization. Subjects received 3 vaginal suppositories at weekly intervals. Depending on the treatment group each suppository contained 1 of 2 vaccine doses or suppository material only. Each patient was followed for 5 months to record infection episodes, and obtain urine, vaginal irrigates and serum to measure immunological responses. RESULTS: Immunogen treated women who were off antibiotic prophylaxis throughout the study had a significant delay in interval to reinfection during the first 8 weeks compared to women receiving placebo. Mean interval until reinfection was delayed from 8.7 weeks for placebo treated to 13 weeks for vaccine treated women. Immunological responses in serum, urine and vaginal fluid were variable. No serious adverse effects were observed. CONCLUSIONS: These data demonstrate that vaginal mucosal immunization can enhance resistance to urinary tract infections in susceptible patients.     

Disulfide bonds in the extracellular calcium-polyvalent cation-sensing receptor correlate with dimer formation and its response to divalent cations in vitro

Extracellular calcium/polyvalent cation-sensing receptors (CaR) couple to G proteins and contain highly conserved extracellular cysteine residues. Immunoblotting of proteins from rat kidney inner medullary collecting duct endosomes with CaR-specific antibodies reveals alterations in the apparent molecular mass of CaR depending on protein denaturation conditions. When denatured by SDS under nonreducing conditions, CaR migrates as a putative dimeric species of 240-310 kDa. This is twice the predicted molecular mass of the CaR monomer observed after SDS denaturation in the presence of sulfhydryl-reducing agents. In sucrose density gradients, Triton X-100-solubilized CaR sediments as a 220-kDa complex, not explainable by binding of G proteins to CaR monomers. Treatment of Triton-soluble CaR with divalent (Ca2+, Mg2+) and trivalent (Gd3+) metal ion CaR agonists, but not monovalent ions (Na+), partially shifts the electrophoretic mobility of CaR under reducing conditions from a predominantly monomeric to this putative dimeric species on immunoblots in a manner similar to their rank order of functional potency for CaR activation (Gd3+ > Ca2+ > Mg2+). This Ca2+ effect is blocked by pretreatment with N-ethylmaleimide. We conclude that disulfide bonds present in CaRs mediate formation of dimers that are preserved in Triton X-100 solution. In addition, CaR exposure to Ca2+ induces formation of additional disulfide bonds within the Triton-soluble CaR complex.     

The pathogenesis of HLA-B27 arthritis: role of HLA-B27 in bacterial defense

Thirty patients with coronary artery disease (CAD) were administered garlic (study group) while another 30 patients received the placebo (control group). Various risk parameters were determined at 1.5 and 3 months of garlic administration. Garlic, administered in a daily dose of 2 x 2 capsules (each capsule containing ethyl acetate extract from 1 g peeled and crushed raw garlic), reduced significantly total serum cholesterol and triglycerides, and increased significantly HDL-cholesterol and fibrinolytic activity. There was no effect on the fibrinogen and glucose levels. In vitro effects of the garlic oil on platelet aggregation (PAg) and eicosanoid metabolism were examined; it inhibited PAg induced by several platelet agonists, and also platelet thromboxane formation. Two important paraffinic polysulphides - diallyl disulphide (DADS) and diallyl trisulphide (DATS) - derived from garlic and are usual constituents of garlic oil, showed antiplatelet activity, and also inhibited platelet thromboxane formation. In this respect DATS was more potent than DADS. The nature of inhibition of PAg by DATS was found to be reversible.     

State-coordinated services for traumatic brain injury survivors: toward a model delivery system

Since 1985, the state of Minnesota, through a variety of advocacy, legislative, and interagency efforts, has made incremental gains in public policy and service development for persons with traumatic brain injury (TBI). This article reviews the roles and functions of select state programs and departments in coordinating TBI services. Key initiatives, as well as the current model of public policy and services, are outlined. Current and future service development and initiatives are discussed. Finally, specific implementation recommendations are proposed.     

Why a "benign" mutation kills enzyme activity. Structure-based analysis of the A176V mutant of Saccharomyces cerevisiae L-asparaginase I

A conservative and apparently harmless A176V mutation in intracellular S. cerevisiae L-asparaginase (ScerAI) completely abolishes the enzyme activity. Sequence and structural comparisons with type II bacterial L-asparaginases show that the mutated residue is in a very conservative region and plays a vital role in the cohesion of functional tetramers of these enzymes through participation in side-chain...main-chain (Ser) Oy...O (Ala) hydrogen bonds across the tetramer interface. The fact that bacterial L-asparaginases of type I show less conservation in this region suggests that they may have different quaternary structure while adopting the subunit fold and intimate dimer architecture of type II enzymes. A comparison of all available sequences of microbial L-asparaginases confirms that separate intra- and extra-cellular enzymes evolved in prokaryotes and eukaryotes independently. However, an analysis of the available complete genome sequences reveals a surprising fact that Haemophilus influenzae possesses only a type II asparaginase while the archaebacterium Methanococcus jannaschii has a type I gene, but not a type II.     

Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA

OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.     

Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer

Fas ligand (FasL) is produced by activated T cells and natural killer cells and it induces apoptosis (programmed cell death) in target cells through the death receptor Fas/Apol/CD95. One important role of FasL and Fas is to mediate immune-cytotoxic killing of cells that are potentially harmful to the organism, such as virus-infected or tumour cells. Here we report the discovery of a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds to FasL and inhibits FasL-induced apoptosis. The DcR3 gene was amplified in about half of 35 primary lung and colon tumours studied, and DcR3 messenger RNA was expressed in malignant tissue. Thus, certain tumours may escape FasL-dependent immune-cytotoxic attack by expressing a decoy receptor that blocks FasL.     

Cytokine induction of platelet activation

A three-dimensional, two-part model of the foot, for use in a simulation of human gait, is presented. Previous simulations of gait have not included the foot segment (e.g. Siegler et al., 1982, J. Biomechanics 15, 415-425) or have fastened it to the ground (e.g. Onyshko and Winter, 1980, J. Biomechanics 13, 361-368). A foot model based on viscoelastic elements (e.g. Meglan, 1991, Ph.D. thesis, Ohio State Univ.), allows more freedom of movement and thus models the physical system more closely. The current model was developed by running simulations of the foot in isolation from just before heel contact to just after toe-off. The driving inputs to the simulation were the resultant ankle joint forces and moments taken from a gait analysis. Nine linear, vertically oriented spring/damper systems, positioned along the midline of the foot were used to model the combined viscoelastic behaviour of the foot, shoe and floor. Associated with each vertical spring/damper system were two orthogonally placed, linear, horizontal dampers used to provide the shear components of the ground reaction force. Torques at the metatarsal-phalangeal joint were supplied by a linear, torsional spring and damper. Control about the vertical axis and the long axis of the foot was achieved by the use of linear, torsional dampers. The predicted kinetic and kinematic values are very similar to those taken from the gait analysis. The model represents an improvement over previous work because the transition from swing to stance was smooth and continuous without the foot being constrained to any specific trajectory.