In-vitro activity of PD 131628, a new quinolone antimicrobial agent.

The in-vitro activity of PD 131628, the active metabolite of the prodrug PD 131112, was compared with that of ciprofloxacin and members of other groups of antimicrobial agents against 701 recent clinical isolates and strains with known mechanisms of resistance. The MIC90s of PD 131628 against the Enterobacteriaceae were between 0.008 and 0.5 mg/L; PD 131628 was one- to four-fold more active than ciprofloxacin against these strains and was four-fold more active than ciprofloxacin against Pseudomonas aeruginosa. Against the Gram-positive species tested, PD 131628 was two- to four-fold more active than ciprofloxacin, inhibiting all strains of Staphylococcus aureus and Streptococcus pneumoniae with 0.5 mg/L or less. PD 131628 was very active against Neisseria spp., Haemophilus influenzae and Moraxella catarrhalis, with MIC90s ranging from 0.004 to 0.008 mg/L. Organisms with decreased susceptibility to other quinolones had decreased susceptibility to PD 131628, but there was no cross-resistance between this class of antimicrobial and other classes. The protein binding of PD 131628 was at most 25% across a broad range of concentrations. The addition of 70% human serum had little effect on the MICs, but caused a two- to eight-fold increase in MBCs.     

Influence of elevated pH levels on structural and functional characteristics of the human zona pellucida: Functional morphological aspects

Purpose A total of 86 fresh and salt-stored immature human oocytes derived from postmortem ovarian tissue were used for this study.Methods Oocytes were randomly incubated either in synthetic human tubal fluid medium (untreated zonae) or in a chemically defined medium (treated zonae).Results Sperm binding experiments using hemizona assay conditions exhibited a 10-fold increased binding of sperm to treated compared to untreated oocytes (272.7±43 versus 24.3±15 sperm bound, respectively; P<0.0001). pH recordings during incubation showed elevated pH levels of 8.1 compared to pH 7.2 among treated and untreated zonae, respectively. Ultrastructural examination showed a spongy appearance of the surface of treated zonae, whereas untreated zonae appeared compact with smooth surface.Conclusions The marked increase in sperm binding among treated zonae, together with the ultrastructural findings, suggest that the altered zona surface enhances sperm binding. The physiological maturational process of the zona pellucida might be manipulated in vitro, thus increasing sperm binding to the zona.Presented at the IXth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction, April 3–7, 1995. Vienna, Austria.     

Visual system of a naturally microphthalmic mammal: The blind mole rat,Spalax ehrenbergi

Retinal projections and visual thalamo-cortical connections were studied in the subterranean mole rat, belonging to the superspecies Spalax ehrenbergi, by anterograde and retrograde tracing techniques. Quantitative image analysis was used to estimate the relative density and distribution of retinal input to different primary visual nuclei. The visual system of Spalax presents a mosaic of both regressive and progressive morphological features. Following intraocular injections of horseradish peroxidase conjugates, the retina was found to project bilaterally to all visual structures described as receiving retinal afferents in non-fossorial rodents. Structures involved in form analysis and visually guided behaviors are reduced in size by more than 90%, receive a sparse retinal innervation, and are cytoarchitecturally poorly differentiated. The dorsal lateral geniculate nucleus, as defined by cyto- and myelo-architecture, cytochrome oxidase, and acetylcholinesterase distribution as well as by afferent and efferent connections, consists of a narrow sheet 3–5 neurons thick, in the dorsal thalamus. Connections with visual cortex are topographically organized but multiple cortical injections result in widespread and overlapping distributions of geniculate neurons, thus indicating that the cortical map of visual space is imprecise. The superficial layers of the superior colliculus are collapsed to a single layer, and the diffuse ipsilateral distribution of retinal afferents also suggests a lack of precise retinotopic relations. In the pretectum, both the olivary pretectal nucleus and the nucleus of the optic tract could be identified as receiving ipsilateral and contralateral retinal projections. The ventral lateral geniculate nucleus is also bilaterally innervated, but distinct subdivisions of this nucleus or the intergeniculate leaflet could not be distinguished. The retina sends a sparse projection to the dorsal and lateral terminal nuclei of the accessory optic system. The medial terminal nucleus is not present. In contrast to the above, structures of the “non-image forming” visual pathway involved in photoperiodic perception are well developed in Spalax. The suprachiasmatic nucleus receives a bilateral projection from the retina and the absolute size, cytoarchitecture, density, and distribution of retinal afferents in Spalax are comparable with those of other rodents. A relatively hypertrophied retinal projection is observed in the bed nucleus of the stria terminalis. Other regions which receive sparse visual input include the lateral and anterior hypothalamic areas, the retrochiasmatic region, the sub-paraventricular zone, the paraventricular hypothalamic nucleus, the anteroventral and anterodorsal nuclei, the lateral habenula, the mediodorsal nucleus, and the basal telencephalon. These results indicate that the apparently global morphological regression of the visual system conceals a selective expansion of structures related to functions of photoperiodic perception and photo-neuroendocrine regulation. We suggest that the evolution of an atrophied eye and reduced visual system is an adaptively advantageous response to the unique subterranean environment. Factors favoring regression include mechanical aspects, metabolic constraints, and competition between sensory systems. The primary advantage of sensory atrophy is the metabolic economy gained by the reduction of visual structures which do not contribute significantly to the animal's fitness. © 1993 Wiley-Liss, Inc.     

CORRELATION OF IMMUNOLOGICAL SURFACE ANTIGENS WITH SURVIVAL IN DIFFUSE LARGE CELL LYMPHOMA

The prognostic value of immunophenotyping lymphomas with a panel of monoclonal antibodies (Mab) to various lymphoid antigens was assessed by studying 47 cases of diffuse large cell lymphoma. Cell suspensions were analysed by flow cytometry after labelling by indirect immunofluorescence. Thirty-eight cases were demonstrated to be of B cell and nine of T cell phenotype. Univariate analysis demonstrated that survival was significantly longer in patients expressing higher levels of HLA-DR (p=0·01) and normal levels of CD8 (p=0·04) but was not significantly associated with any of the other antigens. Our results support the possible value of HLA-DR in determining the prognosis of patients with diffuse large cell lymphoma.     

The synthesis and antibacterial activities of quinolones containing five- and six-membered heterocyclic substituents at the 7-position

A series of 6-fluoro-7-substituted-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared. The substituents at the 7-position included five- and six-membered heterocyclic rings such as oxazoline and oxazine as well as five-membered heteroaromatic rings such as oxazoles and imidazoles. The structure--activity relationships (SAR) of these compounds indicated that oxazole substituents containing a 2-methyl group had the greatest in vitro potency. The compounds showed greater in vitro antibacterial activity against Gram-positive organisms than against Gram-negative organisms.     

An evaluation of the trends in analytical performance of international apolipoprotein A-1 and B assays

Two international apolipoprotein A-1 and B (apoA-1 and apoB) surveys were conducted in 1983 and 1986 with use of a lyophilized serum measured by 55 and 91 participants, respectively. The chief source of variability in both surveys was among laboratories, but among-method variation was significant for apoB. Comparing the 1986 with the 1983 findings, we saw a 60% decrease in apoA-1 variability among laboratories, and a similar decrease (53%) was found for apoB. Evaluation of individual measurements suggests that some collaborators may have adjusted their calibrators toward the consensus values published in 1983.     

Animal models of Duchenne and Becker muscular dystrophy

Two animal models have been shown to be related to Duchenne and Becker muscular dystrophy at the molecular level. The mdx mouse is characterized by early onset of muscle degeneration and very mild clinical disease. The disease is minimally progressive and fibrosis of muscle is absent. Linkage studies, absence of dystrophin, and reduced levels of message indicate that the mutation in mdx lies in the gene for dystrophin, the gene that is defective in Duchenne and Becker muscular dystrophy. The xmd dog develops lesions that are essentially indistinguishable from those of Duchenne dystrophy, and there is progressive fibrosis and destruction of muscle tissue. Affected dogs develop severe clinical disease. The absence of dystrophin and its message in muscle, and the linkage of RFLPs recognized by Duchenne cDNA probes, indicate that the mutation in the xmd dog lies in the gene for dystrophin. Exploitation of these models should lead to a greater understanding of molecular and cellular events involved in the pathogenesis of Duchenne and Becker muscular dystrophies.     

Paget's disease of bone in The Netherlands: a population-based radiological and biochemical survey--the Rotterdam Study.

Serum ALP may be a good indicator of Paget's disease in epidemiologic studies. Subjects with raised and normal ALP from a population cohort were matched (1 in 6, total 548), and radiographs were taken. ALP was an excellent marker of the disease (RR, 10.9), but the majority of those affected had normal ALP. INTRODUCTION: Evidence from radiographic surveys of limited skeletal sites has shown that Paget's disease of bone (PDB) is common in the elderly and has a distinct geographic variation. There is no information, however, about the relation of serum alkaline phosphatase (ALP) activity, a marker of the disease, and its prevalence in the population. MATERIALS AND METHODS: We analyzed data from a well-defined Dutch population cohort (the Rotterdam study) with the following specific aims: (1) to assess the relationship between serum ALP activity and prevalence of radiographically diagnosed PDB, (2) to estimate the overall prevalence of the disease in the Netherlands, and (3) to assess the appearance of the disease with time. Using a nested case-control design, subjects with an increased serum ALP and normal serum liver enzymes were matched for gender and age (1 to 6) with subjects with normal serum ALP activity. Radiographs of the thoracic and lumbar spine, pelvis, proximal femurs, knees, wrists, and hands were taken. RESULTS AND CONCLUSIONS: PDB was diagnosed in 20.5% of subjects with elevated serum ALP activity and in 2.3% in those with normal serum ALP activity, increasing with age in both groups. The relative risk (RR) for PDB in the presence of raised serum ALP activity was 10.9 (95% CI, 4.8, 24.9). The estimated prevalence of PDB in the population was 3.6%, and the large majority (about 86%) had normal serum ALP activity, contrasting findings in bone clinics where the opposite is the case. Finally, in subjects with normal and raised serum ALP activity but no PDB at baseline, radiographs taken 6-9 years later showed no evidence of the disease. This study demonstrated that serum ALP activity is a sensitive marker of PDB in men and women >55 years of age, but the majority of those affected have normal serum ALP activity.