Gastrointestinal and renal side effects of bisphosphonates: differentiating between no proof of difference and proof of no difference.

BACKGROUND: This study was aimed at comparing the safety of bisphosphonates in women with osteoporosis by application of equivalence testing. METHODS: Gastrointestinal and renal side effects were evaluated based on information published in randomized controlled trials. RESULTS: The data on gastrointestinal side effects (47 trials) indicated that alendronate, risedronate etidronate, and zolendronate have similar rates of the adverse effects; application of Bayesian network meta-analysis showed that equivalence was demonstrated according to margins around ±10%. The data on renal safety were more sparse and suffered from the use of different outcome measures; hence, a single trial could be evaluated. This trial showed a similar effect of alendronate and risedronate on renal function at 12 months; equivalence was based on differences between the two agents in renal function with margins of less than ±10.4 ml/min. CONCLUSION: Our study provided quantitative information to determine to what extent bisphosphonates can be considered equivalent in terms of gastrointestinal and renal side effects.

The effect of PDGF on the healing of full thickness wounds in hairless guinea pigs.

1. Platelet-derived growth factor (PDGF), administered daily for 5 days and every other day for 9 additional days or the day of wounding and the following day, caused dose dependent (0.2, 1.0 or 5.0 micrograms PDGF/wound) increased granulation tissue. 2. The two day 5.0 micrograms treatment resulted in a 73% increase and the multi-day treatment resulted in a 52% increase of alkaline phosphatase activity three days after wounding. 3. Multi-day treatment resulted in significant increases in protein synthesis (132%), vimentin content (160%) and excised wound weight (76%) three days after wounding. 4. These results indicate that limited administration of PDGF alters wound healing although multiple applications provoke a more dramatic response.

Purification of hybrid beta-galactosidase proteins encoded by phi X174 E phi lacZ and Escherichia coli prlA phi lacZ: a general method for the isolation of lacZ fusion polypeptides produced in low amounts.

A facile immunoaffinity chromatography method is described for the purification of lacZ fusion gene products. The method is general for any molecule antigenically related to beta-galactosidase and involves only a single step. We report its use to purify the products of lacZ fusions with a bacteriophage gene, phi X174E, and an Escherichia coli chromosomal gene, prlA. The hybrid protein products of both of these genes are membrane bound and present in very low molar amounts with respect to total cellular protein. Evidence is presented that substrate-affinity chromatography is not applicable to the isolation of low-level fusion proteins such as these.

Deletion and fusion analysis of the phage phi X174 lysis gene E.

The lysis gene, E, of bacteriophage phi X174 has been subjected to deletion and gene fusion analysis. C-terminal deletions of as few as 17 of the 91 codons inactivate the cloned E gene, which in its intact form can cause lysis of the host cell. Fusion of lacZ to deletion joints at the 59th codon or beyond apparently restores lethal and lytic competence to the respective E deletion alleles, whereas a fusion at the 23rd codon remains non-lethal. The lethal E phi lacZ fusions are also lethal to a mutant, designated slyD, which was isolated as a spontaneous E. coli mutant resistant to the expression of the intact E gene. slyD appears to be linked to rpsE. The data are interpreted in terms of a model in which E-mediated lethality requires oligomerization of the E gene product. Calculations based on the beta-galactosidase activity accumulated by the time of lethal action of E phi lacZ suggest that fewer than 1000 molecules of E gene product are required for lysis and probably fewer than 100 are required for loss of host viability.

Electron microscopic examination of wastewater biofilm formation and structural components.

This research documents in situ wastewater biofilm formation, structure, and physiochemical properties as revealed by scanning and transmission electron microscopy. Cationized ferritin was used to label anionic sites of the biofilm glycocalyx for viewing in thin section. Wastewater biofilm formation paralleled the processes involved in marine biofilm formation. Scanning electron microscopy revealed a dramatic increase in cell colonization and growth over a 144-h period. Constituents included a variety of actively dividing morphological types. Many of the colonizing bacteria were flagellated. Filaments were seen after primary colonization of the surface. Transmission electron microscopy revealed a dominant gram-negative cell wall structure in the biofilm constituents. At least three types of glycocalyces were observed. The predominant glycocalyx possessed interstices and was densely labeled with cationized ferritin. Two of the glycocalyces appeared to mediate biofilm adhesion to the substratum. The results suggest that the predominant glycocalyx of this thin wastewater biofilm serves, in part, to: (i) enclose the bacteria in a matrix and anchor the biofilm to the substratum and (ii) provide an extensive surface area with polyanionic properties.

Ultrastructure of a magnetotactic spirillum.

The ultrastructure of a magnetotactic bacterium (strain MS-1) was examined by transmission, scanning, and scanning-transmission electron microscopy. The organism resembled other spirilla in general cell morphology, although some differences were detected at the ultrastructural level. Electron-dense particles within magnetotactic cells were shown by energy-dispersive X-ray analysis to be localizations containing iron. A non-magnetotactic variant of strain MS-1 lacked these novel bacterial inclusion bodies. A chain of these particles traversed each magnetotactic cell in a specific arrangement that was consistent from cell to cell, seemingly associated with the inner surface of the cytoplasmic membrane. Each particle was surrounded by an electron-dense layer separated from the particle surface by an electron-transparent region. The term "magnetosome" is proposed for the electron-dense particles with their enveloping layer(s) as found in this and other magnetotactic bacteria.

Isolation and pure culture of a freshwater magnetic spirillum in chemically defined medium.

A bipolarly flagellated magnetotactic spirillum containing intracellular chains of single domain-sized magnetite crystals was isolated by applying a magnetic field to sediments from a freshwater swamp. The organism was cultured in a chemically defined medium containing ferric quinate and succinate as sources of iron and carbon, respectively. Nonmagnetic variants of this isolate were maintained in chemically defined medium lacking ferric quinate. In contrast to magnetic cells, these had less iron and lacked measurable magnetic remanence and the intracytoplasmic crystals. In other respects, including moles percent guanine plus cytosine content, growth characteristics, nutrition, and physiology, the two types were similar. The isolate reduced nitrate without accumulating nitrite and produced ammonia during growth. Nitrate or ammonium ions served as a nitrogen source. The organism was microaerophilic and did not grow anaerobically with nitrate in the medium. In chemically defined medium, cells synthesized magnetite only if the initial O2 concentration in the atmosphere of sealed cultures was 6% (vol/vol) or less.