Strontium-modified premixed calcium phosphate cements for the therapy of osteoporotic bone defects.

In this study a premixed strontium-containing calcium phosphate bone cement for the application in osteoporotic bone defects has been developed and characterised regarding its material and in vitro properties as well as minimally invasive applicability in balloon kyphoplasty. Strontium was introduced into the cement by substitution of one precursor component, CaCO3, with its strontium analogue, SrCO3. Using a biocompatible oil phase as carrier liquid, a cement paste that only set upon contact with aqueous environment was obtained. Strontium modification resulted in an increased strength of set cements and radiographic contrast; and the cements released biologically relevant doses of Sr2+-ions that were shown to enhance osteoprogenitor cell proliferation and osteogenic differentiation. Finally, applicability of strontium-containing cement pastes in balloon kyphoplasty was demonstrated in a human cadaver spine procedure. The cement developed in this study may therefore be well suited for minimally invasive, osteoporosis-related bone defect treatment. STATEMENT OF SIGNIFICANCE: Strontium-releasing calcium phosphate bone cements are promising materials for the clinical regeneration of osteoporosis-related bone defects since they have been shown to stimulate bone formation and at the same time limit osteoclastic bone resorption. Today clinical practice favours minimally invasive surgical techniques, e.g. for vertebral fracture treatment, posing special demands on such cements. We have therefore developed a premixed, strontium-releasing bone cement with enhanced mechanical properties and high radiographic visibility that releases biologically relevant strontium concentrations and thus stimulates cells of the osteogenic lineage. In a pilot experiment we also exemplify its excellent suitability for minimally invasive balloon kyphoplasty procedures.

Impact of prenatal diagnosis of fetus-in-fetu.

Fetus in fetu (FIF) is an extremely rare condition (1/500,000 live births) in which a fetiform structure is incorporated into the body of its twin. FIF can be a diagnostic dilemma due to its similarity to a teratoma, but identification of FIF is important for subsequent medical and surgical management. We compare two cases of fetal masses diagnosed on prenatal imaging that were later identified as FIF through further radiological, surgical, and pathologic evaluation. We use these cases to illustrate key pre- and postnatal features of FIF and highlight the benefits of prenatal detection and follow-up for postnatal management.

Ready-to-use injectable calcium phosphate bone cement paste as drug carrier.

Current developments in calcium phosphate cement (CPC) technology concern the use of ready-to-use injectable cement pastes by dispersing the cement powder in a water-miscible solvent, such that, after injection into the physiological environment, setting of cements occurs by diffusion of water into the cement paste. It has also been demonstrated recently that the combination of a water-immiscible carrier liquid combined with suitable surfactants facilitates a discontinuous liquid exchange in CPC, enabling the cement setting reaction to take place. This paper reports on the use of these novel cement paste formulations as a controlled release system of antibiotics (gentamicin, vancomycin). Cement pastes were applied either as a one-component material, in which the solid drugs were physically dispersed, or as a two-component system, where the drugs were dissolved in an aqueous phase that was homogeneously mixed with the cement paste using a static mixing device during injection. Drug release profiles of both antibiotics from pre-mixed one- and two-component cements were characterized by an initial burst release of ∼7-28%, followed by a typical square root of time release kinetic for vancomycin. Gentamicin release rates also decreased during the first days of the release study, but after ∼1 week, the release rates were more or less constant over a period of several weeks. This anomalous release kinetic was attributed to participation of the sulfate counter ion in the cement setting reaction altering the drug solubility. The drug-loaded cement pastes showed high antimicrobial potency against Staphylococcus aureus in an agar diffusion test regime, while other cement properties such as mechanical performance or phase composition after setting were only marginally affected.

Properties of injectable ready-to-use calcium phosphate cement based on water-immiscible liquid.

Calcium phosphate cements (CPCs) are highly valuable materials for filling bone defects and bone augmentation by minimal invasive application via percutaneous injection. In the present study some key features were significantly improved by developing a novel injectable ready-to-use calcium phosphate cement based on water-immiscible carrier liquids. A combination of two surfactants was identified to facilitate the targeted discontinuous exchange of the liquid for water after contact with aqueous solutions, enabling the setting reaction to take place at distinct ratios of cement components to water. This prolonged the shelf life of the pre-mixed paste and enhanced reproducibility during application and setting reactions. The developed paste technology is applicable for different CPC formulations. Evaluations were performed for the formulation of an α-TCP-based CPC as a representative example for the preparation of injectable pastes with a powder-to-carrier liquid ratio of up to 85:15. We demonstrate that the resulting material retains the desirable properties of conventional CPC counterparts for fast setting, mechanical strength and biocompatibility, shows improved cohesion and will most probably show a similar degree of resorbability due to identical mineral structure of the set products.

[Characterization of custom-made biomaterials containing antibiotics]. / Charakterisierung arzneimittelhaltiger Biomaterialien als kundenspezifische Sonderanfertigung.

The aim of this study was to evaluate the quality of custom-made antibiotic carriers which are produced for hospitals in a central service laboratory. These sterile products, made according to antibiogram, showed quality parameters which are comparable with commercially available products in terms of antibiotic release and other relevant properties.

The Ca/P range of nanoapatitic calcium phosphate cements.

Nanoapatites are apatites consisting of nanometer size crystals. The commercial calcium phosphate cements set by the precipitation of nanoapatitic calcium phosphates in the range 1.5 < or = Ca/P < 1.8. In this study it is shown that a continuum of nanoapatites can precipitate in the range 0.8 < Ca/P< or = 1.5. In order to be formed these nanoapatites need to incorporate K+ ions. In addition they can incorporate some Na+ ions. Upon immersion in aqueous solutions these nanoapatites loose phosphate, K+ and Na+ so that in an open system they are transformed into calcium deficient hydroxyapatite Ca9(HPO4)(PO4)5OH within about 2 months.

A comparison of intermittent vaginal administration of two different doses of misoprostol suppositories with continuous dinoprostone for cervical ripening and labor induction.

PURPOSE: To compare the efficacy of a vaginal insert administering continuous dinoprostone with vaginal suppositories containing two different doses of misoprostol for cervical ripening and induction of labor. STUDY DESIGN: In this prospective, randomized, double-blinded study, 118 patients with indications for induction of labor and an unfavorable Bishop score were randomly assigned to receive either continuous dinoprostone, misoprostol 35-microg suppositories, or misoprostol 50-microg suppositories. RESULTS: No significant differences were noted among the three groups in the change of Bishop score, induction of active labor or the time from initial treatment to delivery. Active labor occurred in roughly two-thirds of the patients in an average of about 5.7-6.7 h regardless of treatment assignment. When the two misoprostol groups were combined, a shorter interval from insertion to vaginal delivery was observed in the nulliparous women receiving misoprostol than those receiving continuous dinoprostone (21.3 vs. 27.2 h, p = 0.019). Except for the significantly lower incidence of tachysystole observed in the combined misoprostol group (3.8% vs. 15.4%, p = 0.036), there were no other significant differences between the groups in mode of delivery or in adverse maternal, fetal, or neonatal effects. CONCLUSION: Misoprostol suppositories appeared to be as effective and safe as continuous dinoprostone in inducing cervical ripening in this sample.

Field-portable, high-speed GC/TOFMS.

This work is focused on developing a fast gas chromatograph, time-of-flight mass spectrometer (GC/TOFMS) for man-portable field use. The goal is to achieve a total system solution for meeting performance, size, weight, power, cost, and ruggedness requirements for a laboratory in the field. The core technology will also be adaptable to specific applications including real-time point detection for hazardous chemical releases (e.g., chemical weapons), for biological agent signature identification, and for mobile monitoring platforms (e.g., air, ship, truck). Previously we presented results of a feasibility demonstration for a 30-lb field-portable TOFMS system. In this work we present recent progress in integrating a low-power, high-speed GC and show the capability for accurately recording fast GC transients for targeted compound detection using a quadrupole ion trap, time-of-flight instrument (QitTof).

Chemical and physicochemical characterization of porous hydroxyapatite ceramics made of natural bone.

The properties of a porous hydroxyapatite ceramic produced by sintering of bovine bone were investigated by using a number of physicochemical methods such as scanning electron microscopy (SEM), SEM in combination with energy dispersive X-ray spectroscopy (SEM-EDX), mercury intrusion porosimetry, krypton-adsorption, contact angle measurements, wide angle X-ray diffraction. Fourier transform infrared spectroscopy, thermal analysis, inductively coupled plasma optical atom emissions spectroscopy and flame atomic absorption spectroscopy. The results indicate that there are considerable differences between the ceramic and native bone. However, the most important properties with respect to the use of such ceramics as a biomaterial for filling bone defects namely the high porosity (> or = 57 +/- 2%) and the interconnecting pore system are maintained. While macropores with an average diameter of approx. 300 microm contribute 97% to porosity, micropores with an average diameter of 1.3 microm account for only 3% of the total porosity. The surface area was found to be approx. 0.1 m2/g. The contact angles of water (44.6 +/- 15.4 degrees, n = 5) and tetrahydrofurane (10 degrees) allow the processing of the ceramic to a drug carrier by incubation with aqueous or organic drug solutions. The ceramic is highly crystalline with crystal sizes of 1-7 microm and contains crystal bridges. The investigation of its chemical composition revealed small amounts of other inorganic compounds such as Ca4O(PO4)2, NaCaPO4, Ca3(PO4)2, CaO, and MgO. Besides trace amounts of aluminum, iron, magnesium, potassium, silica, sodium, vanadium and zinc it contains probably carbonated apatite.

Surface coating with cyclic RGD peptides stimulates osteoblast adhesion and proliferation as well as bone formation.

The physiological inertness of synthetic implant materials often results in insufficient implant integration and limited acceptance of implants in tissues. After implantation the implant surface is often separated from the surrounding healthy and regenerating tissue, for example by a fibrous capsule. To avoid this host-versus-graft reaction, a strong mechanical contact between tissue and implant must be ensured. An enhanced contact between graft and the surrounding tissue can be provided by coating the implant with cell-adhesive molecules. The highly active and alpha(v)beta(3)- and alpha(v)beta(5)-integrin-selective peptide c(-RGDfK-) (f=D-phenylalanine) was functionalized with various linker molecules containing an acrylamide end group by using the lysine side chain of c(-RGDfK-). The acrylamide group can be used to bind the peptide covalently to poly(methyl methacrylate) (PMMA) surfaces. The coated surfaces effectively bind to murine osteoblasts as well as human osteoblasts in vitro when a minimum distance of 3.5 nm between surface and the constrained RGD sequence is provided. In contrast to osteoblasts in cell suspension, surface-bound osteoblasts show no apoptosis but proliferate by a factor of 10 over a 22 d period. Coating of inert implant surfaces with highly active and alpha(v)-selective peptides affords a marked improvement in osteoblast binding over current technologies. In vivo studies show that peptide-coated PMMA pellets implanted into the patella groove of rabbits are integrated into the regenerating bone tissue faster and more strongly than uncoated pellets.

Induced tissue integration of bone implants by coating with bone selective RGD-peptides in vitro and in vivo studies.

The optimal function of medical implant materials used in tissue substitution is often limited due to its healing properties. This effect is linked to reduced interactions of the implants with the surrounding tissue. Implant surfaces biologically functionalized with arginine-glycine-aspartic acid (RGD) peptides, a class of cellular adhesion factors, are described in this paper. The RGD-peptides are either bound via bovine serum albumin linking on culture plastic dishes as a model surface or via acrylic acid coupling on PMMA surface as a potential implant material. Resulting functionalized surfaces aquire the capability to bind cultured osteoblasts in high levels and show high proliferation rates in vitro. These results are observed for osteoblast cultures as well as from different species with different preparation procedures. A critical minimum distance between the bioactive portion of the RGD-peptides and the implant surface of 3.0-3.5 nm is crucial for the induction of an optimum cell binding process. In vivo animal studies in the rabbit show that newly formed bone tissue generated a direct contact with the RGD-peptide coated implants. In contrast uncoated implants are separated from newly formed bone tissue by a fibrous tissue layer thereby preventing the formation of a direct implant-bone bonding.

Cytotoxic effect of methotrexate and its solvent on osteosarcoma cells in vitro.

Bone tumours may recur locally even after wide surgical excision and systemic chemotherapy. Local control of growth may be accomplished by the addition of cytostatic drugs such as methotrexate (MTX) to bone cement used to fill the defect after surgery and to stabilise the reconstructive prosthesis. We have studied the elution kinetics of MTX and its solvent N-methyl-pyrrolidone (NMP) from bone cement and their biological activities in five cell lines of osteosarcoma and in osteoblasts, and compared them with the effects of the parent compounds alone and in combination. Our findings show that MTX is released continuously over months at concentrations highly cytotoxic to osteosarcoma cells and suggest that the impregnated bone cement would be effective in the long term. Proliferating osteoblasts, however, were much less sensitive towards MTX. The dose-response relationship for NMP and experiments with MTX/NMP-mixtures show that the eluted concentrations of solvent are not toxic and do not influence the effects of MTX. We suggest that bone cement containing MTX dissolved in NMP releases the drug in a suitable and effective way and may be of value in the treatment of bone tumours.

Antibiotic-impregnated heart valve sewing rings for treatment and prophylaxis of bacterial endocarditis.

Prosthetic heart valve sewing rings were impregnated with gentamicin crobefat (EMD 46217), a poorly soluble gentamicin salt, gentamicin sulfate, and clindamycin palmitate to prevent early prosthetic endocarditis. MICs and MBCs of gentamicin and/or clindamycin were tested against several pathogens of early prosthetic endocarditis. The combination of gentamicin and clindamycin was found to be effective against most relevant bacterial pathogens. With an in vitro pharmacokinetic model, the antibacterial activity of gentamicin and clindamycin was tested against Staphylococcus aureus and Escherichia coli. High gentamicin levels over the first 24 h were required for a strong reduction of bacterial counts of both strains. Equal amounts of gentamicin and clindamycin sustained the antibacterial effect and prevented regrowth. The most effective release curves of gentamicin and clindamycin found with an in vitro model were used for monitoring release profiles of these antibiotics from impregnated sewing rings by investigating combinations of gentamicin sulfate, gentamicin crobefat, and clindamycin palmitate. Sewing rings impregnated with 4 mg of gentamicin sulfate, 14 mg of gentamicin crobefat, and 20 mg of clindamycin palmitate gave an initial gentamicin burst and afterwards yielded a lower sustained release of gentamicin and clindamycin palmitate. These in vitro release kinetics were confirmed in vivo by pharmacokinetic analysis after intramuscular implantation of impregnated sewing ring segments. Gentamicin and active clindamycin palmitate metabolites were obtained at the implantation site for at least 2 weeks in concentrations of 3 and 5 micrograms per g of muscle, respectively. The investigated method of impregnation holds promise for revision implants after prosthetic valve endocarditis. It may also serve as a prophylactic tool for routine use against this disease.

Incorporation of basic fibroblast growth factor into methylpyrrolidinone chitosan fleeces and determination of the in vitro release characteristics.

Methylpyrrolidinone chitosan (MPC), a water-soluble derivative of chitosan, was investigated as a carrier material for basic fibroblast growth factor (bFGF), a combination intended for the treatment of wound healing deficiencies. Soft and flexible fleeces of MPC were prepared by freeze drying. The growth factor was incorporated either before drying of the fleeces by mixing bFGF solution with MPC solution or by soaking bFGF solution into a previously prepared fleece and subsequent freeze drying. Release studies using an immunological assay, radioactivity measurements and cell culture techniques revealed a sustained release of biologically active bFGF from the fleeces. Different bFGF loadings and different fleece sizes did not influence the release kinetics.

Management and therapy of human immunodeficiency virus-infected pregnancies in maternal-fetal medicine fellowship training programs.

OBJECTIVE: To determine attitudes and practices of obstetricians in maternal-fetal medicine fellowship programs regarding the management of human immunodeficiency virus (HIV) infection and the use of zidovudine during pregnancy. METHODS: We sent a questionnaire to the directors of all 78 approved maternal-fetal medicine fellowship programs. The responses, reflecting the consensus of the staffs of each program, were obtained and tabulated. RESULTS: Although their programs annually provide care for more than 2100 pregnant women infected with HIV, less than 25% of all maternal-fetal medicine fellowship directors reported that their patients participate in multicenter studies of HIV infection complicating pregnancy. Nearly two-thirds of the infected women are excluded from such multicenter studies. More than 70% of all program directors believe that zidovudine should be offered to symptomatic pregnant women infected with HIV; one-half question whether zidovudine poses short-term fetal risks. Nevertheless, nearly half of all HIV-infected pregnant women they manage are excluded from trials of zidovudine therapy during pregnancy. CONCLUSIONS: Many HIV-infected pregnant women who receive care in clinics of maternal-fetal medicine fellowship programs are excluded from multicenter studies. Consideration should be given to creating a national registry for this important, currently unreported, clinical resource.

Cystic hygroma and congenital diaphragmatic hernia: early prenatal sonographic evaluation of Fryns' syndrome.

We report a case of cystic hygroma and diffuse lymphangiectasia detected by sonogram at 12 weeks' gestation. Fetal karyotype was normal. At 20 weeks' gestation, herniation of the bowel into the chest was noted. At delivery, the infant was diagnosed as having Fryns' syndrome. This is the first reported case of Fryns' syndrome presenting with cystic hygroma.

Pharmacokinetics and antibacterial activity of daily gentamicin.

Twenty full term neonates with suspected bacterial infection were randomly assigned to a once daily or a twice daily dosage regimen with gentamicin (4 mg/kg/day). Concomitantly all patients were treated with ampicillin (200 mg/kg/day). The gentamicin concentration time curves were analysed by an open two compartment model under steady state conditions on day 4 of treatment. The mean theoretical maximum serum concentration in the group taking gentamicin once daily (10.9 micrograms/ml) was significantly higher than in the group taking it twice daily (7.4 micrograms/ml). Potentially toxic serum concentrations were never reached. Mean trough concentrations were comparable in both groups (once daily 0.8 micrograms/ml; twice daily 1.0 micrograms/ml). Urinary alanine aminopeptidase excretion increased during and even two days after end of treatment in both groups without any significant differences. The results of the dynamic in vitro model revealed that both dosage schedules showed comparable bactericidal effects on pathogens inhibited by low concentrations of gentamicin like Escherichia coli and Staphylococcus aureus. However the once daily regimen was significantly superior in isolates with high minimal inhibitory concentrations.

Lack of effect of cefixime on the metabolism of vitamin K1.

It seems that cephalosporins bearing a N-methyl-thio-tetrazole or a methyl-thiadiazole moiety in their molecule can cause hypoprothombinemia in patients via inhibition of the metabolism of vitamin K1 if they are in addition in a vitamin K1-deficient state. The authors therefore studied the effects of two different oral doses (200 and 400 mg) of the cephalosporin cefixime on the metabolism of vitamin K1 in healthy volunteers, because the accumulation of vitamin K1-2,3-epoxide in plasma is a sensitive marker of coumarin-like activity of drugs. The results indicate that the development of hypoprothrombinemia due to an impairment of the metabolism of vitamin K1 by cefixime seems unlikely because only trace amounts of vitamin K1-2,3-epoxide could be determined in the plasma of the subjects investigated.

Concentration of cefixime in bile, gallbladder wall and serum after preoperative administration in patients undergoing cholecystectomy.

Cefixime is a new oral cephalosporin antibiotic with improved activity against Gram-negative pathogens comparable to the parenteral third generation cephalosporins, high beta-lactamase stability and a long elimination half-life of about 3 h. 15 patients undergoing cholecystectomy received 2 x 200 mg/day cefixime for two days before surgery. The last application was administered 13-17 h preoperatively. Intraoperatively, the mean biliary level of cefexime was 199.3 micrograms/ml (8.8 micrograms/ml-1163.8 micrograms/ml). The mean level in gallbladder wall was 25.02 micrograms/g (0.68 micrograms/g-61.20 micrograms/g). Serum samples were taken simultaneously. Despite relevant concentrations in bile and gallbladder wall, no cefixime could be detected in the serum samples of two patients. The other 13 patients, however, showed relevant serum levels between 0.28 micrograms/ml and 2.98 micrograms/ml (mean 1.01 micrograms/ml). Side effects as well as an influence on laboratory parameters were not seen. After administration of cefixime in bile and gallbladder tissue high antibiotic levels were achieved, even 13-17 hours after the last application.

Hyperlipidemic pancreatitis in pregnancy: a case report and review of the literature.

A case of pancreatitis associated with type I primary hyperlipoproteinemia in pregnancy is reported, with a review of the literature. There have been 11 cases of hyperlipidemic pancreatitis during pregnancy reported in the English literature since 1956. This case is the first report of adult respiratory distress syndrome complicating hyperlipidemic pancreatitis in pregnancy. Guidelines for prevention and management of this rare disorder are presented.