Healing of subcapital femoral osteotomies fixed with self-reinforced poly-L-lactide screws: an experimental long-term study in sheep

Subcapital femoral osteotomies of ten young adult sheep were fixed with two bioabsorbable, self-reinforced, poly- L-lactide (SR-PLLA) lag screws of 4.5 mm in diameter. At 3 weeks radiographs were taken to check the reduction and fixation achieved. After follow-up periods of 12 weeks, 1 year and 3 years with three sheep in each group, and of 7 years and 4 months with one sheep, the sheep were killed, and the healing of the osteotomies, degradation and tissue response of the implants were examined radiographically, histologically and microradiographically. All osteotomies healed with a firm bony union. There was no dislocation or wound infection. Histologically, there was no marked tissue response in the bone tissue. At 12 weeks the implants were grossly intact, at 1 year granulation tissue and new bone formation had started to penetrate into the implant, and at 3 years the implant area was mostly replaced by connective tissue and new bone, but implant material was still seen as little islands surrounded by some lymphocytes. At 7 years and 4 months, the implant material had been degraded and replaced by tight bone. Self-reinforced poly- L-lactide lag screws seem to possess adequate mechanical properties and good biocompatibility for this demanding fixation.     

Permeability Profiles of M-Alkoxysubstituted Pyrrolidinoethylesters of Phenylcarbamic Acid Across Caco-2 Monolayers and Human Skin

Purpose. The purpose of the present research was to study 10 m-alkoxysubstituted pyrrolidinoethylesters of phenylcarbamic acid—potential local anesthetics. The relationships between the structure of the molecule, its physicochemical parameters (log D_oct, log k, R_M, solubility) were correlated to the permeability data obtained from permeation experiments in Caco-2 monolayers and excised human skin in vitro. Methods. The extent and mechanism(s) of permeability of the series were studied through a Caco-2 monolayer in the apical-to-basolateral (a-b) and basolateral-to-apical (b-a) directions. The MTT test was performed to determine cellular damage. In vitro transdermal permeability data were obtained from permeation experiments on excised human skin by using side-by-side chambers. Passive diffusion and iontophoretically enhanced permeability were measured. Results. In Caco-2 monolayers, similar results in the shape of the permeability curves were obtained for the two directions. In the b-a direction, the values of P_app were 2-6 times greater than in the a-b direction. A plot of drug permeability vs. the number of carbons in the alkoxychain plateaued first, after which the permeability decreased by the increasing lipophilicity of the drug. If the log D_oct of the ester was 3.4 and the MW > 385 Da, no measurable Caco-2 permeability was found. Cell damage was also higher by the more lipophilic compounds. In excised human skin, the relationship between the passive diffusion of the drugs and the number of carbons in the alkoxychain was parabolic (r ² = 0.95). Introducing low-level electrical current (iontophoresis), transdermal permeability of the more hydrophilic phenylcarbamic acid esters increased clearly. Conclusions. Lipophilicity and solubility of a compound have crucial roles in the permeation process. A very high lipophilicity has, however, a negative influence on the permeability, both intestinally and transdermally. Iontophoresis significantly increases the diffusion of small and less lipophilic compounds.     

Body build from birth to adulthood and risk of asthma

BACKGROUND: Few reports aimed at the study of adulthood obesity and asthma have taken into account the effects of size at birth and obesity in adolescence. This paper examines the combined effect of size at birth and obesity in both adolescence and adulthood on the risk of asthma at age 31 years. METHODS: The study was derived from a prospectively population-based Finnish birth cohort born in 1966, for which data were collected in pregnancy and at various ages. Adulthood doctor-diagnosed asthma with current symptoms and results of skin prick tests were obtained in 1997. The analysis was limited to 4719 subjects with complete information on asthma and atopy and anthropometric measures at various ages. RESULTS: Ponderal index at birth had a U-shaped association with adult atopy, OR 1.30 (95% CI: 1.11-1.52) for the lowest tertile and OR 1.33 (95% CI: 1.13-1.55) for the highest tertile, as compared to the middle tertile. The association was independent of obesity later in life. Those obese (BMI > or = 95th percentile) in adolescence (OR 2.09, 95% CI: 1.23-3.57) and in adulthood (OR 1.99, 95% CI: 1.14-3.47) had a higher occurrence of adult asthma than those with BMI < 85th percentile. Both estimates were reduced after mutual adjustment. CONCLUSIONS: Size at birth has a long-lasting effect on atopy in adulthood, which is independent of weight in adolescence and adulthood. Those who were obese in adolescence and adulthood tended to have a higher risk of asthma in adulthood. These findings underline the importance of considering the life course of obesity in the analyses of asthma and atopy.     

Experimental Chlamydia pneumoniae infection in NIH/S mice: effect of reinoculation with chlamydial or cell preparation on culture,PCR and histological findings of lung tissue

The cellular components present in chlamydial preparations may contribute to the course of the experimental infection. NIH/S mice were inoculated and reinoculated intranasally with Chlamydia pneumoniae or a cellular preparation. The mock inoculation induced only mild histological changes in the lungs, which possibly induced partial protection against subsequent C. pneumoniae infection and, when given as reinoculation, possibly reactivated the culture-negative infection as culture-positive. In addition, serum antibodies against mouse heat shock protein 60 (Hsp60) were found in a few mice. In conclusion, the main immunopathogenic factors in a C. pneumoniae mouse model are chlamydial components. However, a cellular preparation may participate in an inflammatory reaction. Autoimmunity against Hsp60 may also play a role in the pathogenesis of C. pneumoniae infection.     

The combination of HSV-tk and endostatin gene therapy eradicates orthotopic human renal cell carcinomas in nude mice

BACKGROUND AND METHODS: Gene therapy may offer a new tool for the treatment of renal cell carcinoma (RCC). We have tested a combination of cytotoxic and antiangiogenic gene therapy for wild-type orthotopic human RCC xenografts in nude mice using intratumoral adenovirus-mediated herpes simplex virus thymidine kinase (HSV-tk) and endostatin (ES) gene therapy. In vivo magnetic resonance imaging, morphometry, immunocytochemistry, and survival were used to evaluate the treatment effect. Adenovirus-mediated marker gene transfers (GFP) were used as controls. Results: In vivo transduction efficiency, measured using GFP gene transfer, was 27+/-7%. The combination gene therapy with HSV-tk and ES adenoviruses resulted in a significant antitumor effect (P<.01) compared to single HSV-tk (n.s.) or ES (n.s.). In the survival study, all tumors with single gene therapy using HSV-tk, ES, and marker gene adenoviruses showed progression in magnetic resonance imaging. In contrast, the majority of the tumors in the combination treatment group remained dormant or were eradicated (57%). Survival of these mice equaled healthy nude mice, and was significantly prolonged (P<.0001) compared to HSV-tk (P<.028) and ES (n.s.) groups. Conclusions: It is concluded that the inhibition of angiogenesis using ES gene transfer together with the cytotoxic HSV-tk gene therapy results in a significantly improved treatment effect in RCC compared to the single gene treatments.     

Anterior capsulotomy for treatment of refractory obsessive-compulsive disorder: results in a young and an old patient

The objective of this case report was to assess the effect of anterior capsulotomy for obsessive-compulsive disorder (OCD) in 2 patients beyond extremes of age ranges of published radiofrequency capsulotomy. The youngest patient developed OCD at age 10 with increasing symptoms of tension and worry. The symptoms were refractory to medications and behavioral therapy. He underwent anterior capsulotomy at age 18. The older patient was 64 at the time of surgery. His OCD began about age 17 with checking and counting rituals. His obsessions extended into other areas such as fear of injuring people while driving. His work performance was greatly compromised. Despite medication trials his rituals and obsessions intensified. After 47 years of severe symptoms he underwent surgery. The youngest patient returned to high school full-time and graduated. He was able to read and comprehend without obsessing about the meaning of words. His thinking and behavior became symptom free and he married 4.5 years after surgery. His score on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) after surgery on no medication is zero. The older patient improved gradually without medication. He could play with and touch his grandchildren for the first time. He could drive a car again and his Y-BOCS dropped from 30 preoperatively to 8. Twenty-four months after surgery he is essentially free of obsessions, compulsions and anxiety. We conclude that treatment-refractory OCD may be alleviated by anterior radiofrequency capsulotomy in the young and the old patient. This study expands the documented age range of response from 18 to 64.     

Evaluation of cocktail approach to standardise Caco-2 permeability experiments.

The purpose of this study was to investigate the suitability and reliability of n-in-one approach using FDA suggested compounds for standardising Caco-2 permeability experiments. Special attention was paid to the evaluation of rank order correlation and mechanistic insights of compound permeability. Transport studies with antipyrine, metoprolol, ketoprofen, verapamil, hydrochlorothiazide, ranitidine, mannitol and fluorescein were performed in 12- and 24-well formats, as single compounds and in cocktails under iso-pH 7.4 and pH-gradient (pH 5.5 vs. 7.4) conditions. Compounds were quantified using n-in-one LC/MS/MS analysis. The cocktail-dosing proved to be a feasible method to determine the permeability of the Caco-2 cell line and to introduce external standards for permeability tests. Even though sink conditions were lost in cocktail experiments for highly permeable compounds, the rank order of compound permeability and the classification to low and high permeability compounds remained unchanged between single and cocktail studies and permeability values of 12- and 24-well formats were directly comparable. Under pH-gradient conditions the margin between high and low permeability compounds was narrower due to the lower permeability (higher fraction of ionisation) of basic molecules. Of the compounds studied, antipyrine, metoprolol, hydrochlorothiazide and mannitol are suitable for evaluation and standardisation purposes of passive permeability, while fluorescein would function as paracellular marker under iso-pH 7.4. As efflux activity may vary between cell batches, verapamil is a useful marker for P-glycoprotein.     

Novel approaches to the nutritional management of the allergic infant

The increased prevalence of atopic diseases, i.e. atopic eczema, allergic rhinitis and asthma, has been described as the epidemic of the 21st century in Western societies. New approaches in the fight against allergic diseases are clearly called for, the target being the persistence of the allergic responder pattern beyond infancy. The advantage afforded by elimination diets lies in the silencing of specific allergic inflammation induced by an offending food. Novel nutritional approaches, beyond the treatment of food allergies, have recently attracted research interest subsequent to the identification of the immunomodulatory potential of specific dietary compounds. Dietary lipids as immunomodulators may prevent allergic sensitization by down-regulating inflammatory response whilst protecting the epithelial barrier. Probiotic bacteria have been shown to reinforce the different lines of gut defence: immune exclusion, immune elimination and immune regulation. On this basis, the strategy against allergic disease proposed here is based on the administration of tolerogenic gut-processed peptide fragments of a specific protein, in addition to the use of specific dietary compounds such as fatty acids and antioxidants, and introducing a microbial stimulus for the immature immune system by means of cultures of beneficial live micro-organisms characteristic of the healthy infant gut microbiota.