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.     

Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease

Donepezil and rivastigmine are acetylcholinesterase (AChE) inhibitors used to improve cholinergic neurotransmission and cognitive function in Alzheimer's disease (AD). This study examined direct effects of these drugs on AChE activity in the frontal, temporal, and parietal cortices in AD. Six AD patients were scanned with positron emission tomography before and after 3 months of treatment with donepezil (10 mg/day), and five AD patients were scanned before and after 3 to 5 months of treatment with rivastigmine (9 mg/day). Healthy unmedicated controls were imaged twice to evaluate the reproducibility of the method. A specific AChE tracer, [methyl-11C]N-methyl-piperidyl-4-acetate, and a 3D positron emission tomography system with MRI coregistration were used for imaging. Treatment with donepezil reduced the AChE activity (k3 values) in the AD brain by 39% in the frontal (p < 0.001, Bonferroni corrected), 29% in the temporal (p = 0.02, corrected) and 28% in the parietal cortex (p = 0.05, corrected). The corresponding levels of inhibition for rivastigmine were 37% (p = 0.003, corrected), 28% (p = 0.03, uncorrected) and 28% (p = 0.05, corrected). When the treatment groups were combined, the level of AChE inhibition was significantly greater in the frontal cortex compared to the temporal cortex (p = 0.03, corrected). The test-retest analysis with healthy subjects indicated good reproducibility for the method, with a nonsignificant 0% to 7% intrasubject variability between scans. The present study provides first evidence for the effect of rivastigmine on cortical AChE activity. Our results indicate that the pooled effects of donepezil and rivastigmine on brain AChE are greater in the frontal cortex compared to the temporal cortex in AD. This regional difference is probably related to the prominent temporoparietal reduction of AChE in AD. We hypothesize that the clinical improvement in behavioral and attentional symptoms of AD due to AChE inhibitors is associated with the frontal AChE inhibition.     

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.     

Antifungal evaluation of bis Mannich bases derived from acetophenones and their corresponding piperidinols and stability studies

The development of resistance to current antifungal therapeutics drives the search for effective new agents. The fact that some acetophenone-derived Mannich bases had shown antifungal activities in our previous studies led us to design and synthesize acetophenone-derived bis Mannich bases, B1-B5, bis(beta-aroylethyl)methylamine hydrochlorides, to evaluate their antifungal activity. These bis Mannich bases were then converted to the corresponding piperidinols, C1-C5, which are structural isomers of bis derivatives, 3-aroyl-4-aryl-1-methyl-4-piperidinol hydrochlorides, to see alterations in biological activity. A stability study of B1 and Cl was also carried out to estimate whether they alkylate the thiols. All compounds studied have shown antifungal activity, especially against dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, and Microsporum canis), in the concentration range studied (2-128 microng/ml). The activity was especially apparent against T. tonsurans. All compounds had at least equal antifungal activity compared with the reference compound amphotericin-B against T. tonsurans. Bis Mannich bases were generally found to be more potent compounds than their structural isomer piperidinols. The results of our stability studies suggest that thiol alkylation may contribute to the antifungal activity of the Mannich bases synthesized. Even though all compounds showed antifungal activity against dermatophytes, bis Mannich bases B1, B2, B4, and B5 appear to have potential for developing novel antifungal agents against dermatophytes.     

Herpes simplex virus and risk of cervical cancer: a longitudinal,nested case-control study in the nordic countries

Human papillomaviruses (HPVs) play the major role in cervical carcinogenesis. The authors reevaluated the role of herpes simplex virus type 2 (HSV-2) in this multistage process by conducting a longitudinal, nested case-control study using 1974-1993 data and comparing the results with those from a meta-analysis of studies. A Nordic cohort of 550,000 women was followed up for an average of 5 years, after which 178 cervical carcinoma cases and 527 controls were identified. HSV-2; HPV-16, HPV-18, and HPV-33; and Chlamydia trachomatis antibodies were determined at baseline by HSV-2 glycoprotein gG-2 and HPV virus-like-particle enzyme immunoassays and by using the microimmunofluorescence method. The relative risk of cervical carcinoma was calculated by conditional logistic regression. Longitudinal studies on HSV-2 and cervical neoplasia were identified through MEDLINE (National Library of Medicine, Bethesda, Maryland), and weighted mean relative risks were calculated. Smoking (relative risk = 1.6, 95% confidence interval (CI): 1.1, 2.3) and HPV-16/HPV-18/HPV-33 (relative risk = 2.9, 95% CI: 1.9, 4.3) were both associated with cervical carcinoma. The smoking- and HPV-16/HPV-18/HPV-33-adjusted relative risks for HSV-2 were 1.0 (95% CI: 0.6, 1.7) and 0.7 (95% CI: 0.3, 1.6), respectively, for HPV seropositives. In the meta-analysis, the relative risk for HSV-2 was 0.9 (95% CI: 0.6, 1.3). In both sets of data, HSV-2 did not play a role in cervical carcinogenesis.     

Assessment of feasibility of workplace health promotion

BACKGROUND: A simple empirically based method for assessment of the feasibility of workplace health promotion programs is described, focusing on cancer hazards (lifestyles, workplace hazards, deficient early detection). The basic components of feasibility are addressed: extent of hazards; needs of employees for hazard reduction and acceptability of WHP; and social context. METHODS: The procedure consists of six modules: guidelines on feasibility assessment; employee questionnaire; interview checklists for probing attitudes of management and partners (social context); data form; debriefing; and assessment of feasibility. Pretesting was completed in 16 workplace communities representing industry, construction, transport, telecommunications, health care, lodging and catering, teaching, and municipality jobs in five countries; a total of 1,085 subjects completed the employee questionnaire on health hazards, needs, and acceptability. RESULTS: The method demonstrated its utility in obtaining and summarizing the necessary data. Feasibility was assessed for the 16 test communities. CONCLUSION: The procedure can be customized; it has a high degree of face validity or understandability, and it is applicable in a wide variety of settings.     

Phenotypic spectrum of Salla disease, a free sialic acid storage disorder

Salla disease (MIM 269920) represents the mildest phenotype among recessively inherited lysosomal-free sialic acid storage disorders. Although the vast majority of Salla disease patients in Finland share the same founder mutation, R39C in the SLC17A5 gene, there still is a wide clinical variation among mentally retarded, ataxic patients. We evaluated neurologic and neurocognitive findings of Salla disease in a cross-sectional study of 41 Finnish patients who were 11 months to 63 years of age (median = 19.5 years). The phenotype of Salla disease could be classified into two main categories. The majority of patients (90%) had so-called conventional phenotype, including a subgroup of seven patients with relatively mild symptoms. All but two patients with conventional phenotype were homozygous for the Finnish founder mutation. Four severely disabled, profoundly mentally retarded patients, 15-28 years of age, clearly could be clinically delineated as a separate group, likely reflecting the underlying compound heterozygous genotype. A typical developmental pattern could be outlined in the conventional type of the disease, emphasizing a strong motor handicap in Salla disease. The cognitive profile consisted of better verbal ability, especially speech comprehension, compared with nonverbal functioning in all patients. Our results indicate a partial genotype-phenotype correlation, although factors other than the molecular background are also involved in the phenotypic manifestation of Salla disease.     

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.