Toxicity, inflammation, and anti-human immunodeficiency virus type 1 activity following exposure to chemical moieties of C31G.

C31G, which has potent activity against the human immunodeficiency virus type 1 (HIV-1) and an established record of safety in animal studies and human trials, is a microbicidal agent comprised of a buffered equimolar mixture of two amphoteric, surface-active agents: an alkyl amine oxide (C14AO) and an alkyl betaine (C16B). Studies of long-term in vitro exposure to C31G and its constituents have suggested that the components of C31G may contribute differentially to its toxicity and efficacy. In the present studies, in vitro assays of cytotoxicity and anti-HIV-1 activity demonstrated that C16B was slightly less cytotoxic compared to either C31G or C14AO, whereas the anti-HIV-1 activities of C31G and its individual constituents were similar. In the murine model of cervicovaginal microbicide toxicity, in vivo exposure to C14AO resulted in severe cervical inflammation followed by a delayed disruption of the columnar epithelium. In contrast, exposure to C16B caused severe cervical epithelial disruption and a secondary, less intense inflammatory response. These results demonstrate that (i) there are both mechanistic and temporal differences in toxicity associated with the components of C31G not necessarily predicted by in vitro assessments of cytotoxicity and (ii) contributions of each component to the anti-HIV-1 activity of C31G appear to be equal. In addition, these findings indicate that direct and indirect mechanisms of in vivo toxicity can be observed as separate but interrelated events. These results provide further insight into the activity of C31G, as well as mechanisms potentially associated with microbicide toxicity.     

Mikrofrakturierung bei fokalem Knorpelschaden

The microfracture technique and spongiolization using Pridie drilling are the most commonly used and highly cost-efficient operative therapies for restoration of cartilage in Germany. Microfracturing can be performed arthroscopically in various joints including the knee, ankle, elbow, and shoulder joint. Specifically designed instruments are recommended for this procedure. Steadman recently reported excellent results in a series of 72 patients undergoing microfracturing with a mean follow-up of 11 years showing consistent and long-term reduction of weight-bearing pain and swelling as well as improvement of daily activities. Ideal indications for this easy arthroscopic procedure of microfracture treatment include focal lesions up to 4 cm². Some studies have demonstrated that microfracturing results not merely in the formation of fibrocartilage but also in the induction of hyaline cartilage with superior properties.     

Outcome of 60 neonates who had ARED flow prenatally compared with a matched control group of appropriate-for-gestational age preterm neonates.

OBJECTIVE: To describe the course and outcome of fetuses with absent or reversed end-diastolic (ARED) flow in the umbilical artery (UA) and to examine the influence of prematurity according to gestational age at delivery. METHODS: Sixty pregnancies complicated by ARED flow in the UA were monitored by repeat Doppler measurements of arterial and venous vessels, non-stress tests (cardiotocogram (CTG)) and maternal investigations, and were delivered between 24 and 34 weeks. Fetal outcome was investigated and compared to a control group of appropriate-for-gestational age (AGA) preterm neonates, matched for gestational age. Mortality, birth weight, Apgar scores, postnatal cord arterial pH and need for ventilation were all recorded, as were cases of respiratory distress syndrome, bronchopulmonary dysplasia, persistent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, abnormal neurological findings and those requiring surgical intervention. Additionally, the group of fetuses with ARED flow was divided into three subgroups of different degrees of prematurity (delivery between 24 + 0 and 28 + 6 weeks, delivery between 29 + 0 and 31 + 6 weeks, and delivery after 32 weeks) and compared according to the above parameters. RESULTS: Pre- or postnatal death occurred in 16 cases. Comparing the 44 (61%) that were born alive with the AGA neonates, significant differences were found in birth weight (P < 0.001), arterial pH value (P < 0.001), bronchopulmonary dysplasia (P = 0.002) and intestinal complications (P < 0.01). Prematurity-related complications were: need for ventilation (P = 0.001), respiratory distress syndrome (P < 0.0001), periventricular leukomalacia (P = 0.002) and pathological neurological testing (P = 0.005). CONCLUSIONS: Neonates displaying ARED flow before birth are growth restricted, acidemic at delivery and are at high risk of developing bronchopulmonary dysplasia and intestinal complications. While perinatal mortality seems to be related to abnormal fetal Doppler velocimetry, age at delivery has a significant impact on short-term morbidity. After 32 weeks, morbidity is low and delivery should be considered. It could be speculated from our data that prolongation of pregnancy with Doppler velocimetry monitoring could help to reduce morbidity, although prolongation remains limited in most cases.     

Quantitatively distinct requirements for signaling-competent cell spreading on engineered versus natural adhesion ligands.

To design synthetic microenvironments that elicit desired cell behaviors, we must better understand the molecular mechanisms by which cells interact with candidate biomaterials. Using cell lines with distinct alpha5beta1 integrin expression profiles, we demonstrate that this integrin mediates cell spreading on substrata coated with genetically engineered artificial extracellular matrix (aECM) proteins containing the RGD sequence (RGD-containing aECM protein [aRGD]) but lacking the PHSRN synergy site. Furthermore, aRGD-mediated adhesion stimulates an intracellular focal adhesion kinase (FAK) signal that is indicative of integrin tethering. Although both aRGD and the natural ECM protein fibronectin (FN) support alpha5beta1 integrin-mediated cell spreading, quantitative single-cell analysis revealed that aRGD-mediated spreading requires ten-fold greater threshold amount of integrin expression than FN-mediated spreading. Our analysis demonstrates that aRGD-based substrata mediate both biophysical (cell spreading) and biochemical (FAK signaling) events via the alpha5beta1 integrin, albeit with efficacy quantitatively distinct from that of natural ECM proteins that possess the full spectrum of adhesion and synergy domains.     

The influence of formulation components on the aerosolisation properties of spray-dried powders.

Dry powders suitable for inhalation containing beta-estradiol, leucine as a dispersibility enhancer and lactose as a bulking agent were prepared by spray-drying from aqueous ethanol formulations. The influence of formulation components on the characteristics of the resultant spray-dried powders was examined through the use of a range of ethanol concentrations (10-50% v/v) in the solvent used to prepare the initial formulations. Additionally, the amount of leucine required to act as a dispersibility enhancer was investigated by varying the amount of leucine added to the formulation prior to spray-drying. Following spray-drying, resultant powders were characterised using scanning electron microscopy, laser diffraction and tapped density measurements, and the aerosolisation performance determined using Twin Stage Impinger and Andersen Cascade Impactor analysis. We demonstrate that selection of appropriate solvent systems and leucine concentration allows the preparation of spray-dried powders that display enhanced aerosolisation properties, and would be predicted to exhibit high deposition in the lower regions of the respiratory tract.     

Histological changes over time around the site of sustained release naltrexone-poly(DL-lactide) implants in humans.

In order to assess the histological tissue changes over time around the site of implant, tissue biopsies were taken at 1 to 38 months post-implant from 54 (34 male) consenting human subjects who had received the Australian subcutaneous naltrexone-poly(DL-lactide) implant for heroin dependence. The implant consists of multiple tablets containing compressed naltrexone-poly[trans-3,6-dimethyl-1,4-dioxane-2,5-dione] (DL-lactide) loaded microspheres. Assessment of tissue samples by pathologists showed an early phase (up to 12 months post-implant) of inflammation, foreign body reaction, and fibrosis. This subsided gradually over the next 12 months until tissue returned to normal by 25+ months. Sufficient evidence was not available to conclude that the poly(DL-lactide) implant matrix was totally biodegradable within the study period. While implant material was not identified in most of the latter biopsies, its presence was noted in one biopsy at 26 months post-implant. Nevertheless the study results did demonstrate the implant's biocompatibility by the lack of inflammation, foreign body reaction, and fibrosis detected by 25+ months. It seems highly probable that surgical technique rather than the implant itself was associated with the additional finding of fat necrosis. Moderate fat necrosis was observed as a common feature of biopsies carried out during the first 6 months following implant. It subsided to mild levels over the next 18 months, and was notably absent by 25+ months. The results of the study indicated that the Australian naltrexone-poly(DL-lactide) implant is well tolerated and may have a role for use in the management of medical conditions such as heroin dependence.     

A metropolitan experience with infrainguinal revascularization. Operative risk and late results in northeastern Ohio

Despite being of fundamental importance, the late results of major arterial reconstruction rarely have been documented throughout a large metropolitan area. In this study of 932 patients entered into the computer registry of the Cleveland Vascular Society, 19 surgeons representing 13 community hospitals and referral centers in Cleveland and Akron report the intermediate-term outcome during a mean interval of 35 months after infrainguinal lower extremity revascularization performed in northeastern Ohio from 1978 through 1982. Operative risk (5%), the early amputation rate (7%), and actuarial 5-year survival (48% to 55%) for patients with rest pain or tissue necrosis were significantly worse (p less than 0.05) than comparable figures (0.6%, 0%, and 77%, respectively) for others who underwent procedures for disabling claudication. Although both materials had similar success above the knee, the cumulative 3-year patency rate of autogenous vein bypass to the distal popliteal (69% to 88%; p less than 0.05) and tibioperoneal arteries (43%; 0.05 less than p less than 0.1) was superior to the results of polytetrafluoroethylene grafts (32% to 50% and 19%, respectively). Moreover, polytetrafluoroethylene grafts required reoperations at three times the rate of vein grafts to maintain limb salvage.