Binding, degradation and pressor activity of angiotensins II and III after aminopeptidase inhibition with amastatin and bestatin

In the metabolism of angiotensin peptides by tissue angiotensinases, aminopeptidases A, B, M and leucine aminopeptidase have been identified as being particularly effective. Because the inhibitory actions of amastatin (AM) and bestatin (BE) are relatively specific for these aminopeptidases, we have examined the effects of these inhibitors on the binding, degradation and pressor activity of angiotensin II (AII) and angiotensin III (AIII). Within 30 min at 37 degrees C, significant metabolism of 125I-AII and 125I-AIII by homogenates of a block of tissue containing hypothalamus, thalamus, septum and anteroventral third ventricle regions of the brain was observed. A majority of 125I-AIII metabolism was due to soluble peptidases, whereas that of 125I-AII primarily resulted from membrane-bound peptidases. AM, BE and reduced incubation temperatures significantly decreased the metabolism of 125I-AII and 125I-AIII. After appropriate adjustments to reflect the proportion of intact radioligand bound, temperature- or inhibitor-induced decreases in metabolism were matched by corresponding increases in specific binding. Heat-treated bovine serum albumin, as a nonspecific peptidase inhibitor, had no effect on either the metabolism or binding of the ligands used. In accordance with their actions in vitro, i.c.v. administration of AM and BE prolonged the pressor activity of subsequently applied AII and AIII. Unexpectedly, the amplitude of the pressor response to AIII was increased by BE, whereas that to AII was decreased by AM. The results of this study indicate that the metabolism of AII and AIII by aminopeptidases is relatively specific and acts to modulate the actions of these peptides.(ABSTRACT TRUNCATED AT 250 WORDS)     

An evaluation of the mechanical failure modalities of a rotating hinge knee prosthesis

The clinical and metallurgical performance of 12 retrieved Noiles total knee prostheses was investigated. Clinical histories and serial roentgenograms were used in conjunction with the American Society for Testing and Materials (ASTM) standard implant retrieval and analysis techniques to assess device performance. All of the devices were removed because of implant loosening with pain, while two devices also had a late infection. The average time in situ for all devices was four years. Roentgenographically, all of the devices showed signs of progressive radiolucencies. Ten (83%) of the devices migrated proximally within the femur. A marked varus drift was observed in eight (67%) of the retrieved prostheses. Hypertrophy of the femoral cortex was observed in eight (67%) of the cases. Seventy-three percent of the polyethylene tibial stems exhibited extensive wear on the anterior and medial aspects of the articulating surface. Extensive wear was also seen on the anterior and extreme posterior aspects in 92% of the polyethylene tibial plateau bearings. This wear was a consequence of the migration of the femoral component leading to buttressing of the plastic components against bone or bone cement. This study indicates serious design flaws in the Noiles knee prosthesis that unless corrected would question the use of the device in either primary or revision knee surgery.     

Clostridium difficile colitis following treatment with metronidazole and vancomycin

A 25 year old woman developed Clostridium difficile colitis following a course of vancomycin and metronidazole prescribed for pelvic inflammatory disease. The condition resolved after treatment with vancomycin given alone. Colitis following this combination of antibiotics has not been described previously.     

The apex cardiac beat: not a reliable clinical sign in elderly patients.

To assess its reliability as a marker of cardiomegaly in elderly patients, we compared a clinical assessment of heart size with that calculated from chest radiography. In 100 hospitalized subjects of median age 78 years, the apex beat was palpable in only 35% and its palpability declined with increasing age. Even when palpable, the apex beat had low specificity (74%) and sensitivity (69%) as a marker of cardiomegaly and its positive predictive value (69%) and negative predictive value (74%) were poor. The clinical assessment of heart size in elderly hospitalized patients should be interpreted with caution.     

Pharmacological treatment strategies in age-related cataracts.

Cataract is the major cause of blindness worldwide and at present the only approved treatment in many countries including the UK and USA is surgical removal of the lens. In other countries various anti-cataract drugs are available without proof of their efficacy. Research is continuing into the possible benefits of several groups of drugs and some vitamins. The first to be studied were sorbitol-lowering agents (aldose reductase inhibitors) based on the sorbitol hypothesis for diabetic cataract. Sorbitol-lowering agents have distinct effects in vitro and many of them delay the development of cataract in galactose-fed rats. A few delay cataract in diabetic rats but none have been proved effective in clinical trials, although these continue. Aspirin, paracetamol (acetaminophen) and ibuprofen delay diabetic cataract in rats, and have been shown to delay other experimental cataracts. Case-control studies from 3 continents indicate that these drugs, or at least aspirin, protect against cataract. Results of studies on all 3 drugs indicate a benefit even at low doses. Population-based studies did not identify any protection against early lens opacities but tiny opacities that do not impair vision are not a problem. Bendazac protects lens proteins in vitro and delays cataractogenesis in x-irradiated rats. In humans, it reached the clinical trial stage but most trials have been small and with subjective criteria of opacification. One objectively monitored trial suffered from a high drop-out rate. Other preparations studied less extensively include vitamins, aminoguanidine to prevent protein cross-linking in diabetes and agents designed to boost glutathione levels. It is probable that some agents which may delay or prevent cataract will be proved effective soon, and in the end there may be different drugs to delay cataract in different high risk groups. This is what might be expected of a multifactorial disease, although compounds that intervene in the final common pathways to cataract could have a broad efficacy.     

Flow microfluorometric analysis of murine spermatozoa fails to detect H-2 antigens

The presence of class 1 and class 2 histocompatibility antigens on murine sperm was investigated by flow microfluorometry. Monoclonal anti-H-2Kk (class 1), anti-Iak (specificity 2, class 2) and allo-anti-Iak (class 2) antisera were used in direct or indirect fluorescence labelling experiments to probe the expression of class 1 and class 2 antigens on epididymal mouse spermatozoa. Sperm-specific antibodies were generated by intraperitoneal immunization of both male and female C3H/HeN mice with syngeneic spermatozoa. Sperm-specific antigens were detected in 68-85% of syngeneic mouse sperm and 65-90% of allogeneic mouse sperm examined. Conversely, these antibodies did not stain syngeneic or allogeneic lymphocytes above the background of the negative control. Mouse sperm samples failed to exhibit specific fluorescence above the background of negative control values with antibodies against either class 1 or class 2 MHC antigens. We have established the sensitive, objective and economical assay of sperm membrane antigens with fluorochrome-labelled antibodies by flow microfluorometry. By use of this sensitive and objective technique we have not detected MHC antigens on murine sperm. We conclude that these MHC antigens are not expressed on sperm at a level to be practically detectable.