Forskolin inhibits the release of histamine from human basophils and mast cells

We found that forskolin (10(-7) to 3 X 10(-5) M) caused dose-related inhibition of antigen-induced histamine release from human basophil leukocytes. The dose-response inhibition curve was paralleled by a forskolin-induced increase in cyclic AMP (cAMP) levels in human leukocyte preparations. The kinetics of inhibition of histamine release and of the increase in leukocyte cAMP were the same. In a second series of experiments we evaluated the effect of forskolin on antigen-induced histamine release from chopped human lung passively sensitized with serum from an allergic patient. Forskolin (10(-7) to 3 X 10(-5) M) dose-dependently inhibited the release of histamine from human lung mast cells. Thus forskolin appears to modulate the release of mediators of the immediate hypersensitivity reaction, presumably through activation of adenylate cyclase in human basophils and mast cells.     

Short-Ti inversion-recovery pulse sequence: analysis and initial experience in cancer imaging

Inversion recovery (IR), commonly considered a pulse sequence capable of producing T1-weighted images with excellent display of normal anatomy, is versatile: The null point and peak time provide a useful, succinct summary of the properties of IR and its capacity for producing both T1- and T2-weighted images. Shortening of the inversion time (TI) and creation of a short-TI inversion-recovery (STIR) pulse sequence increases sensitivity to malignancy and other abnormalities by making the effects of prolonged T1 and T2 on signal intensity additive and by nulling the signal from fat. The authors examined over 300 patients with various malignancies and compared STIR images with T1- and T2-weighted images obtained at 0.5 T. In 43 cases, signal-difference-to-noise ratios (SD/Ns) were calculated between tumor, fat, and muscle. In general, STIR images demonstrated tumor as a conspicuously high-intensity area in a background of muted, discernible anatomic detail. The good contrast achieved with STIR sequences between tumor and fat (SD/N = 18.1) and tumor and muscle (SD/N = 12.9) consolidated into a single image the information contained separately on T1- and T2-weighted images, which facilitates efficient detection and localization of malignancy.     

The effects of antioxidant supplementation during Percoll preparation on human sperm DNA integrity

The integrity of sperm DNA is crucial for the maintenance of genetic health. A major source of damage is reactive oxygen species (ROS) generation; therefore, antioxidants may afford protection to sperm DNA. The objectives of the study were, first, to measure the effects of antioxidant supplementation in vitro on endogenous DNA damage in spermatozoa using the single cell gel electrophoresis (comet) assay and, second, to assess the effect of antioxidant supplementation given prior to X-ray irradiation on induced DNA damage. Spermatozoa from 150 patients were prepared by Percoll centrifugation in the presence of ascorbic acid (300, 600 microM), alpha tocopherol (30, 60 microM), urate (200, 400 microM), or acetyl cysteine (5, 10 microM). DNA damage was induced by 30 Gy X-irradiation. DNA strand breakage was measured using the comet assay. Sperm DNA was protected from DNA damage by ascorbic acid (600 microM), alpha tocopherol (30 and 60 microM) and urate (400 microM). These antioxidants provided protection from subsequent DNA damage by X-ray irradiation. In contrast, acetyl cysteine or ascorbate and alpha tocopherol together induced further DNA damage. Supplementation in vitro with the antioxidants ascorbate, urate and alpha tocopherol separately has beneficial effects for sperm DNA integrity.      

How to use Chlamydia antibody testing in subfertility patients

Screening for tubal factor subfertility by means of Chlamydia antibody testing (CAT) was introduced into the initial work-up of subfertile couples several years ago. The results reported, however, are heterogeneous, and no uniformity exists in cut-off levels of titres, or in definitions of tubal factor subfertility. We performed a prospective cohort study to evaluate the implications of varying the definitions of tubal pathology and of modifying the cut-off levels on the clinical impact of CAT in predicting tubal factor subfertility. In 227 consecutive patients who attended our fertility clinic, the Chlamydia IgG antibody titre was determined and related to tuboperitoneal abnormalities at laparoscopy as a reference standard. According to received operating characteristic (ROC) curve analysis, a titre of 16 is the optimum cut-off level. Increasing the cut-off level improves specificity and positive likelihood ratio (LR+), at the expense of sensitivity and negative LR (LR-). Changing the definition of tubal factor subfertility from unspecified tuboperitoneal abnormalities into extensive adhesions and/or bilateral distal tubal occlusion improves LR+, LR- and kappa significantly. We conclude that CAT is more accurate in predicting severe distal tubal pathology than unspecified tuboperitoneal abnormalities. Although from a statistical point of view a titre of 16 is the optimum cut-off level, from a clinical point of view 32 or 64 may be preferable, depending on the aim of screening and the inception cohort.      

Experimental lead arthropathy: an animal model

BACKGROUND: We previously demonstrated short-term effects of intra-articular lead on joint structures in an animal model. We now present histopathologic findings in animals studied over a more extended period. METHODS: Twelve female New Zealand White rabbits had identical lead or stainless steel pellets, or a sham arthrotomy (without implant) inserted in both front knees. The rabbits were killed 4 at a time at 6, 10, and 14 weeks after implantation, and the knee joint structures were evaluated histologically for changes in the synovium, articular cartilage, and meniscus. RESULTS: Histology of the tibial articular surface, femoral articular surface, medial meniscus, lateral meniscus, and synovium showed greater signs of degeneration in the knees with lead implants than controls at all time periods. CONCLUSION: Intrasynovial lead, which does not undergo fibrous encapsulation, has been linked to lead intoxication. Clinical and experimental reports support removal of lead bodies from articular areas in an attempt reduce or slow the degeneration of affected joints. Nonmechanical effects of lead on intraarticular structures may lead to degenerative changes     

Collagen scaffold meniscus implant integration in a canine model: A histological analysis

In the situation of an irreparable meniscus tear, an implant comparable to a normal meniscus is an attractive option. Using a canine model, we assessed the early and late histologic response to a tissue engineered meniscal collagen scaffold (CS). All animals received bilateral arthrotomies, and all joints receiving the CS had an 80% resection of the meniscus. Animals were sacrificed at 3 and 6 weeks, and 12, 13, and 17 months. The CS/tissue complex and host meniscal rim were sectioned for histologic examination with specific focus on the extracellular matrix, angiogenesis, cellular resorption of the scaffold, scaffold appearance, and CS/Host integration. Early histologic samples (3–6 weeks) revealed active angiogenesis and fibrin clots evolving into cellular granulation type tissue. At 12 months, a mature fibrochondrocytic matrix was depositing with gradations of dissolution and integration of the CS implant. Maturing CS/host integration was observed at 18 months. Active cellular resorption of the implant decreased over time. Four cases showed a mild non‐specific chronic inflammation and one additional case showed inflammatory engulfment of the scaffold with giant cells at 3 weeks. No evidence of infection either clinically or histologically was observed at any time point. Overall, this histologic analysis demonstrated the active integration of a meniscal like cartilage into a tissue engineered biological scaffold in a canine model. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1914–1919, 2013     

Toremifene in the treatment of breast cancer

Although more widespread screening and routine adjuvant therapy has improved the outcome for breast cancer patients in recent years, there remains considerable scope for improving the efficacy, safety and tolerability of adjuvant therapy in the early stage disease and the treatment of advanced disease. Toremifene is a selective estrogen receptor modifier (SERM) that has been widely used for decades in hormone receptor positive breast cancer both in early and late stage disease. Its efficacy has been well established in nine prospective randomized phase III trials compared to tamoxifen involving more than 5500 patients, as well as in several large uncontrolled and non-randomized studies. Although most studies show therapeutic equivalence between the two SERMs, some show an advantage for toremifene. Several meta-analyses have also confirmed that the efficacy of toremifene is at least as good as that of tamoxifen. In terms of safety and tolerability toremifene is broadly similar to tamoxifen although there is some evidence that toremifene is less likely to cause uterine neoplasms, serious vascular events and it has a more positive effect on serum lipids than does tamoxifen. Toremifene is therefore effective and safe in the treatment of breast cancer. It provides not only a useful therapeutic alternative to tamoxifen, but may bring specific benefits.