Contortrostatin, a dimeric disintegrin from Agkistrodon contortrix contortrix, inhibits breast cancer progression

We report the results of a multidisciplinary study on the inhibitory effect of a snake venom disintegrin, contortrostatin, a 13.5 kDa homodimeric protein isolated from Agkistrodon contortrix contortrix (southern copperhead) venom, on breast cancer progression. We demonstrate that contortrostatin binds to integrins and blocks the adhesion of human breast cancer cells (MDA-MB-435) to extracellular matrix (ECM) proteins including fibronectin and vitronectin, but it has no effect on adhesion of the cells to laminin and Matrigel. Contortrostatin also prevents invasion of MDA-MB-435 cells through an artificial Matrigel basement membrane. Daily local injection of contortrostatin (5 microg per mouse per day) into MDA-MB-435 tumor masses in an orthotopic xenograft nude mouse model inhibits growth of the tumor by 74% (p = 0.0164). More importantly, it reduces the number of pulmonary macro-metastasis of the breast cancer by 68% (p < 0.001), and micro-metastasis by 62.4% (p < 0.001). Contortrostatin is not cytotoxic to cancer cells, and does not inhibit proliferation of the breast cancer cells in vitro. However, contortrostatin inhibits angiogenesis induced by the breast cancer, as shown by immunohistochemical quantitation of the vascular endothelial cells in tumor tissue removed from the nude mice. We have identified alpha(v)beta3, an important integrin mediating cell motility and tumor invasion, as one of the binding sites of contortrostatin on MDA-MB-435 cells. We conclude that contortrostatin blocks alpha(v)beta3, and perhaps other integrins, and thus inhibits in vivo progression.     

MAKING SENSE OF CLINICAL TRIALS IN GLAUCOMA - GLAUCOMA LASER TRIAL (GLT)

The Glaucoma Laser Trial (GLT), the first randomized controlled clinical trial of glaucoma treatment, substantially influenced subsequent ophthalmic research. Principles of randomization, objective determination of glaucomatous progression with standard definitions of visual field damage, stepped treatment regi-     

Elderly Patients with Suppressed Serum TSH but Normal Free Thyroid Hormone Levels Usually Have Mild Thyroid Overactivity and are at Increased Risk of Developing Overt Hyperthyroidism

The clinical and biochemical characteristics of 15 elderly patientswith low levels of thyrotrophin (TSH) (<0.1 mU/L) but normalfree tri-iodothyronine, (T3) and free thyroxine (T4) (groupS) were compared with 10 euthyroid subjects (group E) and 10hyperthyroid patients (group T). Free T3 and free T4 were significantlyhigher (p<0.05) in group S(6.3±0.5 and 18.6±1.0pmol/l, respectively) than in group E(4.6±0.3, 12.6+0.6).In common with elderly hyperthyroid patients (group T)patientsin group S had few signs or symptoms of thyrotoxocosis, butthe Wayne score (clinical index of hyperthyroidism) was higherin group S than in euthyroid subjects (p<0.05). Thyroid microsomal,thyrogolobulin or thyrotrophin receptor antibodies were commonin group T (n=9)but not in groups S(n=2) or E(n=1). This suggestsa low prevalence of Graves' disease in group S compared to groupT. Combined thyrotrophin releasing hormone (TRH; 200 µgi.v.) and gonadotrophin releasing hormone GnRH; 100 µgi.v.) tests were performed; no cases of low TSH due to hypopituitarismwere identified in group S. During a mean of 7.9 (4–12)months of observation TSH reverted to the normal range (>0.2mU/L)in 7 of 15 patients in group S; thyroid hormone concentrationsrose above the normal range in four, however, only two patientsrequired treatment for hyperthyroidism. It is unlikely thatthe suppressed TSH of patients in group S was due to mild thyroidhormone excess; although this is often a transitory phenomenon,these patients are at increased risk of developing overt hyperthyroidism.     

Laser lithotripsy: animal studies of safety and efficacy

The safety and efficacy of pulsed tunable dye laser fragmentation of common bile duct stones was assessed in pigs. Laser pulses were conducted through a flexible quartz fiber that was in direct contact with stones that had been surgically implanted into the common bile duct. All calculi were rapidly fragmented into small pieces without significant damage to the common bile duct. The immediate and delayed effects of pulsed lasers on the common bile duct were also evaluated. The common bile duct demonstrated a high tolerance to laser-induced damage even when the laser was discharged directly into the bile duct wall. These results suggest that laser lithotripsy can be performed in humans with a high degree of safety and efficacy.     

Nuclear magnetic resonance studies in normal and edematous brain tissue

The nmr relaxation rate results show unequivocally that there are at least two fractions of tissue water in both normal and edematous white matter which do not exchange on an nmr time scale (i.e. at times of the order of milli-seconds to fraction of a second). In conjunction with the electron microscopic determination of the extracellular volumes of normal and edematous white matter, the relaxation results can be interpreted in terms of the following model. The two slowly-exchanging water components giving rise to the non-exponential relaxation correspond to cellular and extracellular water; edema changes the relaxation rate of the extracellular component much more than that of the cellular component (the extracellular component becoming more "liquid-like" in its relaxation). Such behavior is consistent with the properties of the extracellular water being due to rapid exchange between motionally restricted water adsorbed at the surface of myelin sheaths, and relatively unrestricted, bulk water. Edema presumably increases the relative amount of the "bulk" water between the axons.     

Priming effects in the fusiform gyrus: changes in neural activity beyond the second presentation

Repetition priming typically leads to a decrease in the activation of sensory cortical areas upon a second exposure to the same visual stimulus. This effect is thought to reflect more efficient or fluent re-processing of previously seen stimuli so that less neural activity is required. Fluent re-processing has been hypothesized to be a potential link from repetition priming to neural changes associated with visual expertise. To examine this potential connection, the neural correlates of priming were examined across eight stimulus repetitions using functional magnetic resonance imaging. Sizeable regions of bilateral ventral occipito-temporal cortex (including the fusiform gyrus) exhibited reduced responses to the second presentation of a stimulus. Most of these areas displayed no further reduction in response to subsequent repetitions of the same stimuli. Because expertise accrues over many exposures, these areas, while clearly involved in priming, do not exhibit an activity pattern consistent with the development of expertise. In contrast, an area in the right posterior fusiform gyrus exhibited reductions in evoked response that grew in magnitude for stimulus repetitions from the second to the eighth presentations. This region exhibits a pattern of activity consistent with a gradual and cumulative enhancement of the fluency effect across trials, suggesting that it may mediate the link between priming and the development of visual expertise.