Effects of the substance P antagonist, (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP on the miotic response to substance P, antidromic trigeminal nerve stimulation, capsaicin, prostaglandin E1, compound 48/80 and histamine

The effects of the substance P analogue (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP on the ocular inflammatory responses (miosis, vasodilation, protein leakage into the aqueous humour and eye pressure rise) to antidromic trigeminal nerve stimulation (trigeminal stimulation), intracameral injections of substance P (SP), capsaicin, prostaglandin E1 (PGE1), compound 48/80 and histamine were investigated in albino rabbits. The effects of nerve blockade with tetrodotoxin and blockade of histamine receptors on the responses to compound 48/80 and histamine were also investigated. Histamine H1 receptors were blocked with clemastin and H2 receptors with cimetidin. Formation of endogenous prostaglandins was prevented with indomethacin. The pupil size and the eye pressure were measured. The aqueous humour was collected immediately after the animal was killed, and analyzed for protein concentration. (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP had no significant miotic effect, but tended to cause a break-down of the blood-aqueous barrier. Miosis caused by SP, trigeminal stimulation, capsaicin, PGE1, compound 48/80 or histamine was blocked by (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP. Histamine miosis was significantly reduced by blockade of nerve conduction or histamine receptors, while miosis caused by compound 48/80 was not. Nerve blockade abolished the rise in intraocular pressure caused by compound 48/80. Our results indicate that (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP is a specific SP blocker in the sphincter pupillae muscle. They are strong evidence for the hypothesis that trigeminal stimulation and capsaicin cause miosis by release of SP or a related substance (SPLI), and it seems likely that the miosis caused by PGE1 and compound 48/80 is also caused by SPLI release. Histamine miosis is probably mediated both by SP receptors and histamine receptors in the pupillary sphincter muscle.     

New instruments, bone liners, and tray for finger joint arthroplasty

Titanium circumferential grommets have been developed for finger joint arthroplasty that fit on the base of the silicone implant stems to protect the flexible hinge from tearing and fracture. To facilitate grommet insertion, new intramedullary bone rasps have been devised with a reverse cutting tooth pattern, an extended shaft for an improved view of the surgical field, and a redesigned cutting head to allow for grommet insertion. Surgical accessibility and ease of recognition have been facilitated by the development of color-coded sizers. All of the instruments necessary for finger joint surgery are available in a molded tray that has also been redesigned with a transparent lid and clearly labeled compartments for accurate determination of instruments and implant sizers.     

A randomized phase II trial of interferon-α2b versus 5-fluorouracil after trabeculectomy*

Purpose: The aim of the present study was to investigate the safety and potential efficacy of subconjunctival interferon-α2b (IFN-α), either alone or in combination with 5-fluorouracil (5-FU), in reducing the risk of failure of glaucoma surgery. Methods: A prospective, masked randomized phase II study was undertaken in which patients received three subconjunctival injections per week for 3–4 weeks postoperatively. Three treatments were compared: (i) IFN-α (1 × 10 ⁶ IU per dose); (ii) 5-FU (5 mg per dose); and (iii) alternating IFN-α and 5-FU (BOTH). The primary outcome measures were: (i) rate of successful control of intra-ocular pressure without further surgery; and (ii) the incidence of side effects. Results: Fifty-seven patients undergoing glaucoma surgery with an increased risk of failure were evaluated, including 23 patients (40%) undergoing trabeculectomy combined with extracapsular cataract extraction as well as other conventional high-risk groups. With 53 patients (93%) completing 2 years follow up, there was no significant difference in success rates among the three groups. Intra-ocular pressure was controlled without further surgery in 79% of patients (95% confidence interval (CI): 61, 97%) receiving IFN-α, in 89% of patients (76, 100%) receiving 5-FU and in 89% of patients (76, 100%) receiving BOTH. Side effects were similar among the three groups. Conclusions: These results are consistent with a beneficial effect of IFN-α2b given either alone or in combination with 5-FU after glaucoma filtering surgery. However, the lack of a clear and substantial benefit over conventional anti-fibrotic therapy does not support the further clinical evaluation of these treatments.     

Effects of intracameral Na2EDTA and EGTA on aqueous outflow routes in the monkey eye

Intracameral perfusion with 4 to 6 mM Na2EDTA or 4 mM EGTA for 40 to 80 min caused a very large increase in gross outflow facility. This effect was partly reversible when followed by perfusion with mock aqueous humor. Eyes perfused with Na2EDTA were studied morphologically. In the trabecular meshwork the cells separated due to a splitting of the cell junctions. A distention of the cribriform meshwork, a wash-out of extracellular material , and a disintegration of the denuded trabecular cores were also noticed. The inner wall of Schlemm's canal protruded in a "balloonlike" manner into the lumen of the canal and showed frank ruptures, especially after prolonged perfusion times. The conventional outflow pathways beyond Schlemm's canal showed no abnormalities. In the uveoscleral outflow routes the anterior and middle part of the ciliary muscle demonstrated very wide intermuscular clefts and many degenerated muscle fibers. The posterior third of the muscle was normal. So were the ciliary epithelium, the choroid, and the retina. The pupillary sphincter also showed degeneration. The corneal endothelial cells separated, starting at the apical junctional complex.     

Effects of Sex,Handedness, Stimulus and Visual Field on “Mental Rotation”

Shepard's mental rotation paradigm (e.g. Shepard and Metzler, 1971) was modified to allow tachistoscopic presentation of stimuli at varying angles of orientation (0° to 180°) in the right and left visual fields. Thirty male and thirty female subjects divided into three handedness groups (right-handers, non-familial and familial left-handers) judged whether a stimulus was a standard form or its mirror image. In general response times for correct judgements (RT_c) increased monotonically as a function of angle of orientation though the curves tended to be negatively accelerated rather than linear. Right-handers showed a slower rate of increase in RT_c as a function of angle than either left-handed group. Mean RT_c and the rate of increase in RT_c were equivalent for the two sexes and for the two visual fields. Both mean RT_cs and on the rate of increase in RT_c varied as a function of the stimulus.Error rates also increased monotonically as a function of angle of orientation. No sex or handedness differences in error rates were found. However, errors increased significantly less rapidly when stimuli were presented in the left visual field. It is argued that right hemisphere specialization for spatial processing minimizes the rate of increase in errors.The present failure to find sex differences may be of interest and it is argued that rapid presentation of stimuli results in subjects setting maximum and minimun response times. Within this relatively restricted “bandwith” of response times males and females may perform spatial tasks equally efficiently. Some confirmation for this hypothesis vs. an alternative based upon differences in hemispheric organization was found in a second experiment.     

Klinische und molekulargenetische Befunde bei Familien mit Cherubismus über 3 Generationen

Hintergrund  

Cherubismus ist eine seltene genetisch bedingte Erkrankung der Knochen, die fast ausschlie?lich den Ober- und Unterkiefer betrifft.     

Epothilones: mechanism of action and biologic activity.

Drugs that target microtubules are among the most commonly prescribed anticancer therapies. Although the mechanisms by which perturbation of microtubule function leads to selective death of cancer cells remain unclear, several new microtubule-targeting compounds are undergoing clinical testing. In part, these efforts focus on overcoming some of the problems associated with taxane-based therapies, including formulation and administration difficulties and susceptibility to resistance conferred by P-glycoprotein. Epothilones have emerged from these efforts as a promising new class of anticancer drugs. Preclinical studies indicate that epothilones bind to and stabilize microtubules in a manner similar but not identical to that of paclitaxel and that epothilones are effective in paclitaxel-resistant tumor models. Clinical phase I and early phase II data are available for BMS-247550, BMS-310705, EPO906, and KOS-862. The results suggest that these compounds have a broad range of antitumor activity at doses and schedules associated with tolerable side effects.     

Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization

OBJECTIVES: This study tested the hypothesis that a recombinant human C5a antagonist, CGS 32359, attenuates neutrophil activation and reduces infarct size in a porcine model of surgical revascularization. METHODS: CGS 32359 (0.16-16 micromol/L) dose-dependently inhibited superoxide production by human C5a-activated porcine neutrophils (18 +/- 3.7 vs 1.6 +/- 0.5 nmol/5 min/5 x 10(6) neutrophils; P <.05) and reduced neutrophil adherence to coronary endothelium from 194 +/- 9 to 43 +/- 6 neutrophils/mm(2) (P <.05). The left anterior descending coronary artery was occluded for 50 minutes, after which saline solution (n = 8), mannitol-buffer vehicle (n = 9, 102 mg/kg bolus, 102 mg. kg(-1). h(-1)), or CGS 32359 (CGS, n = 7, 60 mg/kg bolus, 60 mg. kg(-1). h(-1)) was infused. After ischemia, 1-hour arrest was achieved by means of multidose hypothermic (4 degrees C) blood cardioplegia, followed by 2.5 hours of off-bypass reperfusion. The ligature on the left anterior descending artery was released before the second infusion of cardioplegic solution. RESULTS: Area at risk was similar in all groups (saline solution, 27% +/- 2%; mannitol-buffer vehicle, 26% +/- 2%; CGS, 26% +/- 2% left ventricular mass). Infarct size (area necrosis/area at risk) was significantly reduced by CGS (18% +/- 6%, P <.05) versus saline solution (52% +/- 3%) and mannitol-buffer vehicle (60% +/- 4%). Postischemic systolic shortening (sonomicrometry) in the area at risk was significantly improved with CGS (0.8% +/- 0.9%) compared with saline solution (-3.7% +/- 1.1%) and mannitol-buffer vehicle (-6.4% +/- 1.0%). Myeloperoxidase activity from accumulated neutrophils was less in the ischemic zone of CGS (0.014 +/- 0.002 U/100 mg tissue; P <.05) than mannitol-buffer vehicle (0.133 +/- 0.012 U/100 mg tissue). CONCLUSIONS: We conclude that the recombinant human C5a receptor antagonist CGS 32359 inhibits surgical ischemia-reperfusion injury after coronary occlusion.