Cardioprotection by St Thomas' solution is mediated by protein kinase C and tyrosine kinase

BACKGROUND: Intracellular signaling pathways, specifically the activation of protein kinase C and tyrosine kinase, are essential to the cardioprotection of ischemic preconditioning. We proposed that activation of PKC and TK contribute to the myocardial protection of St. Thomas' No. 2 cardioplegia solution (STC). MATERIALS AND METHODS: Isolated rat hearts were exposed to 40 min of global ischemia followed by 120 min of reperfusion. Before ischemia, hearts received no treatment (control; n = 7), STC (n = 7), phorbol 12-myristate 13-acetate (PMA; n = 6), PMA + chelerythrine (n = 6), anisomycin (n = 6), anisomycin + genistein (n = 7), STC + chelerythrine (n = 7), STC + genistein (n = 7), PMA + genistein (n = 7) or anisomycin + chelerythrine (n = 7). Left ventricular developed pressure (LVDP) recovery, myocardial infarct size, and lactate dehydrogenase release were measured. RESULTS: STC as well as PMA (protein kinase C activator) and anisomycin (tyrosine kinase activator) significantly reduced infarct size (6.9 +/- 2.9%, 9.6 +/- 2.1%, 14.0 +/- 4.4%) compared with controls (42.4 +/- 2.9%, P < 0.05). The infarct reduction of PMA and anisomycin were blocked by their inhibitors chelerythrine and genistein, respectively. Both chelerythrine (29.2 +/- 4.1%, P < 0.05) and genistein (40.4 +/- 4.3%, P < 0.05) attenuated the reduction of infarct size provided by STC. The recovery of LVDP improved with STC, PMA and anisomycin (72.6 +/- 1.4%, 60.4 +/- 4.7%, 57.2 +/- 4.6%) compared with control (33.8 +/- 3.6%, P < 0.05). Addition of chelerythrine or genistein to STC impaired recovery of LVDP (52.3 +/- 4.4%, 35.1 +/- 2.5%, P < 0.05) compared with STC treatment. CONCLUSION: Administration of the pharmacologic inhibitors chelerythrine and genistein blunts the cardioprotection caused by STC treatment.     

Metalloproteinase inhibition reduces lung injury and improves survival after cecal ligation and puncture in rats

BACKGROUND: Neutrophil activation with concomitant matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) release has been implicated in the development of sepsis-induced acute lung injury. We hypothesized that COL-3, a chemically modified tetracycline known to inhibit MMP-2 and MMP-9, would reduce lung injury and improve survival in rats following cecal ligation and puncture (CLP). METHODS: Sprague-Dawley rats were separated into five groups: 1) sham CLP+ carboxymethylcellulose (CMC; vehicle for COL-3, n = 6); 2) sham CLP + COL-3 (n = 6); 3) CLP + CMC (n = 10); 4) CLP + single-dose (SD) COL-3 administered concomitant with CLP (n = 9); and 5) CLP + multiple-dose (MD) COL-3 administered concomitant with CLP and at 24 h after CLP (n = 15). Rats were sacrificed at 168 h (7 days) or immediately after death, with survival defined as hours after CLP. Histological lung assessment was made based on neutrophil infiltration, alveolar wall thickening, and intraalveolar edema fluid. Lung MMP-2 and MMP-9 levels were assessed by immunohistochemistry. MMP-2 and MMP-9 levels were correlated with survival by simple regression analysis. RESULTS: The mortality of rats in the cecal ligation and puncture without treatment group (CLP + CMC) was 70% at 168 h. A single dose of COL-3 in the CLP + COL-3 (SD) group significantly reduced mortality to 54%. Furthermore, with a repeat dose of COL-3 at 24 h after CLP, mortality was significantly reduced to 33%. Pathologic lung changes seen histologically in the CLP + CMC group were significantly reduced by COL-3. A significant reduction in lung tissue levels of MMP-2 and MMP-9 was noted in both groups treated with COL-3. Reduction of MMP-2 and MMP-9 levels correlated with improved survival. CONCLUSION: Inhibition of MMP-2 and MMP-9 by COL-3 in a clinically relevant model of sepsis-induced acute lung injury reduces pulmonary injury and improves survival in a dose-dependent fashion. Our results suggest that prophylactic treatment with COL-3 in high-risk patients may reduce the morbidity and mortality associated with sepsis-induced acute respiratory distress syndrome.     

Small bowel herniation and gangrene from peritoneal dialysis catheter exit site

Peritoneal dialysis is one of the standard methods for blood purification. It is particularly well suited for treating children with acute renal failure. Here we report a rare case of small bowel herniation at the peritoneal catheter exit site following removal, leading to gangrenous infarction.     

In vitro release: comparative evaluation of vertical diffusion cell system and automated procedure

In vitro release for topical drug products is carried out using a vertical diffusion cell system and a synthetic support membrane. The improvements in vertical diffusion cell design and automated procedures have been carefully studied and evaluated to establish their reproducibility and ruggedness of the experimental procedure. The data were analyzed using 90% confidence interval procedure developed and published by the US Food and Drug Administration in SUPAC-SS (Start Up and Post Approval Changes-Semi Solid) guidance.     

Developing the effectiveness of primary care organisations in the UK National Health Service. A case study

This paper aims to explore the early experiences of a new primary care organisation in the NHS. It reports the findings of a longitudinal qualitative case study of one primary care group in its first year of operation. It concludes and makes recommendations in four key areas relevant to the development of the primary care group: the experiences of individuals and their readiness for change; clarity and consensus about roles and responsibilities in the new organisation; the process of change, and the impact of culture/power structures; and developing relationships with internal and external stakeholders.     

Determinants of intraocular pressure and its association with glaucomatous optic neuropathy in Chinese Singaporeans: the Tanjong Pagar Study

PURPOSE: To examine the relationship between intraocular pressure (IOP), anthropomorphic, demographic, socioeconomic, systemic, and ocular factors and glaucomatous optic neuropathy (GON) in Chinese people. METHODS: Chinese people (n = 2000), aged 40 to 79 years, were selected from the Singapore electoral register. Of the 1717 considered eligible for examination, 1232 participated, representing a response rate of 71.8%. IOP was estimated with Goldmann applanation tonometry. The drainage angle was assessed with static and dynamic gonioscopy. The optic nerve was examined at high magnification through a dilated pupil with a fundus contact lens or a +78-D lens. Static automated visual field testing was performed on subjects with suspected glaucoma. GON was diagnosed on the basis of structural and functional abnormalities of the optic nerve. RESULTS: The main independent determinants of higher IOP were higher systolic blood pressure (P < 0.001), quadrants of any peripheral anterior synechiae (PAS, P = 0.02) and width of the drainage angle (P = 0.049). A 100- micro m increase in corneal thickness was associated with an increase in mean IOP of 1.5 to 1.8 mm Hg (P < 0.001). Odds of GON increased 1.2 times per 1-mm Hg increase in screening IOP. A clear association between corneal thickness and GON was not identified. CONCLUSIONS: Clinical IOP estimates are related to systolic blood pressure and corneal thickness. Variation in IOP with angle width may suggest that trabecular compaction significantly contributes to causes of the increase in IOP, independent of angle-closure. GON is an IOP-related phenomenon among Chinese Singaporeans.     

Cell density ratios in a foveal patch in macaque retina

We examine the assumptions that the fovea contains equal numbers of inner (invaginating or ON) and outer (flat or OFF) midget bipolar cells and equal numbers of inner and outer diffuse bipolar cells. Based on reconstruction from electron photomicrographs of serial thin sections through the fovea of a macaque monkey, we reject both assumptions. First, every foveal L and M cone is presynaptic to one inner and one outer midget bipolar cell; however, S cones are presynaptic to one outer but no inner midget bipolar cell. Second, we measure the density of all foveal cells in the same patch of fovea, affording accurate cell density ratios. For each foveal cone pedicle, at a density of 26,500 mm(-2), there is close to one (0.88) outer diffuse bipolar cell but only 0.40 inner diffuse bipolar cells. This asymmetry may be related to differences in resolution and sensitivity for light increments and decrements. We also find one (1.01) Müller cell, one (1.01) amacrine cell in the inner nuclear layer, and close to one (0.83) horizontal cell for each cone pedicle. In addition, for each S cone, there are two inner S-cone bipolar cells and two small bistratified ganglion cells. In total, there are 3.4 cone bipolar cells per cone but only 2.6 ganglion cells per cone. The latter ratio is enough to accommodate one midget ganglion cell for each midget bipolar cell.