Intravascular ultrasound findings in stenting of unprotected left main coronary artery stenosis

We evaluated the role of intravascular ultrasound (IVUS) in 16 patients with unprotected left main coronary artery (LMCA) stenting compared with 80 patients with other (non-LMCA) native coronary artery stenting and found that (1) additional high-pressure or larger size balloon dilations were more frequently performed in LMCA stenting than in non-LMCA stenting (p <0.05) and (2) after IVUS-guided stent implantation, minimum lumen area was > or = 9 mm2 in 88% of patients who underwent LMCA stenting and in 19% of those who underwent non-LMCA stenting (p <0.001). IVUS guidance may be a more important adjunctive imaging modality in the stenting of unprotected LMCA stenoses than in stenting of non-LMCA stenoses.     

Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: exploring the impact of ring size on structure-activity relationships

Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3-(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in exploring the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalkyl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR, altering the optimal ring size from eight to six. Substitution of a sulfonamide at the meta position of the phenyl ring dramatically increases the potency of these inhibitors, but it does not change the optimal ring size in either the cycloalkylpyranone or the cycloalkyldihydropyrone series. This work has led to the identification of compounds with superb binding affinity for the HIV protease (Ki values in the 10-50 pM range). In addition, the cycloalkyldihydropyrones showed excellent antiviral activity in cell culture, with ED50 values as low as 1 microM.     

Identification of residues in the cysteine-rich domain of Raf-1 that control Ras binding and Raf-1 activity

We have identified mutations in Raf-1 that increase binding to Ras. The mutations were identified making use of three mutant forms of Ras that have reduced Raf-1 binding (Winkler, D. G., Johnson, J. C., Cooper, J. A., and Vojtek, A. B. (1997) J. Biol. Chem. 272, 24402-24409). One mutation in Raf-1, N64L, suppresses the Ras mutant R41Q but not other Ras mutants, suggesting that this mutation structurally complements the Ras R41Q mutation. Missense substitutions of residues 143 and 144 in the Raf-1 cysteine-rich domain were isolated multiple times. These Raf-1 mutants, R143Q, R143W, and K144E, were general suppressors of three different Ras mutants and had increased interaction with non-mutant Ras. Each was slightly activated relative to wild-type Raf-1 in a transformation assay. In addition, two mutants, R143W and K144E, were active when tested for induction of germinal vesicle breakdown in Xenopus oocytes. Interestingly, all three cysteine-rich domain mutations reduced the ability of the Raf-1 N-terminal regulatory region to inhibit Xenopus oocyte germinal vesicle breakdown induced by the C-terminal catalytic region of Raf-1. We propose that a direct or indirect regulatory interaction between the N- and C-terminal regions of Raf-1 is reduced by the R143W, R143Q, and K144E mutations, thereby increasing access to the Ras-binding regions of Raf-1 and increasing Raf-1 activity.     

Collecting and processing records from the ultracentrifuge in "real-time" using an on-line computer

An analytical system consisting of an analytical cantrifuge coupled 'on-line' to a computer was assembled and tested. Collection of records from up to 9 solutions was achieved through programmes which sum readings to reduce noise as well as controlling the positioning of the scanner. With this system it was found that the limit on accuracy for molecular weights at concentrations less than 0.01 g cm-3 was +/- 3% estimated from sedimentation equilibrium experiments. The same system was used to collect records for similar concentrations from velocity experiments by employing a scanning schlieren. In this case the accuracy in estimating sedimentation coefficients was similar to those found when measuring photographs. Since the collection yields detailed information about the shape of the sedimenting boundary, the centroids of the boundary were routinely computed by second moment analysis rather than relying on the position of the maximum of the schlieren peak. In the same analysis estimates of diffusion coefficients were made routinely by calculating corrected height/area ratios for each scan. These calculations were made during the real-time of the experiment, so making available molecular parameters rather than records which must be evaluated some time after stopping the experiment.     

Respiratory failure in acute pancreatitis: the role of free fatty acids

Hypertriglyceridemia has been noted in patients with acute pancreatitis and respiratory failure. Utilizing an isolated, perfused, canine pulmonary lobe, the effect of triglyceride infusion on pulmonary function was evaluated. When heparin was used to anticoagulate the perfusion circuit, the addition of triglyceride to the autologous blood perfusate resulted in massive weight gain (226 gm), intrapulmonary shunting (36%), and a marked drop in pulmonary compliance (congruent to 50%). Heparin activates lipoprotein lipase, and therefore some triglyceride in the perfusate was lipolyzed with a resultant increase in serum free fatty acids (FFAs) to 253 mumole/dl. When anticoagulation of the perfusion circuit was accomplished by defibrinogenation with Arvin, the addition of triglyceride to the autologous blood perfusate caused minimal weight gain (28 gm), no intrapulmonary shunting, and only a slight decrease in pulmonary compliance (22%). Arvin has no effect on lipoprotein lipase, and the FFA level in the perfusate remained normal (less than 70 mumole/dl). Thus it appears that FFA release secondary to the action of pulmonary lipoprotein lipase on blood triglyceride is the important pathogenic step in the induction of respiratory failure in this model.     

Colitis cystica profunda

Colitis cystica profunda is a benign disease of the colon. Its importance lies in differentiating it from mucus-producing adenocarcinoma. It has rarely been described in the surgical literature. A review of records of patients seen at the Mayo Clinic produced 66 clinical cases of localized colitis cystica profunda, and in 21 patients the diagnosis was confirmed histologically. Follow-up, which was available in all patients, ranged from 2 months to 29 years, with a mean follow-up of more than 8 years. The data suggest that local excision is the preferred initial therapy.