Aneurysm of the mitral valve complicating Streptococcus milleri endocarditis

A case of Streptococcus milleri endocarditis which caused an aneurysm of the anterior leaflet of the mitral valve is reported. There is only one previous report of a mitral valve aneurysm secondary to infective endocarditis demonstrated by angiography. Streptococcus milleri normally causes endocarditis in an older age group than the patient we describe. Some salient features of this increasingly recognized human pathogen are emphasized.     

Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers

Objective

Two open‐label, randomized, cross‐over trials in healthy volunteers were conducted to investigate the pharmacokinetic interaction between etravirine and tenofovir disoproxil fumarate.

Methods

Etravirine was administered as either 800 mg twice a day (bid) (phase II formulation in Study 1) or 200 mg bid (phase III formulation in Study 2) for 8 days followed by a 12 h pharmacokinetic evaluation. After a minimum of 14 days washout, tenofovir disoproxil fumarate 300 mg once a day was administered for 16 days. Volunteers were randomized to receive co‐administration of etravirine with tenofovir disoproxil fumarate on either days 1–8 or days 9–16 followed by a 12 h pharmacokinetic evaluation for etravirine on day 8 or 16, respectively. Plasma and urine tenofovir concentrations were determined on days 8 and 16 over 24 h.

Results

The least square mean (LSM) ratio [90% confidence interval (CI)] for the area under the plasma concentration–time curve from 0 to 12 h (AUC_{12 h}) for etravirine co‐administered with tenofovir disoproxil fumarate vs. etravirine alone was 0.69 (0.61–0.79) and 0.81 (0.75–0.88) in Studies 1 and 2, respectively. The LSM ratio (90% CI) for the effect of etravirine on tenofovir AUC_{24 h} was 1.16 (1.09–1.23) in Study 1 and 1.15 (1.09–1.21) in Study 2.

Conclusions

These alterations are not considered clinically relevant for either drug and no dose adjustment is necessary when etravirine and tenofovir disoproxil fumarate are co‐administered.     

Relationship between objective assessment of technical skills and subjective in-training evaluations in surgical residents

BACKGROUND: Technical skills of residents have traditionally been evaluated using subjective In-Training Evaluation Reports (ITERs). We have developed the McGill Inanimate System for Training and Evaluation of Laparoscopic Skills (MISTELS), an objective measure of laparoscopic technical ability. The purpose of the study was to assess the concurrent validity of the MISTELS by exploring the relationship between MISTELS score and ITER assessment. STUDY DESIGN: Fifty surgery residents were assessed on the MISTELS system. Concurrent ITER assessments of technical skill were collected, and the proportion of superior ratings for the year was calculated. Statistical comparisons were performed by ANOVA and chi-square analysis. The Pearson correlation coefficient was used to compare the scores in the MISTELS with the ITER ratings. RESULTS: The 50 residents received 277 ITERs for the year, of which 103 (37%) were "superior," 170 (61%) "satisfactory," 4 (1%) "borderline," and 0 "unsatisfactory." The MISTELS score correlated moderately well with the proportion of superior ITER scores (r = 0.51, p < 0.01). Residents who passed the MISTELS had a higher proportion of superior ITER assessments than those who failed the MISTELS (p = 0.02), but residents who performed below their expected level on the MISTELS still received mainly satisfactory ITERs (82 +/- 18%). CONCLUSIONS: The ITER assessment is poor at identifying residents with below-average technical skills. Residents who perform well in the MISTELS laparoscopic simulator also have better ITER evaluations, providing evidence for the concurrent validity of the MISTELS. Multiple assessment instruments are recommended for assessment of technical competency.     

Inactivation of the cystatin E/M tumor suppressor gene in cervical cancer

We have previously localized a cervical cancer tumor suppressor gene to a 300 kb interval of 11q13. Analysis of candidate genes revealed loss of expression of cystatin E/M, a lysosomal cysteine protease inhibitor, in 6 cervical cancer cell lines and 9 of 11 primary cervical tumors. Examination of the three exons in four cervical cancer cell lines, 19 primary tumors, and 21 normal controls revealed homozygous deletion of exon 1 sequences in one tumor. Point mutations were observed in six other tumors. Two tumors contained mutations at the consensus binding sites for cathepsin L, a lysosomal protease overexpressed in cervical cancer. Introduction of these two point mutations using site directed mutagenesis resulted in reduced binding of mutated cystatin E/M to cathepsin L. Although mutations were not observed in any cell lines, four cell lines and 12 of 18 tumors contained promoter hypermethylation. Reexpression of cystatin E/M was observed after 5'aza 2-deoxycytidiene and/or Trichostatin A treatment of cervical cancer cell lines, HeLa and SiHa, confirming promoter hypermethylation. Ectopic expression of cystatin E/M in these two cell lines resulted in growth suppression. There was also suppression of soft agar colony formation by HeLa cells expressing the cystatin E/M gene. Reexpression of cystatin E/M resulted in decreased intracellular and extracellular expression of cathepsin L. Overexpression of cathepsin L resulted in increased cell growth which was inhibited by the reintroduction of cystatin E/M. We conclude, therefore, that cystatin E/M is a cervical cancer suppressor gene and that the gene is inactivated by somatic mutations and promoter hypermethylation.     

Monoclonal antibodies specific for a tumor-associated membrane phosphoprotein in human cell hybrids

Four monoclonal antibodies, 5/138, 5/32, BD6 and 6/266, are reported which recognize a previously described membrane associated dimeric protein of Mr = 2 X 75,000 and whose expression is correlated with malignant phenotype in HeLa-normal fibroblast hybrids.