Genetic determinants of statin intolerance

Background  

Statin-related skeletal muscle disorders range from benign myalgias – such as non-specific muscle aches or joint pains without elevated serum creatinine kinase (CK) concentration – to true myositis with >10-fold elevation of serum CK, to rhabdomyolysis and myoglobinuria. The genetic basis of statin-related muscle disorders is largely unknown. Because mutations in the COQ2 gene are associated with severe inherited myopathy, we hypothesized that common, mild genetic variation in COQ2 would be associated with inter-individual variation in statin intolerance. We studied 133 subjects who developed myopathy on statin monotherapy and 158 matched controls who tolerated statins without incident or complaint.     

Harvey Cushing's postoperative sketches of pediatric brain tumors

Harvey Cushing was a man of many talents. Not only was he a premier surgeon and scientist, but a prolific author and artist as well. In this paper, we present two postoperative sketches of pediatric brain tumors drawn by Dr. Cushing. These sketches are representative of drawings which accompany many of his operative notes at the Peter Bent Brigham Hospital. About 25% of Cushing's surgical sketches depict operations performed on children. The most commonly drawn childhood tumors were craniopharyngiomas and gliomas of the brain stem and cerebellum. These drawings reveal how Cushing maintained detailed records of his surgical experience. It is clearly evident from these records that Dr. Cushing gained substantial experience in the treatment of pediatric brain tumors.     

Otologic surgery following ear trauma.

OBJECTIVES: To investigate common presentations and expected outcomes in patients with traumatically induced otologic dysfunction. STUDY DESIGN: Retrospective case review of patients who underwent otologic surgery for sequelae of otologic trauma over a 28-year period. Patients were stratified into major and minor trauma cohorts. Major trauma was designated as closed head injury with or without temporal bone fracture; lower-energy insults comprised the minor trauma group. Preoperative and postoperative audiograms were obtained and correlated with extent of injury. SETTING: Tertiary referral center. RESULTS: Major trauma accounted for 44.9 percent of all patients. The remaining 55.1 percent suffered minor trauma, of which simple traumatic tympanic membrane perforation was the most common insult (33.6%). Two hundred twenty-seven cases were performed on 214 patients. Pure tone averages improved a significant 20.8 dB to essentially normal levels postoperatively. CONCLUSION: Regardless of injury extent, surgical rehabilitation of conductive losses attains excellent hearing results that surpass those historically reported for the chronic ear population.     

Peripheral-type benzodiazepine receptor (PBR) gene amplification in MDA-MB-231 aggressive breast cancer cells

Recent studies using human breast cancer cell lines, animal models, and human tissue biopsies have suggested a close correlation between the expression of the peripheral-type benzodiazepine receptor (PBR) and the progression of breast cancer. This study investigates the genetic status of the PBR gene in two human breast cancer cell lines: MDA-MB-231 cells, which are an aggressive breast cancer cell line that contains high levels of PBR, and MCF-7 cells, which are a nonaggressive cell line that contains low levels of PBR. Both DNA (Southern) blot and fluorescence in situ hybridization analyses indicate that the PBR gene is amplified in MDA-MB-231 relative to MCF-7 cells. These data suggest that PBR gene amplification may be an important indicator of breast cancer progression.     

Care at the end of life: a novel curriculum module implemented by medical students.

End-of-life (EOL) and palliative care education in medical school curricula stand at a crossroads. Consensus has emerged that these topics merit systematic instruction throughout medical school training, yet curricula all too often consist of sporadic lectures focused on bioethics instead of clinical skills. The medical student authors identified a deficit in their curriculum, and designed and implemented an EOL curriculum module for their colleagues. In early 2000 the authors surveyed senior medical students about their experiences with EOL and palliative education, identifying deficits in clinical training and recommendations for interventions. They then designed a case-based educational module to teach EOL communication skills to medical students commencing clinical training. Faculty with national and local experience with EOL and palliative care reviewed the curriculum. Twelve of these faculty were oriented to the curriculum and then taught it in pairs to groups of 12 to 16 medical students in 2000 and 2001. The curriculum develops skills, attitudes, and knowledge relevant for communicating bad news and establishing treatment options in the EOL setting by utilizing trigger videos, group discussion, role plays, and case discussions. Approximately 75% of the 86 eligible students attended the module in 2000 and 2001. Feedback has guided the curriculum's refinement by the medical student authors. In addition, a standardized patient exercise, introduced in 2001, allowed students to reinforce the skills learned during the module.     

Direct comparison of umbilical cord blood versus bone marrow-derived endothelial precursor cells in mediating neovascularization in response to vascular ischemia.

Endothelial precursor cells (EPCs) cultured from adult bone marrow (BM) have been shown to mediate neovasculogenesis in murine models of vascular injury. We sought to directly compare umbilical cord blood (UCB)- and BM-derived EPC surface phenotypes and in vivo functional capacity. UCB and BM EPCs derived from mononuclear cells (MNC) were phenotyped by surface staining for expression of stromal (Stro-1, CXCR4, CD105, and CD73), endothelial (CD31, CD146, and vascular endothelial [VE]-cadherin), stem cell (CD34 and CD133), and monocyte (CD14) surface markers and analyzed by flow cytometry. The nonobese diabetic/severe combined immunodeficiency murine model of hind-limb ischemia was used to analyze the potential of MNCs and culture-derived EPCs from UCB and BM to mediate neovasculogenesis. Histologic evaluation of the in vivo studies included capillary density as a measure of neovascularization. Surface CXCR4 expression was notably higher on UCB-derived EPCs (64.29%+/-7.41%) compared with BM (19.69%+/-5.49%; P=.021). Although the 2 sources of EPCs were comparable in expression of endothelial and monocyte markers, BM-derived EPCs contained higher proportions of cells expressing stromal cell markers (CD105 and CD73). Injection of UCB- or BM-derived EPCs resulted in significantly improved perfusion as measured by laser Doppler imaging at days 7 and 14 after femoral artery ligation in nonobese diabetic/severe combined immunodeficiency mice compared with controls (P<.05). Injection of uncultured MNCs from BM or UCB showed no significant difference from control mice (P=.119; P=.177). Tissue samples harvested from the lower calf muscle at day 28 demonstrated increased capillary densities in mice receiving BM- or UCB-derived EPCs. In conclusion, we found that UCB and BM-derived EPCs differ in CXCR4 expression and stromal surface markers but mediate equivalent neovasculogenesis in vivo as measured by Doppler flow and histologic analyses.     

Granulocyte turnover in the feline intestine

The objective of this study was to determine the turnover rate of the extravascular pool of granulocytes in different regions of the feline gastrointestinal tract. Leukocyte emigration from the vasculature was prevented over a 48-h period by repeated intravenous injections of a monoclonal antibody (MAb IB₄) directed against the leukocyte adhesion glycoprotein complex CD11/CD18. Tissue-associated myeloperoxidase (MPO) activity was used to monitor the total tissue granulocyte pool at 0.5, 12, 24, and 48 h after MAb IB₄ administration. The mucosal layer of the duodenum, jejunum, ileum, and colon exhibited different kinetics of granulocyte clearance, with average life-spans (t1/2) ranging between 6.9 (colon) and 10.4 h (duodenum). Granulocyte clearance rates of 0.5 × 10⁶ and 2.4 x 10⁶ cells/h/g tissue were estimated (from measured values oft1/2 and tissue granulocyte pool) for the small bowel and colonie mucosae, respectively. The submucosal layer of the intestine exhibited a biphasic reduction in tissue MPO activity following immunoneutralization of CD11/CD18, with an initialt1/2 0.5 h followed by at1/2 of 36–60 h. The initial rapid decline in tissue MPO suggests that a significant fraction of granulocytes in the submucosa is localized in a readily exchangeable pool (e.g., marginated cells within the vasculature). The results of this study indicate that the average life-span of resident granulocytes varies significantly between different regions of the gastrointestinal tract, with the intestinal mucosa exhibiting at1/2 comparable to that previously reported for circulating feline neutrophils (R 8 h).     

The search for a marsupial XIC reveals a break with vertebrate synteny

X-chromosome inactivation (XCI) evolved in mammals to deal with X-chromosome dosage imbalance between the XX female and the XY male. In eutherian mammals, random XCI of the soma requires a master regulatory locus known as the ‘X-inactivation center’ (XIC/Xic), wherein lies the noncoding XIST/Xist silencer RNA and its regulatory antisense Tsix gene. By contrast, marsupial XCI is imprinted to occur on the paternal X chromosome. To determine whether marsupials and eutherians share the XIC-driven mechanism, we search for the sequence equivalents in the genome of the South American opossum, Monodelphis domestica. Positional cloning and bioinformatic analysis reveal several interesting findings. First, protein-coding genes that flank the eutherian XIC are well-conserved in M. domestica, as well as in chicken, frog, and pufferfish. However, in M. domestica we fail to identify any recognizable XIST or TSIX equivalents. Moreover, cytogenetic mapping shows a surprising break in synteny with eutherian mammals and other vertebrates. Therefore, during the evolution of the marsupial X chromosome, one or more rearrangements broke up an otherwise evolutionarily conserved block of vertebrate genes. The failure to find XIST/TSIX in M. domestica may suggest that the ancestral XIC is too divergent to allow for detection by current methods. Alternatively, the XIC may have arisen relatively late in mammalian evolution, possibly in eutherians with the emergence of random XCI. The latter argues that marsupial XCI does not require XIST and opens the search for alternative mechanisms of dosage compensation.