Citations

Background The origin of advanced arterial and renal calcification remains poorly understood. Self-replicating, calcifying entities have been detected and isolated from calcified human tissues, including blood vessels and kidney stones, and are referred to as nanobacteria. However, the microbiologic nature of putative nanobacteria continues to be debated, in part because of the difficulty in discriminating biomineralized microbes from minerals nucleated on anything else (eg, macromolecules, cell membranes). To address this controversy, the use of techniques capable of characterizing the organic and mineral content of these self-replicated structures at the submicrometer scale would be beneficial. Methods Calcifying gram-negative bacteria ( Caulobacter crescentus, Ramlibacter tataouinensis) used as references and self-replicating calcified nanoparticles cultured from human samples of calcified aneurysms were examined using a scanning transmission x-ray microscope (STXM) at the Advanced Light Source at Lawrence Berkeley National Laboratory. This microscope uses a monochromated and focused synchrotron x-ray beam (80-2,200 eV) to yield microscopic and spectroscopic information on both organic compounds and minerals at the 25 nm scale. Results High-spatial and energy resolution near-edge x-ray absorption fine structure (NEXAFS) spectra indicative of elemental speciation acquired at the C K-edge, N K-edge, and Ca L 2,3 -edge on a single-cell scale from calcified C. crescentus and R. tataouinensis displayed unique spectral signatures different from that of nonbiologic hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ). Further, preliminary NEXAFS measurements of calcium, carbon, and nitrogen functional groups of cultured calcified nanoparticles from humans revealed evidence of organics, likely peptides or proteins, specifically associated with hydroxyapatite minerals. Conclusion Using NEXAFS at the 25 nm spatial scale, it is possible to define a biochemical signature for cultured calcified bacteria, including proteins, polysaccharides, nucleic acids, and hydroxyapatite. These preliminary studies suggest that nanoparticles isolated from human samples share spectroscopic characteristics with calcified proteins.

Since the discovery of the cardiac hormone atrial natriuretic peptide by de Bold and colleagues in 1981, the field of natriuretic peptides has significantly advanced with translation of new knowledge to the clinical practice of heart failure. This new knowledge builds on the importance of cardiorenal mechanisms that contribute to optimal cardiovascular regulation. Recent investigations by our group and others have also established the direct myocardial actions of the natriuretic peptides, broadening their therapeutic potential beyond renal mechanisms. Indeed, a potential therapeutic target is cardiac remodeling and fibrosis based on the unique cardiorenal and humoral protective properties that natriuretic peptides possess. We review new insights into the natriuretic peptide system and specifically focus on the possible role of natriuretic peptides as a new therapeutic strategy to limit cardiac remodeling and fibrosis to delay worsening of cardiac function and the progression of heart failure.

Abstract B7 coregulatory ligands can be aberrantly expressed in human disease. In the context of cancer, these ligands may act as antigen-specific inhibitors of T-cell–mediated antitumoral immunity. We recently reported that B7-H1 expression by carcinomas of the kidney and bladder portends aggressive disease and diminished survival. The expression of these proteins in prostate cancer, however, has not been investigated. We evaluated B7-H3 and B7-H1 protein expression in the pathologic specimens of 338 men treated for clinically localized prostate cancer between 1995 and 1998 with radical retropubic prostatectomy. Expression levels of B7-H3 in prostate cancer were correlated with pathologic indicators of aggressive cancer as well as clinical outcome. We report that B7-H3 is uniformly and aberrantly expressed by adenocarcinomas of the prostate, high-grade prostatic intraepithelial neoplasia, and four prostate cancer cell lines, whereas B7-H1 is rarely expressed. B7-H3 is expressed by benign prostatic epithelia, although at a more reduced level relative to neoplastic tissue. Increasing levels of B7-H3 intensity correlate with worsening clinicopathologic features of prostate cancer. Marked B7-H3 intensity, present in 67 (19.8%) specimens, confers a >4-fold increased risk of cancer progression after surgery (risk ratio, 4.42; P < 0.001). A survey of normal tissues revealed that B7-H3 is expressed within the liver, urothelium, and fetal kidney. In summary, B7-H3 is aberrantly expressed in all prostate cancers and represents an independent predictor of cancer progression following surgery. Moreover, B7-H3 encompasses a novel diagnostic and potential therapeutic target for the clinical management of prostate cancer and, perhaps, other malignancies as well. [Cancer Res 2007;67(16):7893–900]

Background— Quality improvement efforts have focused on strategies to improve the timeliness of reperfusion therapy in ST-elevation myocardial infarction patients who present to hospitals with and without percutaneous coronary intervention (PCI) capability. We implemented and evaluated a protocol to optimize the timeliness of reperfusion therapy and to coordinate systems of care for a PCI center and 28 regional hospitals located up to 150 miles away across 3 states. Methods and Results— The present study focused on a prospective, observational cohort of 597 patients who presented with ST-segment elevation and within 12 hours of symptom onset to Saint Marys Hospital and 28 regional hospitals up to 150 miles away between May 2004 and December 2006. The Mayo Clinic ST-elevation myocardial infarction protocol implemented strategies to improve timeliness of reperfusion therapy and to coordinate systems of care for transfer between hospitals. The study sample consisted of 258 patients who presented to Saint Marys Hospital and were treated with primary PCI (group A), 105 patients who presented to a regional hospital with symptom onset >3 hours and then were transferred for primary PCI (group B), and 131 patients who presented to a regional hospital with symptom onset <3 hours and were treated with full-dose fibrinolytic therapy (group C). For groups A and B, median door-to-balloon times were 71 and 116 minutes, respectively. Door-to-balloon time <90 minutes was achieved in 75% of group A and 12% of group B. Median door-to-needle time was 25 minutes for group C, and 70% had door-to-needle time <30 minutes. Conclusions— The Mayo Clinic ST-elevation myocardial infarction protocol demonstrates the feasibility of implementing strategies to optimize the timeliness of reperfusion therapy and the times that can be achieved through coordinated systems of care for ST-elevation myocardial infarction patients presenting to a PCI center (Saint Marys Hospital) and 28 regional hospitals without PCI capability located up to 150 miles away across 3 states.

Abstract Current users of postmenopausal hormones (PMH) have ∼30% to 40% lower risk of colorectal cancer (CRC), although associations with specific types of hormones have been inconsistent. Further, it is not clear whether some tumor types have a different risk. We conducted a case-control study to examine the relationship between PMH and CRC. Cases (n = 1,004), ages 50 to 74 years, were identified from the Surveillance Epidemiology and End Results registry in Washington from 1998 to 2002; controls (n = 1,062) were randomly selected from population lists. Case tissue samples were obtained for microsatellite instability (MSI) analyses. Interviews collected risk-factor data for CRC, including detailed information on PMH. Multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (95% CI). Current use of any PMH was associated with a 20% reduction in CRC risk (95% CI 0.6–0.9). This reduction in risk was limited to women who had taken estrogen plus progestin (EP) preparations only (OR = 0.6, 95% CI 0.5–0.9); there was no association with estrogen-only (E alone) use (OR = 0.9, 95% CI 0.7–1.1). For women with MSI-low or MSI-stable tumors, there was a statistically significant 40% reduction in CRC risk associated with EP use (95% CI 0.4–0.9); there was no clear association with MSI-high tumors. EP use was associated with a decreased risk of CRC; however, there seemed to be no association with E alone data that are consistent with the recent Women's Health Initiative findings. Progestin may enhance the estrogenic effect of conjugated estrogen so the combination may be more biologically active in the colon than E alone. [Cancer Res 2007;67(15):7534–9]

The transseptal/transsphenoidal approach to the pituitary gland has been the most commonly used approach for resection of pituitary adenomas for the last 50 years. This procedure has a low morbidity and provides direct midline access to the sella and pituitary gland. Recent advancements in endoscopic surgery, however, suggest that a lower morbidity approach to the sella would be possible via transnasal endoscopic route. Prior reports have confirmed effectiveness of this approach to the pituitary gland and we report here an early series of endoscopic transnasal pituitary surgery from our institution. We report seven cases of transnasal endoscopic pituitary surgery. Our technique consists of endoscopic exposure of the sphenoid ostium unilaterally, excision of the posterior septum anterior to the rostrum of the sphenoid sinus with resection of the sphenoid rostrum for bilateral exposure of the sphenoid sinus. A specially designed nasal speculum is positioned to displace the posterior septum and lateralize the middle turbinates, permitting direct midline exposure of the sphenoid sinus and sella. We have progressively modified the technique over the seven cases that we present and will discuss our specific instrumentation, indications, and technique for this procedure. We have encountered one cerebrospinal fluid leak in this series. Patient satisfaction has been high and hospitalization is less than with the conventional transseptal approach, averaging 1 day. Our impression is that the transnasal endoscopic approach to pituitary adenomas is a safe technique with reduced morbidity permitting shortened hospital stay.

AbstractMany congenital disorders of glycosylation (CDG) can be diagnosed by observing the extent of glycosylation of the abundant serum glycoprotein transferrin (Trf). Trf is an N‐glycosylated protein with two asparagine glycation sites. CDG types I are those genetic defects which occur prior to transfer of the complex oligosaccharide to the acceptor asparagine in the cotranslated polypeptide chain. CDG Ia constitutes by far the most frequent form of CDG and is the result of mutations in the phosphomannomutase gene. CDG Ia and the Ib subtype (Phosphomannoisomerase deficiency) result in low cellular mannose‐1‐phosphate levels, a required precursor for oligosaccharide assembly in the endoplasmic reticulum. The deficiency in oligosaccharides with branched mannose structures is thereafter expressed by the appearance of glycoproteins with unoccupied N‐glycosylation sites (hypoglycosylation). Currently, there have been at least 11 Type I defects, type Ia being by far the most frequently occurring. Most, if not all type I defects result in unoccupied N‐glycation sites. Hypoglycosylated Trf, also known as carbohydrate‐deficient Trf (CDT), can be detected using mass spectrometry (MS) to measure the masses of the serum Trf. The methods for sample preparation using affinity chromatography and MS analysis are described in this unit. Curr. Protoc. Hum. Genet. 54:17.4.1‐17.4.9 © 2007 by John Wiley & Sons, Inc.