Spectroscopic imaging with multidimensional pulses for excitation: SIMPLE

Proton spectroscopy and spectroscopic imaging in the human brain require the elimination of both water and lipid signals. Strong lipid signals from subcutaneous fat are usually eliminated by confining the excited volume to lie wholly within the skull. Water suppression, however, can be difficult due to both B0 and RF inhomogeneities, which are particularly troublesome in imaging experiments where a relatively large region-of-interest (ROI) is typical. In this paper, we discuss the use of multidimensional selective-excitation pulses (e.g., pulses that are simultaneously selective along two axes) to both define the ROI and provide the necessary water suppression. Pulse sequences providing three-dimensional localization along with water suppression that is insensitive to a range of B0 and RF inhomogeneities are described. Spectra and spectroscopic images (voxel volume = 3.4 cc. acquisition time = 38 min) of various 1H metabolites from a patient with an astrocytoma show clear differences between normal and cancerous tissues and demonstrate the ability of these techniques to be used in vivo.     

Temperature mapping of frozen tissue using eddy current compensated half excitation RF pulses.

Cryosurgery has been shown to be an effective therapy for prostate cancer. Temperature monitoring throughout the cryosurgical iceball could dramatically improve efficacy, since end temperatures of at least -40 degrees C are required. The results of this study indicate that MR thermometry based on tissue R(*)(2) has the potential to provide this information. Frozen tissue appears as a complete signal void on conventional MRI. Ultrashort echo times (TEs), achievable with half pulse excitation and a short spiral readout, allow frozen tissue to be imaged and MR characteristics to be measured. However, half pulse excitation is highly sensitive to eddy current distortions of the slice-select gradient. In this work, the effects of eddy currents on the half pulse technique are characterized and methods to overcome these effects are developed. The methods include: 1) eddy current compensated slice-select gradients, and 2) a correction for the phase shift between the first and second half excitations at the center of the slice. The effectiveness of these methods is demonstrated in R(*)(2) maps calculated within the frozen region during cryoablation.     

Glycation during human dermal intrinsic and actinic ageing: an in vivo and in vitro model study

BACKGROUND: Non-enzymatic glycation occurring in normal human skin plays an important part in ageing. OBJECTIVES To visualize and quantify, in human subjects, the extent of glycation during human dermal intrinsic and actinic ageing, and to develop a reliable reproducible in vitro model for evaluating the efficacy of potential inhibitors of glycation. METHODS: By immunohistochemistry using a monoclonal antibody recognizing carboxymethyl lysine, an advanced glycation end-product (AGE) (first objective), and by incubating dead de-epidermized dermis (DED) with glucose to simulate ageing-induced glycation in a human dermal equivalent model (second objective). RESULTS: We found that glycation of the dermis generally arises after 35 years, then increases rapidly with intrinsic ageing. We also noticed an enhancement of glycation by solar irradiation that occurred via glycation of the elastic fibre network or solar elastosis tissue. In the model, production of AGEs appeared in a time-dependent way, mimicking glycation observed in vivo during chronological ageing. Irradiation of DED before incubation with glucose strongly enhanced induction of AGEs, corresponding to the effect of solar irradiation on AGEs observed in vivo. CONCLUSIONS: These results confirm a marked increase of AGEs during intrinsic ageing in normal human skin and also suggest that glycation is enhanced in photoaged skin.     

The inhibition of vascular smooth muscle cell migration by peptide and antibody antagonists of the alphavbeta3 integrin complex is reversed by activated calcium/calmodulin- dependent protein kinase II.

The migration of vascular smooth muscle cells (VSMCs) is thought to play a key role in the pathogenesis of many vascular diseases and is regulated by soluble growth factors/ chemoattractants as well as interactions with the extracellular matrix. We have studied the effects of antibodies to rat beta3 and human alphavbeta3 integrins on the migration of VSMCs. Both integrin antibodies as well as cyclic RGD peptides that bind to the vitronectin receptors alphavbeta3 and alphavbeta5 significantly inhibited PDGF-directed migration. This resulted in a reduction in the accumulation of inositol (1,4,5) trisphosphate and the activation of calcium/calmodulin-dependent protein kinase II (CamKII), an important regulatory event in VSMC migration identified previously. PDGF-directed VSMC migration in the presence of the anti-integrin antibodies and cyclic RGD peptides was restored when intracellular CamKII activity was elevated by either raising intracellular calcium levels with the ionophore, ionomycin, or infecting with a replication-defective recombinant adenovirus expressing a constitutively activated CamKII cDNA (AdCMV.CKIID3). Rescue of rat VSMCs was also observed in stably transfected cell lines expressing constitutively activated but not wild-type CamKII. These observations identify a key intermediate in the regulation of VSMC migration by outside-in signaling from the integrin alphavbeta3.     

Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension

OBJECTIVE: Beta-Blocker use can be associated with adverse effects that may have an impact on adherence or harm patients. The commonly prescribed beta-blocker metoprolol is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 enzyme, resulting in widely variable drug exposure. We investigated whether metoprolol plasma concentrations, CYP2D6 polymorphisms, or genotype-derived phenotype was associated with adverse effects or efficacy in patients with hypertension. METHODS: Fifty hypertensive patients received metoprolol by use of a dose-titration algorithm until target blood pressure was reached, intolerable side effects occurred, or maximal daily dose was achieved. CYP2D6 genotype was determined by methods based on polymerase chain reaction-restriction fragment length polymorphism and included 19 allelic variants. Patients were assigned to standard phenotype groups on the basis of genotype. Patients were also assigned activity scores based on functional activity of the alleles. General and dose-limiting adverse events and blood pressure responses were analyzed in relation to metoprolol steady-state pharmacokinetic profile and CYP2D6 genotype-derived phenotype. RESULTS: Poor metabolizers had a significantly longer elimination half-life, higher S-metoprolol area under the plasma concentration-time curve (AUC), and lower oral clearance (P < or = .007 for all parameters). There was a 29.6-fold variability in AUC among extensive metabolizers, which was largely explained by CYP2D6 activity scores (P = .032 for ordered differences in AUC by activity score among extensive metabolizers). Overall general and dose-limiting adverse event rates were 46% and 14%, respectively. General adverse event rates did not differ by AUC quartile (66.7% [95% confidence interval (CI), 35.4%-88.7%] and 41.7% [95% CI, 16.5%-71.4%] in the lowest and highest quartiles, respectively; P = .09 among all quartiles). Dose-limiting adverse event rates were also not different by AUC quartile (16.7% [95% CI, 2.9%-49.1%] and 8.3% [95% CI, 0.4%-40.2%] in the lowest and highest quartiles; P = .35 among all quartiles). Furthermore, adverse event rates did not differ by activity scores or between extensive, intermediate, or poor metabolizers. Antihypertensive response rate and blood pressure changes also were not influenced by differences in plasma concentrations or CYP2D6 genotypes. CONCLUSIONS: As expected, CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics. However, there was no association between variable pharmacokinetics or CYP2D6 genotype and beta-blocker-induced adverse effects or efficacy.     

The ethical, legal and social context of harm reduction

Harm reduction is part of a comprehensive approach to dealing with the harms of drug use. Although the evidence to support implementation of harm reduction strategies for illicit drug use is abundant, it is unlikely that scientific knowledge alone will be enough to facilitate the adoption of harm reduction strategies in many health-care settings. The authors examine the ethical, legal and social context of harm reduction as it pertains to illicit drug use to assist nurses in providing safe, competent and ethical care. Included is an examination of values and accompanying responsibility statements from the Canadian Nurses Association's Code of Ethics for Registered Nurses that can guide nurses in their ethical reflection and provide insights into ethical practice.     

Is lower 30-day mortality posthospital admission among blacks unique to the Veterans Affairs health care system?

BACKGROUND: Several studies have reported lower risk-adjusted mortality for blacks than whites within the Veterans Affairs (VA) health care system, particularly for those age 65 and older. This finding may be a result of the VA's integrated health care system, which reduces barriers to care through subsidized comprehensive health care services. However, no studies have directly compared racial differences in mortality within 30 days of hospitalization between the VA and non-VA facilities in the US health care system. OBJECTIVE: To compare risk-adjusted 30-day mortality for black and white males after hospital admission to VA and non-VA hospitals, with separate comparisons for patients younger than age 65 and those age 65 and older. RESEARCH DESIGN: Retrospective observational study using hospital claims data from the national VA system and all non-VA hospitals in Pennsylvania and California. SUBJECTS: A total of 369,155 VA and 1,509,891 non-VA hospitalizations for a principal diagnosis of pneumonia, congestive heart failure, gastrointestinal bleeding, hip fracture, stroke, or acute myocardial infarction between 1996 and 2001. MEASURES: Mortality within 30 days of hospital admission. RESULTS: Among those under age 65, blacks in VA and non-VA hospitals had similar odds ratios of 30-day mortality relative to whites for gastrointestinal bleeding, hip fracture, stroke, and acute myocardial infarction. Among those age 65 and older, blacks in both VA and non-VA hospitals had significantly reduced odds of 30-day mortality compared with whites for all conditions except pneumonia in the VA. The differences in mortality by race are remarkably similar in VA and non-VA settings. CONCLUSIONS: These findings suggest that factors associated with better short-term outcomes for blacks are not unique to the VA.