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Biomedical subjects

Peter O'Brien

Publications and source records attributed to Peter O'Brien.

At least 19 recordsLinked to original sources

Contamination during a brachytherapy procedure.

This paper describes an unusual contamination incident that occurred during the treatment of a prostate cancer patient with seeds containing 125I. The incident became particularly interesting as the radiation safety procedures in place prior to the incident were, in fact, inappropriate for the type of incident that occurred, resulting in a series of response errors. Strands containing 108 125I seeds with a total activity of 1.61 GBq (43.6 mCi) were implanted into a patient's prostate and the patient was sent to the recovery room. A radiation survey detected radiation levels of up to 15 microR h(-1), 10 cm from the surface of the implantation needles. Multiple individuals entered the room and were potentially exposed to contamination. Contamination was detected in a sample of the patient's urine, indicating that one or more implanted seeds were leaking. Initial test results for staff showed that 12 of 15 had thyroid levels potentially above their corresponding minimum detectable activity levels, with calculated thyroid burdens ranging from 0.17 kBq to 0.94 kBq, but, subsequent measurements, using each staff member's thigh counts as background, suggested that no staff member had been contaminated. The patient showed high uptake of 125I in his neck 10 d following the incident, estimated to correspond to an initial thyroid burden of 58 kBq. The possibility of contamination was not immediately considered due to the suspicion of the more common problem of a misplaced source. The initial measurements suggesting thyroidal contamination in staff point to an error in our thyroid screening method.

Brachytherapy↗

In vitro cytotoxicity assessment.

The most frequent reason cited for withdrawal of an approved drug is toxicity, yet no simple solution exists to adequately predict such adverse effects. Compound prioritization and optimization during in vitro screening cascades need to be based on confidence, not only in efficacy and bioavailability, but also in safety. A wider number and diversity of potential molecular and cellular effects of compound interactions might affect safety than might affect efficacy or bioavailability. Accordingly, cytotoxicity assessment is less specific, more multiparametric, and extrapolatable with less certainty, unless there are specific safety signals indicated by the chemical structure or by precedents. Cytotoxicity assessments have been limited by their inability to measure multiple, mechanistic parameters that capture a wide spectrum of potential cytopathological changes. Assays with multiple parameters for key, multiple, and different features, such as in high content screening (HCS), are more predictive because they cover a wider spectrum of effects. Assays need to be applied to a large set of marketed drugs that produce toxicity by numerous and different mechanisms for assessment of correlation with human toxicity. This will enable determination of the concordance between in vitro and in vivo results. Multiparametric, live cell, prelethal cytotoxic HCS assays for assessing the potential of compounds for causing human toxicity address some of the limitations of traditional in vitro methods. Assays of this class were used to screen a library of drugs with varying degrees of toxicity and it was found that the sensitivity of the assays was 87%, whereas assay specificity was more than 90%, thereby minimizing false positives.

Cell Death↗

DHEA in elderly women and DHEA or testosterone in elderly men.

BACKGROUND: Dehydroepiandrosterone (DHEA) and testosterone are widely promoted as antiaging supplements, but the long-term benefits, as compared with potential harm, are unknown. METHODS: We performed a 2-year, placebo-controlled, randomized, double-blind study involving 87 elderly men with low levels of the sulfated form of DHEA and bioavailable testosterone and 57 elderly women with low levels of sulfated DHEA. Among the men, 29 received DHEA, 27 received testosterone, and 31 received placebo. Among the women, 27 received DHEA and 30 received placebo. Outcome measures included physical performance, body composition, bone mineral density (BMD), glucose tolerance, and quality of life. RESULTS: As compared with the change from baseline to 24 months in the placebo group, subjects who received DHEA for 2 years had an increase in plasma levels of sulfated DHEA by a median of 3.4 microg per milliliter (9.2 micromol per liter) in men and by 3.8 microg per milliliter (10.3 micromol per liter) in women. Among men who received testosterone, the level of bioavailable testosterone increased by a median of 30.4 ng per deciliter (1.1 nmol per liter), as compared with the change in the placebo group. A separate analysis of men and women showed no significant effect of DHEA on body-composition measurements. Neither hormone altered the peak volume of oxygen consumed per minute, muscle strength, or insulin sensitivity. Men who received testosterone had a slight increase in fat-free mass, and men in both treatment groups had an increase in BMD at the femoral neck. Women who received DHEA had an increase in BMD at the ultradistal radius. Neither treatment improved the quality of life or had major adverse effects. CONCLUSIONS: Neither DHEA nor low-dose testosterone replacement in elderly people has physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life. (ClinicalTrials.gov number, NCT00254371 [ClinicalTrials.gov].).

Adult↗

Catalytic asymmetric synthesis of ferrocenes and P-stereogenic bisphosphines.

The catalytic asymmetric synthesis of planar chiral ferrocenes and P-stereogenic phosphines and bisphosphines (important classes of chiral ligands for metal-catalyzed asymmetric processes) is successfully demonstrated using n-BuLi or s-BuLi in combination with substoichiometric quantities (0.1-0.5 equiv) of (-)-sparteine or the (+)-sparteine surrogate.

Journal Article↗

Reactivity series for s-BuLi/diamine-mediated lithiation of N-Boc pyrrolidine: applications in catalysis and lithiation of N-Boc piperidine.

Using competition experiments between a range of ligands and (-)-sparteine, a reactivity series for N-Boc pyrrolidine lithiation using s-BuLi/diamines has been constructed; the results indicate that the s-BuLi/(+)-sparteine surrogate complex is more reactive than s-BuLi/(-)-sparteine and this has been exploited in the selection of ligand pairs for ligand exchange catalytic asymmetric lithiation of N-Boc pyrrolidine and lithiation of N-Boc piperidine.

Journal Article↗

Body radiation exposure in breast cancer radiotherapy: impact of breast IMRT and virtual wedge compensation techniques.

PURPOSE: Recent reports demonstrate a dramatically increased rate of secondary leukemia for breast cancer patients receiving adjuvant high-dose anthracycline and radiotherapy, and that radiation is an independent factor for the development of leukemia. This study aimed to evaluate the radiation body exposure during breast radiotherapy and to characterize the factors associated with an increased exposure. PATIENTS AND METHODS: In a prospective cohort of 120 women, radiation measurements were taken from four sites on the body at the time of adjuvant breast radiotherapy. Multiple regression analysis was performed to analyze patient and treatment factors associated with the amount of scattered radiation. RESULTS: For standard 50 Gy breast radiotherapy, the minimal dose received by abdominal organs is on average 0.45 Gy, ranging from 0.06 to 1.55 Gy. The use of physical wedges as a compensation technique was the most significant factor associated with increased scattered dose (p < 0.001), resulting in approximately three times more exposure compared with breast intensity-modulated radiation therapy (IMRT) and dynamic wedge. CONCLUSIONS: The amount of radiation that is scattered to a patient's body is consistent with exposure reported to be associated with excess of leukemia. In accordance with the As Low As Reasonably Achievable (ALARA) principle, we recommend using breast IMRT or virtual wedging for the radiotherapy of breast cancer receiving high-dose anthracycline chemotherapy.

Body Height↗

A critical role for peroxisomal proliferator-activated receptor-alpha nuclear receptors in the development of cardiomyocyte degeneration and necrosis.

Peroxisomal proliferator-activated receptor (PPAR)-alpha is a ligand-activated transcriptional factor that regulates genes involved in lipid metabolism and energy homeostasis. PPAR-alpha activators, including fibrates, have been used to treat dyslipidemia for several decades. In contrast to their known effects on lipids, the pharmacological consequences of PPAR-alpha activation on cardiac metabolism and function are not well understood. Therefore, we evaluated the role that PPAR-alpha receptors play in the heart. Our studies demonstrate that activation of PPAR-alpha receptors using a selective PPAR-alpha ligand results in cardiomyocyte necrosis in mice. Studies in PPAR-alpha-deficient mice demonstrated that cardiomyocyte necrosis is a consequence of the activation of PPAR-alpha receptors. Cardiac fatty acyl-CoA oxidase mRNA levels increased at doses in which cardiac damage was observed and temporally preceded cardiomyocyte degeneration, suggesting that peroxisomal beta-oxidation correlates with the appearance of microscopic injury and cardiac injury biomarkers. Increased myocardial oxidative stress was evident in mice treated with the PPAR-alpha agonists coinciding with increased peroxisomal biomarkers of fatty acid oxidation. These findings suggest that activation of PPAR-alpha leads to increased cardiac fatty acid oxidation and subsequent accumulation of oxidative stress intermediates resulting in cardiomyocyte necrosis.

Acyl-CoA Oxidase↗

Surgery for osteitis pubis.

BACKGROUND: Osteitis pubis is a rare and self-limited condition. Surgery may be necessary in 5%-10% of cases. The outcome after surgery for osteitis pubis is not known. METHODS: To determine the success of surgical intervention for osteitis pubis, we used a computerized data registry to identify patients (10 women [mean age 40 yr]) who underwent surgery for osteitis pubis. A retrospective chart review was carried out. We also searched the literature for all cases of osteitis pubis managed surgically and identified 73 cases. RESULTS: The 10 patients in our series had had symptoms for a mean of 4 years preoperatively. Onset of pain was insidious in 4 patients, it followed childbirth in 4 and it followed trauma in 2. Depending on the surgeon's preference, either a wedge resection of the symphysis pubis was performed or a symphysiodesis. At the latest follow-up (average 26 mo), although all patients had some improvement, only 6 of 10 patients were satisfied with the outcome. From the literature review, we identified 3 categories of patients with osteitis pubis: elite athletes, patients with postoperative or infectious osteitis pubis and the remainder, which would include the patients in our series. CONCLUSIONS: Four types of surgical intervention are described: curettage, arthrodesis, wedge resection and wide resection. The elite athletes respond well to curettage. Patients with osteitis pubis following urologic or gynecologic procedures or have a proven infection require surgery in roughly 50% of cases. The third group has an unpredictable outcome.

Adult↗

Catalytic asymmetric deprotonation using a ligand exchange approach.

A novel ligand exchange approach to catalytic asymmetric deprotonation-electrophilic trapping has been developed that uses 1.3 equiv of s-BuLi, 0.06-0.2 equiv of chiral diamine ((-)-sparteine or a (+)-sparteine surrogate), and 1.2 equiv of achiral bispidine. The methodology is illustrated with a range of examples and gives access to either enantiomer of useful chiral products in good yields using substoichiometric amounts of chiral diamines.

Journal Article↗

Boldine and its antioxidant or health-promoting properties.

The increasing recognition of the participation of free radical-mediated oxidative events in the initiation and/or progression of cardiovascular, tumoural, inflammatory and neurodegenerative disorders, has given rise to the search for new antioxidant molecules. An important source of such molecules has been plants for which there is an ethno-cultural base for health promotion. An important example of this is boldo (Peumus boldus Mol.), a chilean tree whose leaves have been traditionally employed in folk medicine and is now widely recognized as a herbal remedy by a number of pharmacopoeias. Boldo leaves are rich in several aporphine-like alkaloids, of which boldine is the most abundant one. Research conducted during the early 1990s led to the discovery that boldine is one of the most potent natural antioxidants. Prompted by the latter, a large and increasing number of studies emerged, which have focused on characterizing some of the pharmacological properties that may arise from the free radical-scavenging properties of boldine. The present review attempts to exhaustively cover and discuss such studies, placing particular attention on research conducted during the last decade. Mechanistic aspects and structure-activity data are discussed. The review encompasses pharmacological actions, which arise from its antioxidant properties (e.g., cyto-protective, anti-tumour promoting, anti-inflammatory, anti-diabetic and anti-atherogenic actions), as well as those that do not seem to be associated with such activity (e.g., vasorelaxing, anti-trypanocidal, immuno- and neuro-modulator, cholagogic and/or choleretic actions). Based on the pharmacological and toxicological data now available, further research needs and recommendations are suggested to define the actual potential of boldine for its use in humans.

Animals↗

Concise synthesis of (+/-)-cytisine via lithiation of N-Boc-bispidine.

[reaction: see text] (+/-)-Cytisine has been synthesized in 19% overall yield via a six-step approach from commercially available materials. Key features of this new strategy are as follows: (i) initial construction of the bispidine core, (ii) lithiation-transmetalation-allylation of an N-Boc-bispidine, and (iii) a Pd/C-mediated dihydropyridone oxidation-N-debenzylation process.

Alkaloids↗

Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group.

PURPOSE: To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell CNS lymphoma (TPCNSL). PATIENTS AND METHODS: A retrospective series of patients with TPCNSL was compiled from twelve cancer centers in seven countries. RESULTS: We identified 45 patients with a median age of 60 years (range, 3 to 84 years). Twenty (44%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Twenty-six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Serum lactate dehydrogenase was elevated in 7 (32%) of 22 patients, and CSF protein was elevated in 19 of 24 patients (79%) with available data. The median disease-specific survival (DSS) was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. Univariate and multivariate analyses were conducted for age (</= 60 v > 60 years), PS (0 or 1 v 2, 3, or 4), involvement of deep structures of the CNS (no v yes), and methotrexate (MTX) use in the primary treatment (yes v no). Only PS and MTX use were significantly associated with better outcome with hazard ratios of 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8), respectively. CONCLUSION: This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of B cell PCNSL. PS 0 or 1 and administration of MTX are associated with better survival.

Adolescent↗

An experimental and computational study of the enantioselective lithiation of N-Boc-pyrrolidine using sparteine-like chiral diamines.

The enantioselective lithiation of N-Boc-pyrrolidine using sec-butyllithium and isopropyllithium in the presence of sparteine-like diamines has been studied experimentally and computationally at various theoretical levels through to B3P86/6-31G*. Of the (-)-cytisine-derived diamines (N-Me, N-Et, N-(n)Bu, N-CH(2)(t)Bu, N-(i)Pr) studied experimentally, the highest enantioselectivity (er 95:5) was observed with the least sterically hindered N-Me-substituted diamine, leading to preferential removal of the pro-R proton i.e., opposite enantioselectivity to (-)-sparteine. The experimental result with the N-Me-substituted diamine correlated well with the computational results: at the B3P86/6-31G* level, the sense of induction was correctly predicted; the lowest energy complex of isopropyllithium/diamine/N-Boc-pyrrolidine also had the lowest activation energy (DeltaH++ = 11.1 kcal/mol, DeltaG++= 11.5 kcal/mol) for proton transfer. The computational results with the N-(i)Pr-substituted diamine identified a transition state for proton transfer with activation energies of DeltaH++= 11.7 kcal/mol and DeltaG++= 11.8 kcal/mol (at the B3P86/6-31G* level). Although comparable to (-)-sparteine and the N-Me-substituted diamine, these DeltaH++ and DeltaG++ values are at odds with the experimental observation that use of the N-(i)Pr-substituted diamine gave no product. It is suggested that steric crowding inhibits formation of the prelithiation complex rather than increasing the activation enthalpy for proton transfer in the transition state. Three other ligands (N-H and O-substituted as well as a five-membered ring analogue) were studied solely using computational methods, and the results predict that the observed enantioselectivity would be modest at best.

Computer Simulation↗

Evaluation of (+)-sparteine-like diamines for asymmetric synthesis.

Three new (+)-sparteine-like diamines were prepared from (-)-cytisine and evaluated as sparteine surrogates in the alpha-lithiation rearrangement of cyclooctene oxide and the palladium(II)/diamine catalyzed oxidative kinetic resolution of 1-indanol. The new diamines exhibited opposite enantioselectivity to that observed with (-)-sparteine but increasing the steric hindrance of the N-alkyl group beyond N-Et had a detrimental effect on enantioselectivity. The optimal N-Me diamine was evaluated with much success in five other (-)-sparteine-mediated processes involving different metals (lithium, magnesium, and copper) and different types of reaction mechanisms.

Alkaloids↗

Sub-picomole colorimetric single nucleotide polymorphism discrimination using oligonucleotide-nanoparticle conjugates.

Oligonucleotide-gold nanoparticle conjugates are employed to demonstrate selective colorimetric discrimination of a cystic fibrosis-related genetic mutation in a model oligonucleotide system. Specifically, three strand oligonucleotide complexes are employed, wherein two probe oligonucleotide-gold nanoparticle conjugates are linked together by a third target oligonucleotide strand bearing the chosen CF-related mutation. By monitoring the solution optical absorption behaviour of the complexes as a function of temperature, melting profiles may be accurately acquired and reproducibly compared. Following this method, fully complementary sequences are successfully distinguished from mismatched sequences, with single base mismatch resolution, for the V232D mutation. To extend the detection sensitivity of this oligonucleotide-nanoparticle conjugate assay, a novel and compact LED-based optical monitoring system capable of sub-picomole level colorimetric SNP discrimination is also demonstrated.

Colorimetry↗