Biomedical subjects
Publications and source records attributed to Peter O'Brien.
A six-step asymmetric synthesis of natural (-)-sparteine from ethyl 7-iodohept-2-enoate is reported, involving a connective Michael addition of an amino ester-derived enolate to an alpha,beta-unsaturated amino ester.
BACKGROUND: It is popular belief that the psychologic response to a diagnosis of cancer influences survival in patients with cancer; however, research has produced contradictory results. In this prospective study, the authors investigated the relation between pretreatment levels of optimism and survival in patients with nonsmall cell lung carcinoma (NSCLC). METHODS: Two hundred four patients who were participating in a randomized trial that compared accelerated and conventional radiotherapy with and without carboplatin chemotherapy were asked to complete two questionnaires assessing optimism. The first assessment was just prior to commencing treatment and the second assessment took place after completing treatment. Survival was measured from the date of randomization to the date of death. Surviving patients were followed until February 8, 2001. RESULTS: The pretreatment questionnaire was completed by 179 patients, and 148 of those patients completed the posttreatment questionnaire. There was a small but significant reduction in optimism scores after treatment (P = 0.005). There was no association noted between pretreatment optimism and progression-free survival (P = 0.52, unadjusted; P = 0.22, adjusted for Eastern Cooperative Oncology Group performance status and patient age), nor was there an association noted between pretreatment optimism and overall survival (P = 0.36, unadjusted; P = 0.19, adjusted for disease stage). CONCLUSIONS: There was no evidence that a high level of optimism prior to treatment enhanced survival in patients with NSCLC. Encouraging patients to "be positive" only may add to the burden of having cancer while providing little benefit, at least in patients with NSCLC.
The aim of the present paper is to evaluate how the use of decision models in the review of portal images can eliminate systematic set-up errors during conformal therapy. Sixteen patients undergoing four-field irradiation of prostate cancer have had daily portal images obtained during the first two treatment weeks and weekly thereafter. The magnitude of random and systematic variations has been calculated by comparison of the portal image with the reference simulator images using the two-dimensional decision model embodied in the Hotelling's evaluation process (HEP). Random day-to-day set-up variation was small in this group of patients. Systematic errors were, however, common. In 15 of 16 patients, one or more errors of >2 mm were diagnosed at some stage during treatment. Sixteen of the 23 errors were between 2 and 4 mm. Although there were examples of oversensitivity of the HEP in three cases, and one instance of undersensitivity, the HEP proved highly sensitive to the small (2-4 mm) systematic errors that must be eliminated during high precision radiotherapy. The HEP has proven valuable in diagnosing very small (<4 mm) errors. When combined with the potential for rapid diagnosis of larger (>4 mm) systematic errors using one-dimensional decision models, HEP can eliminate the majority of systematic errors during the first 2 treatment weeks.
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Alzheimer disease and type 2 diabetes are characterized by increased prevalence with aging, a genetic predisposition, and comparable pathological features in the islet and brain (amyloid derived from amyloid beta protein in the brain in Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes). Evidence is growing to link precursors of amyloid deposition in the brain and pancreas with the pathogenesis of Alzheimer disease and type 2 diabetes, respectively. Given these similarities, we questioned whether there may be a common underlying mechanism predisposing to islet and cerebral amyloid. To address this, we first examined the prevalence of type 2 diabetes in a community-based controlled study, the Mayo Clinic Alzheimer Disease Patient Registry (ADPR), which follows patients with Alzheimer disease versus control subjects without Alzheimer disease. In addition to this clinical study, we performed a pathological study of autopsy cases from this same community to determine whether there is an increased prevalence of islet amyloid in patients with Alzheimer disease and increased prevalence of cerebral amyloid in patients with type 2 diabetes. Patients who were enrolled in the ADPR (Alzheimer disease n = 100, non-Alzheimer disease control subjects n = 138) were classified according to fasting glucose concentration (FPG) as nondiabetic (FPG <110 mg/dl), impaired fasting glucose (IFG, FPG 110-125 mg/dl), and type 2 diabetes (FPG >126 mg/dl). The mean slope of FPG over 10 years in each case was also compared between Alzheimer disease and non-Alzheimer disease control subjects. Pancreas and brain were examined from autopsy specimens obtained from 105 humans (first, 28 cases of Alzheimer disease disease vs. 21 non-Alzheimer disease control subjects and, second, 35 subjects with type 2 diabetes vs. 21 non-type 2 diabetes control subjects) for the presence of islet and brain amyloid. Both type 2 diabetes (35% vs. 18%; P < 0.05) and IFG (46% vs. 24%; P < 0.01) were more prevalent in Alzheimer disease versus non-Alzheimer disease control subjects, so 81% of cases of Alzheimer disease had either type 2 diabetes or IFG. The slope of increase of FPG with age over 10 years was also greater in Alzheimer disease than non-Alzheimer disease control subjects (P < 0.01). Islet amyloid was more frequent (P < 0.05) and extensive (P < 0.05) in patients with Alzheimer disease than in non-Alzheimer disease control subjects. However, diffuse and neuritic plaques were not more common in type 2 diabetes than in control subjects. In cases of type 2 diabetes when they were present, the duration of type 2 diabetes correlated with the density of diffuse (P < 0.001) and neuritic plaques (P < 0.01). In this community cohort from southeast Minnesota, type 2 diabetes and IFG are more common in patients with Alzheimer disease than in control subjects, as is the pathological hallmark of type 2 diabetes, islet amyloid. However, there was no increase in brain plaque formation in cases of type 2 diabetes, although when it was present, it correlated in extent with duration of diabetes. These data support the hypothesis that patients with Alzheimer disease are more vulnerable to type 2 diabetes and the possibility of linkage between the processes responsible for loss of brain cells and beta-cells in these diseases.
The first systematic study of the cis and trans stereoselectivity in the m-CPBA epoxidation of N-protected cyclic allylic amines has been completed. Mono-N-protected systems gave epoxides with cis stereochemistry (amides are better cis directors than sulfonamides or carbamates) whereas di-N-protected systems gave trans-epoxides (TsNBoc protection gave complete trans stereoselectivity). [structure: see text]
Three chiral diamines were synthesised and evaluated as sparteine surrogates in the lithiation-substitution of N-(tert-butoxycarbonyl)pyrrolidine. The synthesis and attempted resolution of sparteine-like diamines [(1S*,2R*,8R*)-10-methyl-6,10-diazatricyclo[6.3.1.0(2,6)]dodecane and (1S*,2R*,9R*)-11-methyl-7,11-diazatricyclo[7.3.1.0(2,7)]tridecane] (via inclusion complex formation) are reported. Unfortunately, it was only possible to resolve the diazatricyclo[7.3.1.0(2,7)]tridecane compound. An alternative route to (1R,2S,9S)-11-methyl-7,11-diazatricyclo[7.3.1.0(2,7)]tridecane starting from the natural product, (-)-cytisine, is described. This simple three-step route furnished gram-quantities of a (+)-sparteine surrogate. X-Ray crystallography of an intermediate in the route, (1R,5S,12S)-3-methoxycarbonyldecahydro-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, enabled the stereochemistry of all of the tricyclic diamines described in this paper to be unequivocally established. Two other diamines, starting from (S)-proline and resolved 2-piperidine ethanol, were prepared using standard methods. These diamines lacked the bispidine framework of (-)-sparteine and were found to impart vastly inferior enantioselectivity. It was concluded that, for the asymmetric lithiation substitution of N-Boc pyrrolidine, a rigid bispidine framework and only three of the four rings of (-)-sparteine are needed for high enantioselectivity. Furthermore, it is shown that diamine (1R,2S,9S)-11-methyl-7,11-diazatricyclo[7.3.1.0(2,7)]tridecane is the first successful (+)-sparteine surrogate.
[reaction: see text] A (-)-quinic acid-derived enone, with the trans-1,2-diol protected as a 2,3-dimethoxybutanediyldioxy ketal, provides an excellent template for further highly stereoselective elaboration as exemplified by its conversion into the core of scyphostatin, a potent inhibitor of neutral sphingomyelinase.
Two different chiral lithium amide base routes for the synthesis of amino- and aziridino-containing cyclohexenols have been explored. The first strategy involved the diastereoselective preparation of novel meso-aziridinocyclohexene oxides and their subsequent enantioselective rearrangement using chiral bases. In this approach, the diphenylphosphinoyl nitrogen protecting group proved optimal and aziridinocyclohexenols of 47-68% ee were obtained. Of particular note was the smooth rearrangement of the epoxide to an allylic alcohol in the presence of an aziridine: under optimised chiral base conditions, the aziridine remained essentially unaffected. A second more straightforward strategy for introduction of an amino functionality was also investigated: (1S,4R,5S)- and (1R,4R,5S)-4,5-bis(tert-butyldimethylsilyloxy)cyclohex-2-enols, readily prepared in > 95% ee using a chiral base approach, were subjected to Mitsunobu substitution using a sulfonamide and Overman rearrangement.
Because many head and neck radiotherapy treatment techniques rely on a junction between X-ray fields, it was the aim of the present study to investigate the use of different junctioning techniques and the affect on the dose across the junction. Techniques in use at nine radiotherapy centres in Australia were investigated using thermoluminescence dosimetry (TLD). The techniques could broadly be divided into two groups: (i) use of the light field to match the fields after moving the patient; and (ii) use of asymmetric collimation to create a single isocentre located in the junction. The mean dose at the junction and its reproducibility was studied in five consecutive treatments in each centre using 25 TLD chips placed throughout the junction in an anthropomorphic phantom. There was a tendency for the mono-isocentric technique to deliver a lower, more accurate mean dose at the junction (Group I: 1.22 Gy (n = 8) vs Group II: 0.96 Gy (n = 5) for 1 Gy planned, some centres contributed to both technique) with greater reproducibility (Group I: 9.6%, Group II: 5.1% of the mean dose). We conclude that a mono-isocentric treatment technique has the potential to deliver a more accurate and reproducible dose distribution at the field junction of photon beams in head and neck treatment.
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A "(+)-sparteine-like" chiral diamine, readily synthesized in three steps from (-)-cytisine, has been evaluated in four different asymmetric transformations; in each case, selectivity in an enantiocomplementary fashion to (-)-sparteine was observed.
[reaction: see text] The synthesis of novel substituted meso-aziridines is described: aziridination of 4-tert-butyldiphenylsilyloxy-cyclopent-1-ene is trans selective using Cu(I)/PhI=NSO(2)Ar and cis selective using PhNMe(3)(+)Br(3)(-)/Chloramine-T.
The authors previously reported an increase in the incidence of diabetes mellitus among Rochester, Minnesota, residents during the period 1970-1989. This study provides updated rates from data collected through 1994. Trends in diabetes surveillance, i.e., the proportion of residents who had a blood glucose measurement in each year between 1987 and 1994, are also provided. The authors reviewed medical records to identify residents aged 30 years or more who first met National Diabetes Data Group criteria for diabetes between January 1, 1970, and December 31, 1994. Age- and sex-adjusted incidence rates were calculated for successive quinquennia (5-year periods), and Poisson regression was used to test for an effect of calendar year; calendar period (1970-1989 vs. 1990-1994) was added to assess whether the association with calendar year varied in the most recent quinquennium. Altogether, 1,992 Rochester residents first met National Diabetes Data Group criteria for diabetes between 1970 and 1994. The age-adjusted incidence per 100,000 person-years increased 67% for males (267.0 vs. 444.8) and 42% for females (225.4 vs. 319.1) between 1970-1974 and 1990-1994. Calendar year (p < 0.001) and calendar period (p = 0.026) were significant, suggesting that rates accelerated during 1990-1994. The proportion of residents with at least one blood glucose measurement per year was unchanged (p = 0.181) from 1987 to 1994, while the incidence of diabetes increased (p = 0.033). Thus, the authors conclude that the increase in diabetes incidence accelerated over the last quinquennium and was not due to increased surveillance.
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