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A Hartley

Publications and source records attributed to A Hartley.

At least 19 recordsLinked to original sources
PubMed2006

Comment on "Rapid uplift of the Altiplano revealed through 13C-18O bonds in paleosol carbonates".

Based on stable isotope measurements, Ghosh et al. (Reports, 27 January 2006, p. 511) concluded that the Bolivian Altiplano uplifted 3 to 4 kilometers between approximately 10.3 and approximately 6.7 million years ago as a result of gravitational loss of dense lithosphere. This result stands at odds with current geological knowledge of the Central Andes, and we propose a test for the reliability of the paleoaltimetry method.

Comment↗
PubMed2006

Carboplatin and hypofractionated accelerated radiotherapy: a dose escalation study of an outpatient chemoradiation schedule for squamous cell carcinoma of the head and neck.

AIM: To examine the feasibility and determine the maximum tolerated dose of outpatient carboplatin given with synchronous hypofractionated accelerated radiotherapy for squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Patients with stages II-IV SCCHN and unresected primary tumour were treated with synchronous carboplatin given in an outpatient setting on day 1 and day 21 in cohorts of three to six patients with incremental area under curve (AUC) factors commencing at 3.5. Grade 3 mucositis persisting for 4 weeks in two patients in a cohort was considered dose limiting. RESULTS: A total of 19 patients were enrolled and assessable for toxicity. All 19 patients completed 55 Gy of radiotherapy and were assessable for response. Grade 3 mucositis lasting 4 weeks or more was seen in three patients, two of them received AUC 5 carboplatin. A complete response was seen in 16 patients, with a further patient having a partial response, giving a response rate of 89%. With a median follow-up of 24 months (range 11-30 months), 13 patients were alive with no evidence of recurrent disease. Local recurrence had occurred in four patients with distant spread in three patients. CONCLUSION: Carboplatin with concurrent hypofractionated accelerated radiotherapy is feasible for patients with advanced SCCHN and good performance status. The recommended phase II dose of carboplatin given in week 1 and week 4 with 55 Gy in 20 fractions is AUC 4.5.

Adult↗
PubMed2006

Improved survival after concurrent weekly cisplatin and radiotherapy for cervical carcinoma with assessment of acute and late side-effects.

AIMS: A recent meta-analysis has shown a survival advantage for the addition of concurrent chemotherapy to radiotherapy in the treatment of cervical carcinoma. Controversy persists about the most appropriate chemotherapy schedule and whether similar results for tumour control and toxicity may be achieved with optimally delivered radiotherapy. A single-centre experience of a concurrent chemotherapy regimen is presented. MATERIALS AND METHODS: All women treated with concurrent chemoradiotherapy at a university hospital from 1 January 1999 to 1 May 2002 were identified. Acute and late complications were scored using the National Cancer Institute Common Toxicity Criteria and RTOG/ EORTC system, respectively. Univariate and multivariate analyses were carried out to examine the relationship between demographics, stage, overall treatment time, radiotherapy dose, selectron insertion, number of chemotherapy cycles and occurrence of acute and late toxicity. RESULTS: Seventy-nine women received concurrent weekly cisplatin (40 mg/m2) with radiotherapy. Thirty-eight per cent had early tumours (FIGO IIA or less) and 62% had locally advanced tumours. Twenty-eight per cent of women had surgery as part of primary treatment. Radiation technique included external-beam pelvic radiotherapy (EBRT) (45-50.4 Gy in 25-28 fractions) and medium-dose rate brachytherapy single insertion (25-27 Gy to point A) or EBRT alone. Median overall treatment time was 49 days (range 23-91 days). Three-year survival rate was 87% (95% confidence interval [CI] 79-95%). Three-year, progression-free survival rate was 75% (95% CI 65-85%). At a median follow-up of 35 months: 27 (34%) women experienced 45 episodes of acute grade 3 or 4, and eight women (10%) experienced 12 late grade 3 or 4 complications. CONCLUSIONS: Weekly cisplatin 40 mg/m2 concurrent with radiotherapy is well tolerated when given to an unselected population of patients. Survival rates seem to be excellent, with both local control and overall survival being at least as good as those in published randomised trials.

Adenocarcinoma↗
PubMed2005

Multicentre prospective audit of surgical outcomes and acute complications following short course pre-operative radiotherapy for resectable rectal cancer.

BACKGROUND: The addition of short course pre-operative radiotherapy to total mesorectal excision reduces local recurrence in resectable adenocarcinoma of the rectum. In a previous retrospective study potential factors associated with early complications following this combination were identified. The aim of this study was to examine these relationships in a prospective multicentre audit. METHODS: One hundred and seven patients who received short course pre-operative radiotherapy in four cancer centres between 1 October 2001 and 30 September 2002 were included. Data including patient age, radiotherapy field length, overall treatment time, operation type, surgical outcomes and complications occurring within 3 months of the 1st day of radiotherapy were collected. These were compared and combined with the previously studied cohort of 176 patients treated at one centre between 1st January 1998 and 31st December 1999. RESULTS: In the prospective cohort only patient age (P=0.001) was significantly associated with acute complications. However, both the overall treatment time (median 9.0 vs 11.0 days P <0.0001) and field length (median 16.6 vs 17.0 cm P=0.03) were significantly shorter in this cohort when compared to the previous retrospective study. In patients from both studies (n=283), increasing age (P=0.002) and field length (independent of operation type) (P=0.02) were independently associated with an increased risk of acute complications. CONCLUSIONS: This study suggests that meticulous selection of patients for short course pre-operative radiotherapy and smaller planning target volumes may be associated with a lower risk of acute complications. The use of MRI scanning to stage pelvic disease may reduce the number of patients with R1 resections receiving short course pre-operative radiotherapy.

Acute Disease↗
PubMed2005

Pathological complete response following pre-operative chemoradiotherapy in rectal cancer: analysis of phase II/III trials.

Pathological complete response (pCR) has been used as a marker for the efficacy of pre-operative chemoradiotherapy (CRT) schedules in rectal cancer. To date there have been no randomized trials comparing CRT regimens in rectal cancer. Prospective phase II and CRT arms of randomized trials reported up to January 2004 were included, providing they defined the following minimum variables: drugs employed during CRT, radiotherapy dose and pCR rate. Multivariate analysis was used to examine the relationship of these variables on the pCR rate. In addition, the use of neoadjuvant chemotherapy, the type of publication (peer reviewed vs meeting abstract) and whether the tumours were stated to be unresectable/clinically fixed or to have threatened circumferential margins were investigated. The method of analysis was weighted linear modelling of the pCR rate which was normalized by the arcsine transformation. Phase II and phase III trials were identified including a total of 3157 patients. On multivariate analysis only the use of continuous infusion 5FU (p = 0.01), the use of a second drug (p = 0.001) and radiation dose (p = 0.02) were associated with higher rates of pCR. The use of a two drug regimen, the mode of delivery of 5FU and the radiation dose appear to be related to the incidence of pCR following CRT for rectal cancer. These results may generate hypotheses for future randomized trials. Important factors not considered in this analysis include the variability in pathological examination and in the time interval between CRT and surgery. In addition, the toxicity of the CRT regimens requires further investigation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Late toxicity after short course preoperative radiotherapy and total mesorectal excision for resectable rectal cancer.

AIMS: The late toxicity of short-course preoperative radiotherapy (SCPRT) after total mesorectal excision (TME) in resectable rectal cancer has not been adequately documented. The acute toxicity in a series of 176 consecutive patients has been previously reported. In this study, the late toxicity in the same cohort is presented. MATERIALS AND METHODS: Side-effects occurring more than 3 months after the start of SCPRT were graded using the EORTC/RTOG late radiation toxicity system. We performed multivariate analysis to identify associated factors. RESULTS: Of 176 patients, 15 died within 3 months of SCPRT and five patients were lost to follow-up. One hundred and fifty-six patients were assessable at a median follow-up interval of 41 months: severe (grade 3-4) toxicity was seen in 20 patients (13%), of which 13 were gastrointestinal (8%); three urological (2%); three thromboembolic (2%), and one musculoskeletal (1%). On multivariate analysis, abdomino-perineal (AP) resection (P < 0.02) was associated with a lower risk of grade 3-4 toxicity. CONCLUSIONS: In this retrospective study, the rate of late grade 3-4 toxicity after SCPRT and TME was 13%. Although AP resection seems to be associated with a lower incidence of late toxicity, this could be counterbalanced by the impact of a stoma on quality of life. These factors should be considered when determining the optimal management of resectable rectal cancers.

Aged↗
PubMed2003

External beam radiotherapy in the management of differentiated thyroid cancer.

AIMS: No randomised trials have addressed the use of external beam radiotherapy (EBRT) in the treatment of differentiated thyroid cancer. The indications for EBRT, the technique and recommended dose all remain controversial. MATERIALS AND METHODS: We included patients treated with EBRT with curative intent from two cancer centres between 1988 and 2001. Data were collected from hospital notes, radiotherapy prescriptions and local cancer registry. RESULTS: The indications for treatment in the 41 identified patients were macroscopic residual disease 23 (56%), microscopic residual disease 10 (25%), Hurthle cell variants 3 (7%), multiple lymph-node involvement 3 (7%) and other 2 (5%). Delivered doses ranged from 37.5-66 Gy over 3-6.5 weeks. Rate of local recurrence and overall survival at 5 years were as follows: papillary 26% and 67%; follicular 43% and 48%; well differentiated 21% and 67%; focus of poor differentiation/Hurthle cell variants 69% and 32%; complete excision 25% and 61%; residual disease 37% and 59%; EBRT total dose < 50 Gy 63% and 42%; 50-54 Gy 15% and 72%; > 54 Gy 18%, and 68%. CONCLUSIONS: The results in this study are consistent with previous retrospective studies of EBRT. The wide range of indications and doses used with radical intent highlights the lack of clinical and radiobiological data on the response of differentiated thyroid cancer to EBRT. Despite the small study size, the 5-year local recurrence results indicate a possible dose response within the dose range used.

Carcinoma, Papillary, Follicular↗
PubMed2003

Impaired postoperative neutrophil leucocytosis and acute complications following short course preoperative radiotherapy for operable rectal cancer.

AIM: Postoperative mortality following total mesorectal excision is increased if this is performed more than 3 days after the completion of short course preoperative radiotherapy. Suppression of neutrophil leucocytosis which is normally seen following surgery has been a suggested reason. This study was to determine the relationship between postoperative complications and perioperative neutrophil counts. METHOD: A database of 176 patients treated at a single radiotherapy centre in 1998 and 1999 was used. A two-sample Wilcoxon test was used to compare preoperative neutrophil counts, postoperative neutrophil counts and their ratio in patients with and without complications. RESULTS: There was no association between acute complications and preoperative (P = 0.25) or postoperative (P = 0.45) neutrophil count. The post/preoperative ratio was significantly higher in patients without complications (median 1.61 vs 1.16, P = 0.02). CONCLUSIONS: There appears to be an inverse relationship between the magnitude of postoperative neutrophil leucocytosis and the risk of acute complications following short course preoperative radiotherapy.

Acute Disease↗
PubMed2002

Retrospective study of acute toxicity following short-course preoperative radiotherapy.

BACKGROUND: The use of short-course preoperative radiotherapy (25 Gy in five fractions over 1 week) in resectable rectal cancer reduces local recurrence but is associated with an increased risk of postoperative complications and late toxicity. This study aimed to identify those patients who are unlikely to benefit from short-course preoperative radiotherapy and the factors associated with acute toxicity. METHODS: All patients who received short-course preoperative radiotherapy at a university hospital in 1998 and 1999 were included in this retrospective study. The association between complications occurring within 3 months and patient demographics, radiotherapy technique, surgical details and overall treatment time (OTT) was assessed by univariate and multivariate analysis. RESULTS: The mortality rate at 30 days was 6 per cent in the 177 patients identified. Thirty-seven per cent of patients had either Dukes' A tumours, surgically incurable disease or positive circumferential margins. One or more complications occurred in 38 per cent of patients. On multivariate analysis an OTT of more than 13 days (P = 0.03), age (P = 0.02) and length of the radiotherapy field (P = 0.05) were associated with an increased risk of complications. CONCLUSION: Surgery within 1 week of completing short-course preoperative radiotherapy improved preoperative staging and use of an optimal radiotherapy technique will result in fewer patients at risk of acute toxicity.

Acute Disease↗
PubMed2001

Nitrogen deposition to and cycling in a deciduous forest.

The project described here seeks to answer questions regarding the role increased nitrogen (N) deposition is playing in enhanced carbon (C) sequestration in temperate mid-latitude forests, using detailed measurements from an AmeriFlux tower in southern Indiana (Morgan-Monroe State Forest, or MMSF). The measurements indicate an average atmosphere-surface N flux of approximately 6 mg-N m(-2) day(-1) during the 2000 growing season, with approximately 40% coming from dry deposition of ammonia (NH3), nitric acid (HNO3), and particle-bound N. Wet deposition and throughfall measurements indicate significant canopy uptake of N (particularly NH4+) at the site, leading to a net canopy exchange (NCE) of -6 kg-N ha(-1) for the growing season. These data are used in combination with data on the aboveground C:N ratio, litterfall flux, and soil net N mineralization rates to indicate the level of potential perturbation of C sequestration at this site.

Ammonia↗
PubMed2001

The 1.2 A structure of a novel quorum-sensing protein, Bacillus subtilis LuxS.

In bacteria, the regulation of gene expression in response to changes in cell density is called quorum sensing. The autoinducer-2 production protein LuxS, is involved in a novel quorum-sensing system and is thought to catalyse the degradation of S-ribosylhomocysteine to homocysteine and the autoinducer molecule 4,5-dihydroxy-2,3-pentadione. The crystal structure of Bacillus subtilis LuxS has been determined at 1.2 A resolution, together with the binary complexes of LuxS with S-ribosylhomocysteine and homocysteine to 2.2 and 2.3 A resolution, respectively. These structures show that LuxS is a homodimer with an apparently novel fold based on an eight-stranded beta-barrel, flanked by six alpha-helices. Each active site contains a zinc ion coordinated by the conserved residues His54, His58 and Cys126, and includes residues from both subunits. S-ribosylhomocysteine binds in a deep pocket with the ribose moiety adjacent to the enzyme-bound zinc ion. Access to the active site appears to be restricted and possibly requires conformational changes in the protein involving the movement of residues 125-129 and those at the N terminus. The structure contains an oxidised cysteine residue in the active site whose role in the biological process of LuxS has not been determined. The autoinducer-2 signalling pathway has been linked to aspects of bacterial virulence and pathogenicity. The structural data on LuxS will provide opportunities for targeting this enzyme for the rational design of new antibiotics.

Amino Acid Sequence↗
PubMed2001

Cloning, purification, crystallization and preliminary crystallographic analysis of Bacillus subtilis LuxS.

LuxS of Bacillus subtilis is a member of a novel family of proteins with a potential role in quorum sensing, controlling important aspects of cellular physiology in a range of microbial species. B. subtilis luxS was cloned, expressed in Escherichia coli, purified and crystallized using the hanging-drop method of vapour diffusion with ammonium sulfate as the precipitant. The crystals belong to one of the enantiomorphic space groups P6(1)22 or P6(5)22, with approximate unit-cell parameters a = b = 63.6, c = 151.5 A and one subunit in the asymmetric unit, corresponding to a packing density of 2.5 A(3) Da(-1). The crystals diffract X-rays to at least 1.55 A resolution on a synchrotron-radiation source. Determination of the structure will provide insights into the key determinants of function of this class of proteins, for which no structures are currently available.

Bacillus subtilis↗
PubMed2001

Management of malignant phaeochromocytoma: a retrospective review of the use of MIBG and chemotherapy in the West Midlands.

Metastatic malignant phaeochromocytoma is a rare disorder, with no randomized and few prospective data to facilitate choice between the two main treatment modalities, chemotherapy and radiolabelled metaiodobenzylguanidine (MIBG). In the last decade the latter modality has been preferred and radiological response rates of 30% have been reported. There are fewer patients described in the literature who have received chemotherapy but one prospective trial of chemotherapy reported radiological response rates of 57%. A recent prospective trial combining the two modalities has been disappointing with only one patient completing the treatment schedule. We present six patients with malignant phaeochromocytoma or paraganglioma who received MIBG therapy. Four patients also received chemotherapy. A retrospective review of the case notes was performed. Radiological and hormonal responses were determined and the time to progression after each modality was calculated. One partial hormonal response was seen with MIBG treatment. One complete and one partial hormonal response and one partial radiological response were seen with chemotherapy. The median time to disease progression from commencement of MIBG was 12 months (range 3-44) and from commencement of chemotherapy used as first or second line treatment was 22.5 months (range 7-25). Chemotherapy may be a more active modality in this disease than previously considered. MIBG uptake may increase after a partial radiological response to chemotherapy, enabling subsequent MIBG therapy. Researchers carrying out future trials on combined therapy should consider administering chemotherapy prior to MIBG for the reasons that we outline in this article.

3-Iodobenzylguanidine↗
PubMed2000

Clear cell carcinoma of the fimbria of the fallopian tube in a BRCA1 carrier undergoing prophylactic surgery.

We report the case history of a patient with a family history of breast and ovarian cancer who was subsequently found to be a carrier of the BRCA1 gene, in whom a tiny focus of clear cell carcinoma was found at the fimbrial end of one fallopian tube when she underwent prophylactic hysterectomy and bilateral salpingoophorectomy. The implications of this finding are discussed.

Adenocarcinoma, Clear Cell↗
PubMed2000

Age differences in the frontal lateralization of verbal and spatial working memory revealed by PET.

Age-related decline in working memory figures prominently in theories of cognitive aging. However, the effects of aging on the neural substrate of working memory are largely unknown. Positron emission tomography (PET) was used to investigate verbal and spatial short-term storage (3 sec) in older and younger adults. Previous investigations with younger subjects performing these same tasks have revealed asymmetries in the lateral organization of verbal and spatial working memory. Using volume of interest (VOI) analyses that specifically compared activation at sites identified with working memory to their homologous twin in the opposite hemisphere, we show pronounced age differences in this organization, particularly in the frontal lobes: In younger adults, activation is predominantly left lateralized for verbal working memory, and right lateralized for spatial working memory, whereas older adults show a global pattern of anterior bilateral activation for both types of memory. Analyses of frontal subregions indicate that several underlying patterns contribute to global bilaterality in older adults: most notably, bilateral activation in areas associated with rehearsal, and paradoxical laterality in dorsolateral prefrontal sites (DLPFC; greater left activation for spatial and greater right activation for verbal). We consider several mechanisms that could account for these age differences including the possibility that bilateral activation reflects recruitment to compensate for neural decline.

Adult↗
PubMed2000

Age differences in behavior and PET activation reveal differences in interference resolution in verbal working memory.

Older adults were tested on a verbal working memory task that used the item-recognition paradigm. On some trials of this task, response-conflict was created by presenting test-items that were familiar but were not members of a current set of items stored in memory. These items required a negative response, but their familiarity biased subjects toward a positive response. Younger subjects show an interference effect on such trials, and this interference is accompanied by activation of a region of left lateral prefrontal cortex. However, there has been no evidence that the activation in this region is causally related to the interference that the subjects exhibit. In the present study, we demonstrate that older adults show more behavioral interference than younger subjects on this task, and they also show no reliable activation at the same lateral prefrontal site. This leads to the conclusion that this prefrontal site is functionally involved in mediating resolution among conflicting responses or among conflicting representations in working memory.

Aged↗