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1.
Bull Environ Contam Toxicol ; 112(1): 20, 2023 Dec 25.
Article in English | MEDLINE | ID: mdl-38145443

ABSTRACT

European oyster (Ostrea edulis) can be used for biological monitoring of water and sediment quality and serve as a conduit of trace elements to humans via consumption. Trace element concentrations in seawater, sediment, O. edulis edible tissues and shells from Boston Harbor were studied and found to be elevated relative to comparative studies in native ecosystems in the Adriatic Sea and Bay of Biscay. Average edible oyster tissues concentrations (mg/kg) were: arsenic 6, cadmium 1.7, cobalt 3.1, chromium 1.9, copper 153, mercury 0.265, nickel 1.8, lead 3.3, and zinc 2390. Arsenic was elevated in seawater and oyster shells. Mercury was elevated in sediments and oyster tissues. Lead was elevated in suspended sediments. Total Hazard Quotient (THQ) was < 1 but when summed across trace elements, THQ was nominally > 1 for all sites. Further study is warranted to determine mechanisms and spatial extent of bioaccumulation.


Subject(s)
Arsenic , Mercury , Ostrea , Trace Elements , Humans , Animals , Ecotoxicology , Ecosystem , Massachusetts , Seawater
2.
Data Brief ; 21: 1209-1215, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30456234

ABSTRACT

The data presented here consist of the locations of 839 roadkill points from four years (2012-2015) of roadkill surveys for small and medium-sized mammals (under 30 kg) from a four-lane highway in Quebec (Highway 175) during the months of May to October. Seventeen species or species groups were identified, all local to the area, and none of which were identified as species at risk, threatened, or endangered. The GPS coordinates of each roadkill event are given, along with the date, time of day (morning or evening), location (northbound or southbound lanes) and species (where possible). Within the surveyed road, 18 wildlife passages with 100 m fencing on each side of the passage entrances were built for small and medium-sized mammals. The GPS coordinates of the 18 passages and the end of each corresponding fence are also provided.

3.
Clin Cancer Res ; 24(19): 4643-4649, 2018 10 01.
Article in English | MEDLINE | ID: mdl-29941486

ABSTRACT

Purpose: Although antiangiogenic therapy for high-grade glioma (HGG) is promising, responses are not durable. Correlative clinical studies suggest that the SDF-1α/CXCR4 axis may mediate resistance to VEGFR inhibition. Preclinical data have demonstrated that plerixafor (a reversible CXCR4 inhibitor) could inhibit glioma progression after anti-VEGF pathway inhibition. We conducted a phase I study to determine the safety of plerixafor and bevacizumab in recurrent HGG.Patients and Methods: Part 1 enrolled 23 patients with a 3 × 3 dose escalation design to a maximum planned dose of plerixafor 320 µg/kg subcutaneously on days 1 to 21 and bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle. Cerebrospinal fluid (CSF) and plasma samples were obtained for pharmacokinetic analyses. Plasma and cellular biomarkers were evaluated before and after treatment. Part 2 enrolled 3 patients and was a surgical study to determine plerixafor's penetration in tumor tissue.Results: In Part 1, no dose-limiting toxicities were seen at the maximum planned dose of plerixafor + bevacizumab. Treatment was well tolerated. After plerixafor 320 µg/kg treatment, the average CSF drug concentration was 26.8 ± 19.6 ng/mL. Plerixafor concentration in resected tumor tissue from patients pretreated with plerixafor was 10 to 12 µg/g. Circulating biomarker data indicated that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF-1α and placental growth factor. Progression-free survival correlated with pretreatment plasma soluble mesenchymal-epithelial transition receptor and sVEGFR1, and overall survival with the change during treatment in CD34+ progenitor/stem cells and CD8 T cells.Conclusions: Plerixafor + bevacizumab was well tolerated in HGG patients. Plerixafor distributed to both the CSF and brain tumor tissue, and treatment was associated with biomarker changes consistent with VEGF and CXCR4 inhibition. Clin Cancer Res; 24(19); 4643-9. ©2018 AACR.


Subject(s)
Glioma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Receptors, CXCR4/antagonists & inhibitors , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Adult , Aged , Benzylamines , Bevacizumab/administration & dosage , Bevacizumab/pharmacokinetics , Biomarkers, Tumor/blood , Biomarkers, Tumor/cerebrospinal fluid , Cyclams , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic , Glioma/blood , Glioma/cerebrospinal fluid , Glioma/genetics , Hepatocyte Growth Factor/blood , Hepatocyte Growth Factor/cerebrospinal fluid , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/pharmacokinetics , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/cerebrospinal fluid , Neoplasm Recurrence, Local/genetics , Neoplastic Cells, Circulating/metabolism , Progression-Free Survival , Proto-Oncogene Proteins c-met/blood , Proto-Oncogene Proteins c-met/cerebrospinal fluid , Receptors, CXCR4/genetics , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/genetics
4.
Neuro Oncol ; 18(6): 849-54, 2016 06.
Article in English | MEDLINE | ID: mdl-26902850

ABSTRACT

BACKGROUND: Fatigue is common among glioma patients undergoing radiotherapy (RT) and impacts quality of life (QOL). We evaluated whether armodafinil, a wakefulness-promoting medication, improves fatigue in glioma patients undergoing RT. METHODS: Eligibility criteria included age ≥18 years, Karnofsky performance status ≥60, and grade 2-4 glioma undergoing RT to a total dose of 50-60 Gy. Patients were randomized 1:1 to armodafinil or placebo for 8 weeks beginning within 10 days of starting RT. Fatigue and QOL were assessed at baseline, day 22, day 43, and day 56 with the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F), the Functional Assessment of Cancer Therapy - General (FACT-G), the Brief Fatigue Inventory (BFI), and the Cancer Fatigue Scale (CFS). The primary aim was to detect a difference in the 42-day change in FACIT-F fatigue subscale between the 2 groups using a 2-sample Wilcoxon statistic. RESULTS: We enrolled 81 patients total (42 armodafinil and 39 placebo). Armodafinil did not significantly improve fatigue or QOL based on the 42-day change in FACIT-F fatigue subscale, FACT-G, CFS, or BFI. Further analysis suggests no difference between the arms even after accounting for the potential bias of missing data. Treatment was well tolerated with few grade 3 or 4 toxicities. CONCLUSIONS: While treatment was well-tolerated, an 8-week course of armodafinil did not improve fatigue or QOL in glioma patients undergoing RT in this pilot study. Further studies are needed to determine whether pharmacologic treatment improves fatigue in glioma patients undergoing RT.


Subject(s)
Benzhydryl Compounds/therapeutic use , Fatigue/drug therapy , Glioma/radiotherapy , Wakefulness-Promoting Agents/therapeutic use , Adult , Aged , Aged, 80 and over , Double-Blind Method , Fatigue/etiology , Female , Humans , Male , Middle Aged , Modafinil , Pilot Projects , Radiotherapy/adverse effects , Treatment Outcome
5.
Ann Plast Surg ; 76(6): 640-4, 2016 Jun.
Article in English | MEDLINE | ID: mdl-25003439

ABSTRACT

BACKGROUND: Although breast reconstruction has been shown to improve psychological, physical, and sexual well-being, Australia still has one of the lowest reconstruction rates among well-developed countries. This study explores both the quality-of-life benefits of reconstruction and the factors that influence patients' decisions of whether or not to undergo reconstruction. METHODS: This retrospective cohort study (296 consecutive mastectomy patients from 2000 to 2010) uses an internationally validated questionnaire (BREAST-Q) to evaluate patients' satisfaction with or without breast reconstruction. In addition, we analyzed factors that influence patients' decisions of whether to undergo reconstruction. RESULTS: Two hundred nineteen patients responded (74%) and of the 143 patients who elected to participate, 79 were in the "reconstruction group" and 64 in the "no-reconstruction group" post mastectomy. Patient demographics and cancer variables of the 2 groups were matched with the exception of age (reconstruction group 9.7 years younger: P < 0.01). The reconstruction group showed statistically significantly higher BREAST-Q scores with regard to satisfaction with the breast (P < 0.0001), psychological well-being (P = 0.0068), and sexual well-being (P = 0.0001). For the reconstruction group, the main reasons for undergoing reconstruction included improved self-image, more clothing choices, and the feeling of overcoming the cancer. One third of non-reconstructed patients still feared that reconstruction would mask cancer recurrence. CONCLUSION: Our study confirms the positive effects of breast reconstruction post mastectomy and identifies reasons that influence patients' decisions of whether to undergo reconstruction. Breast reconstruction should be seen as an integral part in the comprehensive care of women with breast cancer and an important health care priority in Australia.


Subject(s)
Decision Making , Mammaplasty/psychology , Mastectomy , Patient Acceptance of Health Care/psychology , Patient Satisfaction/statistics & numerical data , Quality of Life , Adult , Aged , Aged, 80 and over , Australia , Female , Humans , Middle Aged , Patient Reported Outcome Measures , Retrospective Studies
6.
J Med Chem ; 58(22): 9027-40, 2015 Nov 25.
Article in English | MEDLINE | ID: mdl-26524606

ABSTRACT

Both orthosteric and allosteric antagonists of the group II metabotropic glutamate receptors (mGlus) have been used to establish a link between mGlu2/3 inhibition and a variety of CNS diseases and disorders. Though these tools typically have good selectivity for mGlu2/3 versus the remaining six members of the mGlu family, compounds that are selective for only one of the individual group II mGlus have proved elusive. Herein we report on the discovery of a potent and highly selective mGlu2 negative allosteric modulator 58 (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides. The concept for the design of this series centered on morphing a quinoline series recently disclosed in the patent literature into a chemotype previously used for the preparation of muscarinic acetylcholine receptor subtype 1 positive allosteric modulators. Compound 58 exhibits a favorable profile and will be a useful tool for understanding the biological implications of selective inhibition of mGlu2 in the CNS.


Subject(s)
Quinolones/chemical synthesis , Quinolones/pharmacology , Receptors, Metabotropic Glutamate/drug effects , Animals , Central Nervous System/drug effects , Drug Discovery , Mice , Protein Binding , Quinolines/chemical synthesis , Quinolines/pharmacology , Quinolones/pharmacokinetics , Rats , Receptor, Muscarinic M1/antagonists & inhibitors , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Structure-Activity Relationship
7.
Article in English | MEDLINE | ID: mdl-26125528

ABSTRACT

Levels of arsenic in Australian and imported rice (n = 36) were evaluated using inductively coupled plasma mass spectrometry (ICP-MS) for total arsenic and a hyphenated high-performance liquid chromatography ICP-MS system for arsenic species. The study also assessed the daily intake of total As from diets of healthy children (n = 15), collected over three consecutive days. A wide variation of total As levels (range: <0.05-0.42 mg/kg) in Australian and imported rice was found. The mean level of total As (0.24 ± 0.09 mg/kg, n = 10) in the Australian rice was relatively higher than imported rice from other countries (0.09 ± 0.04 mg/kg, n = 26). The mean level (0.25 ± 0.08 mg/kg, n = 7) of dimethylarsenic acid was considerably higher than that of inorganic As (III) (0.07 ± 0.03 mg/kg, n = 7) in the Australian rice. Children's daily intakes of total As varied widely, ranging from 1.7 to 31.2 (11.5 ± 8.9 µg/day), which was comparable to other countries.


Subject(s)
Arsenic/analysis , Food Contamination/analysis , Oryza/chemistry , Australia , Cacodylic Acid/analysis , Child , Chromatography, High Pressure Liquid , Diet , Eating , Humans , Mass Spectrometry
8.
Clin Cancer Res ; 21(16): 3610-8, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-25910950

ABSTRACT

PURPOSE: Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). EXPERIMENTAL DESIGN: We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis. RESULTS: The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0-22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9-20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75). CONCLUSIONS: The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study.


Subject(s)
Dacarbazine/analogs & derivatives , Glioblastoma/drug therapy , Glioblastoma/radiotherapy , Piperidines/administration & dosage , Quinazolines/administration & dosage , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Dacarbazine/administration & dosage , Dacarbazine/adverse effects , Disease-Free Survival , Female , Glioblastoma/blood , Glioblastoma/pathology , Humans , Kaplan-Meier Estimate , Karnofsky Performance Status , Male , Middle Aged , Piperidines/adverse effects , Quinazolines/adverse effects , Temozolomide , Treatment Outcome
9.
Neuro Oncol ; 17(6): 862-7, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25572329

ABSTRACT

BACKGROUND: Panobinostat is a histone deacetylase inhibitor with antineoplastic and antiangiogenic effects in glioma that may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat combined with bevacizumab in patients with recurrent high-grade glioma (HGG). METHODS: Patients with recurrent HGG were treated with oral panobinostat 30 mg 3 times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was a 6-month progression-fee survival (PFS6) rate for participants with recurrent glioblastoma (GBM). Patients with recurrent anaplastic glioma (AG) were evaluated as an exploratory arm of the study. RESULTS: At interim analysis, the GBM arm did not meet criteria for continued accrual, and the GBM arm was closed. A total of 24 patients with GBM were accrued prior to closure. The PFS6 rate was 30.4% (95%, CI 12.4%-50.7%), median PFS was 5 months (range, 3-9 months), and median overall survival (OS) was 9 months (range, 6-19 months). Accrual in the AG arm continued to completion, and a total of 15 patients were enrolled. The PFS6 rate was 46.7% (range, 21%-73%), median PFS was 7 months (range, 2-10 months), and median OS was 17 months (range, 5 months-27 months). CONCLUSIONS: This phase II study of panobinostat and bevacizumab in participants with recurrent GBM did not meet criteria for continued accrual, and the GBM cohort of the study was closed. Although it was reasonably well tolerated, the addition of panobinostat to bevacizumab did not significantly improve PFS6 compared with historical controls of bevacizumab monotherapy in either cohort.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Bevacizumab/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Hydroxamic Acids/therapeutic use , Indoles/therapeutic use , Adult , Aged , Brain Neoplasms/mortality , Disease-Free Survival , Drug Therapy, Combination , Female , Glioblastoma/mortality , Histone Deacetylase Inhibitors/therapeutic use , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Panobinostat , Treatment Outcome , Young Adult
10.
J Neurooncol ; 121(2): 297-302, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25338318

ABSTRACT

Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanib is an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/ß, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to anti-VEGF therapy. This was a two-stage phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab therapy (ClinicalTrials.gov number NCT01380782; 1199.94). The primary endpoint was PFS6 in the bevacizumab-naive arm (Arm A) and PFS3 in the post-bevacizumab arm (Arm B). Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Twenty-two patients enrolled in Arm A and 14 in Arm B. Arm A included 12 GBMs (55 %), 13 patients with one prior regimen (59 %), and median age 54 years (range 28-75). Arm B included 10 GBMs (71 %), one patient with one prior regimen (7 %), and median age 52 years (range 32-70). Median KPS overall was 90 (range 60-100). There were no responses. In Arm A (GBM only), PFS6 was 0 %, median PFS 28 days (95 % CI 27-83), and median OS 6.9 months (3.7-8.1). In Arm B (GBM only), PFS3 was 0 %, median PFS 28 days (22-28), and median OS 2.6 months (1.0-6.9). Among AG patients in each arm, PFS6 was 0 %. Treatment was well tolerated. In conclusion, nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Glioma/drug therapy , Indoles/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/adverse effects , Bevacizumab , Cohort Studies , Female , Glioma/pathology , Humans , Indoles/adverse effects , Kaplan-Meier Estimate , Karnofsky Performance Status , Male , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/pathology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Treatment Outcome
11.
Neurology ; 84(3): 280-6, 2015 Jan 20.
Article in English | MEDLINE | ID: mdl-25527270

ABSTRACT

OBJECTIVE: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective. METHODS: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B). RESULTS: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8-20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12-43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor-1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival. CONCLUSIONS: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Meningeal Neoplasms/drug therapy , Meningioma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Somatostatin/analogs & derivatives , Adult , Aged , Aged, 80 and over , Cohort Studies , Disease-Free Survival , Female , Humans , Insulin-Like Growth Factor I/metabolism , Male , Middle Aged , Receptors, Somatostatin/metabolism , Somatostatin/therapeutic use
12.
ANZ J Surg ; 85(9): 639-43, 2015 Sep.
Article in English | MEDLINE | ID: mdl-24438029

ABSTRACT

BACKGROUND: Percutaneous needle fasciotomy (PNF) is a minimally invasive technique used to manage Dupuytren's contracture. We compared outcomes of PNF versus open fasciectomy (OF) to examine the suitability of PNF in Australia. METHOD: A retrospective cohort study using two questionnaires regarding Dupuytren's treatment was used to assess patients with uncomplicated primary disease. The primary outcomes were immediate and medium-term correction of contracture (2-year mean follow-up to time of survey). Secondary outcomes were patient satisfaction and complications including tendon/nerve injury, infection, skin necrosis and vascular damage. RESULTS: One hundred fifty-five out of 191 surveys were returned (81%). The final analysis included 125 cases (65%), 73 PNF and 52 OF. No significant differences were observed between both groups with regards to follow-up time, gender, smoking status, co-morbidities or preoperative deformity grade. No significant differences were observed in terms of immediate or medium-term deformity correction, tendon/nerve injury or circulatory complications. The postoperative infection rate was higher with OF, with these patients 7.57 (95% confidence interval 1.56, 36.77; P = 0.01) times as likely to have a postoperative infection as patients undergoing PNF. A higher number of patients who underwent PNF were told that they would require another operation (30% versus 12%; P = 0.02). Satisfaction scores were similar (OF 33.2 versus PNF 32.6; P = 0.82). CONCLUSION: The OF and PNF procedures provide comparable deformity correction for uncomplicated primary Dupuytren's disease in the immediate perioperative period. The reduced side effect profile of PNF should prompt surgeons to consider incorporating it in their practice for the first-line management of uncomplicated primary Dupuytren's disease.


Subject(s)
Dupuytren Contracture/surgery , Fasciotomy , Needles , Orthopedic Procedures/instrumentation , Patient Satisfaction , Aged , Dupuytren Contracture/physiopathology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Recovery of Function , Retrospective Studies , Surveys and Questionnaires , Time Factors , Treatment Outcome
13.
Biomed Res Int ; 2014: 347616, 2014.
Article in English | MEDLINE | ID: mdl-24949435

ABSTRACT

DMSO is used as a treatment for interstitial cystitis and this study examined the effects of luminal DMSO treatment on bladder function and histology. Porcine bladder was incubated without (controls) or with DMSO (50%) applied to the luminal surface and the release of ATP, acetylcholine, and LDH assessed during incubation and in tissues strips after DMSO incubation. Luminally applied DMSO caused ATP, Ach, and LDH release from the urothelial surface during treatment, with loss of urothelial layers also evident histologically. In strips of urothelium/lamina propria from DMSO pretreated bladders the release of both ATP and Ach was depressed, while contractile responses to carbachol were enhanced. Detrusor muscle contractile responses to carbachol were not affected by DMSO pretreatment, but neurogenic responses to electrical field stimulation were enhanced. The presence of an intact urothelium/lamina propria inhibited detrusor contraction to carbachol by 53% and this inhibition was significantly reduced in DMSO pretreated tissues. Detection of LDH in the treatment medium suggests that DMSO permeabilised urothelial membranes causing leakage of cytosolic contents including ATP and Ach rather than enhancing release of these mediators. The increase in contractile response and high levels of ATP are consistent with initial flare up in IC/PBS symptoms after DMSO treatment.


Subject(s)
Dimethyl Sulfoxide/administration & dosage , Mucous Membrane/physiology , Urinary Bladder/drug effects , Urothelium/drug effects , Acetylcholine/metabolism , Adenosine Triphosphate/metabolism , Animals , Cystitis, Interstitial/drug therapy , Cystitis, Interstitial/pathology , Humans , L-Lactate Dehydrogenase/metabolism , Mucous Membrane/drug effects , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Swine
14.
J Med Chem ; 56(12): 5208-12, 2013 Jun 27.
Article in English | MEDLINE | ID: mdl-23718281

ABSTRACT

A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu3 NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 µM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.


Subject(s)
Brain/metabolism , Drug Discovery , Piperidines/metabolism , Piperidines/pharmacology , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation/drug effects , Animals , Brain/drug effects , Humans , Inhibitory Concentration 50 , Mice , Piperidines/chemistry , Piperidines/pharmacokinetics , Rats , Substrate Specificity
15.
Neuro Oncol ; 15(7): 930-5, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23553268

ABSTRACT

BACKGROUND: Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O(6)-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance. METHODS: This was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m(2)/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6). RESULTS: Fifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25-79 years) and a median Karnofsky performance score of 90 (range, 60-100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2). CONCLUSIONS: Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.


Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/drug therapy , DNA Methylation/drug effects , Dacarbazine/analogs & derivatives , Glioblastoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adaptor Proteins, Signal Transducing/metabolism , Adult , Aged , Biomarkers, Tumor/genetics , Brain Neoplasms/mortality , Brain Neoplasms/secondary , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Dacarbazine/therapeutic use , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Glioblastoma/mortality , Glioblastoma/pathology , Humans , Immunoenzyme Techniques , Male , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein/metabolism , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Nuclear Proteins/metabolism , Prognosis , Promoter Regions, Genetic/genetics , Real-Time Polymerase Chain Reaction , Survival Rate , Temozolomide , Tumor Suppressor Proteins/genetics
16.
J Shoulder Elbow Surg ; 22(7): e24-9, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23352186

ABSTRACT

BACKGROUND: The etiology of idiopathic adhesive capsulitis (IAC) of the shoulder is poorly understood. In this case control study, we examine potential risk factors for the development of IAC. METHODS: Consecutive patients who presented to the senior author with IAC between 2000 and 2009 were included retrospectively in this case control study. Complete data were available for 87 patients. An age- and sex-matched group of 176 patients who presented to the same practice during the same time period with non-shoulder related orthopedic complaints were recruited as the control group. Health records and patient-completed questionnaires were utilized to identify comorbidities and other risk factors. RESULTS: Bivariate analyses demonstrated that diabetes, hypothyroidism, a lower body weight, a lower body mass index (BMI), and a positive family history of IAC were all risk factors for IAC. Diabetes, BMI, and positive family history of IAC remained independent variables with multivariate logistic regression analyses. There was a trend towards increased incidence of Dupuytren's disease in those with IAC, but this was not statistically significant. With regard to racial predilection, being born in the British Isles or having parents/grandparents born in the British Isles were risk factors for IAC. CONCLUSION: We confirm diabetes as an independent predictor of IAC. In addition, we identify a possible racial predilection for the development of IAC. Future research is needed to confirm whether a specific genetic component or environmental factors is responsible.


Subject(s)
Body Mass Index , Bursitis/etiology , Diabetes Mellitus/diagnosis , Shoulder Joint/physiopathology , Age Distribution , Aged , Bursitis/physiopathology , Case-Control Studies , Diabetes Mellitus/epidemiology , Female , Follow-Up Studies , Humans , Incidence , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Reference Values , Retrospective Studies , Risk Assessment , Severity of Illness Index , Sex Distribution , Shoulder Pain/diagnosis , Shoulder Pain/etiology , Statistics, Nonparametric
17.
Aust Health Rev ; 35(4): 399-403, 2011 Nov.
Article in English | MEDLINE | ID: mdl-22126940

ABSTRACT

Elective surgery waiting list management is a major public healthcare issue. This case study describes an integrated multifaceted approach to waiting list management at Peninsula Health, a public health service in Victoria, Australia. At the commencement of this study it was recognised that several issues associated with the urological surgical service constituted potential clinical risk. These included: recall mechanisms for multiple surveillance procedures; significant resource deficits; and long surgery waiting times. Responding to these issues a multifaceted approach to wait list management was implemented including: audit; direct lines of communication between clinical and administrative staff; urgent caseload management; utilisation of the Elective Surgery Access Scheme; financial and resource analysis justifying the appointment of a full-time urologist, and the establishment of a urology service from a satellite campus; implementation of a recall database; development of an outpatient service; and commencement of a day surgery initiative. This approach yielded results that included a 67% reduction in the number of 'ready for care' patients and a 78% reduction in the number of patients classified as 'overdue for surgery'. Average wait time for semi-urgent and non-urgent patients reduced from 248 days to 180 days in the 10-month period.


Subject(s)
Efficiency, Organizational , Elective Surgical Procedures , Urologic Surgical Procedures , Waiting Lists , Humans , Organizational Case Studies , Victoria
18.
Mar Pollut Bull ; 60(9): 1615-8, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20633905

ABSTRACT

The consumption of fish and shrimp containing omega-3 fatty acids can result in protective health effects including a reduced risk of cardiovascular disease, stroke, and diabetes. These protective effects may be decreased by the presence of mercury in the muscle tissue of fish and shellfish. Mercury can increase the risk of cardiovascular problems and impede neurological development. The objective of this project was to determine appropriate consumption amounts of selected fish species and shrimp based on mercury levels and recommended intake levels of omega-3 fatty acids. Species that are high in omega-3s and low in mercury include salmon, trout, and shrimp. Species with both high levels of mercury and omega-3 fatty acids include tuna, shark, and halibut, swordfish, and sea bass.


Subject(s)
Fatty Acids, Omega-3/analysis , Fishes/metabolism , Food Contamination/analysis , Mercury/analysis , Penaeidae/chemistry , Animals , Humans , Species Specificity
19.
Br J Oral Maxillofac Surg ; 48(1): 11-7, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19481316

ABSTRACT

The complex associations between socioeconomic circumstances and risk for head and neck cancer are under-explored. We investigated components of social class and their relative influence on the risk of head and neck cancers by studying 103 patients (age range 24-80 years) who had been diagnosed with cancer of the head and neck between April 2002 and December 2004, and 91 controls who were randomly selected from general practitioners' lists. Information about occupation, education, smoking, and alcohol consumption was collected at personal interview. Socioeconomic circumstances were measured at an individual level (education, occupational social class, unemployment), and by area-based measures of deprivation. Odds ratios (OR) and 95% confidence intervals (CI) were computed using unconditional logistic regression and multivariate analyses. People living in the most deprived areas (OR=4.66, 95% CI 1.79-12.18); and those who were unemployed (OR=2.27, 95% CI 1.21-4.26) had a significantly higher risk of cancer than those with high levels of educational attainment (OR=0.17, 95% CI 0.05-0.58). Significance was lost for all measures of social class when adjustments were made for smoking and consumption of alcohol. Smoking was the only significant risk factor (OR=15.53, 95% CI 5.36-44.99) in the multivariate analysis. A high risk of head and neck cancer was consistently associated with poor socioeconomic circumstances, and there were strong links for specific components however smoking dominated the overall profile of risk. We propose a framework for future socioeconomic analyses.


Subject(s)
Head and Neck Neoplasms/epidemiology , Social Class , Adult , Aged , Aged, 80 and over , Alcohol Drinking/epidemiology , Case-Control Studies , Cultural Deprivation , Educational Status , Feeding Behavior , Female , Humans , Male , Middle Aged , Occupations/statistics & numerical data , Population Surveillance , Risk Assessment , Risk Factors , Scotland/epidemiology , Smoking/epidemiology , Socioeconomic Factors , Unemployment/statistics & numerical data , Young Adult
20.
J Clin Epidemiol ; 61(11): 1187-93, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18619798

ABSTRACT

OBJECTIVE: We aimed to investigate the association between socioeconomic factors and selection and participation biases in a population-based case-control study of head and neck cancer conducted in the city of Glasgow, UK. METHODS: General Practices (GP) of the case subjects were the sampling frame from which age and sex-matched controls were randomly selected. Participant and nonparticipant postcodes of cases and controls were linked to the area-based Scottish Index of Multiple Deprivation. Comparisons of study selection and participation were made with the Glasgow study-base population. RESULTS: Cases were from significantly more deprived areas than controls. Overall, participation was low for both cases (34.9%) and controls (34.7%). Our overall control sample was not similar to the general population of Glasgow having "over selected" from deprived areas. Individuals from more affluent areas were more likely to participate providing a set of interviewed participants reflecting the socioeconomic distribution of Glasgow. CONCLUSIONS: Low participation rates in case-control studies remain a problem and socioeconomic factors strongly affect participation. A control sample selection biased in one direction was offset by participation bias in the opposite direction -- fortuitously providing a representative control sample. Selecting controls from case GP lists needs to be implemented with care with attention paid to obtaining evidence on the underlying socioeconomic characteristics of GP populations, especially for diseases with a skewed socioeconomic distribution.


Subject(s)
Head and Neck Neoplasms/epidemiology , Patient Selection , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Head and Neck Neoplasms/etiology , Humans , Middle Aged , Poverty Areas , Scotland/epidemiology , Selection Bias , Socioeconomic Factors , Young Adult
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