Altered nociception and morphine tolerance in neuropeptide FF receptor type 2 over-expressing mice.

BACKGROUND: The neuropeptide FF system is thought to act as an anti-opioid modulator and plays a role in nociception, morphine antinociception and dependence. Two receptor subtypes, NPFFR1 and NPFFR2, have been identified, but their respective roles in these processes remain uncertain. METHODS: In the present study, the role of NPFFR2 was investigated using transgenic mice over-expressing NPFFR2 in addition to a NPFFR2 agonist AC-263093. RESULTS: NPFFR2 Tg mice exhibited increased sensitivity to both mechanical and thermal noxious stimuli compared to the WT mice, while the antinociceptive effects of morphine at three different doses (6.25, 12.5 and 25 mg/kg, s.c.) were similar in both strains. The development of tolerance to morphine antinociception after chronic morphine treatment (12.5 mg/kg, s.c.; twice daily × 5 days) was attenuated in NPFFR2 Tg mice when compared to WT mice. Similarly, WT mice receiving AC-263093 pretreatment (2.5 mg/kg, i.p.) showed attenuated morphine tolerance compared to vehicle controls. Most naloxone-precipitated morphine withdrawal symptoms were not attenuated in NPFFR2 Tg mice, with the exception of wet dog shake that was significantly reduced. Both NPFFR2 Tg and WT mice displayed similar degree of morphine rewarding. CONCLUSIONS: Our results suggest that neuropeptide FF R2 is mainly involved in the modulation of nociception and tolerance to morphine antinociception.

Assessment of autonomic nervous system by using empirical mode decomposition-based reflection wave analysis during non-stationary conditions.

Arterial blood pressure (ABP) is an important indicator of cardiovascular circulation and presents various intrinsic regulations. It has been found that the intrinsic characteristics of blood vessels can be assessed quantitatively by ABP analysis (called reflection wave analysis (RWA)), but conventional RWA is insufficient for assessment during non-stationary conditions, such as the Valsalva maneuver. Recently, a novel adaptive method called empirical mode decomposition (EMD) was proposed for non-stationary data analysis. This study proposed a RWA algorithm based on EMD (EMD-RWA). A total of 51 subjects participated in this study, including 39 healthy subjects and 12 patients with autonomic nervous system (ANS) dysfunction. The results showed that EMD-RWA provided a reliable estimation of reflection time in baseline and head-up tilt (HUT). Moreover, the estimated reflection time is able to assess the ANS function non-invasively, both in normal, healthy subjects and in the patients with ANS dysfunction. EMD-RWA provides a new approach for reflection time estimation in non-stationary conditions, and also helps with non-invasive ANS assessment.

Patterns of care for malignant pleural mesothelioma patients compensated by the Dust Diseases Board in New South Wales, Australia.

BACKGROUND: The silent epidemic of mesothelioma in Australia is steadily increasing, and 30% of cases occur in New South Wales (NSW). AIM: To describe the patterns of care and outcomes of patients with malignant pleural mesothelioma (MPM) in NSW. METHODS: MPM patients in NSW applying for compensation at the NSW Dust Diseases Board from 2007 to 2009 were included. Survival from time of diagnosis was determined by the Kaplan-Meier method. The Chi-squared test was used to determine if there was an association between utilisation of treatment and geographical location. RESULTS: A total of 138 patients was included: median age was 72.5; 91.3% male; 60.1% epithelial subtype; and 65.2% lived in major cities. All patients had at least one chest X-ray and computed tomography scan, and 21% had a positron emission tomography scan; 93.5% and 4.3% had histological or cytological confirmation respectively. Thoracoscopy (59.4%) was the most commonly used diagnostic procedure. Treatment utilisation: 53.6% chemotherapy; 35.5% radiotherapy; 9.4% extrapleural pneumonectomy (EPP); and 72.5% had palliative care involvement. There were no major differences in treatment utilisation between patients living in major cities and those in regional NSW (chemotherapy P = 0.42; radiotherapy P = 0.13 and palliative care P = 0.60), except for a higher rate of EPP in regional patients (16.7% vs 5.6%; P = 0.03). Median survival was 9.7 versus 12.3 months for city and regional patients respectively (P = 0.22). CONCLUSION: Survival and treatment utilisation was not significantly different between MPM patients living in major cities and regional NSW, except for a higher rate of EPP in patients in regional NSW.

The eligibility of advanced non-small-cell lung cancer patients for targeted therapy clinical trials.

BACKGROUND: The selection criteria for phase III trials are often stringent. We aimed to determine how many advanced non-small-cell lung cancer (NSCLC) patients would have been eligible for phase III targeted therapy trials and the proportion receiving anticancer treatment. PATIENTS AND METHODS: From March 2007 to May 2008, all advanced NSCLC patients presented at our lung cancer multidisciplinary team meeting were included to assess eligibility for the targeted therapy trials: ECOG-4599, AVAiL, FLEX, TALENT, INTACT-1, INTACT-2, ESCAPE, NEXUS and MONET1. Medical records were examined to determine treatment utilisation and overall survival. RESULTS: A total of 62 patients were registered: 63% male; median age 71 years; 61% stage IIIB disease. Percentages that met criteria were: ECOG-4599 31%, AVAiL 24%, FLEX 69%, TALENT 27%, INTACT-1 50%, INTACT-2 42%, ESCAPE 39%, NEXUS 63% and MONET1 34%. Common reasons for ineligibility were insufficient life expectancy, poor performance status, abnormal bloods, proteinuria and associated cancer problems. Systemic therapies were received by 66% of patients and median survival was 10.3 months. CONCLUSION: Only 24%-69% were eligible for targeted therapy trials but 66% received anticancer treatment. Clinical trials in patients with advanced NSCLC need to be more representative of the majority of patients.

Second-line therapy for castrate-resistant prostate cancer: a literature review.

Despite a survival benefit in the first-line treatment of castrate-resistant prostate cancer (CRPC) with docetaxel, the prognosis remains limited. There are increasing options available for patients with CRPC in the second-line setting, but there is currently little consensus regarding the optimal treatment. There have been numerous phase II and retrospective studies examining second-line options in CRPC, including retreatment with docetaxel, mitoxantrone, cyclophosphamide and carboplatin, which can be associated with meaningful responses in a significant minority of patients. In 2010 three randomized trials were published or presented which demonstrated a survival benefit in the second-line setting. These included cabazitaxel compared with mitoxantrone, sipuleucel-T (immunotherapy) and abiraterone acetate versus placebo. Ongoing research in the second-line setting of CRPC to optimize treatment options, with the objectives of survival prolongation, improvement in quality of life and pain management, is still needed.

Malignant mesothelioma.

Malignant mesothelioma (MM) is an aggressive tumour that commonly affects the mesothelial surfaces of the pleural and peritoneal cavities, and occasionally, the tunica vaginalis and the pericardium. Formerly a rare tumour, MM is increasing in incidence in Australia due to the heavy nationwide use of asbestos from 1940 until the 1980s. The incidence is expected to peak in Australia in the next decade, mirroring the long latency period between asbestos exposure and development of MM. Diagnosis of MM can be difficult. Definitive pathological diagnosis is required and it often requires an experienced pathologist to differentiate MM from other benign or malignant processes. Treatment of MM requires a multidisciplinary approach, regardless of palliative or curative intent. Treatment options, such as surgery, chemotherapy, radiotherapy and active symptom control or a combination of these, may be used. Further research is needed to advance the therapeutic options for MM, and strategies to realize personalisation of therapy through discovery of predictive markers. In the Australian society where asbestos contamination of the built environment is very high, education and stringent public health measures are required to prevent a second wave of increased MM incidence.

Increased oxidative DNA damage, lipid peroxidation, and reactive oxygen species in cultured orbital fibroblasts from patients with Graves' ophthalmopathy: evidence that oxidative stress has a role in this disorder.

PURPOSE: We investigated the oxidative stress in orbital fibroadipose tissues and cultured orbital fibroblasts from patients with Graves' ophthalmopathy (GO). METHODS: The content of 8-hydroxy 2'-deoxyguanosine (8-OHdG), an important biomarker of oxidative DNA damage, was measured in orbital fibroadipose tissues and cultured orbital fibroblasts from patients with GO and compared with age-matched normal controls. A product of lipid peroxidation, malondialdehyde (MDA), and intracellular reactive oxygen species (ROS) in cultured orbital fibroblasts was also determined. RESULTS: There was no significant difference in the 8-OHdG content of orbital fibroadipose tissues between patients with GO and age-matched normal controls (P=0.074). However, the levels of 8-OHdG and MDA in GO orbital fibroblasts were significantly higher than those of normal controls (P=0.0026 and P<0.001, respectively). In addition, GO orbital fibroblasts had higher contents of superoxide anions and hydrogen peroxide compared with those of normal controls (P=0.0133 and 0.0025, respectively). CONCLUSIONS: Orbital fibroblasts represent the most abundant cell type among orbital connective tissues and exhibit great differences in their phenotypes. Increased oxidative DNA damage and lipid peroxidation, as well as higher intracellular ROS levels in GO orbital fibroblasts may have a role in the pathogenesis of GO.

Predictive markers for haematological toxicity of pemetrexed.

Pemetrexed is a multi-targeted anti metabolite that inhibits several key folate-dependent enzymes in the thymidine and purine biosynthetic pathways, including thymidylate synthase. It is currently approved for use in patients with non-small cell lung cancer and malignant mesothelioma. The sporadic and unpredictable occurrence of haematological toxicities of pemetrexed leading to potentially life threatening complications during the early developmental phase, prompted urgent need to identify potential predictive factors for haematological toxicities from pemetrexed. There is a well established association between elevated plasma homocysteine concentration, which is indicative of impaired functional folate status, and increased risk of haematological toxicity from pemetrexed. The decrease in incidence of toxicity after vitamin supplementation confirms the importance of functional folate status as a predictor for haematological toxicity. We review other factors that have a documented impact on haematological toxicity, including pemetrexed schedule, and pharmacokinetic parameters that are indicative of the extent of drug exposure. Further potential factors are explored in this review, such as the genotype of the pemetrexed metabolising enzymes and varying incidences of polymorphism of these genotypes in different ethnic groups that may account for the ethnic differences in neutropenic response to pemetrexed.

Oxidative stress in patients with Graves' ophthalmopathy: relationship between oxidative DNA damage and clinical evolution.

PURPOSE: To evaluate the relationship between oxidative stress and clinical evolution in patients with Graves' ophthalmopathy (GO). METHODS: Thirty-one euthyroid GO patients and 25 healthy subjects participated in this study. Oxidative DNA damage was assessed by determination of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) level in urine by ELISA. The relationship of oxidative DNA damage to the clinical evolutions of GO, especially the smoking status, clinical activity scores (CAS), and ophthalmopathy index was examined. RESULTS: The mean 8-OHdG was significantly higher in GO patients than that of normal controls (12.6+/-5.7 vs 6.7+/-2.5 ng/mg creatinine, P<0.001). Smokers had significant higher 8-OHdG than did never smokers in GO patients (P=0.029), but not in healthy controls (P=0.374). Among GO patients, only CAS remained significantly correlated with 8-OHdG (P=0.001) after adjusting for age, sex, disease duration, the status of antithyroid drug and smoking, and thyroid-stimulating hormone level. Patients with active GO (CAS>3) had higher 8-OHdG than did the patients with CAS

Exophthalmos of patients with Graves' disease in Chinese of Taiwan.

PURPOSE: To determine the exophthalmos measurements in patients with Graves' disease (GD) and to compare with those of normal subjects among the Chinese of Taiwan. METHODS: Hertel's exophthalmometry were performed in 163 consecutive adult GD patients and 419 normal subjects. The values of exophthalmos, asymmetry, and the distance between lateral orbital rims (base) were evaluated. RESULTS: There was a significant difference between GD and normal adults for exophthalmos and asymmetry, with GD patients demonstrating a mean exophthalmos of 18.32 mm and asymmetry of 0.93 mm as compared with 13.91 and 0.55 mm for normal subjects (P<0.001). The mean value of base for GD adults (106.52 mm) is slightly greater than normal subjects (105.82 mm). There was no gender difference in exophthalmometric value or asymmetry in each group. A total of 79 (48.5%) GD patients had exophthalmos greater than the upper limit of normal Chinese in Taiwan (18.6 mm). Asymmetry over 2 mm was observed in 11 (6.7%) patients with GD but in none of the normal subjects. CONCLUSIONS: GD patients have significant exophthalmos and asymmetry compared to normal subjects. In comparison with previous studies, exophthalmos values for Chinese in Taiwan tend to be lower than those of Caucasians and black-American people, but are close to those of Korean, Japanese, Iranian, Indian, and Asian-American people. Adequate adjustment of normal and abnormal values of exophthalmos according to individual differences is important for the diagnosis of orbital morbidity and management of thyroid associated orbitopathy.

Pulsatile ocular blood flow change after treatment with systemic steroid in patients with Graves' ophthalmopathy.

PURPOSE: Our previous study has demonstrated an impairment of pulsatile ocular blood flow (POBF) in patients with Graves'ophthalmopathy (GO). Here we further evaluate the haemodynamic change in GO patients after systemic steroid. METHODS: In a prospective, interventional, consecutive clinical case series, all patients with active and moderately severe GO who underwent systemic steroid treatment were evaluated. The change of POBF and the clinical activity and severity of the disease were assessed. RESULTS: In total, 11 patients underwent intravenous methylprednisolone pulse therapy followed by 2-month oral prednisolone therapy. POBF improved from a mean value of 476.5 to 614.7 microl/min (P<0.001) after treatment. Likewise, the mean clinical activity score reduced from 4.8 to 1.6. However, systemic steroid had less effect on the severity of GO. It also revealed that there is a greater improvement of POBF in those with more clinical activity score (>4) at the onset. CONCLUSIONS: Following treatment with systemic steroid we have demonstrated a significant improvement in POBF in patients with GO.

Increased oxidative DNA damage, 8-hydroxydeoxy- guanosine, in human pterygium.

PURPOSE: Chronic exposure to ultraviolet (UV) light is a widely accepted aetiological factor in the development of pterygium. UV radiation may induce production of reactive oxygen species via photosensitized oxidation, thus causing oxidative damage. This study was conducted to test the hypothesis that oxidative damage to DNA is increased in pterygium. METHODS: Immunohistochemical analysis employing a monoclonal antibody specific for 8-hydroxy-2'-deoxyguanosine (8-OHdG), a ubiquitous maker of oxidative stress, was performed in three patients with primary pterygium. The levels of 8-OHdG in DNA isolated from the other 29 pterygium specimens and their adjacent normal conjunctival tissues were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: Immunohistochemistry of 8-OHdG showed a distinct pattern of more extensive and intense staining in the nuclei of pterygium tissue compared with that in their adjacent normal conjunctiva. ELISA also revealed that the average level of 8-OHdG in the pterygium tissues was 4.7-fold higher than that of the corresponding normal conjunctiva (P<0.001). CONCLUSIONS: The increased levels of 8-OHdG in the pterygium tissues indicate that oxidative stress could play a role in the development of pterygium. These findings provide new information to better understand the pathogenesis of pterygium and are useful in the prevention and treatment of this disease.

Surgical coverage of exposed hydroxyapatite implant with retroauricular myoperiosteal graft.

BACKGROUND: With the increasing use of hydroxyapatite orbital implants, the complication of exposure has become apparent to oculoplastic surgeons. Many kinds of patch grafts, such as sclera, dermis, and hard palate mucosa, have been used to cover exposed hydroxyapatite implants with inconsistent results. In this study, the authors use a newly developed technique, autogenous retroauricular myoperiosteal graft, and the results are reported. METHODS: A piece of retroauricular muscle together with its underlying periosteum was carefully harvested. This myoperiosteal graft was patched to the debrided hydroxyapatite exposure area with the periosteal surface facing outward. The margin of periosteal surface was secured with conjunctiva and left uncovered for the surrounding conjunctiva to epithelialise. RESULTS: Nine eyes with hydroxyapatite exposure more than 3 mm were managed with autogenous retroauricular myoperiosteal grafts. Seven cases were successfully treated with single graft surgery. The other two cases needed an additional graft surgery, and there was no re-exposure noted thereafter. Five patients received a successful insertion of the motility peg. All nine patients have been fitted with prosthesis with reasonable motility. There were no complication noted during more than 1 year of follow up. CONCLUSION: The thick composite nature of the myoperiosteal graft provides a durable and vascularised coverage for exposed hydroxyapatite implants. This technique offers an encouraging alternative for the management of exposed hydroxyapatite implants.

Welded tracheal stent removal in a child under cardiopulmonary bypass.

Metallic tracheal stents have been used in the treatment of paediatric tracheomalacia for more than a decade. We describe a case in which critical airway obstruction occurred during removal of a welded tracheal stent using a rigid bronchoscope under general anaesthesia. Life-saving cardiopulmonary bypass was instituted urgently, and the welded stent was then removed successfully by directly opening the trachea.