Isolevuglandins as a gauge of lipid peroxidation in human tumors.

The cellular production of free radicals or reactive oxygen species (ROS) can lead to protein, lipid or DNA modifications and tumor formation. The cellular lipids undergo structural changes through the actions of enzymes (e.g. cyclooxygenases) or free radicals to form a class of compounds called Isolevuglandins (IsoLGs). The recruitment and continued exposure of tissue to ROS and IsoLGs causes increased cell proliferation, mutagenesis, loss of normal cell function and angiogenesis. The elevated concentration of ROS in cancerous tissues suggests that these mediators play an important role in cancer development. We hypothesized that tumors with elevated ROS levels would similarly possess an increased concentration of IsoLGs when compared with normal tissue. Using D11, an ScFv recombinant antibody specific for IsoLGs, we utilized immunohistochemistry to visualize the presence of IsoLG in human tumors compared to normal adjacent tissue (NAT) to the same tumor. We found that IsoLG concentrations were elevated in human breast, colon, kidney, liver, lung, pancreatic and tongue tumor cells when compared to NAT and believe that IsoLGs can be used as a gauge indicative of lipid peroxidation in tumors.

Revalidation: implications for Australian anaesthetists.

In early 2015, the Medical Board of Australia commissioned research into international revalidation models and what might be applicable for Australia. This review examines the implications for Australian anaesthetists. What problem is revalidation seeking to address? What is happening in similar countries? Is there an issue with Australian anaesthetists' performance? Isn't continuing professional development enough? Could the Medical Board target known high-risk doctors? What is the evidence for the benefit of revalidation? How is and how should the profession be involved? Revalidation has been introduced in other developed countries. It commonly involves continuing professional development, feedback from colleagues, co-workers and patients, clinical audit and peer review. Although its evidence base is limited, the General Medical Council in the United Kingdom is evaluating its revalidation system, which should provide useful guidance for other countries. Australian anaesthetists and their professional organisations must remain informed about, and engaged in, the national debate about revalidation, to ensure that any new process is workable for Australian anaesthesia practice.

Combining cutaneous silent periods with quantitative sudomotor axon reflex testing in the assessment of diabetic small fiber neuropathy.

OBJECTIVE: Routine electrophysiological testing is often normal in the evaluation of painful diabetic neuropathy, as it is unable to detect dysfunction of thinly myelinated (Aδ) and unmyelinated (C) small fibers. Although cutaneous silent periods (CSP) and quantitative sudomotor axon reflex testing (QSART) respectively evaluate these fiber types in the extremities, these two tests have yet to be assessed together. METHODS: 26 patients with a clinical diagnosis of small fiber neuropathy (SFN) and 26 age-matched controls were assessed. Nine patients had Type I diabetes, nine had Type II diabetes, and eight had impaired glucose tolerance. The CSP onset latency and duration were recorded in each extremity. QSART was performed on the right side. RESULTS: 58% (15/26) of patients had abnormal sweat volumes obtained from QSART, while 50% (13/26) of patients had abnormal CSP responses. Combining these two tests increased the sensitivity of testing to 77% (20/26). Abnormalities were seen equally across all patient groups. CONCLUSIONS: Combining CSP with QSART significantly increases the sensitivity of testing when assessing patients with SFN related to diabetes, or prediabetes. SIGNIFICANCE: For clinically suspected SFN, it is preferable to test more than one small fiber type, as each possess different structural and functional properties and may be heterogeneously affected between patients.

Silver spoons in the rough: can environmental enrichment improve survival of hatchery Atlantic salmon Salmo salar in the wild?

This study tested the 'silver spoon' hypothesis which posits that individuals that develop under favourable conditions should enjoy a fitness advantage later in life because they are more likely to recognize and settle in high-quality habitats. Atlantic salmon Salmo salar of two age classes (0+ and 1+ years) were reared in environmentally enriched or standard hatchery tanks for a short period (c. 10 weeks), were then released into a natural river and sampled on repeated occasions to test for silver-spoon effects. Compared with controls, enriched fish had a 6.4% higher recapture rate and settled in higher velocity habitats when they were stocked as 0+ year fry, but not when they were stocked as 1+ year parr. The opportunity for selection was generally higher for environmentally enriched fish than for controls, and also higher for 0+ than for 1+ year fish. Selection favoured individuals with high condition factor, extensive fat reserves and longer than average pectoral fins in both age classes but favoured a small body size in 1+ year and a large body size in 0+ year releases. Stomach analysis showed that enriched fish ate more, and adapted quicker to natural prey than controls. These results provide support for silver-spoon effects in fish and indicate that enrichment can improve post-release performance in conservation programmes, but seemingly only if fish are not kept in captivity for too long.

The relationship of oxidative stress, adiposity and metabolic risk factors in healthy Black and White American youth.

UNLABELLED: What is already known about this subject African Americans are disproportionately affected by obesity and other metabolic risk factors in comparison to White Americans. Increasing prevalence of obesity has been associated with concomitant increases in childhood hypertension, dyslipidaemia and type 2 diabetes. Oxidative stress is associated with obesity in both adults and children. What this study adds Oxidative stress is positively associated with total body fat and truncal fat, but not with body mass index (BMI) or BMI z-score in healthy youth. Oxidative stress is associated with diastolic blood pressure in African American but not in White American healthy youth. BACKGROUND: Oxidative stress is elevated in obese youth, but less is known regarding racial disparities in the relationship of oxidative stress with metabolic risk factors. OBJECTIVES: To determine the relationship between oxidative stress and metabolic risk factors, adiposity, leptin, adiponectin and cardiovascular fitness (VO2PEAK ) in healthy African American and White American youth. METHODS: A marker of oxidative stress (F2 -isoprostane), validated markers of metabolic risk factors, fitness and body composition were measured in African American (n = 82) and White American (n = 76) youth (8-17 years old) recruited over a range of BMI percentiles (4th to 99th). RESULTS: F2 -isoprostane concentration was positively correlated with percentage body fat (r = 0.198) and percentage truncal fat (r = 0.173), but was not different between African American and White American males and females (P = 0.208). African American youth had significantly higher mean systolic and diastolic blood pressure (P = 0.023 and P = 0.011, respectively), body weight, BMI percentile and Tanner stage. After adjusting for gender, age, BMI and Tanner stage, African American youth varied from White Americans in the association of F2 -isoprostane with diastolic blood pressure (P = 0.047), but not with systolic blood pressure, triglycerides, VO2PEAK or homeostatic model assessment for insulin resistance (all P > 0.05). CONCLUSIONS: Oxidative stress, as measured by urinary F2 -isoprostane concentrations, was positively associated with percent body fat and truncal fat in youth. Oxidative stress levels were similar among African American and White American youth. Among markers of the metabolic syndrome, a significant difference between African American and White American youth was demonstrated only in the association of oxidative stress with diastolic blood pressure.

Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial.

BACKGROUND: Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma. DESIGN: Nine subjects received twice-weekly intravenous ascorbate (15-125 g) employing Simon's accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored. RESULTS: Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 µM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months. CONCLUSIONS: Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.

A double-blinded randomized evaluation of alfentanil and morphine vs fentanyl: analgesia and sleep trial (DREAMFAST).

BACKGROUND: Patients using fentanyl patient-controlled analgesia (PCA), the standard first-line choice in our hospitals, commonly complain of postoperative sleep disruption due to pain. The aim of this study was to determine whether the PCA combination of alfentanil and morphine, which provides longer analgesia without compromising onset speed, would improve postoperative pain-related sleep interference. METHODS: Two hundred and twelve adults undergoing major surgery where PCA was the planned principal postoperative analgesic modality were randomized to either the combination of alfentanil and morphine (Group AM) or fentanyl (Group F). The primary outcome was pain-related awakenings during the second postoperative night as measured by the study questionnaire, based on the St Mary's Hospital Sleep Questionnaire. Analgesic efficacy, other sleep measures, and opioid-related side-effects were also assessed. RESULTS: There was no difference in pain-related sleep disturbance between the groups, with 41% of Group AM and 53% of Group F waking due to pain (P=0.10). Group AM had better rest and dynamic analgesia in the first 24 h with fewer requiring rescue ketamine infusion during the 2 day study period (2 vs 14%, P=0.001). Those in Group AM experienced less nausea and vomiting in the second 24 h (18 vs 35%, P=0.028) but more pruritus (40 vs 23%, P=0.013). CONCLUSIONS: Despite better early postoperative analgesia, pain-related sleep interference was not improved by the PCA combination of alfentanil and morphine. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: Ref: ACTRN12608000118303.

Telerheumatology: an idea whose time has come.

Australia is a vast country with one-third of the population living outside capital cities. Providing specialist rheumatologist services to regional, rural and remote Australians has generally required expensive and time-consuming travel for the patient and/or specialist. As a result, access to specialist care for remote Australians is poor. Rheumatoid arthritis is a common disease, but like many rheumatic diseases, it is complex to treat. Time-dependent joint damage and disability occur unless best evidence care is implemented. The relatively poor access to rheumatologist care allotted to nonmetropolitan Australians therefore represents a significant cause of potentially preventable disability in Australia. Telehealth has the potential to improve access to specialist rheumatologists for patients with rheumatoid arthritis and other rheumatic diseases, thereby decreasing the burden of disability caused by these diseases. Advances in videoconferencing technology, the national broadband rollout and recent Federal government financial incentives have led to a heightened interest in exploring the use of this technology in Australian rheumatology practice. This review summarises the current evidence base, outlines telehealth's strengths and weaknesses in managing rheumatic disease, and discusses the technological, medicolegal and financial aspects of this model of care. A mixed model offering both face-to-face and virtual consultations appears to be the best option, as it can overcome the barriers to accessing care posed by distance while also mitigating the risks of virtual consultation.

Acute pain management in opioid-tolerant patients: a growing challenge.

In Australia and New Zealand, in parallel with other developed countries, the number of patients prescribed opioids on a long-term basis has grown rapidly over the last decade. The burden of chronic pain is more widely recognised and there has been an increase in the use of opioids for both cancer and non-cancer indications. While the prevalence of illicit opioid use has remained relatively stable, the diversion and abuse of prescription opioids has escalated, as has the number of individuals receiving methadone or buprenorphine pharmacotherapy for opioid addiction. As a result, the proportion of opioid-tolerant patients requiring acute pain management has increased, often presenting clinicians with greater challenges than those faced when treating the opioid-naïve. Treatment aims include effective relief of acute pain, prevention of drug withdrawal, assistance with any related social, psychiatric and behavioural issues, and ensuring continuity of long-term care. Pharmacological approaches incorporate the continuation of usual medications (or equivalent), short-term use of sometimes much higher than average doses of additional opioid, and prescription of non-opioid and adjuvant drugs, aiming to improve pain relief and attenuate opioid tolerance and/or opioid-induced hyperalgesia. Discharge planning should commence at an early stage and may involve the use of a 'Reverse Pain Ladder' aiming to limit duration of additional opioid use. Legislative requirements may restrict which drugs can be prescribed at the time of hospital discharge. At all stages, there should be appropriate and regular consultation and liaison with the patient, other treating teams and specialist services.

Selective gamma-ketoaldehyde scavengers protect Nav1.5 from oxidant-induced inactivation.

The cardiac sodium channel (SCN5A, Na(V)1.5) is a key determinant of electrical impulse conduction in cardiac tissue. Acute myocardial infarction leads to diminished sodium channel availability, both because of decreased channel expression and because of greater inactivation of channels already present. Myocardial infarction leads to significant increases in reactive oxygen species and their downstream effectors including lipoxidation products. The effects of reactive oxygen species on Na(V)1.5 function in whole hearts can be modeled in cultured myocytes, where oxidants shift the availability curve of I(Na) to hyperpolarized potentials, decreasing cardiac sodium current at the normal activation threshold. We recently examined potential mediators of the oxidant-induced inactivation and found that one specific lipoxidation product, the isoketals, recapitulated the effects of oxidant on sodium currents. Isoketals are highly reactive gamma-ketoaldehydes formed by the peroxidation of arachidonic acid that covalently modify the lysine residues of proteins. We now confirm that exposure to oxidants induces lipoxidative modification of Na(V)1.5 and that the selective isoketal scavengers block voltage-dependent changes in sodium current by the oxidant tert-butylhydroperoxide, both in cells heterologously expressing Na(V)1.5 and in a mouse cardiac myocyte cell line (HL-1). Thus, inhibition of this lipoxidative modification pathway is sufficient to protect the sodium channel from oxidant induced inactivation and suggests the potential use of isoketal scavengers as novel therapeutics to prevent arrhythmogenesis during myocardial infarction.

Crusted scabies: clinical and immunological findings in seventy-eight patients and a review of the literature.

OBJECTIVES: To describe the clinical and immunological features of crusted scabies in a prospectively ascertained cohort of 78 patients. METHODS: All patients requiring inpatient treatment for crusted scabies in the 'top end' of the northern territory of Australia over a 10 year period were prospectively identified. Demographics, risk factors, and immunological parameters were retrospectively compiled from their medical records and pathology databases. RESULTS: More than half the patients with crusted scabies had identifiable immunosuppressive risk factors. Eosinophilia and elevated IgE levels occurred in 58% and 96% of patients, respectively, with median IgE levels 17 times the upper limit of normal. Seventeen percent had a history of leprosy but 42% had no identifiable risk factors. There was a decrease in mortality after the introduction of a treatment protocol consisting of multiple doses of ivermectin combined with topical scabicides and keratolytic therapy. CONCLUSIONS: Crusted scabies often occurs in patients with identifiable immunosuppressive risk factors. In patients without such risk factors, it is possible that the crusted response to infection results from a tendency to preferentially mount a Th2 response. The treatment regime described was associated with a reduction in mortality. This is the largest reported case series of crusted scabies.

Biomarkers of oxidative stress study II: are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning?

Oxidation products of lipids, proteins, and DNA in the blood, plasma, and urine of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. This article is the second report of the nationwide Biomarkers of Oxidative Stress Study using acute CCl4 poisoning as a rodent model for oxidative stress. The time-dependent (2, 7, and 16 h) and dose-dependent (120 and 1200 mg/kg i.p.) effects of CCl4 on concentrations of lipid hydroperoxides, TBARS, malondialdehyde (MDA), isoprostanes, protein carbonyls, methionine sulfoxidation, tyrosine products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), leukocyte DNA-MDA adducts, and DNA-strand breaks were investigated to determine whether the oxidative effects of CCl4 would result in increased generation of these oxidation products. Plasma concentrations of MDA and isoprostanes (both measured by GC-MS) and urinary concentrations of isoprostanes (measured with an immunoassay or LC/MS/MS) were increased in both low-dose and high-dose CCl4-treated rats at more than one time point. The other urinary markers (MDA and 8-OHdG) showed significant elevations with treatment under three of the four conditions tested. It is concluded that measurements of MDA and isoprostanes in plasma and urine as well as 8-OHdG in urine are potential candidates for general biomarkers of oxidative stress. All other products were not changed by CCl4 or showed fewer significant effects.

Biomarkers of oxidative stress study III. Effects of the nonsteroidal anti-inflammatory agents indomethacin and meclofenamic acid on measurements of oxidative products of lipids in CCl4 poisoning.

Plasma and urinary levels of malondialdehyde-like products (MDA) and isoprostanes were identified as markers of in vivo lipid peroxidation in an animal model of CCl4 poisoning. We sought to determine the extent to which the formation of these oxidation products is influenced by inhibition of the cyclooxygenase enzymes which catalytically generate proinflammatory lipid peroxidation products known as prostaglandins and thromboxane. In the present studies, after induction of oxidant stress in rats with CCl4, lipid peroxidation products measured in plasma and urine demonstrate that isoprostanes and MDA can be partially inhibited by cyclooxygenase inhibitors, albeit to different extents. The lowering of isoprostane and MDA formation, however, may not to due primarily to the diminution of catalytic generation of isoprostanes or MDA by the cyclooxygenases but, rather, may be the result of the suppression of nonenzymatic lipid peroxidation. This is suggested since 8,12-iso-iPF2alpha-VI is also reduced by indomethacin, yet, unlike other isoprostanes and MDA, it is not generated catalytically by the cyclooxygenase. Thus, although the two cyclooxygenase inhibitors we tested have statistically significant effects on the measurements of both isoprostanes and MDA in this study, the results provide evidence that these lipid-degradation products primarily constitute markers of oxidative stress.