Adaptive ecological niche migration does not negate extinction susceptibility.

Extinction rates in the modern world are currently at their highest in 66 million years and are likely to increase with projections of future climate change. Our knowledge of modern-day extinction risk is largely limited to decadal-centennial terrestrial records, while data from the marine realm is typically applied to high-order (> 1 million year) timescales. At present, it is unclear whether fossil organisms with common ancestry and ecological niche exhibit consistent indicators of ecological stress prior to extinction. The marine microfossil record, specifically that of the planktonic foraminifera, allows for high-resolution analyses of large numbers of fossil individuals with incredibly well-established ecological and phylogenetic history. Here, analysis of the isochronous extinction of two members of the planktonic foraminiferal genus Dentoglobigerina shows disruptive selection differentially compounded by permanent ecological niche migration, "pre-extinction gigantism", and photosymbiont bleaching prior to extinction. Despite shared ecological and phylogenetic affinity, and timing of extinction, the marked discrepancies observed within the pre-extinction phenotypic responses are species-specific. These behaviours may provide insights into the nature of evolution and extinction in the open ocean and can potentially assist in the recognition and understanding of marine extinction risk in response to global climate change.

Socioeconomic inequalities and the equity impact of population-level interventions for adolescent health: an overview of systematic reviews.

OBJECTIVES: Despite robust evidence on health inequalities in adulthood, less attention has been paid to inequalities in adolescence. The aim of this overview was to examine systematic review (SR) evidence on the equity impact of population-level interventions intended to improve health, happiness and wellbeing for adolescents. STUDY DESIGN: An overview (review of systematic reviews). METHODS: Eleven electronic databases were systematically searched to identify SRs of population-level interventions for adolescent health. A secondary data analysis of socioeconomic inequality was conducted to identify whether SRs reported on primary studies in terms of disadvantage, by measures of socioeconomic status (SES) and by differential effects. RESULTS: 35,310 review titles were screened; 566 full texts were retrieved and 140 SRs met the predefined selection criteria. Differential intervention effects were considered in 42/140 (30%) SRs, 18/140 (13%) reported primary studies using an SES measure and 16/140 (11%) explicitly reported differential effects. 15/140 SRs (11%) explicitly focused on socioeconomic inequalities; of these 4/15 reported differential intervention effects in more detail, 7/15 concluded there was insufficient primary evidence to identify the impact of interventions on socioeconomic inequalities and 4/15 planned to examine differential effects by SES, but this was not reported further. CONCLUSIONS: Our overview identifies that there is limited SR evidence on the equity impact of population-level interventions for adolescent health. Strengthening the evidence on whether interventions narrow or widen inequalities for adolescents must be a priority for public health research.

Predictors for global perceived effect after physiotherapy in patients with neck pain: an observational study.

OBJECTIVE: To investigate the prognostic importance of a number of sensorimotor and psychological factors for global perceived effect (GPE) after physiotherapy in patients with neck pain. In addition to baseline values, change scores were used as independent variables to identify treatment-modifiable factors. DESIGN: Clinical cohort study. SETTING: Primary and secondary healthcare physiotherapy clinics. PARTICIPANTS: Patients (n=70) with non-specific neck pain. INTERVENTION: Usual care physiotherapy. METHODS: A three-dimensional motion tracking system was used to measure neck motion and sensorimotor variables, in addition to self-reported outcomes covering personal, somatic and psychological factors at baseline (before treatment) and at 2 months. Logistic regression was used to analyse associations between the prognostic variables and the primary outcome (GPE) at 2 months. RESULTS: At baseline, neck motion and motor control, pain duration and functioning were the strongest predictors for GPE, with no effect of psychological factors. Among the change variables, reduced pain intensity [odds ratio (OR) 1.86; 95% confidence interval (CI) 1.31 to 2.62], increased functioning (OR 1.46; 95% CI 1.11 to 1.92), reduced disability (OR 1.12; 95% CI 1.05 to 1.20), reduced kinesiophobia (OR 1.21; 95% CI 1.07 to 1.37), reduced catastrophising (OR 1.09; 95% CI 1.09 to 1.18) and increased self-efficacy (OR 1.12; 95% CI 1.03 to 1.21) were significantly associated with GPE. CONCLUSIONS: Both baseline values and change in pain intensity and functioning predicted GPE at 2 months. Psychological factors such as kinesiophobia, catastrophising and self-efficacy were only able to predict outcome by their change scores, indicating that these factors are modifiable by common physiotherapy practice and are important for GPE.

Development and course of chronic pain over 4 years in the general population: The HUNT pain study.

BACKGROUND: Epidemiological studies of chronic pain frequently report high prevalence estimates. However, there is little information about the development and natural course of chronic pain. METHODS: We followed a random sample of participants from a population-based study (HUNT 3) with annual measures over 4 years. RESULTS: Among those without chronic pain at baseline, the probability of developing moderate to severe chronic pain (cumulative incidence) during the first year was 5%, a pain status that was maintained among 38% at the second follow-up. The probability of developing chronic pain diminished substantially for those who maintained a status of no chronic pain over several years. Subjects with moderate to severe chronic pain at baseline had an 8% probability of recovery into no chronic pain, a status that was maintained for 52% on the second follow-up. The probability of recovery diminished substantially as a status of chronic pain was prolonged for several years. Pain severity, widespread pain, pain catastrophizing, depression and sleep were significant predictors of future moderate to severe chronic pain, both among subjects with and without chronic pain at baseline. CONCLUSION: These findings suggest that the prognosis is fairly good after a new onset of chronic pain. When the pain has lasted for several years, the prognosis becomes poor. The same social and psychological factors predict new onset and the prognosis of chronic pain. SIGNIFICANCE: The development and recovery of chronic pain is highly dependent on previous pain. The prognosis of chronic pain may be predicted well when considering its duration in combination with other clinical, social and psychological factors. Targeting modifiable prognostic factors may be particularly important for newly developed chronic pain.

Neuron-glia interactions underlie ALS-like axonal cytoskeletal pathology.

Amyotrophic lateral sclerosis (ALS) is a devastating disorder involving loss of movement due to degeneration of motor neurons. Studies suggest that in ALS axonal dysfunction precedes the death of motor neurons. Pathologically, ALS is characterized by neurofilamentous swellings (spheroids) within the axons of motor neurons. However, the causes of this axonopathy and possible resulting axonal dysfunction are not known. Using a novel model of cultured mouse motor neurons, we have determined that these neurons are susceptible to proximal axonopathy, which is related to the glial environment. This axonopathy showed remarkable similarity, both morphologically and neurochemically, to spheroids that develop over months in SOD1(G93A) transgenic mice. Focal ubiquitination, as well as perturbations of neurofilaments and microtubules, occurred in the axonal spheroid-like swellings in vitro, and visualization of mitochondrial dynamics demonstrated that axonopathy resulted in impaired axonal transport. These data provide strong evidence for the involvement of non-neuronal cells in axonal dysfunction in ALS. This cell culture model may be of benefit for the development of therapeutic interventions directed at axonal preservation.

Good outcome in HIV-infected refugees after resettlement in New Zealand: population study.

BACKGROUND: The aims of this study were to determine the clinical characteristics on arrival and the subsequent clinical outcome of HIV-infected UN quota refugees who settled in New Zealand during the last 11 years and to estimate their rate of HIV transmission. METHODS: A population study was conducted. Data were provided by the Mangere Refugee Resettlement Centre, the infectious disease physicians caring for the subjects, the New Zealand AIDS Epidemiology Group and laboratories carrying out HIV viral load assays. RESULTS: One hundred of 7732 (1.3%) UN quota refugees were HIV positive; mean age 30 years, 56% were men, median initial CD4 count was 320 (range 20-1358). HIV infection was most commonly acquired by heterosexual intercourse (74%). The median follow up was 5.0 years (range 1 month to 9.7 years). Five died and 15 subjects had 16 AIDS-defining illnesses, most commonly tuberculosis (n = 10). Sixty subjects commenced highly active antiretroviral therapy of whom 36/59 (61%) had an undetectable HIV viral load after 1 year of treatment. None of the six children born to HIV-infected women in New Zealand were infected. There were two known cases of horizontal transmission of HIV infection. CONCLUSION: Although HIV-infected quota refugees often have to overcome severe social, cultural and financial handicaps, their clinical outcome is generally very good, with response rates to highly active antiretroviral therapy that are similar to other patient groups. Furthermore, they have not been a significant source of transmission of HIV infection after resettlement in New Zealand.

The human lipid regulator, gemfibrozil bioconcentrates and reduces testosterone in the goldfish, Carassius auratus.

Human and veterinarian pharmaceuticals have been detected in the aquatic environment for a number of years, but the potential for biological effects in exposed aquatic organism is only now being reported. The lipid regulator, gemfibrozil (GEM) is detected at microg/L concentrations in domestic wastewater and ng/L concentrations in surface waters. We investigated the uptake of GEM in goldfish (Carassius auratus) over a 96 h time period by measuring GEM in blood plasma using LC-MS/MS. Results indicated that GEM can be taken up from water through the gills. In goldfish exposed to GEM by a single intraperitoneal injection, concentrations of GEM in the blood plasma declined rapidly over 96 h post-injection, with a half-life estimated at approximately 19 h. Exposure of goldfish to waterborne GEM at an environmentally relevant concentration over 14 days resulted in a plasma bioconcentration factor of 113. In goldfish exposed to aqueous concentrations of GEM for 96 h or 14 days, plasma testosterone (T) was reduced by over 50% in fish from all treatments. As a possible mechanistic explanation for the observed reduction in T, levels of steroid acute regulatory (StAR) protein transcript in goldfish testes were assessed by RT-PCR. StAR protein is involved in the transport of cholesterol from the outer to the inner mitochondrial membrane for transformation by the first enzyme in steroidogenesis. After exposure to GEM for 96 h, a 50% decrease in StAR mRNA levels was observed in goldfish. Gonadal StAR mRNA levels were not affected in the 14 days exposure, indicating that the observed decreases in plasma testosterone were not solely due to impaired delivery of cholesterol to the inner mitochondrial membrane. Our results demonstrate that exposure to environmental levels of GEM leads to bioconcentration of the drug in plasma and the potential for endocrine disruption in fish.

Short course intravenous benzylpenicillin treatment of adults with meningococcal disease.

BACKGROUND: Short-course treatment of meningococcal disease (including meningitis) with 4-5 days of an i.v. beta-lactam is of proven efficacy. Since April 1998, all adult patients with meningococcal disease admitted to Auckland Hospital were prospectively treated with 3 days of i.v. benzylpenicillin. AIMS: To assess the clinical features, laboratory findings, disease complications and outcome of patients with meningococcal disease prospectively treated with 3 days of i.v. benzylpenicillin. METHODS: A retrospective chart review of all adult patients with meningococcal disease admitted to Auckland Hospital from April 1998 to December 2002 was conducted. RESULTS: Ninety patients with definite (n = 72) or -probable (n = 16) meningococcal disease were admitted during the study period. Two were excluded on the basis of treatment duration. The remaining 88 patients received a mean +/- standard deviation duration of treatment of 3.1 +/- 0.5 days (excluding those who died while receiving treatment). Six patients (7%) died, four of whom while on treatment. There were no relapses. CONCLUSION: Three days of i.v. benzylpenicillin for the treatment of adults with meningococcal disease is effective.

Olfactory ensheathing cells promote neurite sprouting of injured axons in vitro by direct cellular contact and secretion of soluble factors.

Olfactory ensheathing cells (OECs) represent an exciting possibility for promoting axonal regeneration within the injured spinal cord. A number of studies have indicated the ability of these cells to promote significant reactive sprouting of injured axons within the injured spinal cord, and in some cases restoration of functional abilities. However, the cellular and/or molecular mechanisms OECs use to achieve this are unclear. To investigate such mechanisms, we report for the first time the ability of OECs to promote post-injury neurite sprouting in an in vitro model of axonal injury. Using this model, we were able to differentiate between the direct and indirect mechanisms underlying the ability of OECs to promote neuronal recovery from injury. We noted that OECs appeared to act as a physical substrate for the growth of post-injury neurite sprouts. We also found that while post-injury sprouting was promoted most when OECs were allowed to directly contact injured neurons, physical separation using tissue culture inserts (1 mm pore size, permeable to diffusible factors but not cells) did not completely block the promoting properties of OECs, suggesting that they also secrete soluble factors which aid post-injury neurite sprouting. Furthermore, this in vitro model allowed direct observation of the cellular interactions between OECs and sprouting neurites using live-cell-imaging techniques. In summary, we found that OECs separately promote neurite sprouting by providing a physical substrate for growth and through the expression of soluble factors. Our findings provide new insight into the ability of OECs to promote axonal regeneration, and also indicate potential targets for manipulation of these cells to enhance their restorative ability.

The minimum effective concentration of opioids: a revisitation with patient controlled analgesia fentanyl.

BACKGROUND AND OBJECTIVES: Whether patients titrate themselves to an individualized blood or plasma opioid concentration (the so-called minimum effective concentration or [MEC]) has been debated extensively. Nevertheless, there is consistent opinion that during patient controlled analgesia (PCA) patients balance acceptable pain relief against unacceptable side effects. This study sought to characterize fentanyl used by PCA with respect to MEC and factors influencing PCA use. METHODS: An intensive study of 25 patients with observations over the first 24 hours after orthopedic surgery was planned on the premise that this approach would provide a measure of the fentanyl MEC. This necessitated repeated measurements of pain scores and plasma fentanyl concentrations before and 10 minutes after every PCA demand. In addition, a battery of psychological tests was given before and approximately 48 hours after surgery. RESULTS: Logistic difficulties of maintaining a 24-hour study design resulted in its termination after 5 patients. The patients had convincingly distinct MECs (ranging from 0.23 to 0.99 ng/mL). The relationship between plasma fentanyl concentration and pain score was steep, such that small changes in concentration coincided with marked changes in pain relief. Despite preoperative expectations of achieving satisfaction in postoperative analgesia, not all patients titrated themselves to a pain-free state; all but one were satisfied with PCA. Surprisingly few side effects were reported. Unfortunately, the small sample size made systematic analysis of the psychological tests impossible. CONCLUSIONS: This study found evidence to support the concepts of an individual MEC and a therapeutic window of fentanyl used with PCA.

Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery.

AIMS: Pulmonary drug delivery is a promising noninvasive method of systemic administration. Our aim was to determine whether a novel breath-actuated, microprocessor-controlled metered dose oral inhaler (SmartMist, Aradigm Corporation) could deliver fentanyl in a way suitable for control of severe pain. METHODS: Aersolised pulmonary fentanyl base 100-300 microg was administered to healthy volunteers using SmartMist and the resultant plasma concentration-time data were compared with those from the same doses administered by intravenous (i.v.) injection in the same subjects. RESULTS: Plasma concentrations from SmartMist were similar to those from i.v. injection. Time-averaged bioavailability based upon nominal doses averaged approximately 100%, and was > 50% within 5 min of delivery. Fentanyl systemic pharmacokinetics were similar to those previously reported with no trends to dose-dependence from either route. Side-effects (e.g. sedation, lightheadedness) were the same from both routes. CONCLUSIONS: Fentanyl delivery using SmartMist can provide analgetically relevant plasma drug concentrations. This, combined with its ease of noninvasive use and transportability, suggests a strong potential for field and domicilliary use, and for patient controlled analgesia without the need for i.v. cannulae.

The effect of duration of dose delivery with patient-controlled analgesia on the incidence of nausea and vomiting after hysterectomy.

AIMS: Postoperative nausea and vomiting (PONV) may be exacerbated by postoperative opioid analgesics and may limit patients' successful use of these medications when used with patient controlled analgesia (PCA). We tested the hypothesis that the rapid change in blood morphine concentration associated with PCA bolus delivery contributed to PONV, and that prolonging its delivery to a brief infusion would result in decreased PONV. METHODS: Patients, who were receiving morphine for pain relief via patient-controlled analgesia (PCA) after total abdominal hysterectomy, received 1 mg morphine sulphate incremental doses either over 40 s with a 5 min lockout interval or over 5 min delivery with a 1 min lockout interval. Episodes of nausea, retching and vomiting, along with the use of morphine and the pain relief obtained, were recorded. RESULTS: Data from 20 patients in each group were analysed. Contrary to expectations, most patients in both groups reported nausea postoperatively. Those patients receiving morphine over 5 min experienced more episodes of emesis (36) than those receiving the dose over 40 s (17). Most patients receiving the 40 s doses vomited in the first 12 h (median time 8 h), while those receiving the 5 min doses vomited between 12 and 24 h (median time 19 h) (P = 0.01). There were no differences between groups in the visual analogue pain scores or use of morphine between groups. CONCLUSIONS: Reasons for these unexpected findings remain speculative. The high incidence of PONV appears to be inherently high in gynaecological surgery patients and standard antiemetic medication regimens appear to be poorly efficacious. Reasons for the differences in the time-course of emetic episodes between the two groups may be related to differences in the time-course of central opioid receptor occupancy.

Pain description and severity of chronic orofacial pain conditions.

A multidisciplinary pain centre study of 120 consecutive chronic orofacial pain patients assessed pain description and intensity ratings, gender differences, prevalence of concurrent conditions, and interinstrument relationships of the McGill Pain Questionnaire and visual analogue scale. Pain words chosen by patients to describe conditions were predominantly sensory words, and patients with concurrent conditions often listed words indicating a substantial affective component. Results showed pain intensity ratings of chronic orofacial pain conditions have similar or higher pain ratings when compared with other medical chronic pain conditions such as back pain, cancer pain and arthritis. There was a significantly higher female: male ratio (88:32) with gender playing an important but poorly understood causal role. The most frequent condition diagnosed was atypical facial pain (n = 40), followed by temporomandibular disorder (n = 32), atypical odontalgia (n = 29) and pathology of the orofacial region (n = 19). Temporomandibular disorder was present in 75 of the 120 subjects, as the sole pain complaint (n = 32) or as an associated secondary condition (n = 43), indicating concurrent pain conditions exist and may be related. There were significantly higher total pain scores of the McGill Pain Questionnaire in patients with multiple conditions compared with patients with a single condition. The visual analogue scale showed a significant correlation to the number of words chosen index of the McGill Pain Questionnaire for orofacial pain.

Using cross-check questions to address the problem of mis-reporting of specific food groups on Food Frequency Questionnaires. UKWCS Steering Group. United Kingdom Women's Cohort Study Steering Group.

OBJECTIVE: To explore the potential mis-reporting of specific food groups from food frequency questionnaire (FFQ) data and to examine the effect of using a weighting factor on estimated nutrient intake and ranking of subjects within the cohort according to nutrient intake. DESIGN AND SUBJECTS: A weighting factor was calculated for each of the individual 6572 women aged 35-69 y for four food groups, fish, meat, vegetables and fruit, using FFQ data and cross-check responses. RESULTS: The vegetables weighting had most effect on median intakes, particularly of fibre, vitamins A, C and E and folate. When all the weightings were applied, the median intakes of vitamins A and E were reduced by 35% and 27% respectively and the vitamin C intake was reduced by 44%. Ranking of subjects within the cohort according to nutrient intake was barely affected by the fish and meat weightings. The vegetable weighting had most effect on vitamin A with a rank correlation coefficient of 0.88. When all the weightings were applied the rank correlations for vitamins A, C and E and folate were all less than 0.90. CONCLUSION: Inclusion of cross-check questions in FFQs can provide an additional source of information on food group intake. This can be compared with FFQ data to help identify possible over-reporting and then to adjust frequency of intake accordingly.

The influence of age upon opioid analgesic use in the patient-controlled analgesia (PCA) environment.

It is often asserted that older patients are more sensitive to opioid analgesics than younger patients but experimental evidence for this assertion remains sparse. Two studies were conducted investigating the relationship between age and opioid analgesic use in the patient-controlled analgesia environment. In study I, the relationship was analysed subsequent to our publication of a study investigating patients' responses to opioid use with patient-controlled analgesia. Fifty-five postoperative patients, stratified into 'older' and 'younger' patients by median age, received morphine or pethidine or fentanyl patient-controlled analgesia. A strong inverse relationship was found between age and fentanyl and morphine use but not between age and pethidine use. Study II was a retrospective study of the medical records of 199 patient-controlled analgesia patients who had received morphine or pethidine patient-controlled analgesia; there were insufficient patients who had used fentanyl for a reasonable sample. There was a difference in morphine use with the younger patients using significantly more morphine than the older patients (< 60 years). Findings were less clear for patients receiving pethidine but there was an inverse correlation between age and pethidine use as well. Overall, the findings of these two studies supported the common clinical belief that older patients require less opioids than younger patients.

Nausea and vomiting in the postoperative patient-controlled analgesia environment.

Despite common clinical opinion that patient-controlled analgesia should be renamed 'patient-controlled nausea', there is little evidence in support of the notion that postoperative nausea and vomiting are exacerbated by the method. Indeed, data indicate that opioid-sparing techniques are not associated with less postoperative nausea and vomiting. Although some evidence suggests that certain opioids are less emetogenic than others, this too does not stand scrutiny when compared across patients, although research is still required to find whether individual patients are better treated with a particular opioid. Similarly, the emerging practice of combining anti-emetics with patient-controlled analgesia needs wider study before it can be supported.

Determination of subnanogram concentrations of fentanyl in plasma by gas chromatography-mass spectrometry: comparison with standard radioimmunoassay.

A method was devised to determine fentanyl plasma concentrations by GC-MS using selected-ion monitoring (SIM) with sufentanil as internal standard. This was compared with a commonly used commercial radioimmunoassay (RIA). Sample preparation for GC-MS involved basification of plasma then extraction using n-butyl chloride followed by concentration to dryness and reconstitution in toluene for chromatography. Using 1-ml plasma samples, the estimated limit of detection of fentanyl was 20 pg/ml. Blood samples for pharmacokinetic studies were split and assayed by GC-MS and RIA which had a limit of detection of 200 pg/ml. Pearson's r (r - 0.80, p < 0.0001) indicated the methods were highly correlated at all plasma concentrations. Owing to the greater sensitivity of the method, GC-MS is recommended over RIA for subnanogram determination of fentanyl in plasma.

Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system.

BACKGROUND: Successful pharmacotherapy of pain often depends on the mode of drug delivery. A novel, unit dose, aqueous aerosol delivery system (AERx Pulmonary Drug Delivery System) was used to examine the feasibility of the pulmonary route for the noninvasive systemic administration of morphine. METHODS: The study had two parts: (1) a dose-ranging study in four subjects with three consecutive aerosolized doses of 2.2, 4.4, and 8.8 mg (nominal) morphine sulfate pentahydrate at 40-minute intervals, and (2) a crossover study, on separate days, in six subjects with 4.4 mg (nominal) aerosolized morphine sulfate administered over 2.1 minutes on three occasions and intravenous infusions of 2 and 4 mg over 3 minutes. Subjects were healthy volunteers from 19 to 34 years old. Arterial blood was sampled for a total of 6 hours and plasma morphine concentrations were measured by gas chromatography-mass spectrometry. RESULTS: In part 1, plasma morphine concentrations were proportional to dose. In part 2, the mean +/- SD peak plasma concentration (Cmax) occurred at 2.7 +/- 0.8 minutes after the aerosol dose, with mean values for Cmax of 109 +/- 85, 165 +/- 22, and 273 +/- 114 ng/ml for the aerosol and 2 and 4 mg intravenous doses, respectively. The bioavailability [AUC(0-360 min)] of aerosol-delivered morphine was approximately 100% relative to intravenous infusion, with similar intersubject variability in AUC for both routes (coefficient of variation < 30%). CONCLUSION: The time courses of plasma morphine concentrations after pulmonary delivery by the AERx system and by intravenous infusions were similar. This shows the utility of the pulmonary route in providing a noninvasive method for the rapid and reproducible systemic administration of morphine if an appropriate aerosol drug delivery system is used.

A late shift in accident and emergency.

The Accident and Emergency (A & E) department at Harrogate District Hospital in North Yorkshire, UK, serves a population of 142,000 in a catchment area that covers Harrogate, Knaresborough, Ripon, Nidderdale, part of Wetherby, and occasionally Ilkley and Otley. In 1994, 29,884 new patients attended the department, and 6760 return visits were made. There are large fluctuations in the workload of the department that are difficult to predict. This account of a late shift demonstrates particular problems that are associated with a split site hospital, the transfer of acutely ill and injured patients to specialised units, and how the nursing workforce is depleted by 25% if one nurse is absent due to sickness.