Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC-AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making.

Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

A royal college of radiologists national audit of radiotherapy in the treatment of metastatic spinal cord compression and implications for the development of acute oncology services.

AIMS: To audit the current use of radiotherapy in UK cancer centres for the treatment of metastatic spinal cord compression against national standards that seek to optimise functional and quality of life outcomes. MATERIALS AND METHODS: A Royal College of Radiologists prospective national audit of patients treated with radiotherapy in UK cancer centres was carried out over a 3 month period between September and December 2008, with a repeat audit carried out in August 2012. RESULTS: Five hundred and ninety-six cases were received from 42 cancer centres (74%) in 2008, with data from 323 cases received from 52 (90%) centres in 2012. Ninety-three per cent (358) of patients had a diagnostic magnetic resonance imaging scan carried out within 24 h of referral for radiotherapy in 2008 compared with 205 patients (97%) in 2012. One hundred and eleven (32%) good prognosis patients were discussed with spinal surgeons; only 10 good prognosis patients were recorded as proceeding to surgery in 2008. This improved in 2012, with 94 (41% of good prognosis patients recorded as having been discussed with nine proceeding to surgery). Sixty-nine per cent of paraplegic patients in 2008 received multiple fractions of radiotherapy, which was similar to 2012 when 62% received more than a single fraction. A metastatic spinal cord compression co-ordinator was available in just over 50% of cases (164/323) and was involved in patient management in 26% of cases in 2012. CONCLUSION: Despite level 1 evidence of the superior functional outcome and survival benefit for surgery, few good prognosis patients were recorded as having been discussed with surgeons and even fewer proceeded to surgery.

Education, population, environment and sustainable development.

PIP: Attention is focused worldwide on the overlapping concerns of population growth, environmental change, inequalities in development, and political instability. There is awareness that the earth is one unit of interrelated activity, which can disrupt the single fragile ecosystem. A diverse set of explanations for these interrelationships is offered. Ehrlich and Ehrlich propose that population growth is a driving force that must be reckoned with for a sustainable planet. Both Simon and Kahn and Boserup suggest that human ingenuity is a viable solution for overcoming environmental challenges. The Commoner thesis is that social, economic, technological, and political factors are important intervening factors between the environment and population views. Now the focus is on research. Researching the interrelationships is a complex operation of multiple major, minor, and intervening factors, which may be approached at a local, national, regional, or world scale. Comparisons between scales is difficult. The primary policy question is how does population increase impact locally on the environment. The examination of this policy issue is dependent on human perceptions and values. Who is blameworthy and the bridging of economic gaps between rich and poor nations is now important. The world's population is becoming increasingly more urbanized, which lessons the impact on the environment, but the problem remains of how to adjust to rapid population growth. The goal of sustainable development for the present and future generations is important conceptually. Sustainable development implies that population activities must be integrated with environmental awareness, changes must be made in lifestyles and consumption, land tenure and use must be reformed, and poverty alleviated. The UN Population Fund directs activity toward reordering priorities and emphasizes greater energy efficiency and resource conservation, poverty alleviation, and reduced population growth. Population education is slowly gaining in respectability as is environmental education, both of which are policy- and problem-oriented. Population-environmental education is best linked with human geography syllabuses, which pertain to multiple levels and periods of analysis and are sensitive to the great diversity of cultures, economies, politics, and environments.^ieng

Demographic transition in small countries.

Half of the world's 200 countries have less than 3.37 million inhabitants, and many of these small countries are often assumed to experience rapid demographic transition. This is true of many of the small island populations of the developing world, especially those with largely immigrant and pluralistic populations, unusual family structures, and rapid economic development. Smallness of population alone, however, is not sufficient to ensure rapid demographic transition and many small countries of mainland Africa have experienced little transition.

Population geography.

PIP: The author reviews recent research activities and policy-oriented studies that reflect the increasing concern of population geographers with population redistribution and related government policies^ieng

Population policies and dynamics in Tunisia.

PIP: A family planning program was introduced in Tunisia in 1964 by the government. However, the present rate of growth is contrary to the government's hopes and expectations. This paper analyzes the reasons for this. Factors such as population growth, rate of increase, mortality decrease, internal migration patterns are analyzed with the result that the estimates of future decline in rate of population growth were overly optimistic. Fertility in general remained uncontrolled and high. Islam stresses large families and dominance of the male sex. Consequently, women marry very young and bear many children. This is in spite of remarkable achievements of the government in rising the status of women. In 1961, import and sale of contraceptives was permitted. In 1966, president Burgida delivered a pronatalist televised speech which adversely affected the family planning program. However, a new one was launched in January 1968 with U.S. aid, and it was encouraging to see a Muslim Arab country consciously taking the first steps toward a population policy.^ieng