The Inexorable Spread of a Newly Arisen Neo-Y Chromosome

A newly arisen Y-chromosome can become established in one part of a species range by genetic drift or through the effects of selection on sexually antagonistic alleles. However, it is difficult to explain why it should then spread throughout the species range after this initial episode. As it spreads into new populations, it will actually enter females. It would then be expected to perform poorly since it will have been shaped by the selective regime of the male-only environment from which it came. We address this problem using computer models of hybrid zone dynamics where a neo-XY chromosomal race meets the ancestral karyotype. Our models consider that the neo-Y was established by the fusion of an autosome with the ancestral X-chromosome (thereby creating the Y and the ‘fused X’). Our principal finding is that sexually antagonistic effects of the Y induce indirect selection in favour of the fused X-chromosomes, causing their spread. The Y-chromosome can then spread, protected behind the advancing shield of the fused X distribution. This mode of spread provides a robust explanation of how newly arisen Y-chromosomes can spread. A Y-chromosome would be expected to accumulate mutations that would cause it to be selected against when it is a rare newly arrived migrant. The Y can spread, nevertheless, because of the indirect selection induced by gene flow (which can only be observed in models comprising multiple populations). These results suggest a fundamental re-evaluation of sex-chromosome hybrid zones. The well-understood evolutionary events that initiate the Y-chromosome's degeneration will actually fuel its range expansion

The current status of the case report: Terminal or viable?

The case report, which has a long history in medicine, has seen its fortune wax and wane with time. We discuss the challenges facing the continued survival of the case report, including the inability of journals to cope with the increased load and increased cost of publication, ethical issues, the impact factor and the rise of evidence-based medicine. We highlight the important role that the case report will continue to play in medical research and education, as a means of sharing information and detecting novelty through observations. Most importantly, the case report serves as a stepping stone for young physicians and practitioners into the world of medical writing

A comparison of two systems of patient immobilization for prostate radiotherapy

2013-2014 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Prognostic indicators in adults hospitalized with falciparum malaria in Western Thailand.

Background: Severe malaria remains a major cause of death and morbidity amongst adults in the Asiatic tropics. Methods: A retrospective analysis of the clinical and laboratory data of 988 adult patients, hospitalized with Plasmodium falciparum malaria and prospectively recruited to malaria studies in western Thailand between 1986 and 2002, was performed to assess the factors associated with a fatal outcome. Different severity scores and classifications for defining severe malaria were compared and, using multiple logistic regression, simple models for predicting mortality developed. Results: The proportion of patients fulfilling the WHO 2000 definition of severe malaria was 78.1%, and their mortality was 10%. Mortality in patients given parenteral artesunate or artemether (16/317, 5%) was lower than in those given parenteral quinine (59/442, 13%) (P < 0.001). Models using parameter sets based on WHO 1990, 2000 and Adapted AQ criteria plus blood smear parasite-stage assessment gave the best mortality prediction. A malaria prognostic index (MPI), derived from the dataset using five clinical or laboratory variables gave similar prognostic accuracy. Conclusions: The mortality of severe malaria in adults has fallen and the switch from quinine to artesunate has probably been an important contributor. Prognostic indices based on WHO 2000 definitions, and other simpler indices based on fewer variables, provide clinically useful predictions of outcome in Asian adults with severe malaria

Cytomegalovirus Infections among African-Americans

<p>Abstract</p> <p>Background</p> <p>Since African-Americans have twice the prevalence of cytomegalovirus (CMV) infections as age-matched Caucasians we sought to determine the ages and possible sources of infection of African-American children.</p> <p>Methods</p> <p>Subjects were 157 African-American healthy children and adolescents and their 113 household adults in Richmond VA. Families completed a questionnaire, provided saliva for antibody testing, and adolescents were interviewed regarding sexual activity.</p> <p>Results</p> <p>Regardless of age CMV seropositivity was not associated with gender, breast feeding, health insurance, sexual activity, or household income, education, or size. In the final regression model, prior CMV infection in adults was over two-fold higher than in children (chi-square = 18.8, p < 0.0001). At one year of age the CMV seropositivity rate was 11% (95%CI = 4% – 24%) and increased 1.8% each year until age 13 years. Between ages 13 and 20 years the CMV seropositivity rate remained between 22% and 33%. For adults, the CMV seropositivity rate was 84% in 21 year olds (95%CI = 69%–.92%). There was no association between CMV infections of the children and their mothers but CMV infections among siblings were associated.</p> <p>Conclusion</p> <p>We observed that African-American children had CMV seroprevalence rates by age 20 years at less than one-half of that of their adult mothers and caregivers. Sibling-to-sibling transmission was a likely source of CMV infections for the children. The next generation of African-American women may be highly susceptible to a primary CMV infection during pregnancy and may benefit from a CMV vaccine.</p

MJA Practice Essentials - 2: Recent advances in therapy of diabetes - Endocrinology

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.As suboptimal blood glucose control has a lasting harmful effect even if control improves later, intensive insulin therapy to minimise hyperglycaemia is now recommended for all patients with type 1 diabetes. The new rapid- and long-acting insulin analogues offer more physiological insulin profiles than traditional insulin preparations. Continuous insulin infusion (“pump therapy”) may provide a solution for some patients with frequent hypoglycaemia or hypoglycaemic unawareness. Continuous blood glucose monitoring reveals postprandial hyperglycaemia and asymptomatic nocturnal hypoglycaemia and may be especially useful for programming overnight basal insulin rates for pump therapy. In type 2 diabetes, management should change with disease progression; introduction of insulin should not be delayed if metabolic control becomes suboptimal. More individualised and physiological therapy is now possible.Jennifer J Couper and Johannes B Prin

Quantification of fractional flow reserve based on angiographic image data

Coronary angiography provides excellent visualization of coronary arteries, but has limitations in assessing the clinical significance of a coronary stenosis. Fractional flow reserve (FFR) has been shown to be reliable in discerning stenoses responsible for inducible ischemia. The purpose of this study is to validate a technique for FFR quantification using angiographic image data. The study was carried out on 10 anesthetized, closed-chest swine using angioplasty balloon catheters to produce partial occlusion. Angiography based FFR was calculated from an angiographically measured ratio of coronary blood flow to arterial lumen volume. Pressure-based FFR was measured from a ratio of distal coronary pressure to aortic pressure. Pressure-wire measurements of FFR (FFRP) correlated linearly with angiographic volume-derived measurements of FFR (FFRV) according to the equation: FFRP = 0.41 FFRV + 0.52 (P-value < 0.001). The correlation coefficient and standard error of estimate were 0.85 and 0.07, respectively. This is the first study to provide an angiographic method to quantify FFR in swine. Angiographic FFR can potentially provide an assessment of the physiological severity of a coronary stenosis during routine diagnostic cardiac catheterization without a need to cross a stenosis with a pressure-wire

Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance

BACKGROUND: Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. METHODS: The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. RESULTS: Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. CONCLUSION: Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women). Patients with hyperparasitaemia who receive outpatient treatments provide the greatest risk of selecting de-novo resistant parasites. This emphasizes the importance of ensuring that only quality-assured anti-malarial combinations are used, that treatment doses are optimized on the basis of pharmacodynamic and pharmacokinetic assessments in the target populations, and that patients with heavy parasite burdens are identified and receive sufficient treatment to prevent recrudescence

Alcohol affects neuronal substrates of response inhibition but not of perceptual processing of stimuli signalling a stop response

Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits. In contrast, alcohol appears to have little impact on the early visual processing of infrequent perceptual cues. These observations clarify clinically-important effects of alcohol on behaviour