Mitochondrial membrane potential in a small subset of artemisinin-induced dormant plasmodium falciparum parasites in vitro

Artemisinin induced dormancy is a proposed mechanism for failures of mono-therapy and is linked with artemisinin resistance in Plasmodium falciparum. The biological characterization and dynamics of dormant parasites are not well understood. Here we report that following dihydroartemisinin (DHA) treatment in vitro, a small subset of morphologically dormant parasites was stained with rhodamine 123 (RH), a mitochondrial membrane potential (MMP) marker, and persisted to recovery. FACS sorted RH-positive parasites resumed growth at 10,000/well while RH-negative parasites failed to recover at 5 million/well. Furthermore, transcriptional activity for mitochondrial enzymes was only detected in RH-positive dormant parasites. Importantly, after treating dormant parasites with different concentrations of atovaquone, a mitochondrial inhibitor, the recovery of dormant parasites was delayed or stopped. This demonstrates that mitochondrial activity is critical for survival and regrowth of dormant parasites and that RH staining provides a means of identifying these parasites. These findings provide novel paths for studying and eradicating this dormant stage.

Novel polymer synthesis methodologies using combination of thermally and photochemically-induced nitroxide mediated polymerisation

The combination of thermally- and photochemically-induced polymerization using light sensitive alkoxyamines was investigated. The thermally driven polymerizations were performed via the cleavage of the alkoxyamine functionality, whereas the photochemically-induced polymerizations were carried out either by nitroxide mediated photo-polymerization (NMP2) or by a classical type II mechanism, depending on the structure of the light-sensitive alkoxyamine employed. Once the potential of the various structures as initiators of thermally- and photo-induced polymerizations was established, their use in combination for block copolymer syntheses was investigated. With each alkoxyamine investigated, block copolymers were successfully obtained and the system was applied to the post-modification of polymer coatings for application in patterning and photografting.

Challenges in field monitoring of energy performance of air conditioners

Experimental work could be conducted in either laboratory or at field site. Generally, the laboratory experiments are carried out in an artificial setting and with a highly controlled environment. By contrast, the field experiments often take place in a natural setting, subject to the influences of many uncontrolled factors. Therefore, it is necessary to carefully assess the possible limitations and appropriateness of an experiment before embarking on it. In this paper, a case study of field monitoring of the energy performance of air conditioners is presented. Significant challenges facing the experimental work are described. Lessons learnt from this case study are also discussed. In particular, it was found that on-going analysis of the monitoring data and the correction of abnormal issues are two of the keys for a successful field test program. It was also shown that the installation of monitoring systems could have a significant impact on the accuracy of the data being collected. Before monitoring system was set up to collect monitoring data, it is recommended that an initial analysis of sample monitored data should be conducted to make sure that the monitoring data can achieve the expected precision. In the case where inevitable inherent errors were induced from the installation of field monitoring systems, appropriate remediation may need to be developed and implemented for the improved accuracy of the estimation of results. On-going analysis of monitoring data and correction of any abnormal issues would be the key to a successful field test program.

Eye rubbing-induced changes in intraocular pressure and corneal thickness measured at five locations, in subjects with ocular allergy

AIM To assess the effects of eye rubbing on corneal thickness (CT) and intraocular pressure (IOP) measurements obtained 0-30min after habitual eye rubbing in symptomatic patients. METHODS Measurements of IOP and CT were obtained at five locations (central, temporal, superior, nasal and inferior) before, and every 5min for 30min interval after 30s of eye rubbing, for 25 randomly selected eyes of 14 subjects with ocular allergy and 11 age-matched normals. Differences in measurements were calculated in each group [Baseline measurements minus measurements recorded at each time interval after eye rubbing (for IOP), and for each corneal location (for CT)] and comparison were then made between groups (allergic versus control) for differences in any observed effects. RESULTS Within groups, baseline mean IOPs in the allergic patient-group (14.2±3.0 mm Hg) and in the control group (13.1±1.9 mm Hg) were similar at all times, after eye rubbing (P >0.05, for all). The maximum reduction in IOP was 0.8 mm Hg in the control subjects and the maximum increase was also 0.8 mm Hg in the allergic subjects. Between groups (allergic versus control), the changes in IOP remained under 1 mm Hg at all times (P=0.2) after 30min of eye rubbing. Between 0 and 30min of CT measurements after eye rubbing, the mean central CT (CCT), inferior CT (ICT), superior CT (SCT), temporal CT (TCT) and nasal CT (NCT) did not vary significantly from baseline values in the control and allergic-subject groups (P>0.05, for both). Between both groups, changes in CT were similar at all locations (P>0.05) except for the TC which was minimally thinner by about 4.4 µm (P=0.001) in the allergic subjects than in the control subjects, 30min following 30s of eye rubbing. CONCLUSION IOP measured in allergic subjects after 30s of habitual eye rubbing was comparable with that obtained in normal subjects at all times between 0 and 30min. Although, CT in the allergic subjects were similar to those of the control subjects at all times, it varied between +10 and -7.5 µm following eye rubbing, with the temporal cornea showing consistent reductions in thickness in the subjects with allergy. However, this reduction was minimal and was considered to not be clinically relevant.

Cell type-dependent, infection-induced, aberrant DNA methylation in gastric cancer

Epigenetic changes correspond to heritable modifications of the chromatin structure, which do not involve any alteration of the DNA sequence but nonetheless affect gene expression. These mechanisms play an important role in cell differentiation, but aberrant occurrences are also associated with a number of diseases, including cancer and neural development disorders. In particular, aberrant DNA methylation induced by H. Pylori has been found to be a significant risk factor in gastric cancer. To investigate the sensitivity of different genes and cell types to this infection, a computational model of methylation in gastric crypts is developed. In this article, we review existing results from physical experiments and outline their limitations, before presenting the computational model and investigating the influence of its parameters.

Biophysical correlates of intrinsic and stress-induced morphological variability in lateral amygdaloid neurons: A computational study

Morphological and physiological characteristics of neurons located in the dorsolateral and two ventral subdivisions of the lateral amygdala (LA) have been compared in order to differentiate their roles in the formation and storage of fear memories (Alphs et al, SfN abs 623.1, 2003). Briefly, in these populations, significant differences are observed in input resistance, membrane time constant, firing frequency, dendritic tortuosity, numbers of primary dendrites, dendritic segments and dendritic nodes...

The prevention, detection and management of cancer treatment-induced cardiotoxicity: a meta-review

Background The benefits associated with some cancer treatments do not come without risk. A serious side effect of some common cancer treatments is cardiotoxicity. Increased recognition of the public health implications of cancer treatment-induced cardiotoxicity has resulted in a proliferation of systematic reviews in this field to guide practice. Quality appraisal of these reviews is likely to limit the influence of biased conclusions from systematic reviews that have used poor methodology related to clinical decision-making. The aim of this meta-review is to appraise and synthesise evidence from only high quality systematic reviews focused on the prevention, detection or management of cancer treatment-induced cardiotoxicity. Methods Using Cochrane methodology, we searched databases, citations and hand-searched bibliographies. Two reviewers independently appraised reviews and extracted findings. A total of 18 high quality systematic reviews were subsequently analysed, 67 % (n = 12) of these comprised meta-analyses. Results One systematic review concluded that there is insufficient evidence regarding the utility of cardiac biomarkers for the detection of cardiotoxicity. The following strategies might reduce the risk of cardiotoxicity: 1) The concomitant administration of dexrazoxane with anthracylines; 2) The avoidance of anthracyclines where possible; 3) The continuous administration of anthracyclines (>6 h) rather than bolus dosing; and 4) The administration of anthracycline derivatives such as epirubicin or liposomal-encapsulated doxorubicin instead of doxorubicin. In terms of management, one review focused on medical interventions for treating anthracycline-induced cardiotoxicity during or after treatment of childhood cancer. Neither intervention (enalapril and phosphocreatine) was associated with statistically significant improvement in ejection fraction or mortality. Conclusion This review highlights the lack of high level evidence to guide clinical decision-making with respect to the detection and management of cancer treatment-associated cardiotoxicity. There is more evidence with respect to the prevention of this adverse effect of cancer treatment. This evidence, however, only applies to anthracycline-based chemotherapy in a predominantly adult population. There is no high-level evidence to guide clinical decision-making regarding the prevention, detection or management of radiation-induced cardiotoxicity.

Modulating exercise-induced hormesis: Does less equal more?

Hormesis enco 16 mpasses the notion that low levels of stress stimulate or upregulate 17 existing cellular and molecular pathways that improve the capacity of cells and organisms to 18 withstand greater stress. This notion underlies much of what we know about how exercise 19 conditions the body and induces long-term adaptations. During exercise, the body is 20 exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and 21 mechanical stress. These stressors activate biochemical messengers, which in turn activate 22 various signaling pathways that regulate gene expression and adaptive responses. 23 Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and 24 cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress 25 and inflammation. However, reactive oxygen species and inflammatory mediators are key 26 signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. 27 Conversely, withholding dietary carbohydrate and restricting muscle blood flow during 28 exercise may augment adaptations to exercise. In this review article, we combine, integrate, 29 and apply knowledge about the fundamental mechanisms of exercise adaptation. We also 30 critically evaluate the rationale for using interventions that target these mechanisms under 31 the overarching concept of hormesis. There is currently insufficient evidence to establish 32 whether these treatments exert dose-dependent effects on muscle adaptation. However, 33 there appears to be some dissociation between the biochemical/molecular effects and 34 functional/performance outcomes of some of these treatments. Although several of these 35 treatments influence common kinases, transcription factors and proteins, it remains to be 36 determined if these interventions complement or negate each other, and whether such 37 effects are strong enough to influence adaptations to exercise.

Effects of different levels of refractive blur on night-time pedestrian visibility

Purpose The aim of this study was to systematically investigate the effect of different levels of refractive blur and driver age on night-time pedestrian recognition and determine whether clothing that has been shown to improve pedestrian conspicuity is robust to the effects of blur. Methods Night-time pedestrian recognition was measured for 24 visually normal participants (12 younger M=24.9±4.5 years and 12 older adults M=77.6±5.7 years) for three levels of binocular blur (+0.50 D, +1.00 D, +2.00 D) compared to baseline (optimal refractive correction). Pedestrians walked in place on a closed road circuit and wore one of three clothing conditions: i) everyday clothing, ii) a retro-reflective vest and iii) retro-reflective tape positioned on the extremities in a configuration that conveyed biological motion (known as “biomotion”); the order of conditions was randomized between participants. Pedestrian recognition distances were recorded for each blur and pedestrian clothing combination while participants drove an instrumented vehicle around a closed road course. Results The recognition distances for pedestrians were significantly reduced (p<0.05) by all levels of blur compared to baseline. Pedestrians wearing “biomotion” clothing were recognized at significantly longer distances than for the other clothing configurations in all blur conditions. However, these effects were smaller for the older adults, who had much shorter recognition distances for all conditions tested. Conclusions In summary, even small amounts of blur had a significant detrimental effect on night-time pedestrian recognition. Biomotion retro-reflective clothing was effective, even under moderately degraded visibility conditions, for both young and older drivers.

In response: Changes in ultraviolet transmittance of hydrogel and silicone hydrogel contact lenses induced by wear

We thank Dr Shedden and Dr Pall for their insightful comments and the opportunity to clarify a number of points from our work.1 The “protection factor” (PF) expressed as the inverse of the transmittance of contact lens (CL) material (1/Tλ), where T is the percentage transmittance of ultraviolet radiation (UVR) in a given waveband (UVC, UVB or UVA) of the UV spectrum for contact lenses is the standard method for reporting PF values and as such there should not be any controversy. We have calculated the PF for each wavelength across the entire UV spectrum (UVC, UVB, UVA) as presented in figure 3 of our previous publication.1 In that article, we were simply stating the observation when transmission in the UVC spectra band is considered especially because appreciable amounts of potentially carcinogenic short UV wavelengths was shown to be present in sunlight in our region three decades ago2 and these short wavelength photons are reported to be more biologically damaging to ocular tissues.3 In addition, the depletion of the Ozone layer is still continuing. Nevertheless, we understand the concern of the authors that the results of the PF might be confusing to those who are not familiar with the science of UVR and as such we have made some revisions to the findings of the calculated PF...

BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell cycle arrest and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here we report that estrogen and estrogen metabolites can cause DNA double strand breaks (DSB) in estrogen receptor-α negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolising enzymes, such as CYP1A1, in breast cells. Lastly, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumours in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.

Ocular refractive and biometric characteristics in patients with tilted disc syndrome

BACKGROUND Tilted disc syndrome (TDS) is associated with characteristic ocular findings. The purpose of this study was to evaluate the ocular, refractive, and biometric characteristics in patients with TDS. METHODS This case-control study included 41 eyes of 25 patients who had established TDS and 40 eyes of 20 healthy control subjects. All participants underwent a complete ocular examination, including refraction and analysis using Fourier transformation, slit lamp biomicroscopy, pachymetry, keratometry, and ocular biometry. Corneal topography examinations were performed in the syndrome group only. RESULTS There were no significant differences in spherical equivalent (P = 0.13) and total astigmatism (P = 0.37) between groups. However, mean best spectacle-corrected visual acuity (Log Mar) was significantly worse in TDS patients (P = 0.003). The lenticular astigmatism was greater in the syndrome group, whereas the corneal component was greater in controls (P = 0.059 and P = 0.028, respectively). The measured biometric features were the same in both groups, except for the lens thickness and lens-axial length factor, which were greater in the TDS group (P = 0.007 and P = 0.055, respectively). CONCLUSIONS Clinically significant lenticular astigmatism, more oblique corneal astigmatism, and thicker lenses were characteristic findings in patients with TDS.

Ocular refractive and biometric characteristics in patients with tilted disc syndrome

Purpose: To evaluate the ocular refractive and biometric characteristics in patients with tilted disc syndrome (TDS). Methods: This case-control study comprised 41 eyes of 25 patients with established TDS and forty eyes of 20 age- and sex-matched healthy control subjects. All had a complete ocular examination including refraction and analysis using Fourier transformation, slit lamp biomicroscopy, pachymetry keratometry, and ocular biometry. Corneal topography examinations were performed in the syndrome group only. Results: There were no significant differences in spherical equivalent (p = 0.334) and total astigmatism (p= 0.246) between groups. However, mean best spectacular corrected visual acuity was significantly worse in TDS patients (P < 0.001). The lenticular astigmatism was significantly greater in the syndrome group, while the corneal component was greater in the controls (p = 0.004 and p = 0.002, respectively). The measured biometric features were the same in both groups, except for the lens thickness, relative lens position, and lens-axial length factor which were greater in the TDS group (p = 0.002, p = 0.015, and p = 0.025, respectively). Conclusions: Clinically significant lenticular astigmatism, more oblique corneal astigmatism, and thicker lens were characteristic findings in patients with TDS.

Biomarkers of exercise-induced myocardial stress in relation to inflammatory and oxidative stress

Increased concentrations of biomarkers reflecting myocardial stress such as cardiac troponin I and T and brain natriuretic peptide (BNP) have been observed following strenuous, long-lasting endurance exercise. The pathophysiological mechanisms are still not fully elucidated and the interpretations of increased post-exercise concentrations range from (i) evidence for exercise-induced myocardial damage to (ii) non-relevant spurious troponin elevations, presumably caused by assay imprecision or heterophilic antibodies. Several lines of evidence suggest that inflammatory processes or oxidative stress could be involved in the rise of NT-proBNP and Troponin observed in critically ill patients with sepsis or burn injury. We tested the hypothesis that inflammatory or oxidative stress is also responsible for exercise-induced cardiomyocyte strain in a large cohort of triathletes following an Ironman triathlon. However, the post-race increase in cardiac troponin T and NT-proBNP was not associated with several markers of exercise-induced inflammation, oxidative stress or antioxidant vitamins. Therefore, we clearly need more studies with other inflammatory markers and different designs to elucidate the scientific background for increases in myocardial stress markers following strenuous endurance events.

Exercise-induced DNA damage: Is there a relationship with inflammatory responses?

Both a systemic inflammatory response as well as DNA damage has been observed following exhaustive endurance exercise. Hypothetically, exercise-induced DNA damage might either be a consequence of inflammatory processes or causally involved in inflammation and immunological alterations after strenuous prolonged exercise (e.g. by inducing lymphocyte apoptosis and lymphocytopenia). Nevertheless, up to now only few studies have addressed this issue and there is hardly any evidence regarding a direct relationship between DNA or chromosomal damage and inflammatory responses in the context of exercise. The most conclusive picture that emerges from available data is that reactive oxygen and nitrogen species (RONS) appear to be the key effectors which link inflammation with DNA damage. Considering the time-courses of inflammatory and oxidative stress responses on the one hand and DNA effects on the other the lack of correlations between these responses might also be explained by too short observation periods. This review summarizes and discusses the recent findings on this topic. Furthermore, data from our own study are presented that aimed to verify potential associations between several endpoints of genome stability and inflammatory, immune-endocrine and muscle damage parameters in competitors of an Ironman triathlon until 19 days into recovery. The current results indicate that DNA effects in lymphocytes are not responsible for exercise-induced inflammatory responses. Furthermore, this investigation shows that inflammatory processes, vice versa, do not promote DNA damage, neither directly nor via an increased formation of RONS derived from inflammatory cells. Oxidative DNA damage might have been counteracted by training- and exercise-induced antioxidant responses. However, further studies are needed that combine advanced -omics based techniques (transcriptomics, proteomics) with state-of-the-art biochemical biomarkers to gain more insights into the underlying mechanisms.