Presenilin is necessary for the function of CBP in the adult Drosophila CNS

Dominant mutations in Presenilin (Psn) have been correlated with the formation of Aß- containing plaques in patients with inherited forms of Alzheimer\u27s disease (AD). However, a clear mechanism directly linking amyloid plaques to the pathology of familial or sporadic forms of AD has remained elusive. Thus, recent discoveries of several new substrates for Psn protease activity have sparked alternative hypotheses to explain the preclinical symptoms of AD. CBP (CREB-binding protein) is a haplo- insufficient transcriptional co-activator with histone acetyltransferase (HAT) activity that has been proposed to be a downstream target for Psn signaling. Individuals with reduced CBP levels have cognitive deficits that have been linked to several neurological disorders. However, there are contradictory reports in the vertebrate literature regarding the relationship between Psn activity and CBP levels. This dissertation using Drosophila melanogaster, provides evidence for the first time that Psn is required for normal CBP levels and for maintaining global acetylations of the central nervous system of the adult fly. This work also demonstrates that adult flies conditionally compromised for CBP display an altered geotaxis response to gravity that likely reflects a neurological defect. The association between Psn and CBP is most likely not direct, but through a signaling molecule released via Psn-mediated substrate processing. One possible candidate for this intermediate molecule is the transmembrane receptor Notch. Notch is attractive because it has been shown previously to be required for long-term memory, and I have provided evidence here that suggests Notch is required for neurite outgrowth through the culturing of primary neurons of the mushroom body (a region known to be important for learning and memory in flies). In addition I have located putative DNA binding sites for the Notch transcription factor Su(H) in the CBP enhancer, which suggests a regulatory role for Notch in CBP transcription. Although this is an attractive model, my data do not support it. Therefore it is likely that Notch and Psn/CBP control functions of the adult CNS through independent signaling molecules or pathways. If the model proves correct for vertebrates, it will have a significant impact on the development of new therapies and pharmaceuticals agents for the treatment of Alzheimer\u27s disease

Diagnosis of bacterial infection

Accurate diagnosis of bacterial infection is crucial to avoid unnecessary antibiotic use and to focus  appropriate therapy. Bacterial infection is the combination of the presence of bacteria and inflammation or  systemic dysfunction; therefore, more than one diagnostic modality is usually required for  confirmation. History and examination to determine if a patient fits a clinical case definition is sometimes adequate to confirm or exclude a diagnosis. The second stage is bedside tests – some are used widely, such as urine dipstick tests, but  others, such as skin scrapings of petechial rashes, are underutilised. The third stage is laboratory tests – indirect non-culture-based tests, including C-reactive protein and procalcitonin tests, when negative, can be used to prevent the unnecessary use of antibiotics. Direct non-culture-based tests detect antigens or specific antibodies, e.g. group A streptococcal antigen testing can be employed to reduce antibiotic use. Culture-based tests are often considered the reference standard in modern microbiology. Because of slow turnaround times, these tests are frequently used to focus or stop antibiotic therapy after empiric initiation. Nucleic acid  amplification tests raise the possibility of detecting organisms with high sensitivity, specificity and reduced turnaround time, and novel diagnostic modalities relying on nanotechnology and mass spectrometry may dramatically alter the practice of microbiology in future

Teaching Livestock Producers to Use Handheld Computers

Mandatory animal ID is a well-discussed topic among livestock producers. A national ID program will probably require animal records to be maintained in electronic format. A 2-day intensive training was held to help cattle producers become proficient in using a handheld computer for animal record keeping. On an end-of-meeting evaluation, 99% of the participants felt a handheld computer would make record keeping tasks easier. A follow-up survey was mailed 1 year after the program generated a 70% response rate. After one year, only 57% of the participants felt that the handheld computer made their record-keeping task easier

Human ApoD, an apolipoprotein up-regulated in neurodegenerative diseases, extends lifespan and increases stress resistance in Drosophila

Apolipoprotein D (ApoD) expression increases in several neurological disorders and in spinal cord injury. We provide a report of a physiological role for human ApoD (hApoD): Flies overexpressing hApoD are long-lived and protected against stress conditions associated with aging and neurodegeneration, including hyperoxia, dietary paraquat, and heat stress. We show that the fly ortholog, Glial Lazarillo, is strongly up-regulated in response to these extrinsic stresses and also can protect in vitro-cultured cells in situations modeling Alzheimer's disease (AD) and Parkinson's disease (PD). In adult flies, hApoD overexpression reduces age-associated lipid peroxide accumulation, suggesting a proximal mechanism of action. Similar data obtained in the mouse [Ganfornina, M.D., et al., (2008) Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress. Aging Cell 10.1111/j.1474-9726.2008.00395.] as well as in plants (Charron et al., personal communication) suggest that ApoD and its orthologs play an evolutionarily conserved role in response to stress, possibly managing or preventing lipid peroxidation

VLBI astrometry of PSR J2222-0137: a pulsar distance measured to 0.4% accuracy

The binary pulsar J2222-0137 is an enigmatic system containing a partially recycled millisecond pulsar and a companion of unknown nature. Whilst the low eccentricity of the system favors a white dwarf companion, an unusual double neutron star system is also a possibility, and optical observations will be able to distinguish between these possibilities. In order to allow the absolute luminosity (or upper limit) of the companion object to be properly calibrated, we undertook astrometric observations with the Very Long Baseline Array to constrain the system distance via a measurement of annual geometric parallax. With these observations, we measure the parallax of the J2222-0137 system to be 3.742 +0.013 -0.016 milliarcseconds, yielding a distance of 267.3 +1.2 -0.9 pc, and measure the transverse velocity to be 57.1 +0.3 -0.2 km/s. Fixing these parameters in the pulsar timing model made it possible to obtain a measurement of Shapiro delay and hence the system inclination, which shows that the system is nearly edge-on (sin i = 0.9985 +/- 0.0005). Furthermore, we were able to detect the orbital motion of J2222-0137 in our VLBI observations and measure the longitude of ascending node. The VLBI astrometry yields the most accurate distance obtained for a radio pulsar to date, and is furthermore the most accurate parallax for any radio source obtained at "low" radio frequencies (below ~5 GHz, where the ionosphere dominates the error budget). Using the astrometric results, we show the companion to J2222-0137 will be easily detectable in deep optical observations if it is a white dwarf. Finally, we discuss the implications of this measurement for future ultra-high-precision astrometry, in particular in support of pulsar timing arrays.Comment: 22 pages, 7 figures, accepted for publication in Ap

Factors influencing retention in care after starting antiretroviral therapy in a rural South African programme

The prognosis of patients with HIV in Africa has improved with the widespread use of antiretroviral therapy (ART) but these successes are threatened by low rates of long-term retention in care. There are limited data on predictors of retention in care, particularly from rural sites. METHODS: Prospective cohort analysis of outcome measures in adults from a rural HIV care programme in Madwaleni, Eastern Cape, South Africa. The ART programme operates from Madwaleni hospital and seven primary care feeder clinics with full integration between inpatient and outpatient services. Outreach workers conducted home visits for defaulters. RESULTS: 1803 adults initiated ART from June 2005 to May 2009. At the end of the study period 82.4% were in active care or had transferred elsewhere, 11.1% had died and 6.5% were lost to follow-up (LTFU). Independent predictors associated with an increased risk of LTFU were CD4 nadir >200, initiating ART as an inpatient or while pregnant, and younger age, while being in care for >6 months before initiating ART was associated with a reduced risk. Independent factors associated with an increased risk of mortality were baseline CD4 count 6 months before initiating ART and initiating ART while pregnant were associated with a reduced risk. CONCLUSIONS: Serving a socioeconomically deprived rural population is not a barrier to successful ART delivery. Patients initiating ART while pregnant and inpatients may require additional counselling and support to reduce LTFU. Providing HIV care for patients not yet eligible for ART may be protective against being LTFU and dying after ART initiation

Preparing healthcare facilities to operate safely and effectively during the COVID-19 pandemic: The missing piece in the puzzle

The stated objective of the COVID-19 lockdown was to allow time to prepare healthcare facilities. Preparation must include administrative and environmental measures, which when combined with personal protective equipment, minimise the risk of the spread of infection to patients and healthcare workers (HCWs) in facilities, allowing HCWs to safely provide essential services during the pandemic and limit the indirect effects of COVID-19 caused by healthcare disruption. We present our model for facility preparation based on colour-coded zones, social distancing, hand hygiene, rapid triage and separate management of symptomatic patients, and attention to infection transmission prevention between HCWs in communal staff areas. This model specifically addresses the challenges in preparing a facility for COVID-19 in a low-resource setting and in rural areas. In addition, we include links to resources to allow workers in low-resource settings to prepare their facilities adequately

A Population Of Non-Recycled Pulsars Originating In Globular Clusters

We explore the enigmatic population of long-period, apparently non-recycled pulsars in globular clusters, building on recent work by Boyles et al. This population is difficult to explain if it formed through typical core-collapse supernovae, leading many authors to invoke electron capture supernovae. While Boyles et al. dealt only with non-recycled pulsars in clusters, we focus on the pulsars that originated in clusters but then escaped into the field of the Galaxy due to the kicks they receive at birth. The magnitude of the kick induced by electron capture supernovae is not well known, so we explore various models for the kick velocity distribution and size of the population. The most realistic models are those where the kick velocity is 10 km s–1 and where the number of pulsars scales with the luminosity of the cluster (as a proxy for cluster mass). This is in good agreement with other estimates of the electron capture supernovae kick velocity. We simulate a number of large-area pulsar surveys to determine if a population of pulsars originating in clusters could be identified as being separate from normal disk pulsars. We find that the spatial and kinematical properties of the population could be used, but only if large numbers of pulsars are detected. In fact, even the most optimistic surveys carried out with the future Square Kilometer Array are likely to detect \u3c10% of the total population, so the prospects for identifying these as a separate group of pulsars are presently poor

South African medical students’ perceptions and knowledge about antibiotic resistance and appropriate prescribing: Are we providing adequate training to future prescribers?

Background. Education of medical students has been identified by the World Health Organization as an important aspect of antibiotic resistance (ABR) containment. Surveys from high-income countries consistently reveal that medical students recognise the importance of antibiotic prescribing knowledge, but feel inadequately prepared and require more education on how to make antibiotic choices. The attitudes and knowledge of South African (SA) medical students regarding ABR and antibiotic prescribing have never been evaluated.Objective. To evaluate SA medical students’ perceptions, attitudes and knowledge about antibiotic use and resistance, and the perceived quality of education relating to antibiotics and infection.Methods. This was a cross-sectional survey of final-year students at three medical schools, using a 26-item self-administered questionnaire. The questionnaires recorded basic demographic information, perceptions about antibiotic use and ABR, sources, quality, and usefulness of current education about antibiotic use, and questions to evaluate knowledge. Hard-copy surveys were administered during whole-class lectures.Results. A total of 289 of 567 (51%) students completed the survey. Ninety-two percent agreed that antibiotics are overused and 87% agreed that resistance is a significant problem in SA – higher proportions than those who thought that antibiotic overuse (63%) and resistance (61%) are problems in the hospitals where they had worked (p<0.001). Most reported that they would appreciate more education on appropriate use of antibiotics (95%). Only 33% felt confident to prescribe antibiotics, with similar proportions across institutions. Overall, prescribing confidence was associated with the use of antibiotic prescribing guidelines (p=0.003), familiarity with antibiotic stewardship (p=0.012), and more frequent contact with infectious diseases specialists (p<0.001). There was an overall mean correct score of 50% on the knowledge questionnaire, with significant differences between institutions. Students who used antibiotic prescribing guidelines and found their education more useful scored higher on knowledge questionnaires.Conclusion. There are low levels of confidence with regard to antibiotic prescribing among final-year medical students in SA, and most students would like more education in this area. Perceptions that ABR is less of a problem in their local setting may contribute to inappropriate prescribing behaviours. Differences exist between medical schools in knowledge about antibiotic use, with suboptimal scores across institutions. The introduction and use of antibiotic prescribing guidelines and greater contact with specialists in antibiotic prescribing may improve prescribing behaviours