Optogenetic stimulation of striatal patches modifies habit formation and inhibits dopamine release.

Habits are inflexible behaviors that develop after extensive repetition, and overreliance on habits is a hallmark of many pathological states. The striatum is involved in the transition from flexible to inflexible responding, and interspersed throughout the striatum are patches, or striosomes, which make up ~15% of the volume of the striatum relative to the surrounding matrix compartment. Previous studies have suggested that patches are necessary for normal habit formation, but it remains unknown exactly how patches contribute to habit formation and expression. Here, using optogenetics, we stimulated striatal patches in Sepw1-NP67 mice during variable interval training (VI60), which is used to establish habitual responding. We found that activation of patches at reward retrieval resulted in elevated responding during VI60 training by modifying the pattern of head entry and pressing. Further, this optogenetic manipulation reduced subsequent responding following reinforcer devaluation, suggesting modified habit formation. However, patch stimulation did not generally increase extinction rates during a subsequent extinction probe, but did result in a small 'extinction burst', further suggesting goal-directed behavior. On the other hand, this manipulation had no effect in omission trials, where mice had to withhold responses to obtain rewards. Finally, we utilized fast-scan cyclic voltammetry to investigate how patch activation modifies evoked striatal dopamine release and found that optogenetic activation of patch projections to the substantia nigra pars compacta (SNc) is sufficient to suppress dopamine release in the dorsal striatum. Overall, this work provides novel insight into the role of the patch compartment in habit formation, and provides a potential mechanism for how patches modify habitual behavior by exerting control over dopamine signaling.

Relating student perceptions of readiness to student success: A case study of a mathematics module.

This study correlates the readiness survey scores of bona fide first year university students with their success in a mathematically based first year module. It follows on the need for skilled individuals in the fields of Science and Technology that exists across the globe and is continually becoming the focus of educational institutions world-wide. Similarly, in South Africa, universities were instructed to increase their intake of students in the fields of Science and Technology so as to provide for the technology orientated needs of the country, as well as to increase participation of previously disadvantaged race groups in these fields. In response to this instruction, universities increased the number of students enrolled in Science and Technology fields by 23% in recent years. The challenge is now to ensure that these students exit the university with a suitable degree in the shortest possible time. Statistics published by the South African Council of Higher Education affirms the extent of this challenge faced by universities-only 51% of students enrolled in the fields of Science and Technology complete their 3-year undergraduate degrees, and some of them took as long as 6 years to complete the 3-year degrees. This still leaves 49% of students that either took more than 6 years to complete their degrees, or did not complete their degrees at all. The underlying cause(s) for these failures must be identified and addressed. As a starting point in this discussion, the questions that this study aim to answer are whether first year students are in fact as prepared for the challenges at university as they perceive themselves to be; and whether student readiness (or lack thereof) can be a root cause for the low throughput rates. This study determines how prepared first year students, at a leading South African university, perceive themselves to be for the demands of university and, specifically, how their perceptions of their readiness in different areas correlate with their academic success in a mathematically based module. The correlation is determined by analysing data gathered through a readiness survey that is completed by first year students at the beginning of the academic year, and their final mark in the mathematics based first year module. The survey is a standardised, self-evaluation tool originally developed by the University of Pretoria. It is also applied at the university where this study is conducted. The survey measures the preparedness of students in different areas and the empirical study shows that there is a statistically significant correlation between the perception of the students regarding their planning ability and the final mark obtained in the mathematics based module.

Whole genome sequencing reveals genomic heterogeneity and antibiotic purification in Mycobacterium tuberculosis isolates.

BACKGROUND: Whole genome sequencing has revolutionised the interrogation of mycobacterial genomes. Recent studies have reported conflicting findings on the genomic stability of Mycobacterium tuberculosis during the evolution of drug resistance. In an age where whole genome sequencing is increasingly relied upon for defining the structure of bacterial genomes, it is important to investigate the reliability of next generation sequencing to identify clonal variants present in a minor percentage of the population. This study aimed to define a reliable cut-off for identification of low frequency sequence variants and to subsequently investigate genetic heterogeneity and the evolution of drug resistance in M. tuberculosis. METHODS: Genomic DNA was isolated from single colonies from 14 rifampicin mono-resistant M. tuberculosis isolates, as well as the primary cultures and follow up MDR cultures from two of these patients. The whole genomes of the M. tuberculosis isolates were sequenced using either the Illumina MiSeq or Illumina HiSeq platforms. Sequences were analysed with an in-house pipeline. RESULTS: Using next-generation sequencing in combination with Sanger sequencing and statistical analysis we defined a read frequency cut-off of 30% to identify low frequency M. tuberculosis variants with high confidence. Using this cut-off we demonstrated a high rate of genetic diversity between single colonies isolated from one population, showing that by using the current sequencing technology, single colonies are not a true reflection of the genetic diversity within a whole population and vice versa. We further showed that numerous heterogeneous variants emerge and then disappear during the evolution of isoniazid resistance within individual patients. Our findings allowed us to formulate a model for the selective bottleneck which occurs during the course of infection, acting as a genomic purification event. CONCLUSIONS: Our study demonstrated true levels of genetic diversity within an M. tuberculosis population and showed that genetic diversity may be re-defined when a selective pressure, such as drug exposure, is imposed on M. tuberculosis populations during the course of infection. This suggests that the genome of M. tuberculosis is more dynamic than previously thought, suggesting preparedness to respond to a changing environment.

Phage-based detection of bacterial pathogens.

Bacterial pathogens cause significant morbidity and mortality annually to both humans and animals. With the rampant spread of drug resistance and the diminishing effectiveness of current antibiotics, there is a pressing need for effective diagnostics for detection of bacterial pathogens and their drug resistances. Bacteriophages offer several unique opportunities for bacterial detection. This review highlights the means by which bacteriophages have been utilized to achieve and facilitate specific bacterial detection.

The bioequivalence of liquid and freeze-dried formulations of recombinant human chorionic gonadotrophin.

OBJECTIVE: To compare the bioavailability and tolerability of liquid and freeze-dried formulations of recombinant human chorionic gonadotrophin (r-hCG). SUBJECTS AND METHODS: In an open-label, randomised, single-centre, Phase I study, healthy adult volunteers (18-50 years of age) received single injections of r-hCG 250 microg from reconstituted freeze-dried (1.0 mL of 250 microg/mL) and liquid (0.5 mL of 250 microg/0.5 mL) formulations in random order, separated by a 10-day wash-out period. Pharmacokinetics (C(max), AUC, AUC(last), t(max)) and local and systemic tolerability were assessed. RESULTS: Pharmacokinetic properties of the two formulations were very similar, with mean C(max) 125 mIU/mL (liquid formulation) vs 129 mIU/mL (freeze-dried formulation), mean AUC 10,350 mIU.h/mL vs 10,480 mIU(.)h/mL, mean AUC(last) 10,050 mIU.h/mL vs 10,210 mIU.h/mL, and median t(max) 20 vs 24h. The 90% confidence intervals of the ratios of the treatment means for C(max), AUC and AUC(last) all fell within the pre-defined FDA acceptance range of 0.8-1.25, demonstrating the bioequivalence of the two formulations. Both formulations were equally well tolerated; the most frequent adverse events were headache and nausea. CONCLUSION: The liquid formulation of r-hCG was shown to be bioequivalent to the freeze-dried formulation, with no clinically significant differences in tolerability. The liquid formulation of r-hCG can be expected to provide the same efficacy and tolerability as the freeze-dried formulation when used to trigger final follicular maturation in women undergoing therapies for assisted reproduction, together with a greater convenience of use.

Spontaneous drainage of an infratentorial extradural empyema: case report.

We describe a 21-year-old male who presented with spontaneous drainage of an infratentorial extradural empyema secondary to mastoiditis. Following eradication of the primary source, the patient was commenced on high dose intravenous antibiotics. Serial computed tomography (CT) revealed complete resolution of the pus collection. Antibiotic therapy was successful and no neurosurgical intervention was necessary.

Chronological age is a multifactorial prognostic variable in patients with non-Hodgkin's lymphoma.

In order to assess the predictive capacity of chronological age for survival, an analysis of prognostic variables was performed on 277 patients with Non-Hodgkin's Lymphoma, 84 of whom were older than 65 years. All patients were seen at a single institution, and elderly patients, who might otherwise have been excluded from study analysis, were included. Seventeen clinical, radiological and laboratory parameters were evaluated and subjected to univariate and multivariate analyses. Patients older than 65 years had a significantly poorer survival than those younger than 65 years. When the whole group was considered in a multivariate (Cox) model, the factors that independently predicted a longer survival were a good performance status, age less than 65 years and a low grade histological subtype. When patients older and younger than 65 years were analyzed separately the prognostic variables in the elderly were found to be similar to those in younger patients. The predictive capacity of chronological age was found to be influenced by a poor performance status, the presence of concomitant disease, the dose intensity and tolerance of the treatment given, as well as the physiological reserve of the patient. It is concluded that chronological age is a multifactorial prognostic parameter encompassing a number of patient and treatment factors, all of which must be considered when evaluating the capacity of chronological age to predict survival in patients with Non-Hodgkin's Lymphoma.

Factors influencing prognosis in elderly patients with primary breast cancer.

A retrospective analysis was performed on 260 elderly and 294 middle-aged patients with primary breast cancer. Cox regression analysis showed that the classic prognostic factors, such as negative lymph node status, small tumour size and positive oestrogen receptor (ER) status, were favourable indicators of survival and were similar in both the elderly and the middle-aged. When the elderly and middle-aged were considered together, older age (favourable) and the presence of association disease (detrimental) were additional significant prognostic factors. It is concluded that a physically fit elderly woman in the present study had a more favourable survival outlook than a younger counterpart with similar tumor size, lymph node and ER status and should be given the best available treatment based on tumour characteristics and not on age alone.

Metastatic breast cancer--age has a significant effect on survival.

The data on 217 elderly (aged greater than or equal to 65 years) and 209 middle-aged postmenopausal patients with metastatic breast cancer treated in the Department of Medical Oncology, University of Pretoria, from 1976 to 1985 were analysed to determine the effect of age on survival. When considered as a group, the elderly have a more favourable prognosis (median survival 20.3 months) than the middle-aged (median survival 15.54 months) (P = 0.0457). Multivariate age subset analysis (taking into account all other major prognostic factors) reveal a distinct bimodal pattern. The median survival of patients aged 45-54 years is 21.2 months and decreases to 16.2 months for patients aged 55-64 years (P = 0.08; Cox model). The median survival improves again to 24.6 months for patients aged 64-74 years (P = 0.0001; Cox model), followed by an apparent but non-significant decrease to 17.1 months in the very old (aged 75-84 years) (P = 0.52; Cox model). The more favourable prognosis in the elderly dictates effective non-toxic treatment.