Extracellular levels of glucose in the hippocampus and striatum during maze training for food or water reward in male rats.

Glucose potently enhances cognitive functions whether given systemically or directly to the brain. The present experiments examined changes in brain extracellular glucose levels while rats were trained to solve hippocampus-sensitive place or striatum-sensitive response learning tasks for food or water reward. Because there were no task-related differences in glucose responses, the glucose results were pooled across tasks to form combined trained groups. During the first 1-3 min of training for food reward, glucose levels in extracellular fluid (ECF) declined significantly in the hippocampus and striatum; the declines were not seen in untrained, rewarded rats. When trained for water reward, similar decreases were observed in both brain areas, but these findings were less consistent than those seen with food rewards. After the initial declines in ECF glucose levels, glucose increased in most groups, approaching asymptotic levels ∼15-30 min into training. Compared to untrained food controls, training with food reward resulted in significant glucose increases in the hippocampus but not striatum; striatal glucose levels exhibited large increases to food intake in both trained and untrained groups. In rats trained to find water, glucose levels increased significantly above the values seen in untrained rats in both hippocampus and striatum. The decreases in glucose early in training might reflect an increase in brain glucose consumption, perhaps triggering increased brain uptake of glucose from blood, as evident in the increases in glucose later in training. The increased brain uptake of glucose may provide additional neuronal metabolic substrate for metabolism or provide astrocytic substrate for production of glycogen and lactate.

Aging is not equal across memory systems.

The present experiments compared the effects of aging on learning several hippocampus- and striatum-sensitive tasks in young (3-4 month) and old (24-28 month) male Fischer-344 rats. Across three sets of tasks, aging was accompanied not only by deficits on hippocampal tasks but also by maintained or even enhanced abilities on striatal tasks. On two novel object recognition tasks, rats showed impaired performance on a hippocampal object location task but enhanced performance on a striatal object replacement task. On a dual solution task, young rats predominately used hippocampal solutions and old rats used striatal solutions. In addition, on two maze tasks optimally solved using either hippocampus-sensitive place or striatum-sensitive response strategies, relative to young rats, old rats had impaired learning on the place version but equivalent learning on the response version. Because glucose treatments can reverse deficits in learning and memory across many tasks and contexts, levels of available glucose in the brain may have particular importance in cognitive aging observed across tasks and memory systems. During place learning, training-related rises in extracellular glucose levels were attenuated in the hippocampus of old rats compared to young rats. In contrast, glucose levels in the striatum increased comparably in young and old rats trained on either the place or response task. These extracellular brain glucose responses to training paralleled the impairment in hippocampus-sensitive learning and the sparing of striatum-sensitive learning seen as rats age, suggesting a link between age-related changes in learning and metabolic substrate availability in these brain regions.

The cross-sectional association between diabetes and orthostatic hypotension in community-dwelling older people.

AIMS: Orthostatic hypotension is a recognized complication of diabetes, but studies examining prevalence in diabetes are limited. The aim of this study was to ascertain the prevalence of orthostatic hypotension and the pattern of orthostatic BP response in a cohort of people with diabetes aged ≥ 50 years, embedded within the Irish Longitudinal Study of Ageing. METHODS: Orthostatic hypotension was defined as a drop in systolic blood pressure (SBP) ≥ 20 mmHg or drop in diastolic blood pressure (DBP) ≥ 10 mmHg at 30 s after standing. Diabetes was defined by self-report but cross-checked against HbA1c and medication records. Multilevel mixed effects linear regression models were used to compare orthostatic BP in people with and without diabetes. RESULTS: Some 3222 people were included, 7% (213 of 3222) of whom had diabetes. Prevalence of orthostatic hypotension in the group with diabetes was 22% (46 of 213) vs. 13% in those without diabetes; χ2 = 12.43; P < 0.001. Multilevel models demonstrated prolonged recovery of DBP in people with diabetes, with only 41% (87 of 213) returning to baseline by 60 s. Logistic regression models demonstrated that diabetes was associated with a significantly increased likelihood of orthostatic hypotension (odds ratio 1.84, 95% confidence interval 1.30-2.59; P = 0.001) and this remained robust after controlling for covariates. CONCLUSION: Over one-fifth of older people with diabetes had orthostatic hypotension. Recovery of DBP is related to dynamic changes in total peripheral resistance and impairment of this baroreflex-mediated response may explain the higher prevalence in diabetes. Given the prognostic implications when co-existing with diabetes, orthostatic hypotension may represent a potentially modifiable risk factor for adverse outcomes in late-life diabetes.

Spatial Accuracy of a Clinically Established Noninvasive Electrocardiographic Imaging System for the Detection of Focal Activation in an Intact Porcine Model.

BACKGROUND: Noninvasive electrocardiographic imaging (ECGi) is used clinically to map arrhythmias before ablation. Despite its clinical use, validation data regarding the accuracy of the system for the identification of arrhythmia foci is limited. METHODS: Nine pigs underwent closed-chest placement of endocardial fiducial markers, computed tomography, and pacing in all cardiac chambers with ECGi acquisition. Pacing location was reconstructed from biplane fluoroscopy and registered to the computed tomography using the fiducials. A blinded investigator predicted the pacing location from the ECGi data, and the distance to the true pacing catheter tip location was calculated. RESULTS: A total of 109 endocardial and 9 epicardial locations were paced in 9 pigs. ECGi predicted the correct chamber of origin in 85% of atrial and 92% of ventricular sites. Lateral locations were predicted in the correct chamber more often than septal locations (97% versus 79%, P=0.01). Absolute distances in space between the true and predicted pacing locations were 20.7 (13.8-25.6) mm (median and [first-third] quartile). Distances were not significantly different across cardiac chambers. CONCLUSIONS: The ECGi system is able to correctly identify the chamber of origin for focal activation in the vast majority of cases. Determination of the true site of origin is possible with sufficient accuracy with consideration of these error estimates.

Clinical utility of portable electrophysiology to measure fatigue in treatment-naïve non-small cell lung cancer.

PURPOSE: Cancer-related fatigue (CRF) biology remains poorly understood. Responsible mechanisms may be central or peripheral and originate anywhere from the brain to muscle fiber. Objective measurement is complex and previously limited to specialized laboratories. Portable electroencephalography (EEG) and electromyography (EMG) may enhance objective measurement. This study evaluated the feasibility and acceptability of portable EMG-EEG in CRF assessment. METHODS: A prospective observational feasibility study compared ten outpatients with inoperable, treatment-naïve non-small cell lung cancer and CRF to ten healthy volunteers. All completed a sustained isometric hand-grip contraction at 30% maximal level until self-perceived exhaustion. 128-channel EEG and 2-channel EMG signals of forearm muscles were recorded. Device acceptability was evaluated by questionnaire. RESULTS: The task was evaluated in two stages; first and last 20 s. CRF cohort perceived exhaustion earlier than volunteers (mean 137 ± 76 s vs 208 ± 51 s). As fatigue progressed, EMG amplitude increased significantly (CRF p = 0.02; volunteers: p = 0.04) in both groups as did EMG beta band power (CRF p = 0.008; volunteers: p = 0.006). The increase was significantly less in CRF (amplitude p = 0.032; beta power: p = 0.014). EEG beta band power in the contralateral motor cortex increased significantly (CRF p = 0.03; volunteers: p = 0.019) in both cohorts but to greater extent (p = 0.024) in CRF. One hundred percent device acceptability was reported. CONCLUSIONS: A laboratory-based evaluation was successfully adapted to the outpatient setting during routine visits. High acceptability supports clinical utility. In CRF, a higher degree of cortical activation was required to drive a much lower level of muscle performance. This suggests impairment of both central and peripheral mechanisms in CRF.

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. METHODS: We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. RESULTS: Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. CONCLUSIONS: HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

Staging of squamous cell carcinoma of the tongue: extrinsic lingual muscles and the 8th editions of the American Joint Committee on Cancer/Union for International Cancer Control staging manuals.

Our aim was to find out first whether the extrinsic muscles of the tongue are histologically identifiable, and secondly to what degree the use of the new criteria in the 8th editions of the American Joint Committee on Cancer(AJCC)/Union for International Cancer Control (UICC) manuals (which have recognised the importance of depth of invasion of tumour, rather than invasion of the extrinsic muscles of the tongue and extranodal extension), will alter staging of lingual squamous cell carcinoma (SCC). The histological sections from 165 patients who had had primary resection of lingual SCC were reviewed, and one or more extrinsic muscles of the tongue was identified in 100 patients (61%), with the genioglossus seen the most often (in 96). By contrast, the hyoglossus was identified in only eight patients, the styloglossus in two, and the palatoglossus in none. Identification was straightforward only in extensive resections. Applying the criteria from the 8th edition increased the number of pT3 SCC with a simultaneous reduction in pT4a tumours. The number of pN2b SCC was also reduced, but the new category of pN3b meant that overall 53% of tumours were upstaged. The kappa scores for agreement between the two sets of criteria were 0.221 (weighted 0.410) for the pT values, 0.508 (0.713) for pN values (but 0.227, weighted 0.386, if the pN0 values were removed before calculation), and 0.243 (0.514) for overall stage, indicating poor to fair agreement. We conclude that the removal of invasion of extrinsic muscles of the tongue as a criterion for a pT4a SCC is justified, and that many SCC of the tongue will be upstaged as a result of implementation of the 8th editions.

Inflammatory pseudotumour of the maxilla.

Inflammatory pseudotumour (IP), also known as inflammatory myofibroblastic tumour (IMT), is a rare lesion of the maxillofacial skeleton and a diagnosis by exclusion. We describe three cases which affected the maxilla, two women and one man of ages 67, 56 and 70 years at presentation. All showed the typical, rather non-specific histopathological features. IgG4-positive plasma cells varied greatly in prominence, and none of the three lesions expressed ALK-1. Both women responded to steroids and radiotherapy, though one also required azathioprine. Despite maxillectomy, radiotherapy, steroids and cyclophosphamide, the man suffered intracranial spread and succumbed to persistent disease. The cases described here demonstrate the clinicopathological difficulties presented by this entity and its aggressive, unpredictable behaviour.

Current Concepts in Osteoradionecrosis after Head and Neck Radiotherapy.

Osteoradionecrosis (ORN) of the jaws is a feared complication of head and neck radiotherapy. ORN causes significant morbidity for patients and controversy among clinicians. This overview considers the variations in definition and classification of the condition that affect estimates of incidence and also the interpretation of evidence. The influence of newer radiotherapy techniques in reducing ORN through reduced dose and xerostomia is balanced against a probable increase in a vulnerable population through a rising head and neck cancer incidence. Theories of pathophysiology of ORN include radiation-induced osteomyelitis, hypoxic and hypovascular theory and fibroatrophic theory. Prevention strategies include restorative dentistry and radiation planning techniques. Treatments range from conservative 'watch and wait' through to more radical surgical strategies. Newer medical management strategies are available with a limited evidence base. The use of hyperbaric oxygen therapy remains controversial and the background and need for newer hyperbaric oxygen trials is discussed.

Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist.

RATIONALE: Scopolamine, a muscarinic antagonist, impairs learning and memory for many tasks, supporting an important role for the cholinergic system in these cognitive functions. The findings are most often interpreted to indicate that a decrease in postsynaptic muscarinic receptor activation mediates the memory impairments. However, scopolamine also results in increased release of acetylcholine in the brain as a result of blocking presynaptic muscarinic receptors. OBJECTIVES: The present experiments assess whether scopolamine-induced increases in acetylcholine release may impair memory by overstimulating postsynaptic cholinergic nicotinic receptors, i.e., by reaching the high end of a nicotinic receptor activation inverted-U dose-response function. RESULTS: Rats tested in a spontaneous alternation task showed dose-dependent working memory deficits with systemic injections of mecamylamine and scopolamine. When an amnestic dose of scopolamine (0.15 mg/kg) was co-administered with a subamnestic dose of mecamylamine (0.25 mg/kg), this dose of mecamylamine significantly attenuated the scopolamine-induced memory impairments. We next assessed the levels of acetylcholine release in the hippocampus in the presence of scopolamine and mecamylamine. Mecamylamine injections resulted in decreased release of acetylcholine, while scopolamine administration caused a large increase in acetylcholine release. CONCLUSIONS: These findings indicate that a nicotinic antagonist can attenuate impairments in memory produced by a muscarinic antagonist. The nicotinic antagonist may block excessive activation of nicotinic receptors postsynaptically or attenuate increases in acetylcholine release presynaptically. Either effect of a nicotinic antagonist-to decrease scopolamine-induced increases in acetylcholine output or to decrease postsynaptic acetylcholine receptor activation-may mediate the negative effects on memory of muscarinic antagonists.

T cell anergy and activation are associated with suboptimal humoral responses to measles revaccination in HIV-infected children on anti-retroviral therapy in Nairobi, Kenya.

HIV-infected children are less capable of mounting and maintaining protective humoral responses to vaccination against measles compared to HIV-uninfected children. This poses a public health challenge in countries with high HIV burdens. Administration of anti-retroviral therapy (ART) and revaccinating children against measles is one approach to increase measles immunity in HIV-infected children, yet it is not effective in all cases. Immune anergy and activation during HIV infection are factors that could influence responses to measles revaccination. We utilized a flow cytometry-based approach to examine whether T cell anergy and activation were associated with the maintenance of measles-specific immunoglobulin (Ig)G antibodies generated in response to measles revaccination in a cohort of HIV-infected children on ART in Nairobi, Kenya. Children who sustained measles-specific IgG for at least 1 year after revaccination displayed significantly lower programmed cell death 1 (PD-1) surface expression on CD8(+) T cells on a per-cell basis and exhibited less activated CD4(+) T cells compared to those unable to maintain detectable measles-specific antibodies. Children in both groups were similar in age and sex, CD4(+) T cell frequency, duration of ART treatment and HIV viral load at enrolment. These data suggest that aberrant T cell anergy and activation are associated with the impaired ability to sustain an antibody response to measles revaccination in HIV-infected children on ART.

Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) in squamous cell carcinoma of the tongue: markers of nerve invasion?

PURPOSE: Perineural invasion (PNI) in oral squamous cell carcinoma (SCC) is an independent predictor of poor prognosis. As PNI is not always identified with routine histology, a surrogate marker of PNI would improve detection and better inform treatment planning. The chemokines fractalkine (CX3CL1) and its receptor (CX3CR1) have shown such potential in other cancers, but have yet to be investigated with respect to PNI in oral SCC. METHODS: Thirty SCCs of the tongue in which PNI was identified histologically, and 30 in which it was not, were stained for fractalkine and fractalkine receptor using polyclonal antibodies and an immunoperoxidase technique. Tumours were assessed as either positive or negative; no attempt was made to subjectively assess staining intensity or extent. RESULTS: Both markers labelled myofibroblasts in the stroma surrounding the tumour, various neural components, leucocytes, endothelium and salivary myoepithelial cells. Fractalkine also labelled salivary ductal epithelium, vascular smooth muscle and 12/30 SCC which showed PNI. Eight of 30 positive SCCs in which PNI was not identified were also positive for this marker. There was no statistically significant association between fractalkine staining and PNI (p = 0.273). No SCC was positive for fractalkine receptor, but immune dendritic cells within tumour islands were strongly positive, as was striated muscle. CONCLUSIONS: Neither fractalkine nor fractalkine receptor is a reliable surrogate marker of PNI in lingual SCC.

Improving access to health information for older migrants by using grounded theory and social network analysis to understand their information behaviour and digital technology use.

Migrant well-being can be strongly influenced by the migration experience and subsequent degree of mainstream language acquisition. There is little research on how older Culturally And Linguistically Diverse (CALD) migrants who have 'aged in place' find health information, and the role which digital technology plays in this. Although the research for this paper was not focused on cancer, we draw out implications for providing cancer-related information to this group. We interviewed 54 participants (14 men and 40 women) aged 63-94 years, who were born in Italy or Greece, and who migrated to Australia mostly as young adults after World War II. Constructivist grounded theory and social network analysis were used for data analysis. Participants identified doctors, adult children, local television, spouse, local newspaper and radio as the most important information sources. They did not generally use computers, the Internet or mobile phones to access information. Literacy in their birth language, and the degree of proficiency in understanding and using English, influenced the range of information sources accessed and the means used. The ways in which older CALD migrants seek and access information has important implications for how professionals and policymakers deliver relevant information to them about cancer prevention, screening, support and treatment, particularly as information and resources are moved online as part of e-health.

Menstrual migraine: treatment options.

More than half of women with migraine note an association of headache attacks and their menstrual cycles. Headaches associated with menses are often more severe and disabling than headaches that occur other times of the month. First-line therapies include acute agents used for migraine in general; however, for many women, these therapies provide incomplete relief. In these situations, treatment options include short-term perimenstrual prevention employing nonsteroidal anti-inflammatory medications, triptans, or hormone-containing preparations. Should these options not suffice, or if menstrual cycles are irregular, continuous prevention using hormonal therapies or standard anti-migraine prophylaxis should be considered.

Biodegradation of Polychlorinated Dibenzo--Dioxins by Strain NSYSU.

The dioxin-degrading bacterium strain NSYSU (NSYSU strain) has been isolated from dioxin-contaminated soil by selective enrichment techniques. In the present study, the NSYSU strain was investigated for its capability to biodegrade polychlorinated dibenzo--dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) under aerobic and anaerobic conditions. High-resolution gas chromatography-mass spectrometry and a chemically activated luciferase gene expression bioassay were performed to determine the presence of dioxin compounds. The results indicate that the NSYSU strain could degrade PCDDs and PCDFs under anaerobic conditions in liquid cultures. The main intermediates of the dechlorination process were identified. The results of the bioreactor test indicate that the NSYSU strain could also degrade PCDDs and PCDFs effectively in soil slurries under aerobic conditions. Results from the bioreactor experiment show that approximately 98 and 97% of octachlorodibenzofuran and OCDD were degraded, respectively. The dioxin concentrations in soil slurry decreased from 5823 to 1198 pg toxic equivalency g, resulting in total dioxin removal of 79%. These first findings suggest that the NSYSU strain has the potential to be an effective tool for the bioremediation of soils contaminated with highly recalcitrant organic compounds.

Biomarker evaluation of self-reported condom use among women in HIV-discordant couples.

Self-reported condom use is a commonly collected statistic, yet its use in research studies may be inaccurate. We evaluated this statistic among women in HIV-discordant couples enrolled in a clinical trial in Nairobi, Kenya. Vaginal swabs were acquired from 125 women and tested for prostate-specific antigen (PSA), a biomarker for semen exposure, using an enzyme-linked immunosorbent assay. Ten (10%) of 98 women who reported 100% use of condoms in the previous month tested PSA positive. In a bivariate logistic regression analysis, among women who reported 100% condom use in the previous month, those with ≤8 years of school had significantly higher odds of testing PSA-positive (odds ratio [OR] = 8.39, 95% confidence interval [CI] 1.02-69.13) than women with more schooling. Our estimate may be conservative, as the ability to detect PSA may be limited to 24-48 hours after exposure. Less educated women may be a target group for counselling regarding reporting sexual behaviour in clinical trials.

'I could never do that before': effectiveness of a tailored Internet support intervention to increase the social participation of youth with disabilities.

BACKGROUND: Youth use the Internet for a variety of purposes including social networking. Youth with disabilities are limited in their social networks and friendships with peers. The aim was to investigate the effectiveness of tailored one-on-one support strategies designed to facilitate social participation of youth with disabilities through the use of the Internet for social networking. METHODS: Eighteen youth aged 10-18 years with cerebral palsy, physical disability or acquired brain injury received support, training and assistive technology at their home to learn to use the Internet for building social networks. The Canadian Occupational Performance Measure (COPM) and Goal Attainment Scale (GAS) were used to evaluate objective changes in performance and satisfaction. Interviews with the youth identified subjective changes they experienced through participation in the programme and to determine whether and how the intervention influenced their social participation. RESULTS: Youth showed an increase in performance and satisfaction with performance on identified goals concerning social networking on the COPM; Paired T-test showed that these differences were statistically significant at P < 0.001. GAS T-scores demonstrated successful outcomes (>50) for 78% of the youth. Interviews showed that youth were positive about the benefits of hands-on training at home leading to increased use of the Internet for social networking. CONCLUSIONS: The Internet could be a viable method to facilitate social participation for youth with disabilities. Youth identified the benefits of one-to-one support at home and training of the family compared with typical group training at school. Despite its success with this group of youth, the time and effort intensive nature of this approach may limit the viability of such programmes. Further longitudinal research should investigate whether Internet use is sustained post intervention, and to identify the factors that best support ongoing successful and safe use.

The Capsella rubella genome and the genomic consequences of rapid mating system evolution.

The shift from outcrossing to selfing is common in flowering plants, but the genomic consequences and the speed at which they emerge remain poorly understood. An excellent model for understanding the evolution of self fertilization is provided by Capsella rubella, which became self compatible <200,000 years ago. We report a C. rubella reference genome sequence and compare RNA expression and polymorphism patterns between C. rubella and its outcrossing progenitor Capsella grandiflora. We found a clear shift in the expression of genes associated with flowering phenotypes, similar to that seen in Arabidopsis, in which self fertilization evolved about 1 million years ago. Comparisons of the two Capsella species showed evidence of rapid genome-wide relaxation of purifying selection in C. rubella without a concomitant change in transposable element abundance. Overall we document that the transition to selfing may be typified by parallel shifts in gene expression, along with a measurable reduction of purifying selection.