Impaired posterior cingulate cortex-parahippocampus connectivity is associated with episodic memory retrieval problems in amnestic mild cognitive impairment.

Episodic memory retention and retrieval decline are the most common impairments observed in amnestic mild cognitive impairment (aMCI) patients who progress to Alzheimer's disease (AD). Clinical electroencephalography research shows that patients with dementia due to AD exhibit a slowing of neural electrical activity in the parietal cortex. Memory research has further suggested that successful memory performance is associated with changes in a posterior cingulate-parahippocampal cortical network together with increased θ-γ oscillatory coupling, where θ oscillations act as carrier waves for γ oscillations, which contain the actual information. However, the neurophysiological link between the memory research and clinical studies investigating aMCI and AD is lacking. In this study, we look at brain activity in aMCI and how it relates to memory performance. We demonstrate decreased γ power in the posterior cingulate cortex and the left and right parahippocampus in aMCI patients in comparison to control participants. This goes together with reduced θ coherence between the posterior cingulate cortex and parahippocampus associated with altered memory performance aMCI patients in comparison to control participants. In addition, comparing patients with aMCI to control participants reveals an effect for θ-γ coupling for the posterior cingulate cortex, and the left and right parahippocampus. Taken together, our results show that parahippocampus and posterior cingulate cortex interact via θ-γ coupling, which is associated with memory recollection and is altered in aMCI patients, offering a potential candidate mechanism for memory decline in aMCI.

Replacing stressful challenges with positive coping strategies: a resilience program for clinical placement learning.

Clinical education is foundational to health professional training. However, it is also a time of increased stress for students. A student's perception of stressors and their capacity to effectively manage them is a legitimate concern for educators, because anxiety and decreased coping strategies can interfere with effective learning, clinical performance and capacity to care for patients. Resilience is emerging as a valuable construct to underpin positive coping strategies for learning and professional practice. We report the development and evaluation of a psycho-education resilience program designed to build practical skills-based resilience capacities in health science (physiotherapy) students. Six final year undergraduate physiotherapy students attended four action research sessions led by a clinical health psychologist. Resilience strategies drawn from cognitive behavioural therapy, and positive and performance psychology were introduced. Students identified personal learning stressors and their beliefs and responses. They chose specific resilience-based strategies to address them, and then reported their impact on learning performance and experiences. Thematic analysis of the audio-recorded and transcribed action research sessions, and students' de identified notes was conducted. Students' initial descriptions of stressors as 'problems' outside their control resulting in poor thinking and communication, low confidence and frustration, changed to a focus on how they managed and recognized learning challenges as normal or at least expected elements of the clinical learning environment. The research suggests that replacing stressful challenges with positive coping strategies offers a potentially powerful tool to build self-efficacy and cognitive control as well as greater self-awareness as a learner and future health practitioner.

Construct validity of the FOCUS© (Focus on the Outcomes of Communication Under Six): a communicative participation outcome measure for preschool children.

OBJECTIVE: The aim of this study was to establish the construct validity of the Focus on the Outcomes of Communication Under Six (FOCUS©). This measure is reflective of concepts in the International Classification of Functioning Disability and Health--Children and Youth framework. It was developed to capture 'real-world' changes (e.g. communicative participation) in preschoolers' communication following speech-language intervention. METHOD: A pre-post design was used. Fifty-two parents of 3- to 6-year-old preschoolers attending speech-language therapy were included as participants. Speech-language therapists provided individual and/or group intervention to preschoolers. Intervention targeted: articulation/phonology, voice/resonance, expressive/receptive language, play, and use of augmentative devices. Construct validity for communicative participation was assessed using pre-intervention and post-intervention parent interviews using the FOCUS© and the communication and socialization domains of the Vineland Adaptive Behavior Scales-II (VABS-II). RESULTS: Significant associations were found between the FOCUS©, measuring communicative participation, and the VABS-II domains for: (i) pre-intervention scores in communication (r = 0.53, P < 0.001; 95% CI 0.30-0.70) and socialization (r = 0.67, P < 0.001; 95% CI 0.48-0.80); (ii) change scores over-time in communication (r = 0.45, P < 0.001; 95% CI 0.201-0.65) and socialization (r = 0.39, P = 0.002; 95% CI 0.13-0.60); and (iii) scores at post-intervention for communication (r = 0.53, P < 0.001; 95% CI 0.30-0.70) and for socialization (r = 0.37, P = 0.003; 95% CI 0.11-0.50). CONCLUSIONS: The study provided evidence on construct validity of the FOCUS© for evaluating real-world changes in communication. We believe that the FOCUS© is a useful measure of communicative participation.

Intravenous drug use: not a barrier to achieving a sustained virological response in HCV infection.

Hepatitis C virus (HCV) is commonly transmitted by intravenous drug use (IDU) but drug users are under represented in many treatment cohorts, this is because of the assumption of lowered treatment success. We assessed HCV treatment outcomes in active intravenous drug users and patients on opiate substitution therapy. The Tayside HCV treatment database was retrospectively analysed for consecutively treated patients based on risk factor for acquisition of HCV. Primary end point was sustained virological response (SVR). Two hundred and ninety-one consecutively treated patients were assessed. The overall SVR rate was 55.3%. The SVR rates by risk factor were; Non-IDU 61.4%, Ex-IDU 54.8% and Active IDU 47.1% (P = n/s). In the groups G1 patients SVR was; Non-IDU 52.7%, Ex-IDU 30.7% and active IDU 35.4% (P = n/s). In the non-G1 patients: non-IDU 65.1%, Ex-IDU 76.7% and active IDU 53.5%. Ex-IDU had a significantly better SVR than active IDU, other differences were not significant. Our results demonstrate that SVR rates in the active drug users and those on opiate substitution therapy can be achieved which are comparable with non-IDU infected individuals. Intravenous drug use in those engaged with treatment services should not be seen as a barrier to treatment of HCV.

Energy and water use by invasive goats (Capra hircus) in an Australian rangeland, and a caution against using broad-scale allometry to predict species-specific requirements.

Feral goats (Capra hircus) are ubiquitous across much of Australia's arid and semi-arid rangelands, where they compete with domestic stock, contribute to grazing pressure on fragile ecosystems, and have been implicated in the decline of several native marsupial herbivores. Understanding the success of feral goats in Australia may provide insights into management strategies for this and other invasive herbivores. It has been suggested that frugal use of energy and water contributes to the success of feral goats in Australia, but data on the energy and water use of free-ranging animals are lacking. We measured the field metabolic rate and water turnover rate of pregnant and non-pregnant feral goats in an Australian rangeland during late summer (dry season). Field metabolic rate of pregnant goats (601 ± 37 kJ kg(-0.73)d(-1)) was 1.3 times that of non-pregnant goats (456 ± 24 kJ kg(-0.73)d(-1)). The water turnover rate of pregnant goats (228 ± 18 mL kg(-0.79)d(-1)) was also 1.3 times that of non-pregnant goats (173 ± 18 kg(-0.79)d(-1)), but the difference was not significant (P=0.07). There was no significant difference in estimated dry matter digestibility between pregnant and non-pregnant goats (mean ca. 58%), blood or urine osmolality, or urine electrolyte concentrations, indicating they were probably eating similar diets and were able to maintain osmohomeostasis. Overall, the metabolic and hygric physiology of non-pregnant goats conformed statistically to the predictions for non-marine, non-reproductive placental mammals according to both conventional and phylogenetically independent analyses. That was despite the field metabolic rate and estimated dry matter intake of non-pregnant goats being only 60% of the predicted level. We suggest that general allometric analyses predict the range of adaptive possibilities for mammals, but that specific adaptations, as present in goats, result in ecologically significant departures from the average allometric curve. In the case of goats in the arid Australian rangelands, predictions from the allometric regression would overestimate their grazing pressure by about 40% with implications for the predicted impact on their local ecology.

Potential role for peripheral nerve stimulation on learning and long-term memory: A comparison of alternating and direct current stimulations.

BACKGROUND: In the past decade, a rising interest in transcranial electrical stimulation has emerged owing to its advantageous capacity to facilitate the extraction of casual links between neuromodulation and the obtained behavioral effects in cognitive performance. However, an insufficient number of direct comparative studies between transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) effects on associative memory have caused optimal parameters and procedural application to remain undefined. OBJECTIVE: The current study aimed to comparatively investigate the effects of tDCS and tACS applied to the occipital nerve (ON), targeting the locus coeruleus, on associative memory performance. METHODS: We employed a randomized, double-blind, two-visit, active-controlled study design. 85 cognitively normal adults were assigned to receive either active ON-tDCS, 40 Hz ON-tACS, sham ON-tDCS, or 1 Hz ON-tACS during encoding of a 50-word Swahili-English associative memory recall task. To evaluate the effects of electrical stimulation, we measured the cumulative rate of learning on Day 1 and to assess possible long-term effects, we measured the number of words recalled on Day 7. RESULTS: Results presented two notable findings: (1) participants who received 40 Hz ON-tACS learned significantly more words on Day 1 (F3,81 = 4.37, p = .007, η2 = 0.14), and (2) participants who received 40 Hz ON-tACS or active ON-tDCS recalled significantly more words on Day 7 (F3,81 = 11.08, p < .001, η2 = 0.29). CONCLUSIONS: The evidence from this study alludes to 40 Hz ON-tACS and active ON-tDCS inducing distinct behavioral effects, whereby 40 Hz ON-tACS generated an effect during memory encoding via enhanced attention, however, active ON-tDCS elicited an offline effect transpiring during consolidation. Further neuroimaging studies are needed to validate these findings and proposed mechanisms of action.

Polarity-specific high-definition transcranial direct current stimulation of the anterior and posterior default mode network improves remote memory retrieval.

BACKGROUND: Previous studies show that activity in the posterior default mode network (pDMN), including the posterior cingulate cortex and the precuneus, is correlated with the success of long-term episodic memory retrieval. However, the role of the anterior DMN (aDMN) including the medial prefrontal cortex is still unclear. Some studies show that activating the medial prefrontal cortex improves memory retrieval while other studies show deactivation of the medial prefrontal cortex in successful retrieval of episodic memories, suggesting a possible functional dissociation between the aDMN and pDMN. OBJECTIVE: In the current study, we aim to causally explore this probable dissociation using high-definition transcranial direct current stimulation (HD-tDCS). METHODS: We perform a randomised double-blinded two-visit placebo-controlled study with 84 healthy young adults. During Visit 1 they learn 75 Swahili-English word-associations. Seven days later, they randomly receive either anodal, cathodal or sham HD-tDCS targeting the pDMN or aDMN while they recall what they have previously learned. RESULTS: We demonstrate that anodal stimulation of the pDMN and cathodal stimulation of the aDMN, equally improve the percentage of Swahili-English word-associations recalled 7 days after learning. CONCLUSIONS: Modulating the activity in the aDMN and pDMN causally affect memory retrieval performance. HD-tDCS of the aDMN and pDMN shows that anodal stimulation of the pDMN and cathodal stimulation of the aDMN increases memory retrieval performance one week after the learning phase. Given consistent evidence, it is highly likely that we are increasing the activity in the pDMN with anodal pDMN stimulation. However, it is not clear if cathodal HD-tDCS targetting aDMN works via decoupling from the pDMN or via indirectly disinhibit pDMN.

The impact of a managed care network on attendance, follow-up and treatment at a hepatitis C specialist centre.

Infection with the hepatitis C virus commonly occurs in patient groups who have difficulty accessing conventional medical care, reducing their chance of successful antiviral therapy. Managed care networks (MCNs) have been suggested as a mechanism of improving access to care; however, there is little evidence to support their use in patients with hepatitis C. The aim of this study was to evaluate the impact of a MCN for patients with hepatitis C. This was a retrospective cohort study of all individuals in our area who had received a positive hepatitis C antibody test between August 1994 and June 2008. The MCN introduced a new referral pathway, which included nonmedical referrals and outreach nurse-led clinics. These interventions were introduced in 2004 and evaluated in 2008. After the introduction of the MCN, the proportion of individuals who accessed care increased from 61% (280/430) to 82.4% (721/875). There was an increase in nonmedical referrals with 81 (18.3%) being directly referred from Drug Problem Services and 75 (17%) from the Prison Service. The changes to referral did not have a negative impact on treatment outcomes as the number who completed treatment increased from 66.1% (43/65) to 73.7% (98/133) and the sustained virological response increased from 50.7% (33/65) to 60.9% (81/133). This study provides evidence that the collaboration of health care professionals within a network can have a radical effect in improving access to care in a traditionally hard to reach population. This has been achieved with little additional resource, but rather working smarter with existing staff.

Effects of supplementing dairy cows with chromium propionate on milk and tissue chromium concentrations.

Eight primiparous and 8 multiparous Holstein cows were used to determine the effects of Cr supplementation, in the form of Cr propionate (Cr Prop), on milk and tissue Cr concentrations. Cows were randomly assigned by parity to one of 2 diets: 1) control diet or 2) 2 mg of supplemental Cr/kg of DM. The level of Cr Prop supplemented exceeded by 4-fold the concentration of 0.5 mg of Cr/kg permitted by the FDA. Experimental diets were fed from approximately 30 d prepartum until at least 91 d postpartum, resulting in a minimum of 121 d of exposure to supplemental Cr. The control prepartum and postpartum diets analyzed 0.48 and 0.38 mg of Cr/kg of DM, respectively. Milk samples were obtained from the a.m. milking on d 0 (colostrum), 7, 14, 21, 28, 42, 56, 77, and 90 and on the final day of the study for Cr analysis. Cows were harvested after lactating for a minimum of 91 d and samples of liver, kidney, semitendinosus muscle, and fat were obtained for Cr analysis. Chromium was measured using electrothermal atomic absorption spectrophotometry. Milk Cr concentration averaged 1.7 ng/mL and was affected by day of lactation but not by Cr or a Cr × day interaction. Supplementation of 2 mg of Cr/kg of DM increased kidney Cr by approximately 3-fold and liver Cr concentrations by approximately 2-fold. Chromium concentrations in muscle and fat were not affected by Cr supplementation. In summary, supplementation of Cr Prop at a level of 2 mg of Cr/kg of DM did not affect Cr concentration in milk, muscle, or fat, the major bovine products consumed by humans.

Greater Occipital Nerve Stimulation Boosts Associative Memory in Older Individuals: A Randomized Trial.

Transcutaneous electrical stimulation (tES) is a new approach that aims to stimulate the brain. Recently, we have developed tES approaches to enhance plasticity that modulate cortical activity via the greater occipital nerve (ON) in a "bottom-up" way. Thirty subjects between the ages of 55 and 70 years were enrolled and tested using a double-blind, sham-controlled, and randomized design. Half of the participants received active stimulation, while the other half received sham stimulation. Our results demonstrate that ON-tES can enhance memory in older individuals after one session, with effects persisting up to 28 days after stimulation. The hypothesized mechanism by which ON-tES enhances memory is activation of the locus coeruleus-noradrenaline (LC-NA) pathway. It is likely that this pathway was activated after ON-tES, as supported by observed changes in α-amylase concentrations, a biomarker for noradrenaline. There were no significant or long-lasting side effects observed during stimulation. Clinicaltrial.gov (NCT03467698).

The peripheral effect of direct current stimulation on brain circuits involving memory.

An ongoing debate surrounding transcranial direct current stimulation (tDCS) of the scalp is whether it modulates brain activity both directly and in a regionally constrained manner enough to positively affect symptoms in patients with neurological disorders. One alternative explanation is that direct current stimulation affects neural circuits mainly indirectly, i.e., via peripheral nerves. Here, we report that noninvasive direct current stimulation indirectly affects neural circuits via peripheral nerves. In a series of studies, we show that direct current stimulation can cause activation of the greater occipital nerve (ON-tDCS) and augments memory via the ascending fibers of the occipital nerve to the locus coeruleus, promoting noradrenaline release. This noradrenergic pathway plays a key role in driving hippocampal activity by modifying functional connectivity supporting the consolidation of a memory event.

Methotrexate for the treatment of unruptured tubal ectopic pregnancy.

OBJECTIVE: The objective of this study was to determine the outcomes of women who presented to the emergency department (ED) with suspected ectopic pregnancy and received methotrexate as first-line treatment. METHODS: This was a retrospective chart review of pregnant (< 12 week' gestational age) women from an academic tertiary care ED with a diagnosis of ectopic pregnancy, rule-out ectopic pregnancy, or pregnancy of unknown location over a 7-year period. RESULTS: Of 612 patients with a suspected ectopic pregnancy at initial ED presentation, 326 (53.3%) had non-ectopic pregnancy outcomes, 30 (4.9%) were diagnosed with a ruptured ectopic pregnancy at the index ED visit, and 18 (2.9%) were diagnosed and managed as non-tubal ectopic pregnancies and excluded from further analyses; 238 patients were diagnosed with a tubal ectopic pregnancy, and 152 (63.9%) were treated with methotrexate at the index ED visit or in follow-up. Of patients treated with methotrexate, 27 (17.8%) went on to require surgical management, with 17 (11.2%) documented as having ruptured on surgical evaluation. CONCLUSION: The proportion of patients failing methotrexate as first-line treatment was higher than previously reported. Further investigation is needed to determine whether methotrexate failure was due to non-adherence to recommended guidelines.

Control of transcription by nucleoid proteins.

Nucleoid proteins are a group of abundant DNA binding proteins that modulate the structure of the bacterial chromosome. They have been recruited as specific negative and positive regulators of gene transcription and their fluctuating patterns of expression are often exploited to impart an additional level of control with respect to environmental conditions.

Rapid identification of single nucleotide polymorphisms and estimation of allele frequencies using sequence traces from DNA pools.

Millions of single nucleotide polymorphisms (SNP) are now known in the chicken, but the ones that segregate may differ among populations. The current study characterized a simple method to simultaneously identify SNP in populations and to estimate allele frequencies by using relative peak heights of nucleotides in sequencing traces from DNA pools. In the first experiment, known concentration gradients of alleles were produced by measured admixture of DNA from highly inbred individual chickens. In the second experiment, pools of DNA from 100 individuals of each of 3 populations were produced, and the estimated frequencies were compared with those from genotyping of individuals sampled from the same populations. Linear relationships (slope = 0.93 to 1.02) were demonstrated between relative peak heights of nucleotide sequence traces and allelic frequency from both types of experimental samples. The correlation of frequency estimates from pools and individual genotyping was 0.917 to 0.997. Therefore, relative peak heights of nucleotides in sequence traces from DNA isolated from blood pools provide accurate estimates of SNP frequencies of the population from which the pool individuals were sampled and can, therefore, increase efficiency of selecting SNP to genotype in specific populations.

Localization of amino acids required for Fis to function as a class II transcriptional activator at the RpoS-dependent proP P2 promoter.

ProP is an integral membrane transporter of proline, glycine betaine, and several other osmoprotecting compounds. Fis plus RpoS collaborate to promote a burst of proP transcription in late exponential growth phase. This brief period of ProP synthesis enables stationary phase cells to cope with a potential hyperosmotic shock. Fis activates the RpoS (sigma(38))-dependent proP P2 promoter by binding to a site within the promoter region centered at -41 and thus functions as a class II activator. We show here that activation by Fis at this promoter is completely dependent upon the alpha-CTD of RNA polymerase and that the activation domain on Fis is localized to a four amino acid ridge on the surface of Fis adjacent to the helix-turn-helix DNA binding domain in only one subunit of the homodimer. Fis mutants containing amino acid substitutions within this region are defective in cooperative binding interactions with the sigma(38)-form of RNA polymerase. Some of these substitutions also alter interactions with DNA sequences flanking the core binding site, but we show that changes in Fis-mediated curvature do not affect promoter activity. We conclude that the same amino acids are used by Fis to activate transcription from a class I (-71, rrnB P1) and class II (-41, proP P2) location, but this region is distinct from that required to regulate the Hin site-specific DNA inversion reaction.

Short latency somatosensory evoked potentials in patients with neurological lesions.

Short latency somatosensory potentials following median nerve stimulation were recorded in patients grouped according to anatomic location of neurological lesion. Patients with cerebral lesions causing severe sensory deficit lacked a major positive wave of cortical origin that in normal subjects peaked at a mean latency of 20.5 ms. Patients with severe cervical spinal cord disease lacked all of the normal somatosensory response except for the earliest component attributed to peripheral nerve activity. Patients with brain-stem lesions showed delayed latencies of later waves and prolonged interwave latencies. However, auditory evoked potentials measured in the group with brain-stem lesions were more helpful in localization. Analysis of short latency somatosensory potentials can discriminate between peripheral nerve, spinal cord, brain-stem, and cerebral lesions. Further experience and refinement of technique of measurement should increase the value of this procedure.

Anxiolytic-like action of neuropeptide Y: mediation by Y1 receptors in amygdala, and dissociation from food intake effects.

Evidence from animal and human studies suggests that neuropeptide Y (NPY) may be a potent endogenous anxiolytic. The anatomic structures mediating this action of the peptide remain unknown. Furthermore, in addition to its anxiolytic-like effects, intracerebroventricular administration of NPY induces food intake through hypothalamic mechanisms, making the anxiolytic-like action of the peptide more difficult to interpret. The purpose of this study was to examine the anatomic substrate for the effects of NPY on anxiety, and to characterize the NPY receptors mediating these effects. Intracerebroventricular injection of NPY produced increased food intake in free-feeding animals, and dose-dependent anticonflict/anxiolytic-like effects in an established animal model of anxiety, the Geller-Seifter punished responding test. In contrast, microinjection of NPY into the central nucleus of the amygdala did not increase food intake in free-feeding animals, did not affect unpunished lever pressing for food, but did reproduce the anticonflict/anxiolytic-like effect with high potency. The selective NPY-Y1 agonist, p[Leu31,Pro34]NPY was approximately equipotent with native NPY in the conflict paradigm, and markedly more potent than the Y2 agonist, NPY13-36. Intrastriatal injections had no effect on conflict behavior. Thus, activation of Y1 receptors in the central nucleus of the amygdala produces effects similar to established anxiolytics without affecting food intake, suggesting that Y1-receptors in the amygdala may be a substrate for anxiolytic actions of NPY.

A longitudinal study of the relationship between intraocular and blood pressures.

The relationship between intraocular and systemic blood pressures was investigated in a prospective study of 572 middle-aged men. There was no consistent relationship between intraocular pressure at first visit and age. Subjects with an intraocular pressure greater than 20 mm Hg had a significantly higher systolic blood pressure than controls matched for age. An autoregressive model was used to examine the relationship between change in intraocular pressure and initial intraocular pressure, age, and blood pressure. When the authors compared data obtained 1 or 2 years apart, a change in intraocular pressure was positively correlated with a change in systolic blood pressure. Thus, the results of this study indicate that changes in intraocular pressure over time are associated with changes in systolic blood pressure and that intraocular pressure does not necessarily increase with age.

Development and application of polymerase chain reaction (PCR) tests for the detection of subgroup J avian leukosis virus.

Subgroup J avian leukosis virus (ALV) is a recently identified avian retrovirus associated with myeloid leukosis in meat-type chickens. The env gene of the HPRS-103 strain of ALV, the prototype of this subgroup, differs considerably from that of other subgroups, but shows close homology to the env-like sequences of members of the EAV family of endogenous retroviruses. Polymerase chain reaction (PCR) tests using two sets of primers were developed for the specific detection of the members of this new subgroup along with another pair of primers for detecting other subgroup viruses. The specificity and sensitivity of this detection system was compared with the conventional detection methods in experimentally and naturally infected samples. The use of PCR was found to be rapid, specific and more sensitive than the conventional diagnostic tests for the detection of ALV. Moreover, the two subgroup J ALV-specific PCR tests were found to be capable of differentiating between 'prototype-like' viruses and more recent isolates which show extensive antigenic and sequence variations. The use of this test as a rapid and sensitive method of detection of viruses in epidemiological studies and eradication programs is discussed.

Activation and function of the Rap1 GTPase in B lymphocytes.

Rap1 is a monomeric GTPase that is closely related to Ras. In this review, we summarize our recent work showing that the B cell antigen receptor (BCR), as well as chemokine receptors, activate Rap1 via a pathway that involves phospholipase C-dependent production of diacylglycerol (DAG). The possible identities of the DAG-regulated guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that regulate the activation of Rap1 by the BCR and chemokine receptors will be discussed. Although initially thought to be an antagonist of Ras-mediated signaling, Rap1 does not appear to modulate the ability of the BCR to activate downstream targets of Ras. Instead, activation of Rap1 promotes B cell adhesion as well as B cell migration toward chemokines. Thus, Rap1 may play a key role in a number of processes that are essential for B cell development and activation.