Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.

Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha. (PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.

Coercive parenting: modifiable and nonmodifiable risk factors in parents of children with developmental disabilities.

BACKGROUND: Parents of children with developmental or intellectual disabilities tend to report greater use of coercive parenting practices relative to parents of typically developing children, increasing the risk of adverse child outcomes. However, to date, there is limited research exploring the role and relative contribution of modifiable and nonmodifiable risk factors in parents of children with a disability. The present study aimed to explore the role of various modifiable and nonmodifiable parenting, family and sociodemographic factors associated with the use of coercive parenting practices in parents of children with a disability. METHODS: Caregivers (N = 1392) enrolled in the Mental Health of Young People with Developmental Disabilities (MHYPeDD) programme in Australia completed a cross-sectional survey about their parenting and their child aged 2-12 years with a disability. Measures covered a range of domains including relevant demographic and family background, use of coercive parenting practices, intensity of child behavioural difficulties and questions relating to parent and family functioning such as parental self-efficacy, adjustment difficulties and quality of family relationships. RESULTS: Parents of older children, those who were younger at the birth of their child, and parents who were co-parenting or working reported more use of coercive parenting practices. Greater intensity of child difficulties, poorer parental self-efficacy and parent-child relationships, and more parental adjustment difficulties were also significantly associated with more use of coercive parenting. Examination of the relative contribution of variables revealed parent-child relationship was a key contributing factor, followed by intensity of child behaviour problems, parent adjustment and parent confidence. CONCLUSIONS: These findings highlight a range of factors that should be targeted and modified through upstream prevention programmes and further inform our understanding of how coercive practices may be influenced through targeted parenting interventions.

The basolateral amygdala differentially regulates conditioned neural responses within the nucleus accumbens core and shell.

The ability to process information regarding reward-predictive cues involves a diverse network of neural substrates. Given the importance of the nucleus accumbens (NAc) and the basolateral amygdala (BLA) in associative reward processes, recent research has examined the functional importance of BLA-NAc interactions. Here, multi-neuron extracellular recordings of NAc neurons coupled to microinfusion of GABAA and GABAB agonists into the BLA were employed to determine the functional contribution of the BLA to phasic neural activity across the NAc core and shell during a cued-instrumental task. NAc neural response profiles prior to BLA inactivation exhibited largely indistinguishable activity across the core and shell. However, for NAc neurons that displayed cue-related increases in firing rates during the task, BLA inactivation significantly reduced this activity selectively in the core (not shell). Additionally, phasic increases in firing rate in the core (not shell) immediately following the lever press response were also significantly reduced following BLA manipulation. Concurrent with these neural changes, BLA inactivation caused a significant increase in latency to respond for rewards and a decrease in the percentage of trials in which animals made a conditioned approach to the cue. Together, these results suggest that an excitatory projection from the BLA provides a selective contribution to conditioned neural excitations of NAc core neurons during a cued-instrumental task, providing insight into the underlying neural circuitry that mediates responding to reward-predictive cues.

Lacustrine radiations in African Synodontis catfish.

Synodontis catfish are a species-rich, tropical pan-African genus that predominately occur in fluviatile environments, but which also form a small radiation within Lake Tanganyika (LT). Here we estimate Synodontis relationships, based on mitochondrial and nuclear DNA, greatly expanding previous sampling. Data were analysed using different methods of phylogenetic inference: Bayesian (also testing compositional heterogeneity), likelihood and parsimony, in order to investigate biogeographic history and the extent of intralacustrine speciation within this group. Bayesian-relaxed clock analyses were used to estimate timings of radiations. Our analyses reveal a single origin of the LT flock with the inclusion of the nonendemic S. victoriae, and that these taxa evolved relatively recently (5.5 Ma), considerably later than the formation of LT (9-12 Ma). Two internal endemic clades diversified at a similar time (2-2.5 Ma), corresponding to a period of climate change, when lake levels dropped. We find evidence for a further species flock, composed of riverine southern African taxa, the diversification of which is very rapid, 0.8 Ma (95% HPD: 0.4-1.5) and infer a similar scenario for the diversification of this flock to southern African serrachromine cichlids in that they radiated in the now extinct lake Makgadikgadi. We also reveal that the biogeographic history of Synodontis catfish is more complex than previously thought, with nonmonophyletic geographic species groupings.

Effects of 5' leader and 3' trailer structures on pre-tRNA processing by nuclear RNase P.

Eukaryotic transfer RNA precursors (pre-tRNAs) contain a 5' leader preceding the aminoacyl acceptor stem and a 3' trailer extending beyond this stem. An early step in pre-tRNA maturation is removal of the 5' leader by the endoribonuclease, RNase P. Extensive pairing between leader and trailer sequences has previously been demonstrated to block RNase P cleavage, suggesting that the 5' leader and 3' trailer sequences might need to be separated for the substrate to be recognized by the eukaryotic holoenzyme. To address whether the nuclear RNase P holoenzyme recognizes the 5' leader and 3' trailer sequences independently, interactions of RNase P with pre-tRNA(Tyr) containing either the 5' leader, the 3' trailer, or both were examined. Kinetic analysis revealed little effect of the 3' trailer or a long 5' leader on the catalytic rate (k(cat)) for cleavage using the various pre-tRNA derivatives. However, the presence of a 3' trailer that pairs with the 5' leader increases the K(m) of pre-tRNA slightly, in agreement with previous results. Similarly, competition studies demonstrate that removal of a complementary 3' trailer lowers the apparent K(I), consistent with the structure between these two sequences interfering with their interaction with the enzyme. Deletion of both the 5' and 3' extensions to give mature termini resulted in the least effective competitor. Further studies showed that the nuclear holoenzyme, but not the B. subtilis holoenzyme, had a high affinity for single-stranded RNA in the absence of attached tRNA structure. The data suggest that yeast nuclear RNase P contains a minimum of two binding sites involved in substrate recognition, one that interacts with tRNA and one that interacts with the 3' trailer. Furthermore, base pairing between the 5' leader and 3' trailer hinders recognition.

Arthritis in Indian country: determining the prevalence and effects.

OBJECTIVE: This project was designed to determine the prevalence of self-reported arthritis and its effect on the daily lives of Chippewa Indian people on tribal lands in Wisconsin. DESIGN AND METHODS: After review and approval by the LCO Tribal Council and the University of Minnesota Human Subjects Committee, face-to-face interviews with randomly selected tribal residents were conducted, followed by focus group formation, and medical chart reviews. RESULTS: Eighty-one percent (N = 82) of the eligible sample were interviewed. Fifty-six percent (N = 46) self-reported a diagnosis of arthritis, either by physician report or description of symptoms confirmed by a rheumatologist. Seventy-eight percent of this group (N = 36) reported limitations in their activities that can be attributed to arthritis. Only half of the medical charts included the diagnosis of arthritis or any tests to document its diagnosis. CONCLUSIONS: In this Chippewa population, the prevalence of and limitations due to arthritis are extremely high. Reasons for this need further investigation. The implications of these findings for tribal and health planning include housing, community activities, and medical services to accommodate the needs of this group.

Enhancing Cancer Pain Control among American Indians (ECPCAI): a study of the Ojibwe of Minnesota.

BACKGROUND AND OBJECTIVES: This study addressed one American Indian group's experience with cancer, its associated pain, and the resulting barriers in cancer pain management (CPM). METHODS: The project researched the identified problems and implemented solutions. Focus groups at four reservations with clinic personnel and tribal elders reviewed culturally specific experiences and barriers to CPM. Culturally sensitive brochures for patients and guidelines for providers were developed, and health care providers participated in CME sessions. RESULTS: Ojibwe elders report pain when it is >6 (1-10 scale), believe pain always accompanies cancer, and do not believe it can be relieved, although traditional healers can help. They also have addiction concerns. Developed materials changed knowledge (pre-post tests, p = 0.000) and are culturally sensitive (> 92% agreement). CONCLUSION: Medically sound CPM for this population can also be culturally sensitive.

Barium enema or computed tomography for the frail elderly patient?

In order to determine whether abdominopelvic computed tomography (CT) offers an alternative to barium enema (BE) for the investigation of the large bowel in frail elderly patients, we have assessed and compared the results of both tests performed in each patient. Thirty-seven patients aged 71 to 88 (mean 80) with a history or clinical findings suggestive of large bowel disease were studied. The seven colonic neoplasms in this group were demonstrated by both techniques (apart from one patient who did not undergo BE as CT had shown an obstructing lesion). CT showed useful additional data in four patients (e.g. abdominal wall involvement) and demonstrated numerous extracolonic lesions (e.g. ovarian carcinoma). However, CT did raise the possibility of a large bowel neoplasm in four patients where none was shown by BE and missed one case of Crohn's disease. CT was the preferred test amongst the 25 patients where the acceptability of the two techniques could be compared. Only in 16 patients were the BE studies adjudged to be of good quality. CT should be the initial investigation of the large bowel in frail elderly patients requiring inpatient bowel preparation; the more unpleasant BE could be reserved for those cases where CT is equivocal or severe symptoms are unexplained.

Incidence of AIDS dementia in a two-year follow-up of AIDS and ARC patients on an initial phase II AZT placebo-controlled study: San Diego cohort.

In a prospective study to determine the incidence of clinical dementia in patients with AIDS and ARC, 29 men and 3 women, 19 with ARC and 13 with AIDS, were examined neurologically and neuropsychologically every 6 months for 2 years during a placebo-controlled zidovudine (AZT) licensing trial. Most received two MRI brain scans. Although no patient was clinically demented at baseline, 9 (28%) developed dementia during the 2 years. Progression to dementia was associated with neuropsychological deterioration and with worsening on MRI during a preceding 6-month period, but not with baseline treatment group assignment. The results suggest that patients at CDC Stage IV who do not receive antiretroviral treatment earlier in their illness may develop clinical dementia at an annual rate of about 14%.

Magnetic resonance imaging of the brain and brain-stem in elderly patients with dizziness.

Twenty elderly patients (mean age 82 years) with dizziness were examined by magnetic resonance imaging (MRI). The findings have been compared with those from nine healthy subjects of similar age who acted as a control group. The technique proved acceptable to all these patients, and in the majority (65%) the overall radiographic quality of the resulting images was adequate, good or excellent. Nineteen of the 20 patients showed evidence of abnormal high signal intensity within white matter, often close to the frontal horns but also more widely scattered within the cerebral hemispheres; similar lesions were seen in the brain-stem in eight of the patients. However these white matter changes were equally prevalent in the control group. No cause for dizziness has been shown by MRI.

Myocardial infarction in old people. The influence of diabetes mellitus.

The clinical features and outcome were determined for 100 consecutive patients aged 65 years or older with a history of diabetes mellitus who presented to hospital with acute myocardial infarction. Each case was compared with an age- and sex-matched nondiabetic control also admitted to hospital with acute myocardial infarction. Chest pain was equally common in both groups and was the main presenting symptom. Cardiac failure was a more frequent accompaniment in the diabetics, despite the lack of evidence for greater infarct size in this group. The outcome was worst for female diabetics, of whom 46% died. Contrary to popular teaching, painless myocardial infarction is not a specific feature of elderly diabetics.

A geriatric high dependency unit--an innovation in the care of the acutely ill elderly patient?

A geriatric High Dependency Unit has been in operation at Cardiff Royal Infirmary for the past 7 years to provide "special-care" for acutely ill elderly people requiring careful bedside monitoring and intensive nursing and medical treatment. The background to the unit, its present functioning and the results of a prospective study of 432 consecutive admissions are described. The unit offers more appropriate and better continuity of hospital care for many very ill geriatric patients and may be a satisfactory alternative to admission to coronary or intensive care units where resources are not freely available.

Bioavailability and acceptability of a dispersible formulation of levodopa-benserazide in parkinsonian patients with and without dysphagia.

The bioavailability of levodopa-benserazide in a standard capsule and a new dispersible tablet was compared in Parkinsonian patients, with (n = 8) and without (n = 8) swallowing difficulties. There was considerable variation within and between subjects, but no significant differences between formulations for any pharmacokinetic parameters, other than an earlier time-peak concentration following the dispersible tablets (P less than 0.01) in non-dysphagic patients. The acceptability of the dispersible tablets in the dysphagic patients was also determined following 7 days regular use. It was felt there were advantages in four of the patients because it was easier to administer or to swallow. The dispersible formulation may offer practical benefits to a minority of Parkinsonian patients without any anticipated loss of therapeutic efficacy.

Thiamine status, vitamin supplements and postoperative confusion.

In a prospective, randomized, controlled study an intravenous vitamin B complex and vitamin C preparation was administered pre- and post-operatively to 28 elderly patients with a fractured proximal femur and compared with 32 nonsupplemented postoperative controls. Vitamin supplementation significantly, though only transiently, improved postoperative thiamine status (P less than 0.001), but had no influence on mental state or outcome during the postsurgical period. Therefore, the use of parenteral vitamins for postoperative confusion cannot be justified on a routine basis.

Acute myocardial infarction: diagnostic difficulties and outcome in advanced old age.

The diagnostic features and outcome of acute myocardial infarction in 100 very elderly (aged 85 years or more) hospitalized patients are reviewed and compared with those in a group of younger elderly (aged 65-84 years). The diagnostic triad of chest pain, sequential ECG changes and raised cardiac enzymes was present in only 24 very elderly patients and in 27 the diagnosis was not initially suspected. Presenting symptoms were often atypical and characteristic ECG changes could not be demonstrated in 25 patients. Very elderly patients had a higher mortality during the first few days in hospital, despite no greater incidence of cardiac failure and similar infarct size to the younger patients. Subsequent in-hospital mortality was similar in both groups. A higher index of suspicion of myocardial infarction in acutely ill very elderly patients should lead to earlier diagnosis, more appropriate management and may improve immediate prognosis.