The rostromedial tegmental nucleus modulates the development of stress-induced helpless behavior.

A growing body of clinical and preclinical research suggests that structural and functional changes in the habenula, a component of the epithalamus, are associated with major depressive disorder. A major excitatory, efferent projection from the habenula targets the rostromedial tegmentum (RMTg), a mesopontine region that provides significant input to the ventral tegmentum and raphe nuclei. While the RMTg contributes to monoaminergic responses to aversive events, its role in stress-based animal models of depression has yet to be determined. In the present study, we test the hypothesis that the RMTg is a component of the circuitry mediating the development of a maladaptive behavior in which rats repeatedly exposed to inescapable footshock, fail to avoid or escape the same stressor when subsequently given the opportunity to do so. Excitotoxic lesions of the RMTg significantly diminished the frequency of these escape failures 24 h after exposure to inescapable footshock. Conversely, electrical stimulation of the Hb during the initial uncontrollable aversive event, a manipulation that enhances excitatory input to the RMTg, increased the number of trials in which subjects failed to escape an aversive stimulus when presented the option 24 h later. These complementary results provide evidence supporting a role for the RMTg in the expression of stress-induced helpless phenotype and are an important step in understanding the contribution made by this region to the development of depression-related maladaptive behaviors.

Effects of a green tea extract, Polyphenon E, on systemic biomarkers of growth factor signalling in women with hormone receptor-negative breast cancer.

BACKGROUND: Observational and experimental data support a potential breast cancer chemopreventive effect of green tea. METHODS: We conducted an ancillary study using archived blood/urine from a phase IB randomised, placebo-controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I-III breast cancer who completed adjuvant treatment were randomised to Poly E 400 mg (n = 16), 600 mg (n = 11) and 800 mg (n = 3) twice daily or matching placebo (n = 10) for 6 months. Blood and urine collection occurred at baseline, and at 2, 4 and 6 months. Biological endpoints included growth factor [serum hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers. RESULTS: From July 2007-August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2 months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (-12.7% versus +6.3%, P = 0.04). This trend persisted at 4 and 6 months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2 months (P = 0.02) and 13.9% at 4 months (P = 0.05) but did not differ compared to placebo. At 2 months, there was a trend toward a decrease in serum cholesterol with Poly E (P = 0.08). No significant differences were observed for other biomarkers. CONCLUSIONS: Our findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism.

Psychosocial care for cancer: a framework to guide practice, and actionable recommendations for Ontario.

OBJECTIVES: We set out to create a psychosocial oncology care framework and a set of relevant recommendations that can be used to improve the quality of comprehensive cancer care for Ontario patients and their families.meet the psychosocial health care needs of cancer patients and their families at both the provider and system levels. DATA SOURCES AND METHODS: The adapte process and the practice guideline development cycle were used to adapt the 10 recommendations from the 2008 U.S. Institute of Medicine standard Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs into the psychosocial oncology care framework. In addition, the evidence contained in the original document was used, in combination with the expertise of the working group, to create a set of actionable recommendations. Refinement after formal external review was conducted. DATA EXTRACTION AND SYNTHESIS: The new framework consists of 8 defining domains. Of those 8 domains, 7 were adapted from recommendations in the source document; 1 new domain, to raise awareness about the need for psychosocial support of cancer patients and their families, was added. To ensure high-quality psychosocial care and services, 31 actionable recommendations were created. The document was submitted to an external review process. More than 70% of practitioners rated the quality of the advice document as high and reported that they would recommend its use. CONCLUSIONS: This advice document advocates for a multidisciplinary approach to cancer care in response to the distress experienced by cancer patients and their families. The recommendations will be useful in future to measure performance, quality of practice, and access to psychosocial services.

QRS subtraction for atrial electrograms: flat, linear and spline interpolations.

The main objective of this article is to implement and compare QRS subtraction techniques for intra-cardiac atrial electrograms based on using the surface ECG as a reference. A band-pass filter between 8 and 20 Hz followed by rectification, and then a low-pass filter at 6 Hz are used for QRS detection. QRS subtraction was performed using three different approaches: flat, linear and spline interpolations. QRS subtraction affects the power of the signals but it normally does not affect the dominant frequency. The average power of the atrial electrograms after QRS subtraction is significantly reduced for frequencies above 10 Hz.

Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone.

BACKGROUND AND PURPOSE: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib. EXPERIMENTAL APPROACH: Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models. KEY RESULTS: Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats. CONCLUSIONS AND IMPLICATIONS: Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands.

Effects of dietary supplementation of an enzyme blend on the ileal and fecal digestibility of nutrients in growing pigs.

The objective of this experiment was to determine the effect of a beta-glucanase-protease enzyme blend product (EBP) on fecal digestibility (FD), apparent ileal digestibility (AID), standardized ileal digestibility, and digestibility in the hindgut of growing pigs. Twelve ileal-cannulated, growing barrows (38.2 +/- 0.5 kg) were housed in individual metabolism crates, blocked by previous feed intake into 3 groups with 4 pigs each, and randomly assigned to 1 of 4 treatments within a square (group) of 3 replications of 4 x 4 Latin square design. Treatments were basal diet (Basal), Basal + 0.05% of EBP (0.05% EBP), Basal + 0.10% of EBP (0.10% EBP), and hydrolyzed casein for measurement of endogenous amino acids. The Basal diet consisted of corn and soybean meal and was calculated to have 3.36 Mcal of ME/kg and 1.1% of total lysine, as-fed basis. Feed intake of each replicate of the Latin square during the first period was 85% of the minimum feed intake of the 4 pigs during the preliminary period and was equalized within each square. The feeding level was increased by 100 g/d in each subsequent period. Each of the experimental periods was 14 d, including 4 d of dietary adaptation, 5 d of fecal collection, 3 d of transition period, and 2 d of ileal collection. Ileal effluents were collected continuously for the same 12-h interval each day. Pigs fed the EBP demonstrated increased (P < 0.05) FD of DM, OM, energy, CP, nonfiber carbohydrate, total dietary fiber, insoluble dietary fiber, acid-hydrolyzed fat, ash, Ca, and P compared with pigs fed Basal. The AID of NDF and hemicellulose was increased (P < 0.05) by supplying the EBP either at 0.05 or 0.10% in the diets, but AID of DM and energy was not increased. The AID of acid-hydrolyzed fat tended to be greater (P = 0.051) for the pigs fed the EBP than for those fed Basal. Ileal digestibility of most amino acids was not affected by treatment, but the EBP reduced the apparent and standardized digestibility of methionine, alanine, and serine (P < 0.05). The difference between FD and AID of hemicellulose was lower (P < 0.05) for the pigs fed the EBP than for those fed Basal. These results demonstrated that the EBP fed to growing pigs improved the FD of DM, OM, energy, CP, nonfiber carbohydrate, total dietary fiber, acid-hydrolyzed fat, Ca, and P, and the AID of NDF and hemi-cellulose, but the standardized ileal digestibility of amino acids was not improved by supplying the EBP in corn-soybean meal-based diets of growing pigs.

Brain edema and breakdown of the blood-brain barrier during methamphetamine intoxication: critical role of brain hyperthermia.

To clarify the role of brain temperature in permeability of the blood-brain barrier (BBB), rats were injected with methamphetamine (METH 9 mg/kg) at normal (23 degrees C) and warm (29 degrees C) environmental conditions and internal temperatures were monitored both centrally (nucleus accumbens, NAcc) and peripherally (skin and nonlocomotor muscle). Once NAcc temperatures peaked or reached 41.5 degrees C (a level suggesting possible lethality), animals were administered Evans blue dye (protein tracer that does not normally cross the BBB), rapidly anaesthetized, perfused and had their brains removed. All METH-treated animals showed brain and body hyperthermia associated with relative skin hypothermia, suggesting metabolic activation coupled with peripheral vasoconstriction. While METH-induced NAcc temperature elevation varied from 37.60 to 42.46 degrees C (or 1.2-5.1 degrees C above baseline), it was stronger at 29 degrees C (+4.13 degrees C) than 23 degrees C (+2.31 degrees C). Relative to control, METH-treated animals had significantly higher brain levels of water, Na(+), K(+) and Cl(-), suggesting brain edema, and intense immunostaining for albumin, indicating breakdown of the BBB. METH-treated animals also showed strong immunoreactivity for glial fibrillary acidic protein (GFAP), possibly suggesting acute abnormality or damage of astrocytes. METH-induced changes in brain water, albumin and GFAP correlated linearly with NAcc temperature (r = 0.93, 0.98 and 0.98, respectively), suggesting a key role of brain hyperthermia in BBB permeability, development of brain edema and subsequent functional and structural neural abnormalities. Therefore, along with a direct destructive action on neural cells and functions, brain hyperthermia, via breakdown of the BBB, may be crucial for both decompensation of brain functions and cell injury following acute METH intoxication, possibly contributing to neurodegeneration resulting from chronic drug use.

The subthalamic region is activated during valence-related emotional processing in patients with Parkinson's disease.

Visual stimuli are judged for their emotional significance based on two fundamental dimensions, valence and arousal, and may lead to changes in neural and body functions like attention, affect, memory and heart rate. Alterations in behaviour and mood have been encountered in patients with Parkinson's disease (PD) undergoing functional neurosurgery, suggesting that electrical high-frequency stimulation of the subthalamic nucleus (STN) may interfere with emotional information processing. Here, we use the opportunity to directly record neuronal activity from the STN macroelectrodes in patients with PD during presentation of emotionally laden and neutral pictures taken from the International Affective Picture System (IAPS) to further elucidate the role of the STN in emotional processing. We found a significant event-related desynchronization of STN alpha activity with pleasant stimuli that correlated with the individual valence rating of the pictures. Our findings suggest involvement of the human STN in valence-related emotional information processing that can potentially be altered during high-frequency stimulation of the STN in PD leading to behavioural complications.

Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents.

Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP(Sc), which is a misfolded isoform of the normal cellular prion protein PrP(C). Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP(C) and the suppression of PrP(Sc) accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC50s in the nanomolar range.

A randomised trial comparing the levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding.

OBJECTIVE: To compare the levonorgestrel intrauterine system (LNG-IUS) (Mirena); Schering Co., Turku, Finland) and thermal balloon ablation (Thermachoice; Gynecare Inc., Menlo Park, CA, USA) for the treatment of heavy menstrual bleeding. DESIGN: An open, pragmatic, prospective randomised trial. SETTING: A menstrual disorders clinic at National Women's Hospital, Auckland, New Zealand. POPULATION: Seventy-nine women with heavy menstrual bleeding randomised to the LNG-IUS (40 women) or the thermal balloon ablation (39 women). METHODS: Women were randomised to treatment with the LNG-IUS or thermal balloon ablation and followed up by a postal and telephone questionnaire. MAIN OUTCOME MEASURES: Menstrual loss measured by a pictorial bleeding assessment chart (PBAC) at 3, 6, 12 and 24 months. Patient satisfaction, quality of life and menstrual symptoms were assessed by questionnaire administered at 3, 6, 12 and 24 months. Treatment side effects and treatment failures were also recorded. RESULTS: Both the treatments resulted in a significant reduction in PBAC scores. At 12 and 24 months, median PBAC scores were significantly lower in women treated with the LNG-IUS compared with women treated by thermal balloon ablation (11.5 versus 60.0 at 12 months [P= 0.002]; 12.0 versus 56.5 [P= 0.002] at 24 months). At 24 months, nine (35%) women still using the LNG-IUS had amenorrhoea compared with one (5%) woman successfully treated by thermal balloon ablation (P = 0.025). There were no significant differences in patient satisfaction between two treatments during follow up. Treatment failed in 11 (28%) women using the LNG-IUS and in 10 (26%) women treated with thermal balloon ablation. Overall, women in both groups showed an increased quality of life as a result of the treatment, with Short Form-36 scores increasing from 63.7 at randomisation to 76.1 at 24 months. CONCLUSIONS: At 12 and 24 months of follow up, women with heavy menstrual bleeding treated with the LNG-IUS have significantly lower PBAC scores than women treated with thermal balloon ablation. Both the treatments resulted in a significant increase in overall quality of life, but there were no significant differences between either treatment in quality of life, patient satisfaction or the number of women requesting an alternative treatment during 24 months of follow up.

Effects of combined cortical and acoustic stimuli on muscle activity.

Hitherto, it has proven difficult to investigate interactions between cerebral and brainstem motor systems in the human. We hypothesised that transcranial magnetic stimulation (TMS) centred over the dorsal premotor and primary motor cortices might elicit net facilitatory cortico-reticular effects that could interact at the level of the brainstem with a habituated startle to give a reticulospinal discharge and electromyographic (EMG) response with a longer latency than the direct corticospinal response. Conversely, any reticulo-cortical activity evoked by a habituated startle should influence the size of the direct response to cortical TMS. EMG was recorded from active left deltoid muscle in nine healthy volunteers. Acoustic stimulation was delivered binaurally through headphones and repeated until the startle response was habituated. When TMS was centred over the right dorsal premotor or primary motor cortices and delivered 50 ms after the habituated acoustic stimulus, the contralateral direct motor evoked potential was inhibited, compared with the response elicited by TMS alone. The contralateral silent period was shortened and associated with less of a decrease in EMG levels relative to TMS alone. Indeed, an actual increase in EMG over baseline levels occurred in the later half of the silent period in all subjects. We conclude that both cortico-reticular and reticular-cortical effects could be elicited in deltoid through the combination of acoustic stimulation and TMS at short interstimulus intervals. Effects were similar with TMS over premotor and primary motor cortex.

Effects of plasmid-mediated growth hormone releasing hormone supplementation in young, healthy Beagle dogs.

Our study focused on the evaluation of the pharmacological and toxicological effects of plasmid-mediated GHRH supplementation with electroporation in normal adult dogs over a 180-d period. Twenty-eight dogs (< 2 yr of age) were randomized to four groups. Three groups (four dogs/sex for each group) were treated with ascending doses of GHRH-expressing plasmid: 0.2, 0.6, and 1 mg. One group (two dogs of each sex) served as the control. Clinical observations and body weights were recorded. Hematological, serum biochemical, and urine analyses were performed. Serum IGF-I, ACTH, and insulin were determined. Necropsies were performed on d 93 and 180; organs were weighed and tissues were fixed and processed for light microscopy. Selected tissues were used to assess plasmid biodistribution on d 93. At all doses, plasmid GHRH caused increased weight gain (P < 0.001), without organomegaly. Serum glucose and insulin in fasted dogs remained within normal ranges at all time points. Adrenocorticotropic hormone was normal in all groups. Significant increases in number of red blood cells, hematocrit, and hemoglobin (P < 0.01) were observed. In conclusion, our study shows that plasmid-mediated GHRH supplementation is safe in electroporated doses up to 1.0 mg in young healthy dogs.

Mass spectral analysis of PC-SPES confirms the presence of diethylstilbestrol.

INTRODUCTION/OBJECTIVES: PC-SPES is an herbal mixture available over the counter for the treatment of prostate cancer. It was re-called in January 2002 due to alleged contamination with warfarin. Other laboratories, including our own, claim that the potent synthetic estrogen, diethylstilbestrol (DES) which has been used for many years to treat hormone dependent prostate cancer, could be detected in the herbal mixture. Recent clinical studies report objective responses in men with hormone dependent and naïve prostate cancer, and also describe isolated cases of estrogenic side effects. A lack of effective conventional treatments for advanced hormone refractory prostate cancer has led to a widespread use of PC-SPES by patients across the North America continent. The presence of DES in PC-SPES might explain both clinical response and observed side effects in men taking 6-9 capsules per day. METHODS: We tested five batches of commercially available PC-SPES using gas chromatography (GC) and high performance liquid chromatography (HPLC) upon methanolic extraction. Duplicate aliquots were tested for each batch and the results compared to standard curves generated using DES (99% purity). RESULTS AND CONCLUSIONS: We detected significant levels of DES in three out of five tested batches. The presence of a synthetic steroid in PC-SPES is not likely to have occurred as a result of its extraction from a herbal source. The implications of this finding highlight the necessity of regulated quality control and standardization of natural health products.

Pre-clinical applications of transgenic mouse mammary cancer models.

Breast cancer is a leading cause of cancer morbidity and mortality. Given that the majority of human breast cancers appear to be due to non-genetic factors, identifying agents and mechanisms of prevention is key to lowering the incidence of cancer. Genetically engineered mouse models of mammary cancer have been important in elucidating molecular pathways and signaling events associated with the initiation, promotion, and the progression of cancer. Since several transgenic mammary models of human breast cancer progress through well-defined cancer stages, they are useful pre-clinical systems to test the efficacy of chemopreventive and chemotherapeutic agents. This review outlines several oncogenic pathways through which mammary cancer can be induced in transgenic models and describes several types of preventive and therapeutic agents that have been tested in transgenic models of mammary cancer. The effectiveness of farnesyl inhibitors, aromatase inhibitors, differentiating agents, polyamine inhibitors, anti-angiogenic inhibitors, and immunotherapeutic compounds including vaccines have been evaluated in reducing mammary cancer and tumor progression in transgenic models.

Dietary conjugated linoleic acids and lipid source alter fatty acid composition of juvenile yellow perch, Perca flavescens.

A study was conducted to examine the effects of dietary conjugated linoleic acids (CLA; 0, 0.5 or 1.0 g/100 g total CLA) and lipid source (menhaden oil, soybean oil or a 1:1 mixture of menhaden:soybean oil) on growth rates and fatty acid composition of yellow perch. Dietary treatments were fed to apparent satiation to triplicate groups of fish initially weighing 37.9 g/fish. At the end of the 9-wk feeding trial, no significant differences were detected in weight gain or feed intake among fish fed any of the dietary treatments. Dietary CLA, lipid source and/or their interaction significantly affected feed efficiency, total liver lipid concentration, and muscle and liver fatty acid concentrations. Feed efficiency (g gain/g feed) was significantly lower in fish fed diets containing soybean oil (0.51) compared with fish fed menhaden oil (0.58) or menhaden:soybean oil (0.60). Liver total lipid concentrations were significantly reduced in fish fed 0.5 and 1.0 g/100 g CLA compared with fish fed the diets containing no CLA and in fish fed menhaden oil compared with those fed soybean oil or a 1:1 mixture of menhaden:soybean oil. Total CLA levels increased in both liver and muscle as dietary CLA concentration increased, irrespective of lipid source. However, total CLA concentrations were significantly lower in liver and muscle of fish fed soybean oil. Total muscle CLA concentrations were 0, 1.26 and 2.92 g/100 g fatty acids in fish fed diets containing menhaden oil and 0, 0.5 and 1.0 g/100 g CLA, respectively. Mono- and polyunsaturated fatty acid (PUFA) concentrations were significantly lower in muscle and liver of fish fed CLA compared with fish fed the diets containing no CLA. In contrast, liver concentrations of saturated fatty acids, 14:0, 16:0 and 18:0, were significantly higher in fish fed 1.0 g/100 g CLA.

Intermuscular coherence in Parkinson's disease: relationship to bradykinesia.

We hypothesised that bradykinesia may be partly due to the failure of the corticomuscular system to engage in high frequency oscillatory activity in Parkinson's disease (PD). In healthy subjects such oscillations are evident in coherence between active muscles at 15--30 Hz. We therefore investigated the effects of therapeutic stimulation of the basal ganglia on this coherence and related it to changes in bradykinesia in the contralateral arm. Increases in coherence at 15--30 Hz and improvements in bradykinesia upon stimulation were correlated (r = 0.564, p < 0.001). This suggests that the basal ganglia modulate oscillatory activity in the corticomuscular system and that impairment of the motor system's ability to engage in synchronised oscillations at high frequency may contribute to bradykinesia in PD.

Divalent metal accumulation in freshwater bivalves: an inverse relationship with metal phosphate solubility.

Whole soft tissue concentrations of Mn, Co, Ni, Cu, Zn, Pb, Cd and U were measured in two species of freshwater (unionid) bivalves (Hyridella depressa and Velesunio ambiguus) from a minimally polluted site in the Hawkesbury-Nepean River, south-eastern Australia. Although the mean concentrations of metals in the tissue were similar for each bivalve species, their patterns of accumulation were dissimilar. For each metal, positive linear relationships between tissue concentration and shell length (r2 = 0.37-0.77; P < or = 0.001) and tissue dry weight (r2 = 0.29-0.51; P < or = 0.01) were found in H. depressa, but not in V. ambiguus. However, for both species, positive linear relationships were found between the tissue concentration of each divalent metal and Ca tissue concentration (r2 = 0.59-0.97; P < or = 0.001). For both bivalve species, the normalised rates of accumulation of the metals relative to increasing Ca concentration and/or size, were U approximately = Cd > or = Pb > or = Mn > Co > or = Zn > Cu > Ni. The differential rates of accumulation of divalent metals are interpreted as being predominantly governed by their varying loss rates, which are controlled by the differing solubilities (log Ksp values) of the metals in the phosphatic extracellular granules, the demonstrated major sites of metal deposition in the tissue of H. depressa and V. ambiguus. The rates of accumulation of Mn, Co, Zn, Cu and Ni were linearly and inversely related (r2 = 0.91-0.97; P < or = 0.001) to their solubilities as hydrogen phosphates, a finding consistent with the bioaccumulation model previously developed for the alkaline-earth metals. However, for U, Cd and Pb, this linear inverse relationship did not continue to hold, i.e. their rates of accumulation did not increase with decreasing solubility. However, these results are still consistent with the model if U, Cd and Pb are so insoluble in the granules of H. depressa and V. ambiguus over their lifetime (up to approx. 50 years) that there is effectively no loss of these metals, and hence, no differential between their rates of accumulation. The present results reaffirm the use of Ca tissue concentration to predict the tissue concentrations of other divalent metals by explaining up to 94 and 97% of the variability between individual bivalves of H. depressa and V. ambiguus, respectively. The use of Ca tissue concentration to effectively minimise the inherent variability between individuals in their metal tissue improves the ability of an investigator to discern smaller spatial and/or temporal differences in the metal tissue concentrations of these bivalves, and thus to detect metal pollution.

Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions.

In a search for novel transcriptional intermediary factors for the estrogen receptor (ER), we used the ligand-binding domain and hinge region of ER as bait in a yeast two-hybrid screen of a cDNA library derived from tamoxifen-resistant MCF-7 human breast tumors from an in vivo athymic nude mouse model. Here we report the isolation and characterization of the forkhead homologue in rhabdomyosarcoma (FKHR), a recently described member of the hepatocyte nuclear factor 3/forkhead homeotic gene family, as a nuclear hormone receptor (NR) intermediary protein. FKHR interacts with both steroid and nonsteroid NRs, although the effect of ligand on this interaction varies by receptor type. The interaction of FKHR with ER is enhanced by estrogen, whereas its interaction with thyroid hormone receptor and retinoic acid receptor is ligand-independent. In addition, FKHR differentially regulates the transactivation mediated by different NRs. Transient transfection of FKHR into mammalian cells dramatically represses transcription mediated by the ER, glucocorticoid receptor, and progesterone receptor. In contrast, FKHR stimulates rather than represses retinoic acid receptor- and thyroid hormone receptor-mediated transactivation. Most intriguingly, overexpression of FKHR dramatically inhibits the proliferation of ER-dependent MCF-7 breast cancer cells. Therefore, FKHR represents a bifunctional NR intermediary protein that can act as either a coactivator or corepressor, depending on the receptor type.

Intermuscular coherence in Parkinson's disease: effects of subthalamic nucleus stimulation.

It remains unclear how high frequency stimulation of the subthalamic nucleus (STN) improves parkinsonism. We hypothesized that stimulation may affect the organization of the cortical drive to voluntarily activated muscle. Normally this is characterized by oscillations at 15-30 Hz, manifest in coherence between muscles in the same frequency band. We therefore investigated the effects of STN stimulation on electromyographic (EMG) activity in co-contracting distal arm muscles in nine subjects with Parkinson's disease off drugs. Without stimulation, coherence between EMG signals was diminished at 15-30 Hz compared with nine controls. STN stimulation increased coherence in the 15-30 Hz band, so that it approached that in healthy subjects. The results suggest that STN stimulation facilitates the normal cortical drive to muscles.