Identification of Potent, Selective,Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2

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Renal function in mice with targeted disruption of the A isoform of the Na-K-2Cl co-transporter

Three different full-length splice isoforms of the Na-K-2Cl co-transporter (NKCC2/BSC1) are expressed along the thick ascending limb of Henle (TAL), designated NKCC2A, NKCC2B, and NKCC2F. NKCC2F is expressed in the medullary, NKCC2B mainly in the cortical, and NKCC2A in medullary and cortical portions of the TAL. NKCC2B and NKCC2A were shown to be coexpressed in the macula densa (MD) segment of the mouse TAL. The functional consequences of the existence of three different isoforms of NKCC2 are unclear. For studying the specific role of NKCC2A in kidney function, NKCC2A-/- mice were generated by homologous recombination. NKCC2A-/- mice were viable and showed no gross abnormalities. Ambient urine osmolarity was reduced significantly in NKCC2A-/- compared with wild-type mice, but water deprivation elevated urine osmolarity to similar levels in both genotypes. Baseline plasma renin concentration and the effects of a high- and a low-salt diet on plasma renin concentration were similar in NKCC2A+/+ and -/- mice. However, suppression of renin secretion by acute intravenous saline loading (5% of body weight), a measure of MD-dependent inhibition of renin secretion, was reduced markedly in NKCC2A-/- mice compared with wild-type mice. Cl and water absorption along microperfused loops of Henle of NKCC2A-/- mice were unchanged at normal flow rates but significantly reduced at supranormal flow. Tubuloglomerular feedback function curve as determined by stop flow pressure measurements was left-shifted in NKCC2A-/- compared with wild-type mice, with maximum responses being significantly diminished. In summary, NKCC2A activity seems to be required for MD salt sensing in the high Cl concentration range. Coexpression of both high- and low-affinity isoforms of NKCC2 may permit transport and Cl-dependent tubuloglomerular feedback regulation to occur over a wider Cl concentration range.     

Non-pharmacological interventions in older people with heart failure: effects of exercise training and relaxation therapy

BACKGROUND: Effective management of heart failure relies on optimal use of non-pharmacological therapy alongside medical treatment. Yet, there is an inadequate use of non-pharmacological therapy in caring for older people with heart failure. OBJECTIVE: To examine the effects of relaxation therapy and exercise training on psychological outcomes and disease-specific quality of life of older heart failure patients. METHODS: Subjects undertook relaxation (n = 59), exercise training (n = 32) or received attention placebo (n = 62) for 12 weeks. The relaxation group attended two training sessions, one revision workshop, and continued with twice-daily taped-directed home relaxation practice, with support from the intervener through bi-weekly telephone contact, for 12 weeks. The exercise group undertook 12 weekly sessions of resistance training and aerobic exercise and thrice weekly home exercise. The control group received regular telephone calls for general 'greetings'. RESULTS: The relaxation and exercise groups reported a significantly greater improvement in psychological [F(2, 149) = 6.69, p = 0.002] and various disease-specific quality of life outcomes [dyspnea: F(2, 149) = 5.72, p = 0.004; fatigue: F(2, 149) = 3.78, p = 0.25; emotion: F(2, 149) = 6.68, p = 0.001], compared with those who received the attention placebo. While relaxation therapy was more effective to reduce psychological distress, with depression in particular (p < 0.001), exercise therapy worked better to control fatigue symptoms (p = 0.03). CONCLUSION: Relaxation therapy and exercise training are effective to improve the psychological and physical health of older heart failure patients. They should be used as an individual treatment modality, or as care components of a disease management program.     

Functional mobility and postural control in essential tremor

OBJECTIVE: To evaluate functional mobility and postural control in participants with essential tremor (ET). DESIGN: Cross-sectional cohort study. SETTING: Motor performance research laboratory. PARTICIPANTS: Sixteen participants with ET including head tremor (age, 59.4+/-12.0 y), 14 participants with ET and no head tremor (age, 57.1+/-15.9 y), and 28 healthy controls (age, 58.4+/-12.4 y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We assessed the Timed Up & Go, time to ascend and descend stairs, Dynamic Gait Index, and Berg Balance Scale (BBS). Participants completed the Activities-specific Balance Confidence Scale and the Human Activity Profile. We assessed postural control using center-of-pressure measures from force platform recordings of quiet standing in 5 conditions. RESULTS: Participants with ET including head tremor performed worse than controls on all functional mobility performance and self-report measures (P<.05) except the BBS and stair descent time. Mean performance of ET participants without head tremor was intermediate between the other 2 groups. Sway speed measures of postural control showed similar patterns, but no significant group differences in post hoc analysis. There were no statistically significant or clinically important correlations between measures of tremor status and functional mobility status. CONCLUSIONS: Participants with ET show reduced functional mobility, especially those with head tremor.     

Single-Unit Recordings Reveal the Selectivity of a Human Face Area

The exquisite capacity of primates to detect and recognize faces is crucial for social interactions. Although disentangling the neural basis of human face recognition remains a key goal in neuroscience, direct evidence at the single-neuron level is limited. We recorded from face-selective neurons in human visual cortex in a region characterized by functional magnetic resonance imaging (fMRI) activations for faces compared with objects. The majority of visually responsive neurons in this fMRI activation showed strong selectivity at short latencies for faces compared with objects. Feature-scrambled faces and face-like objects could also drive these neurons, suggesting that this region is not tightly tuned to the visual attributes that typically define whole human faces. These single-cell recordings within the human face processing system provide vital experimental evidence linking previous imaging studies in humans and invasive studies in animal models.SIGNIFICANCE STATEMENT We present the first recordings of face-selective neurons in or near an fMRI-defined patch in human visual cortex. Our unbiased multielectrode array recordings (i.e., no selection of neurons based on a search strategy) confirmed the validity of the BOLD contrast (faces–objects) in humans, a finding with implications for all human imaging studies. By presenting faces, feature-scrambled faces, and face-pareidolia (perceiving faces in inanimate objects) stimuli, we demonstrate that neurons at this level of the visual hierarchy are broadly tuned to the features of a face, independent of spatial configuration and low-level visual attributes.     

Characterization of trigeminal C-fiber reactivity through capsaicin-induced release of calcitonin gene-related peptide

Objective

We hypothesized that the response of trigeminal dermal blood flow (DBF) in the trigeminal system and consecutive expansion of flare response to capsaicin would differ from the somatosensory system (arm). We also investigated whether there are differences between patients with migraine and healthy controls (HC).

Background

Functional differences between the trigeminal and extracephalic somatosensory systems may partly explain the susceptibility for headaches in patients with migraine. Capsaicin-induced activation of nociceptive C-fibers in the skin is mainly mediated by calcitonin gene-related peptide (CGRP) and induces cutaneous vessel dilatation and flare response.

Methods

Female patients with migraine (n = 38) and age-matched HC (n = 35) underwent DBF measurement at baseline and after topical capsaicin administration using laser speckle imaging. DBF before and after capsaicin stimulation was analyzed over ophthalmic nerve/maxillary nerve/mandibular nerve (V1/V2/V3) dermatomes and the forearm as an extracephalic control.

Results

Capsaicin-induced DBF increased more in the trigeminal dermatomes than on the forearm. The V1 dermatome showed a smaller increase of DBF in patients with migraine compared to HC.

Conclusion

Our results suggest that the trigeminovascular system reacts differently from extracephalic areas, which may explain the trigeminal susceptibility to CGRP-mediated pain attacks. By demonstrating a different reactivity of the V1 dermatome in patients with migraine, our finding suggests that the first trigeminal branch is functionally different from the second and third branches; however, only in patients with migraine.