Objective Contemporary deep brain stimulation for Parkinson’s disease is delivered continuously, and adjustments based on patient’s changing symptoms must be made manually by a trained clinician. Patients may be subjected to energy intensive settings at times when they are not needed, possibly resulting in stimulation-induced adverse effects, such as dyskinesia. One solution is “adaptive” DBS, in which stimulation is modified in real time based on neural signals that co-vary with the severity of motor signs or of stimulation-induced adverse effects. Here we show the feasibility of adaptive DBS using a fully implanted neural prosthesis. Approach We demonstrate adaptive deep brain stimulation in two patients with Parkinson’s disease using a fully implanted neural prosthesis that is enabled to utilize brain sensing to control stimulation amplitude (Activa PC+S). We used a cortical narrowband gamma (60-90 Hz) oscillation related to dyskinesia to decrease stimulation voltage when gamma oscillatory activity is high (indicating dyskinesia) and increase stimulation voltage when it is low. Main Results We demonstrate the feasibility of “adaptive deep brain stimulation” in two patients with Parkinson’s disease. In short term in-clinic testing, energy savings were substantial (38-45%), and therapeutic efficacy was maintained. Significance This is the first demonstration of adaptive DBS in Parkinson’s disease using a fully implanted device and neural sensing. Our approach is distinct from other strategies utilizing basal ganglia signals for feedback control.

Tissue-specific transcriptional activators initiate differentiation towards specialized cell types by inducing chromatin modifications permissive for transcription at target loci, through the recruitment of SWItch/Sucrose NonFermentable (SWI/SNF) chromatin-remodelling complex. However, the molecular mechanism that regulates SWI/ SNF nuclear distribution in response to differentiation signals is unknown. We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/ SNF core to muscle genes. BAF60c phosphorylation on a conserved threonine by differentiation-activated p38a kinase is the signal that promotes incorporation of MyoD-BAF60c into a Brg1-based SWI/SNF complex, which remodels the chromatin and activates transcription of MyoD-target genes. Our data support an unprecedented two-step model by which pre-assembled BAF60c-MyoD complex directs recruitment of SWI/SNF to muscle loci in response to differentiation cues.

Highlights d Demonstration of a monosynaptic, prefrontal hyperdirect pathway in humans d Fastest fibers between the inferior frontal gyrus and ventral subthalamic nucleus d Stopping elicits co-activation of the origin and target of this pathway d Degree of co-activation predicts stopping speed

Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I.Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M 1 dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 Amol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M 1 dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.

Activation of innate immunity (natural killer [NK] cell/interferon‐γ [IFN‐γ]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2‐week or a 10‐week carbon tetrachloride (CCl4) challenge, respectively. Injection of polyinosinic‐polycytidylic acid (poly I:C) or IFN‐γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2‐week CCl4 model. Such activation was diminished in the 10‐week CCl4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN‐γ on liver fibrosis was markedly reduced in the 10‐week versus the 2‐week CCl4 model. In vitro coculture experiments demonstrated that 4‐day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D/retinoic acid–induced early gene 1–dependent mechanism. Such activation was reduced when cocultured with 8‐day cultured (intermediately activated) HSCs due to the production of transforming growth factor‐β (TGF‐β) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN‐γ–mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN‐γ inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN‐γ signaling and functioning, whereas production of TGF‐β by HSCs inhibited NK cell function and cytotoxicity against HSCs. Conclusion: The antifibrogenic effects of NK cell/IFN‐γ are suppressed during advanced liver injury, which is likely due to increased production of TGF‐β and expression of SOCS1 in intermediately activated HSCs. (HEPATOLOGY 2011;)