Congressional Budget Office: Appointment and Tenure of the Director and Deputy Director

Section 20 1 (a) requires that the selection be made "without regard to political affiliation and solely on the basis of his fitness to perform his duties." Media reports over the years indicate that the CBO director is selected under informal practices in which the House and Senate Budget Committees alternate in recommending a nominee to the Speaker and President pro tempore of the Senate. These reports also indicate that the Speaker and President pro tempore have adhered to the Budget Committees' recommendations in making past selections. To the extent that these practices are informal, there may be disagreement with regard to their operation in the future selection of a CBO director

Fiscal Year 2006

The House and Senate reached final agreement on April 28, 2005, on a budget resolution for FY2006 (H.Con.Res. 95) which included reconciliation directives expected to lead to the consideration of three different reconciliation bills during the session: (1) an omnibus spending reduction measure, incorporating submissions from eight House and eight Senate committees; (2) a revenue reduction measure; and (3) a public debt limit increase measure. The omnibus spending bill is intended to reduce outlays by $1.519 billion for FY2006 and$34.658 billion for the five-year period covering FY2006 through FY2010; the revenue bill is intended to reduce revenues by $11 billion for FY2006 and$70 billion for the period FY2006-FY2010; and the third bill is intended to increase the public debt limit by $781 billion

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

Congressional Budget Office: Appointment and Tenure of the Director and Deputy Director

This report provides a brief background of the Congressional Budget Office (CBO), as well as the appointment process of director and deputy director

Structural determinants of TRPV1 functionality

Multimerization The capsaicin receptor TRPV1 ( The Drosophila TRP channels have been shown to form a heteromultimeric channel complex. These complexes in turn form part of a larger signaling complex that also contains a G-protein-coupled receptor (rhodopsin), an effector [phospholipase C (PLC)], regulators [protein kinase C (PKC) and CaM], and the scaffolding protein INAD (inactivation no-after potential D

Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers

This double-blind randomized controlled study was designed to evaluate the analgesic effects of topical treatments with clonidine (CLON) and pentoxifylline (PTX) tested alone or as low- and high-dose combinations in a human experimental model of pain. Of 69 healthy subjects aged 18 to 60 years, 23 each were randomly allocated to low-dose (0.04% + 2%) and high-dose (0.1% + 5%) CLON + PTX groups. Both of these groups also received their corresponding placebos in one of 2 treatment periods separated by at least 48 hours. Twenty-three additional subjects received either CLON (0.1%) or PTX (5%) as single drug treatments, in each of 2 treatment periods. Assessment of analgesic efficacy was based on allodynic effects of previous intraepidermal capsaicin injection, as well as postcapsaicin tourniquet-induced pain 50 minutes following capsaicin injection. Visual Analogue Scale (VAS) ratings of pain intensity and the area of dynamic mechanical allodynia were the primary outcome measures, whereas area of punctate mechanical allodynia (PMA) served as a secondary outcome measure. Topical treatments with high- or low-dose combinations significantly reduced VAS ratings compared with corresponding placebo treatments throughout the period of postcapsaicin tourniquet-induced pain. Importantly, the high-dose combination produced lower VAS ratings than CLON alone, which were lower than PTX alone. Results also revealed significant inhibition of postcapsaicin dynamic mechanical allodynia and PMA for the high-dose combination compared with placebo, and of PMA for CLON compared with the low-dose combination. Hence, the present data are supportive of further clinical investigation of the high-dose topical combination of CLON + PTX in complex regional pain syndrome and neuropathic pain patients, for which our preclinical data predict efficacy

RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists

1. Prostacyclin (PGI(2)) possesses various physiological functions, including modulation of nociception, inflammation and cardiovascular activity. Elucidation of these functions has been hampered by the absence of selective IP receptor antagonists. 2. Two structurally distinct series of IP receptor antagonists have been developed: 4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) and R-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO3244794). 3. RO1138452 and RO3244794 display high affinity for IP receptors. In human platelets, the receptor affinities (pK(i)) were 9.3±0.1 and 7.7±0.03, respectively; in a recombinant IP receptor system, pK(i) values were 8.7±0.06 and 6.9±0.1, respectively. 4. Functional antagonism of RO1138452 and RO3244794 was studied by measuring inhibition of carbaprostacyclin-induced cAMP accumulation in CHO-K1 cells stably expressing the human IP receptor. The antagonist affinities (pK(i)) of RO1138452 and RO3244794 were 9.0±0.06 and 8.5±0.11, respectively. 5. Selectivity profiles for RO1138452 and RO3244794 were determined via a panel of receptor binding and enzyme assays. RO1138452 displayed affinity at I(2) (8.3) and PAF (7.9) receptors, while RO3244794 was highly selective for the IP receptor: pK(i) values for EP(1) (<5), EP(3) (5.38), EP(4) (5.74) and TP (5.09). 6. RO1138452 (1–10 mg kg(−1), i.v.) and RO3244794 (1–30 mg kg(−1), i.v.) significantly reduced acetic acid-induced abdominal constrictions. RO1138452 (3–100 mg kg(−1), p.o.) and RO3244794 (0.3–30 mg kg(−1), p.o.) significantly reduced carrageenan-induced mechanical hyperalgesia and edema formation. RO3244794 (1 and 10 mg kg(−1), p.o.) also significantly reduced chronic joint discomfort induced by monoiodoacetate. 7. These data suggest that RO1138452 and RO3244794 are potent and selective antagonists for both human and rat IP receptors and that they possess analgesic and anti-inflammatory potential

Kinesin spindle protein (KSP) inhibitors in combination with chemotherapeutic agents for cancer therapy

A diverse group of proteins, the activities of which are precisely orchestrated during mitosis, have emerged as targets for cancer therapeutics; these include the Aurora kinases (AKs), Polo‐like kinases (PLKs), and the kinesin spindle protein (KSP). KSP is essential for the proper separation of spindle poles during mitosis. Agents that target KSP selectively act on cells undergoing cell division, which means that KSP inhibitors are mitosis‐specific drugs, and have demonstrated remarkable activities in vitro. However, a significant obstacle to the success of KSP inhibitors is that these compounds, with tremendous efficacy in vitro, have demonstrated little or even no antitumor activity in vivo. Accumulated data suggest that a combination of KSP inhibitors with various cytostatic drugs will result in a more powerful tumor‐killing effect than monotherapy. Combination therapies might predominate and represent the next frontier in the discovery research of KSP inhibitors as potential anticancer drugs. Few published studies have reviewed combination therapy using KSP inhibitors. Herein we provide a comprehensive review of the literature on KSP inhibitor monotherapy and therapeutic combinations. The current state and problems are also discussed. Two are better than one: Targeted therapies in the form of antibodies and small molecules have been studied in combination with kinesin spindle protein (KSP) inhibitors to enhance their efficacy against cancer in preclinical investigations. Accumulated data suggest that a combination of KSP inhibitors with various cytostatic drugs will result in a more powerful tumor‐killing effect than monotherapy. Combination therapies may predominate and represent the next frontier in discovery research for KSP inhibitors as potential anticancer drugs