Search for a Nonrelativistic Boson in Two-Body Antimuon Decay.

We demonstrate the feasibility of probing the charged lepton-flavor-violating decay µ^{+}→e^{+}X^{0} for the presence of a slow-moving neutral boson X^{0} capable of undergoing gravitational binding to large structures and, as such, able to participate in some cosmological scenarios. A short exposure to surface antimuons from beam line M20 at TRIUMF generates a branching ratio limit of ≲10^{-5}. This is comparable to or better than previous searches for this channel, although in a thus-far-unexplored region of X^{0} phase space very close to the kinematic limit of the decay, where m_{X^{0}} approaches m_{µ^{+}}. The future improved sensitivity of the method using a customized p-type point-contact germanium detector is described.

Dark Matter Search Results from the PICO-60 C_{3}F_{8} Bubble Chamber.

New results are reported from the operation of the PICO-60 dark matter detector, a bubble chamber filled with 52 kg of C_{3}F_{8} located in the SNOLAB underground laboratory. As in previous PICO bubble chambers, PICO-60 C_{3}F_{8} exhibits excellent electron recoil and alpha decay rejection, and the observed multiple-scattering neutron rate indicates a single-scatter neutron background of less than one event per month. A blind analysis of an efficiency-corrected 1167-kg day exposure at a 3.3-keV thermodynamic threshold reveals no single-scattering nuclear recoil candidates, consistent with the predicted background. These results set the most stringent direct-detection constraint to date on the weakly interacting massive particle (WIMP)-proton spin-dependent cross section at 3.4×10^{-41} cm^{2} for a 30-GeV c^{-2} WIMP, more than 1 order of magnitude improvement from previous PICO results.

Dark Matter Search Results from the PICO-2L C3F8 Bubble Chamber.

New data are reported from the operation of a 2 liter C3F8 bubble chamber in the SNOLAB underground laboratory, with a total exposure of 211.5 kg days at four different energy thresholds below 10 keV. These data show that C3F8 provides excellent electron-recoil and alpha rejection capabilities at very low thresholds. The chamber exhibits an electron-recoil sensitivity of <3.5×10(-10) and an alpha rejection factor of >98.2%. These data also include the first observation of a dependence of acoustic signal on alpha energy. Twelve single nuclear recoil event candidates were observed during the run. The candidate events exhibit timing characteristics that are not consistent with the hypothesis of a uniform time distribution, and no evidence for a dark matter signal is claimed. These data provide the most sensitive direct detection constraints on WIMP-proton spin-dependent scattering to date, with significant sensitivity at low WIMP masses for spin-independent WIMP-nucleon scattering.

Healthcare provider targeted interventions to improve medication adherence: systematic review and meta-analysis.

OBJECTIVE: This systematic review applied meta-analytic procedures to synthesise medication adherence (also termed compliance) interventions that focus on healthcare providers. DESIGN: Comprehensive searching located studies testing interventions that targeted healthcare providers and reported patient medication adherence behaviour outcomes. Search strategies included 13 computerised databases, hand searches of 57 journals, and both author and ancestry searches. Study sample, intervention characteristics, design and outcomes were reliably coded. Standardised mean difference effect sizes were calculated using random-effects models. Heterogeneity was examined with Q and I(2) statistics. Exploratory moderator analyses used meta-analytic analogue of ANOVA and regression. RESULTS: Codable data were extracted from 218 reports of 151,182 subjects. The mean difference effect size was 0.233. Effect sizes for individual interventions varied from 0.088 to 0.301. Interventions were more effective when they included multiple strategies. Risk of bias assessment documented larger effect sizes in studies with larger samples, studies that used true control groups (as compared with attention control), and studies without intention-to-treat analyses. CONCLUSION: Overall, this meta-analysis documented that interventions targeted to healthcare providers significantly improved patient medication adherence. The modest overall effect size suggests that interventions addressing multiple levels of influence on medication adherence may be necessary to achieve therapeutic outcomes.

Improved limits on spin-dependent WIMP-proton interactions from a two liter CF3I bubble chamber.

Data from the operation of a bubble chamber filled with 3.5 kg of CF3I in a shallow underground site are reported. An analysis of ultrasound signals accompanying bubble nucleations confirms that alpha decays generate a significantly louder acoustic emission than single nuclear recoils, leading to an efficient background discrimination. Three dark matter candidate events were observed during an effective exposure of 28.1 kg day, consistent with a neutron background. This observation provides strong direct detection constraints on weakly interacting massive particle (WIMP)-proton spin-dependent scattering for WIMP masses >20 GeV/c2.

Cholesterol kinetics in subjects with bile fistula. Positive relationship between size of the bile acid precursor pool and bile acid synthetic rate.

Our aim was to identify and quantitate cholesterol pools and transport pathways in blood and liver. By studying bile fistula subjects, using several types of isotopic preparations, simultaneous labeling of separate cholesterol pools and sampling all components of blood and bile at frequent intervals, we developed a comprehensive multicompartmental model for cholesterol within the rapidly miscible pool. Data in six components (bile acids, esterified cholesterol in whole plasma, and free cholesterol in blood cells, bile, alpha lipoproteins, and beta lipoproteins) were modeled simultaneously with the SAAM program. The analysis revealed extensive exchange of free cholesterol between HDL and liver, blood cells, and other tissues. There was net free cholesterol transport from HDL to the liver in most subjects. The major organ that removed esterified cholesterol from blood was the liver. A large portion (4,211 mumol) of total hepatic cholesterol comprised a pool that turned over rapidly (t1/2 of 72 min) by exchanging mainly with plasma HDL and was the major source of bile acids and biliary cholesterol. Only 6% of hepatic newly synthesized cholesterol was used directly for bile acid synthesis: the analysis showed that 94% of newly synthesized cholesterol was partitioned into the large hepatic pool (putative plasma membrane free cholesterol) which exchanged rapidly with plasma lipoproteins. Bile acid synthetic rate correlated directly with the size of the large hepatic pool. In conclusion, hepatic and blood cholesterol pools and transports have been quantitated. HDL plays a central role in free cholesterol exchange/transport between all tissues and plasma. In humans, the metabolically active pool comprises a large portion of total hepatic cholesterol that, in part, regulates bile acid synthesis.

What peptides these deltorphins be.

The deltorphins are a class of highly selective delta-opioid heptapeptides from the skin of the Amazonian frogs Phyllomedusa sauvagei and P. bicolor. The first of these fascinating peptides came to light in 1987 by cloning of the cDNA of from frog skins, while the other members of this family were identified either by cDNA or isolation of the peptides. The distinctive feature of deltorphins is the presence of a naturally occurring D-enantiomer at the second position in their common N-terminal sequence, Tyr-D-Xaa-Phe, comparable to dermorphin, which is the prototype of a group of mu-selective opioids from the same source. The D-amino acid and the anionic residues, either Glu or Asp, as well as their unique amino acid compositions are responsible for the remarkable biostability, high delta-receptor affinity, bioactivity and peptide conformation. This review summarizes a decade of research from many laboratories that defined which residues and substituents in the deltorphins interact with the delta-receptor and characterized pharmacological and physiological activities in vitro and in vivo. It begins with a historical description of the topic and presents general schema for the synthesis of peptide analogues of deltorphins A, B and C as a means to document the methods employed in producing a myriad of analogues. Structure activity studies of the peptides and their pharmacological activities in vitro are detailed in abundantly tabulated data. A brief compendium of the current level of knowledge of the delta-receptor assists the reader to appreciate the rationale for the design of these analogues. Discussion of the conformation of these peptides addresses how structure leads to further hypotheses regarding ligand receptor interaction. The review ends with a broad discussion of the potential applications of these peptides in clinical and therapeutic settings.

Evolution of the Dmt-Tic pharmacophore: N-terminal methylated derivatives with extraordinary delta opioid antagonist activity.

The delta opioid antagonist H-Dmt-Tic-OH (2',6'-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) exhibits extraordinary delta receptor binding characteristics [Ki delta = 0.022 nM; Ki mu/Ki delta = 150,000] and delta antagonism (pA2 = 8.2; Ke = 5.7 nM). A change in chirality of Dmt at C alpha (1, 2, 6, 8, 10, 13) curtailed delta receptor parameters, while replacement of its alpha-amino function by a methyl group (3) led to inactivity; Tyr-Tic analogues 4 and 11 weakly interacted with delta receptors. N-Alkylation of H-Dmt-Tic-OH and H-Dmt-Tic-Ala-OH with methyl groups produced potent delta-opioid ligands with high delta receptor binding capabilities and enhanced delta antagonism: (i) N-Me-Dmt-Tic-OH 5 had high delta opioid binding (Ki delta = 0.2 nM), elevated delta antagonism on mouse vas deferens (MVD) (pA2 = 8.5; Ke = 2.8 nM), and nondetectable mu activity with guinea pig ileum (GPI). (ii) N,N-Me2-Dmt-Tic-OH (12) was equally efficacious in delta receptor binding (Ki delta = 0.12 nM; Ki mu/Ki delta = 20000), but delta antagonism rose considerably (pA2 = 9.4; Ke = 0.28 nM) with weak mu antagonism (pA2 = 5.8; Ke = 1.58 microM; GPI/MVD = 1:5640). N-Me-(9) and N,N-Me2-Dmt-Tic-Ala-OH (15) also augmented delta opioid receptor binding, such that 15 demonstrated high affinity (Ki delta = 0.0755 nM) and selectivity (Ki mu/Ki delta = 20132) with exceptional antagonist activity on MVD (pA2 = 9.6; Ke = 0.22 nM) and weak antagonism on GPI (pA2 = 5.8; Ke = 1.58 microM; GPI/MVD = 1:7180). Although the amidated dimethylated dipeptide analogue 14 had high Ki delta (0.31 nM) and excellent antagonist activity (pA2 = 9.9; Ke = 0.12 nM), the increased activity toward mu receptors in the absence of a free acid function at the C-terminus revealed modest delta selectivity (Ki mu/Ki delta = 1655) and somewhat comparable bioactivity (GPI/MVD = 4500). Thus, the data demonstrate that N,N-(Me)2-Dmt-Tic-OH (12) and N,N-Me2-Dmt-Tic-Ala-OH (15) retained high delta receptor affinities and delta selectivities and acquired enhanced potency in pharmacological bioassays on MVD greater than that of other peptide or non-peptide delta antagonists.

Further studies on the Dmt-Tic pharmacophore: hydrophobic substituents at the C-terminus endow delta antagonists to manifest mu agonism or mu antagonism.

Twenty N- and/or C-modified Dmt-Tic analogues yielded similar K(i) values with either [(3)H]DPDPE (delta(1) agonist) or [(3)H]N, N(Me)(2)-Dmt-Tic-OH (delta antagonist). N-Methylation enhanced delta antagonism while N-piperidine-1-yl, N-pyrrolidine-1-yl, and N-pyrrole-1-yl were detrimental. Dmt-Tic-X (X = -NHNH(2), -NHCH(3), -NH-1-adamantyl, -NH-tBu, -NH-5-tetrazolyl) had high delta affinities (K(i) = 0.16 to 1 nM) with variable mu affinities to yield nonselective or weakly mu-selective analogues. N, N-(Me)(2)Dmt-Tic-NH-1-adamantane exhibited dual delta and mu receptor affinities (K(i)delta = 0.16 nM and K(i)mu = 1.12 nM) and potent delta antagonism (pA(2) = 9.06) with mu agonism (IC(50) = 16 nM). H-Dmt-betaHTic-OH (methylene bridge between C(alpha) of Tic and carboxylate function) yielded a biostable peptide with high delta affinity (K(i) = 0.85 nM) and delta antagonism (pA(2) = 8.85) without mu bioactivity. Dmt-Tic-Ala-X (X = -NHCH(3), -OCH(3), -NH-1-adamantyl, -NHtBu) exhibited high delta affinities (K(i) = 0.06 to 0.2 nM) and elevated mu affinities (K(i) = 2.5 to 11 nM), but only H-Dmt-Tic-Ala-NH-1-adamantane and H-Dmt-Tic-Ala-NHtBu yielded delta receptor antagonism (pA(2) = 9.29 and 9.16, respectively). Thus, Dmt-Tic with hydrophobic C-terminal substituents enhanced mu affinity to provide delta antagonists with dual receptor affinities and bifunctional activity.

Inhibition of human multidrug resistance P-glycoprotein 1 by analogues of a potent delta-opioid antagonist.

Analogues Dmt-Tic (2',6'-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) pharmacophore, a potent delta-opioid receptor antagonist, inhibited hMDR1 P-GP expressed in a G-185 fibroblast cell line in a manner similar to verapamil. N,N(Me)2-Dmt-Tic-NH-1-adamantane, H-Dmt-Tic-NH-1-adamantane, H-Dmt-Tic-Ala-NH-1-adamantane and N,N(Me)2-Dmt-Tic-NH-tBut were highly effective inhibitors. Weaker inhibition was observed with N,N(Et)2-Dmt-Tic-OH, H-Dmt-Tic-Ala-NH-tert-butyl amide and cyclo(Dmt-Tic). Results demonstrate that N- and C-terminal hydrophobic/lipophilic analogues of the Dmt-Tic pharmacophore inhibit hMDR1 and point to a potential role as chemosensitizing agents in chemotherapy for cancers containing hMDR1.

Design enhancement of a solid ankle-foot orthosis: real-time contact pressures evaluation.

The purpose of our study was to evaluate all contact pressures between the molded ankle-foot orthosis (MAFO) and the subject during activities of daily living. The MAFOs studied are used clinically to reduce plantar contact pressures associated with foot ulcers in adult neuropathic diabetic subjects, alleviating abnormal pressures by redistributing them to low-pressure plantar regions. While effective, MAFOs are often not used by the subject due to weight and comfort issues. An understanding of the contact pressures between the subject and the orthosis is a first step in improving basic MAFO design. Four nonimpaired, young adult males were tested in this study. A right-side MAFO was custom-molded and fitted for each subject by the same orthotist. Real-time pressures were obtained for the entire contact area using the F-Scan pressure measurement system. The data obtained demonstrated high contact pressures along the metatarsals of the foot, around the heel and ankle, and adjacent to the strap attachment sites. No contact pressures were noted along the posterior calf region during any of the activities performed. These data suggest the calf region would be a suitable site for material removal for weight reduction and increased comfort, especially in warm weather. In addition, these data may be useful to orthotists in improving the basic design and to researchers as a starting point for performing complex finite element analysis on the MAFO.

Arthroscopy of the foot and ankle in the athlete.

Ankle arthroscopy has evolved over the past decade to address many acute and chronic injuries in the athlete. Although similar outcomes are reported with established open procedures, arthroscopic intervention confers the advantages of decreased postoperative morbidity and earlier return to sports activity. Arthroscopic procedures for the foot are evolving; however, most are considered investigational at this time.

Flexor hallucis longus tendon injury in dancers and nondancers.

Thirty-one cases of flexor hallucis longus injuries in 26 patients were treated over a 16-year period (1977-1993). Groups were divided into dance-related injuries (group I) and other causes (group II). The two groups were compared with regard to age, activity, duration of symptoms, operative findings, histopathology, and postoperative time to resumption of full activities. Twenty-seven cases required surgery for unsuccessful nonoperative treatment. In group I, 71% of patients had a partial longitudinal tear of the flexor hallucis longus compared with 30% in group II. Another common finding was isolated tenosynovitis (21% in group I and 53% in group II). Eight cases had magnetic resonance imaging (MRI) evaluations before surgery. Clinical correlation was found to be an important factor in interpreting the MRI. Dancers tended to have symptoms for a longer period of time before seeking treatment than did nondancers. Follow-up was 19.2 months for dancers and 25 months for nondancers. Surgical correction of tenosynovitis, pseudocyst, and tendon tear yielded good or excellent results in 14 of 15 dancers and 9 of 11 nondancers. Surgical treatment of tendon tears and other pathologic tendon conditions gave consistently good results in patients with refractory flexor hallucis longus disease.

Calcaneocuboid joint pressures with lateral column lengthening (Evans) procedure.

Calcaneocuboid joint pressures were evaluated with eight cadaver specimens. Real-time pressures were recorded using a TekScan 4200 sensor pad at lengths of 0, 5, and 10 mm in both unloaded and 350-newton loaded models. Recorded pressures exceeded 2.3 MPa in the loaded model at 10 mm lateral column lengthening. Although an acceptable procedure in the pediatric population, application of the Evans lateral column lengthening procedure for management of adult acquired flatfoot may generate excessive pressures leading to joint arthrosis. Lengthening by calcaneocuboid distraction arthrodesis may avoid this problem.

Orthopedic considerations in wound healing of the lower extremity.

The advancing technologies available to the orthopedist are a necessary adjunct to heal wounds about the foot and ankle successfully. Successful wound healing should be viewed as a multidisciplinary approach, using the strengths of each discipline. Critical to an integrated method is communication preoperatively between the orthopedist and the plastic surgeon to create a streamlined process. This leads not only to improved rates of wound healing, but also to improved functional outcomes while reducing risks for recurrence.

Triple arthrodesis.

Triple arthrodesis is the surgical fusion of the calcaneocuboid, talonavicular, and talocalcaneal joints of the foot. This is a palliative surgical procedure used to treat many painful hindfoot disorders (eg, clubfoot deformity, arthritis, Charcot's joint disease). Patient benefits include pain relief and improvement in foot function. Several anesthesia options are available for intraoperative and postoperative pain management. Perioperative nurses should be knowledgeable about foot anatomy, the sequence of surgical events, and possible postoperative complications from triple arthrodesis. A systems approach to patient care throughout the perioperative phase can ensure optimal patient outcomes.

Spin-dependent WIMP limits from a bubble chamber.

Bubble chambers were the dominant technology used for particle detection in accelerator experiments for several decades, eventually falling into disuse with the advent of other techniques. We report here on a new application for these devices. We operated an ultraclean, room-temperature bubble chamber containing 1.5 kilograms of superheated CF3I, a target maximally sensitive to spin-dependent and -independent weakly interacting massive particle (WIMP) couplings. An extreme intrinsic insensitivity to the backgrounds that commonly limit direct searches for dark matter was measured in this device under operating conditions leading to the detection of low-energy nuclear recoils like those expected from WIMPs. Improved limits on the spin-dependent WIMP-proton scattering cross section were extracted during our experiments, excluding this type of coupling as a possible explanation for a recent claim of particle dark-matter detection.

New measurement of the K+-->pi+ nunu branching ratio.

Three events for the decay K+-->pi+ nunu have been observed in the pion momentum region below the K+-->pi+pi0 peak, 140 < Ppi < 199 MeV/c, with an estimated background of 0.93+/-0.17(stat.) -0.24+0.32(syst.) events. Combining this observation with previously reported results yields a branching ratio of B(K+-->pi+ nunu) = (1.73(-1.05)+1.15) x 10(-10) consistent with the standard model prediction.