Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans.

Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the µ-OR sub-type. In a sample of healthy volunteers, we used [(11)C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-ß-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.

Effect of use of different landmark methods on determining stifle angle and on calculated tibial tuberosity advancement.

OBJECTIVES: Firstly, to investigate the effect that using different landmarks has on the measured stifle angle. Secondly, to determine whether any differences in measured stifle angle would lead to variations in the required extent of tibial tuberosity advancement (TTA). METHODS: Three greyhound stifles were positioned in a total of 66 different angles. Radiographic exposures of each stifle angle were made. For each radiograph i) the stifle angle was measured using each of three sets of landmarks and ii) the extent of TTA required to obtain a patella tendon angle of 90° was measured. Each radiograph was plotted graphically according to the stifle angle and the extent of TTA required. Linear regression analysis was used to calculate the TTA required for a stifle angle of 135° measured using each of the three landmark sets. RESULTS: On average, the stifle angle determined by the Long Axes method differed by 18° from the stifle angle determined with the Kinematic method. The stifle angle determined using the Eminence method differed from that determined using the Kinematic method by three degrees. The use of the Long Axes of the tibia and femur as landmarks to determine a stifle angle resulted in 5 mm and 4 mm over-advancement of the tibial tuberosity compared to the use of Kinematic or Eminence landmark methods respectively. CLINICAL SIGNIFICANCE: The method used to measure the stifle joint angle can influence the value of the required TTA advancement. This is an additional variable that should be considered during TTA planning and when comparing in vivo and in vitro studies.

Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects.

AIMS: Albiglutide is a glucagon-like peptide-1 (GLP-1) mimetic generated by genetic fusion of a dipeptidyl peptidase-IV-resistant GLP-1 dimer to human albumin. Albiglutide was designed to retain the therapeutic effects of native GLP-1 while extending its duration of action. This study was conducted to determine the pharmacokinetics and initial safety/tolerability profile of albiglutide in non-diabetic volunteers. METHODS: In this single-blind, randomized, placebo-controlled trial, 39 subjects (18-60 years, body mass index 19.9-35.0 kg/m(2)) received placebo (n = 10) or escalating doses of albiglutide (n = 29) on days 1 and 8 in the following sequential cohorts: cohort 1: 0.25 + 1 mg; cohort 2: 3 + 6 mg; cohort 3: 16 + 24 mg; cohort 4: 48 + 60 mg; and cohort 5: 80 + 104 mg. Dose proportionality was evaluated based on area under the plasma drug concentration versus time curve [area under the curve (AUC((0-7 days)))] and maximum plasma drug concentration (C(max)) for cohorts 2-5 during week 1. RESULTS: Albiglutide had a terminal elimination half-life (T(1/2)) of 6-8 days and time to maximum observed plasma drug concentration (T(max)) of 3-4 days. A greater-than-dose proportional increase in albiglutide exposure was observed. Albiglutide demonstrated a dose-dependent trend in reductions of glucose weighted mean AUC and fructosamine levels in healthy subjects. The incidence and severity of adverse events (AEs) was similar between placebo and albiglutide groups. Headache was the most frequent drug-related AE, followed by constipation, flatulence and nausea. CONCLUSIONS: Albiglutide has a half-life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non-diabetic subjects.

Modification of the ventral approach to the caudal cervical spine by resection of the manubrium in a dog.

A five-year-old neutered female Bassett Hound weighing 29 kg was presented with a two-day history of paraparesis. Neurological examination and magnetic resonance imaging confirmed the presence of extruded disc material ventral to the spinal cord, from the C7-T1 intervertebral disc. A ventral slot was performed to decompress the cord. In making the approach to the caudal cervical spine, the cranial aspect of the manubrium of the sternum was resected. This improved the exposure of a region normally difficult to expose via a conventional ventral approach to the cervical spine. The successful performance of the ventral slot procedure was greatly facilitated by this adaptation, which was quick and simple to perform, without any apparent adverse affects to the animal.

Short-term outcome and complications of TPLO using anatomically contoured locking compression plates in small/medium-breed dogs with "excessive" tibial plateau angle.

OBJECTIVES: To report short-term radiographic and clinical outcome and complications following tibial plateau levelling osteotomy for the treatment of cranial cruciate ligament insufficiency in dogs less than 18·1 kg with tibial plateau angle greater than 35° using anatomically contoured six-hole locking compression plates. METHODS: Retrospective data were collected on: preoperative, postoperative and follow-up tibial plateau angles, plateau segment rotation, tibial tuberosity width and length of the cranial aspect of tibial tuberosity segment from the patellar tendon insertion and rotation of the tibial plateau below the level of the insertion of the patellar ligament. RESULTS: In 26 small dogs (29 stifles in total), mean preoperative, postoperative and follow-up tibial plateau angles were 38·2°, 4·8°, and 4·4°, respectively. Documented postoperative complications were limited to patellar tendinopathy in a single case (3·4%) and tibial tuberosity or fibula fracture were not observed. CLINICAL SIGNIFICANCE: Short-term radiographic and clinical outcome of tibial plateau levelling osteotomy stabilised with anatomically contoured six-hole locking compression plates for the treatment of small dogs with large tibial plateau angle suggests a very low risk of complications. Rotation beyond the "safe point" is necessary to perform full rotation in some cases, but does not appear to incur an increased risk of tibial tuberosity fracture.

A method to redefine stays on the 1985 National Nursing Home Survey.

This report describes a method for standardizing definitions of episodes of nursing home care in the 1985 National Nursing Home Survey. The method shows how the information on nursing home admissions and discharges collected on the Current and Discharged Resident Questionnaires can be used to redefine the endpoints of nursing home stays. The report also explains how errors caused by missing and inconsistent nursing home admission and discharge data were resolved.

Effects of caloric restriction and exercise on insulin receptors in obesity: association with changes in membrane lipids.

We have studied the effects of supervised caloric restriction and exercise on mononuclear leukocyte lipid composition, membrane fluidity, and insulin receptors in ten nondiabetic obese adults, (175 +/- 9.3% of ideal body weight) and ten normal adult subjects. In a second study, we examined the effects of caloric restriction alone using a very low calorie liquid diet in the treatment of another ten obese adults. In both groups of obese adults, fasting insulin levels were elevated and fell to normal levels following treatment. Insulin binding to monocytes, which was reduced in obese subjects, increased toward normal after short-term treatment; this was due to the restoration of total insulin binding capacity to levels one half of that seen in the normal adult group. Obese subjects undergoing either treatment had elevated membrane cholesterol/phospholipid ratios prior to treatment (0.499 +/- 0.050 and 0.446 +/- 0.011 v 0.400 +/- 0.025 mol/mol in normal adults P less than 0.005 by ANOVA). Prior to treatment, for all subjects there was a significant inverse correlation between insulin tracer binding and membrane cholesterol/phospholipid ratios (r = .484, n = 34, P less than 0.005). This relationship did not change significantly in obese subjects in either treatment group. Cell membrane microviscosity was determined by fluorescence polarization (FP) using DPH (2 X 10(-6) mol/L). Prior to weight loss, obese subjects had significantly higher FP values than controls (0.304 +/- 0.006 and 0.319 v 0.259 +/- 0.009, P less than 0.005, by ANOVA) indicating greater microviscosity.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease.

Fibroblast growth factor-2 (FGF-2) is a heparin-binding protein capable of inducing angiogenesis in multiple animal models of chronic ischemia. The pharmacokinetics and pharmacodynamics of a single dose of recombinant FGF-2 (rFGF-2) administered by intracoronary or intravenous infusion were evaluated in a Phase I trial in 66 patients with severe coronary artery disease. rFGF-2 displayed biphasic elimination with a mean studywide distribution t1/2 of 21 minutes and a mean apparent terminal elimination t1/2 of 7.6 hours. Systemic exposure to rFGF-2 was comparable following intracoronary or intravenous administration. Peak plasma concentration and area under the concentration-time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 micrograms/kg). Greater systemic exposure was observed when heparin was administered closer to rFGF-2 infusion, consistent with slower clearance of heparin/rFGF-2 complexes. Infusion of rFGF-2 was associated with changes in acute hemodynamics. While a clear PK/PD dose-response relationship was not established, a trend toward hypotension and tachycardia with higher rFGF-2 doses was observed.

Effects of a social support group, as an adjunct to diabetes training, on metabolic control and psychosocial outcomes.

The purpose of this present study was to evaluate a social support group as an adjunct to an intensive outpatient diabetes training program. Insulin-treated and non-insulin-treated patients (n = 204) were randomized into two groups: the control group received the training program only, whereas the experimental group was offered the same program plus eight support group meetings. At the 7-month follow-up, patients in both groups showed improved metabolic control, diabetes knowledge, frequency of practicing recommended diabetes management behaviors, and emotional adjustment. Although no additional improvement was seen in those outcome measures in patients who attended support group meetings, results of a subjective evaluation of the support group showed that patients experienced positive feelings in the groups that may contribute to patient health. A better understanding of the possible contribution of support groups to health is necessary before such groups are routinely recommended to patients.

What can be done about home health fieldwork?

The literature indicates that health care is moving away from institutional care and specialization to the community and home where providers need generalist competencies. As educators strive to prepare students for this environment, fieldwork experiences in the community and home are opportunities for students to develop generalist competencies. Because of the current scarcity of fieldwork sites, in general, scheduling placements is difficult. As educators seek new sites, home health settings and therapists who provide home health care as a component of their service need to be considered. Home health occupational therapy requires a practitioner to adopt a holistic perspective in order to assist clients to function optimally in their home environment. Because a large number of students work in addition to taking classes, they can be encouraged to find jobs as home health aides or chore providers as part-time employment before and during their didactic education. This work experience can help them to acculturate to the home setting. By encouraging students' participation in home health experiences, educators are helping to facilitate generalist competencies.

Spherical grip strength in children 3 to 6 years of age.

OBJECTIVE: The purpose of this study was to establish normative data on spherical grip strength of children 3 to 6 years of age with the Martin Vigorimeter. METHOD: Two hundred twenty-five preschoolers in the Kalamazoo, Michigan, area were tested with standardized positioning and instructions. The mean of three trials for each hand was used as the grip-strength score. A repeated measure design was used and the right and left hands were alternated during testing to allow a 20-sec rest period between trials. Hand width also was measured in inches from the head of the second metacarpal to the head of the fifth metacarpal. RESULTS: Hand width and grip strength were significantly correlated for both the right (p < .0001) and the left hands (p < .001). Grip strength increased linearly across all of the age groups (p < .001). The results of paired t tests did not show a significant difference in grip strength between the right and left hands or between boys and girls. A table of mean grip-strength scores and hand width measurements along with their standard deviations is presented for clinical use. CONCLUSION: The vigorimeter could be used to assess the grip strength of children with rheumatic disorders without putting excessive pressure on the joints or skin of the hand.

Comparison of performance in materials-based occupation, imagery-based occupation, and rote exercise in nursing home residents.

Materials-based occupation, imagery-based occupation, and rote exercise have been examined individually by several researchers. The present study compares all three approaches with one another (i.e., kicking a balloon, imagining kicking a balloon, and a control rote exercise) in nursing home residents. The dependent variable was the number of exercise repetitions. The subjects were 12 women and 3 men between 56 and 93 years of age residing in two nursing homes. All subjects experienced the three approaches but in different orders. One-way analysis of variance for related measures indicated a significant difference among conditions (p = .004). The Tukey procedure (Stevens, 1986) determined that the materials-based occupation condition elicited significantly more repetitions than the other two conditions. The difference between the imagery-based occupation and rote exercise was not statistically significant. These findings support our profession's historical emphasis on the use of physical materials to enhance performance.

Adding purpose to the repetitive exercise of elderly women through imagery.

Many studies have documented the effectiveness of verbally elicited imagery in the enhancement of motor skills in young, nondisabled populations. The present study examined the effects of verbally elicited imagery in the encouragement of two exercises (i.e., reaching up to pick apples and reaching down to pick up coins) in elderly women. The subjects were 27 women between 62 and 96 years of age who were selected from a nursing home, a residential retirement home, and a foster care home. All of the subjects received imagery as well as control conditions, but in a counterbalanced fashion. The Wilcoxon matched-pairs signed rank tests indicated that the imagery condition elicited significantly more repetitions of the reaching-up exercise than did the control condition (z = 2.25, p [one-tailed] = .012). The results in the reaching-down exercise were generally in the same direction but difficult to interpret statistically. The results are discussed in terms of other recent research investigating ways to add purpose to therapeutic exercise through occupation. Clinicians are urged to explore the advantages and disadvantages of imagery-based occupations in treatment.

Management of feline distal tibial fractures using a hybrid external skeletal fixator.

OBJECTIVE: To document the results of management of feline distal tibial fractures with circular-linear hybrid external skeletal fixators. METHODS: Retrospective examination of case records and radiographs of cats with distal tibial fractures managed with hybrid external skeletal fixators. Signalment, pre-operative fracture conformation, post-operative fracture reduction, implant complications, time to tibial and fibular fracture healing and time to hybrid external skeletal fixators removal were analysed. RESULTS: Case records of eight cats were reviewed and included three closed fractures and five type 1 open fractures. Post-operative fracture reduction was considered appropriate in all cases. Healing of five tibial fractures was complete and hybrid external skeletal fixators were removed within a mean of 13 weeks. Healing of the fibular fracture was complete within a mean of 12 · 1 weeks. Three tibial fractures demonstrated non-union and were revised after a mean duration of 24 weeks. All three non-union fractures were open on presentation. CLINICAL SIGNIFICANCE: Feline distal tibial fractures may be managed with hybrid external skeletal fixators, however, non-union still occurs. In this study type I open feline distal tibial fractures appeared more likely to develop non-union.

Healing of patellar fractures in two kittens.

Two kittens aged between four and five months were presented having sustained patellar fractures. In both cases, healing was subsequently documented radiographically; this has not been reported previously in the literature. One kitten had bilateral patellar fractures - the symptomatic right stifle was treated with a pin and tension-band-wire which later failed, at which point partial patellectomy was performed. The fracture of the left patella was minimally displaced and was treated conservatively. A radiograph of the left patella taken eleven months after initial presentation showed complete healing of the fracture. The second case was treated surgically with a circumferential wire; healing of the fracture was demonstrated radiographically at twelve weeks postoperatively. Radiographic images taken five weeks postoperatively had shown some narrowing of the fracture gap. These two cases demonstrate that bony union of patellar fractures can be documented, given a long enough duration of radiographic follow-up; circumferential wire was an effective treatment in a displaced fracture, and conservative treatment resulted in complete healing of a minimally displaced fracture.

Propagation of a partial incomplete ossification of the humeral condyle in an American cocker spaniel.

A hypoattenuating lesion in the left humeral condyle of an American cocker spaniel consistent with partial incomplete ossification of the humeral condyle was observed on computed tomography. Left forelimb lameness developed over the following three weeks at which time repeat computed tomography examination confirmed propagation of the lesion. Lameness resolved following placement of a transcondylar positional screw, suggesting that lameness was secondary to condylar instability. To the authors' knowledge this is the first report of propagation of an intracondylar lesion in a dog.

Probabilistic risk analysis: improving early drug development decision making.

Model-based drug development (MBDD) is advocated by industry, academia, and regulatory agencies as a powerful tool to improve the efficiency of drug development. Clinical pharmacologists play key roles in implementing MBDD because of their ability to integrate mechanistic, preclinical, and clinical information, using quantitative approaches to address the complex questions arising during drug development. Use of probabilistic risk analysis (PRA) approaches (e.g., value of information, combining uncertain information, and modeling expert opinion) can improve the implementation of MBDD.