In vitro and in vivo activities of C-terminally truncated PTH peptides reveal a disconnect between cAMP signaling and functional activity

There is considerable evidence implicating the cAMP-signaling pathway in the anabolic action of PTH; and to date, all PTH and PTHrp peptides that stimulate cyclic AMP are active in animal models of osteogenesis. We have tested two C-terminally truncated peptides, PTH(1–29) and a modified PTH(1–21) (MPTH(1–21)), in in vitro and in vivo assays of PTH action. Each of the C-terminally truncated peptides was of low nanomolar potency in assays of receptor binding and cAMP stimulation. However, when we tested these peptides for functional response in Saos-2 cells stably transfected with a cyclic AMP response element (CRE) reporter, the C-terminally truncated peptides were two to four times less potent than would be expected from their binding and cAMP-stimulating properties. Furthermore, PTH(1–29), although active, was approximately 20-fold less potent than PTH(1–34) in a rat model of osteogenesis while MPTH(1–21) was inactive. The relative lack of activity of these peptides in vivo suggests that while activation of the cAMP pathway may be important for the anabolic effect of PTH fragments, it is not, of itself, predictive of their in vivo activity.     

Dementia Deficits Scale. Rating self-awareness of deficits

Impaired deficit awareness is important to detect because of its clinical implications; for example, patients with impaired awareness are more likely to engage in potentially dangerous activities, such as operating the stove. This study evaluated the reliability and validity of the Dementia Deficits Scale (DDS), a new multidimensional instrument for the assessment of self-awareness of cognitive, emotional, and functional deficits associated with dementia. Three parallel forms of the DDS were independently completed by the patient, clinician, and informant. The DDS yields two measures of deficit awareness: the discrepancy between clinician and patient assessments of the patient's deficits, and the discrepancy between informant and patient assessments. The DDS demonstrated adequate reliability and good divergent and convergent validity. Clinician and informant reports each added unique information, highlighting the importance of including both perspectives in the awareness assessment process. The DDS is recommended as a reliable and valid tool for the clinical and empirical assessment of deficit awareness in patients with dementia.     

Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity

Background  

Controlled clinical trials of health care interventions are either explanatory or pragmatic. Explanatory trials test whether an intervention is efficacious; that is, whether it can have a beneficial effect in an ideal situation. Pragmatic trials measure effectiveness; they measure the degree of beneficial effect in real clinical practice. In pragmatic trials, a balance between external validity (generalizability of the results) and internal validity (reliability or accuracy of the results) needs to be achieved. The explanatory trial seeks to maximize the internal validity by assuring rigorous control of all variables other than the intervention. The pragmatic trial seeks to maximize external validity to ensure that the results can be generalized. However the danger of pragmatic trials is that internal validity may be overly compromised in the effort to ensure generalizability. We are conducting two pragmatic randomized controlled trials on interventions in the management of hypertension in primary care. We describe the design of the trials and the steps taken to deal with the competing demands of external and internal validity.     

Risedronate Pharmacokinetics and Intra- and Inter-Subject Variability Upon Single-Dose Intravenous and Oral Administration

Purpose. To determine the pharmacokinetics and absolute bioavailability of risedronate after single-dose oral administration of 30 mg risedronate as a tablet and an aqueous solution, and 0.3 mg risedronate as an intravenous infusion. Methods. This study was a randomized, three-treatment, four-period, partial replicate crossover study involving 33 healthy volunteers. Treatments were administered 7 weeks apart, and the third treatment was repeated during the fourth period. Serum and urine were collected over 72 hours and 672 hours, respectively. Results. Following intravenous administration, renal clearance accounted for 87% of total clearance, with 65% of the dose excreted within 24 hours and 85% of the dose excreted within four weeks. The absolute bioavailability was approximately 0.62% after both oral formulations, and the relative bioavailability of the tablet compared with the oral solution was 104%. The rate and extent of absorption from the two formulations were bioequivalent based on the range proposed for highly variable drugs. Intrasubject variability following oral administration was 50-80%, and was primarily associated with absorption. Conclusion. The majority of the total clearance after intravenous administration of risedronate was renal clearance, indicating that only a small percentage of a systemic dose is potentially incorporated, or cleared, into bone. The absolute bioavailability of orally administered risedronate is 0.6%, and is independent of formulation. Variability in the pharmacokinetics following oral administration is primarily associated with intrasubject variability in absorption.     

The effect of midterm peer feedback on student functioning in problem-based tutorials

Within Problem-Based Learning successful learning depends on the quality of cognitive, social and motivational contributions students make to the tutorial group. But at the same time, not all students in PBL automatically contribute in a high quality manner, which might impede successful group functioning. This study investigated whether peer process feedback combined with goal setting can be used to improve the quality of students’ individual contributions. A mixed-methods explanatory design, in which 74 second-year Health Sciences students participated, combined a pre- and posttest with a focus group. The results indicated that the quality of the contributions only increased for students with a below average score on the pre-test. The qualitative data confirmed that the impact of the feedback could be increased by combining individual reflection by means of goal setting with face-to-face discussion. Another suggestion is to investigate whether midterm peer process feedback is more effective for first year students, because they are still developing their tutorial behavior, as opposed to second year students.     

International medical graduates (IMGs) needs assessment study: comparison between current IMG trainees and program directors

Background  

International Medical Graduates (IMGs) training within the Canadian medical education system face unique difficulties. The purpose of this study was to explore the challenges IMGs encounter from the perspective of trainees and their Program Directors.     

Efficacy and safety of a subacromial continuous ropivacaine infusion for post-operative pain management following arthroscopic rotator cuff surgery: A protocol for a randomised double-blind placebo-controlled trial

Background  

Major shoulder surgery often results in severe post-operative pain and a variety of interventions have been developed in an attempt to address this. The continuous slow infusion of a local anaesthetic directly into the operative site has recently gained popularity but it is expensive and as yet there is little conclusive evidence that it provides additional benefits over other methods of post-operative pain management.