The psychometric properties of patient preferences in osteoporosis

OBJECTIVE: Osteoporosis is a chronic disease manifested by wrist, vertebral, and hip fractures that results in significant morbidity and burden to society. About 30% of postmenopausal women have osteoporosis according to the WHO criteria. Women with one vertebral fracture have a 4-fold increased risk of a subsequent fracture. The goal of treatment is to prevent fractures and improve quality of life. Preferences or utilities are now recommended for incorporating quality of life into evaluations of the cost effectiveness of new therapeutic interventions. We evaluated the psychometric properties of preference based measures in osteoporosis. METHODS: Preference scenarios were constructed with a health state classification system. The reliability and validity of the feeling thermometer and the standard gamble was assessed by interviewing 42 women from 4 different patient groups. The sensitivity to change of the feeling thermometer and standard gamble was compared with the Health Utilities Index Mark 2 (HUI2) and SF-36. All subgroups were reassessed about 2 months after their first interview. RESULTS: Preference measurement was feasible in women of different age groups. The reliability coefficients for health states ranged from 0.65 to 0.87. The preference scores for the marker states demonstrated content validity. Convergent validity of the feeling thermometer was supported by a significant correlation with the HUI2 (r = 0.38, p < 0.05) and the physical health summary of the SF-36 (r = 0.56, p < 0.005). The standard gamble did not correlate with the HUI2 (r = 0.15) or the feeling thermometer (r = 0.09), but correlated with 2 domains of the SF-36. The preference measures were sensitive to change, with the efficiency scores ranging from 0.78 to 1.0. CONCLUSION: Preference measurements in the evaluation of osteoporosis are feasible. The feeling thermometer and standard gamble appear to be related to different aspects of health related quality of life. Both instruments were sensitive to change over a 2 month period.     

Canadian CT head rule study for patients with minor head injury: methodology for phase II (validation and economic analysis)

Prospective validation on a new set of patients is an essential test of a new decision rule. However, many clinical decision rules are not prospectively assessed to determine their accuracy, reliability, clinical sensibility, or potential impact on practice. This validation process is important because many statistically derived rules or guidelines do not perform well when tested in a new population. The methodologic standards for a validation study are similar to those described in the article on phase I for derivation studies in the August 2001 issue of Annals of Emergency Medicine. The goal of phase II is to prospectively assess the accuracy, reliability, and acceptability of the decision rule in a new set of patients with minor head injury. This will determine the clinical utility of the rule and is essential if such a rule is to be widely adopted into clinical practice.     

Acute thrombocytopenic purpura in relation to the use of drugs

The relation of acute thrombocytopenic purpura (TP) to the use of drugs was investigated in a case-control study conducted in eastern Massachusetts, Rhode Island, and the Philadelphia region; 62 cases over the age of 16 years with acute onset and with a rapid recovery were compared with 2,625 hospital controls. After control for confounding by multiple logistic regression, use of the following drugs in the week before the onset of symptoms was significantly associated: trimethoprim/sulfamethoxazole (relative risk [RR] estimate, 124), quinidine/quinine (101), dipyridamole (14), sulfonylureas (4.8), and salicylates (2.6). The overall annual incidence of acute TP was estimated to be 18 cases per million population. The excess risks for the associated drugs were estimated to be 38 cases per million users of trimethoprim/sulfamethoxazole per week, 26 per million for quinidine/quinine, 3.9 per million for dipyridamole, 1.2 per million for sulfonylureas, and 0.4 per million for salicylates. Associations with sulfonamides, quinidine/quinine, sulfonylureas, and salicylates have been previously reported, but the present study has provided the first quantitative measures of the risk. The association with dipyridamole was unexpected. In general, despite large RRs, the incidence rates attributable to the drugs at issue (excess risks) were low, suggesting that TP is not an important consideration in the use of the various drugs.     

Recombinant activated factor VII for the treatment of life-threatening haemorrhage.

To describe the use of recombinant activated factor VII (rFVIIa) in patients with life-threatening haemorrhage. We report a case series of Australian patients with life-threatening haemorrhage who were treated with rFVIIa prior to August 2002 namely 21 patients, median age 45 years (range 22-79 years), 33% (seven of 21) female. The major causes for bleeding were multi-trauma, cardiac or vascular surgery, or orthoptic liver transplantation. In the 24 h prior to the administration of rFVIIa, the median blood usage was 22 U packed cells (range 3-66 U), the median International Normalized Ratio was 1.6 (range 1.4-3.6) and the median activated partial thromboplastin time was 55 s (range 31-180 s). During the 24 h after administration of rFVIIa, the median blood usage was 2 U packed cells (range 0-16 U), the median International Normalized Ratio was 1.0 (range 0.9-1.2) and the median activated partial thromboplastin time was 40 s (range 30-94 s); P < 0.001 for each comparison. Sixteen of the 21 patients were discharged from hospital or were alive at 30 days. There were no thrombotic complications following the administration of rFVIIa. These uncontrolled data suggest a role for rFVIIa as an adjunctive haemostatic measure in surgical patients with life-threatening haemorrhage for whom conventional measures to achieve haemostasis have failed.     

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine–glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D₁ and D₃ receptors. Using in vivo microdialysis, we show that D₁ and D₃ receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D₃R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine–glutamate cross-talk.

The prefrontal cortex (PFC) supports the higher-order and top–down coordination of complex behaviors, including executive function, working memory, and social interactions (1). Dopaminergic (DAergic) inputs exert a marked influence on the activity of frontocortical circuits, and the dynamic regulation of background dopamine (DA) levels allows for the optimization of PFC cognitive performances (2). Interestingly, DA exerts opposite effects on glutamatergic activity through activation of D₁-type (D₁ and D₅) and D₂-type (D₂, D₃, and D₄) receptors, respectively (3, 4). Specifically, D₁ receptor (D₁R) activation increases neuronal excitability and synaptic efficacy through modulation of N-methyl d-aspartate receptors (NMDARs), while D₂ receptor (D₂R) signaling produces opposite effects (4). Furthermore, activation of D₁R promotes Long-Term Potentiation (LTP) in the PFC (5, 6), whereas D₂R stimulation is required for inducing Long-Term Depression (LTD) (6). These observations support the current view that distinct cortical DA receptors differentially regulate cognitive functions through the modulation of NMDARs. However, the underlying mechanisms still await clarification. While D₁R activation in the PFC consistently facilitates working memory and executive function (7), the significance of PFC-localized D₂-type receptors is more complex inasmuch as D₂R and D₃R subtypes enact contrasting roles: activation of D₂R favors cognitive processes, whereas D₃R stimulation exerts a negative impact on cognition (8). Accordingly, blockade of D₃Rs results in a broad-based positive influence upon cognition, including improvements in social novelty discrimination and novel object recognition (NOR) and a reduction in the cognitive deficits associated with a developmental model for schizophrenia (SCZ) (9, 10). Moreover, it has been proposed that DAR and NMDARs can form clusters at the surface of neurons (11) and that their reciprocal dialogue relies on intracellular signaling cascades involving protein kinases (12). Whether functional DA–NMDAR cross-talk involves others mechanisms is not known.Activation of the canonical GluN1-GluN2 containing NMDARs requires binding of both glutamate and a coagonist, either glycine or d- serine (13). We have previously shown that d-serine rather than glycine is the primary endogenous coagonist of synaptic NMDARs at glutamatergic synapses connecting pyramidal neurons in the PFC of adult rats (14). This is important since genetic linkage and association studies show that the genes encoding the d-serine–producing and degrading enzymes serine racemase (SR) and d-amino acid oxidase (DAAO), respectively, are risk genes for SCZ (15, 16). Accordingly, serum and cerebrospinal fluid levels of d-serine are reduced in SCZ patients (16–18). Moreover, clinical trials of d-serine supplementation or the administration of dAAO inhibitors have yielded encouraging results (17, 18). An involvement of d-serine in SCZ is further supported by animal studies showing that multiple risk pathways for SCZ converge in SR-deficient mice (19). Yet, our understanding of the significance of d-serine to the pathology and symptoms of SCZ remains limited, and the question of how it interacts with DA signaling remains to be resolved. This issue is, moreover, of broader pertinence in view of accumulating evidence that a malfunction of NMDAR is central to the pathophysiology of multiple brain disorders (20).In the current study, we sought to determine whether and how d-serine and DA interact in the PFC. We show that d-serine is indeed required for the DAergic modulation of NMDARs in the PFC, as expressed in measures of neuronal excitability, synaptic plasticity, and cognitive function, providing a framework for understanding PFC integrated DA–glutamate cross-talk under physiological and pathological conditions.     

Energy Impairments in Older Adults With Low Back Pain and Radiculopathy: A Matched Case-Control Study

Objectives

To investigate the impact that the presence of chronic low back pain with radiculopathy (CLBPR) may have on (1) energy efficiency and (2) energy capacity among community-dwelling older adults.