Improved arthritic knee health in a pilot RCT of phytotherapy

Although practitioner-prescribed 'western' herbal medicine (phytotherapy) is a popular complementary therapy in the UK, no clinical studies have been reported on patient-orientated outcomes. The objective of this pilot study was to investigate the effects of phytotherapy on symptoms of osteoarthritis of the knee. A previous study of Chinese herbal medicine for the treatment of irritable bowel syndrome, published in the Journal of the American Medical Association,(1) acted as a model in the development of the protocol of this investigation. Twenty adults, previously diagnosed with osteoarthritis of the knee, were recruited from two Inner London GP practices into this randomized, double-blind, placebo-controlled, pilot study carried out in a primary-care setting. All subjects were seen in consultation three times by a herbal practitioner who was blinded to the randomization coding. Each subject was prescribed treatment and given lifestyle advice according to usual practice: continuation of conventional medication where applicable, healthy-eating advice and nutrient supplementation, Individualized herbal medicine was prescribed for each patient, but only dispensed for those randomized to active treatment - the remainder were supplied with a placebo. At baseline and outcome (after ten weeks of treatment), subjects completed a food frequency questionnaire and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee health and Measure Yourself Outcome Profile (MYMOP) wellbeing questionnaires. Subjects completing the study per protocol (n = 14) reported an increased intake of wholegrain foods (p = 0.045) and oily fish (p = 0.039) compared to baseline, but no increase in fruit and vegetables and dairy products intakes. There was no difference in the primary outcome measure of knee health assessed as the difference in the mean response (baseline-week 10) in WOMAC score between the two treatment groups. However, there was, compared with baseline, improvement in the active group (n = 9) for the mean WOMAC stiffness sub-score at week 5 (p = 0.035) and week 10 (p = 0.060) but not in the placebo group (n = 5). Furthermore, for the active, but not the placebo group, the mean WOMAC total and sub-scores all showed clinically significant improvement (>= 20%) in knee symptoms at weeks 5 and 10 compared with baseline. Moreover, the mean MYMOP symptom 2 sub-score, mostly relating to osteoarthritis (OA), showed significant improvement at week 5 (p = 0.02) and week 10 (p = 0.008) compared with baseline for the active, but not for the placebo group. This pilot study showed that herbal medicine prescribed for the individual by a herbal practitioner resulted in improvement of symptoms of OA of the knee.

Solvent influences on metastable polymorph lifetimes: real-time interconversions using energy dispersive X-ray diffractometry

Solvent influences on the crystallization of polymorph and hydrate forms of the nootropic drug piracetam (2-oxo-pyrrolidineacetamide) were investigated from water, methanol, 2-propanol, isobutanol, and nitromethane. Crystal growth profiles of piracetam polymorphs were constructed using time-resolved diffraction snapshots collected for each solvent system. Measurements were performed by in situ energy dispersive X-ray diffraction recorded in Station 16.4 at the synchrotron radiation source (SRS) at Daresbury Laboratory, CCLRC UK. Crystallizations from methanol, 2-propanol, isobutanol, and nitromethane progressed in a similar fashion with the initial formation of form I which then converted relatively quickly to form II with form III being generated upon further cooling. However, considerable differences were observed for the polymorphs lifetime and both the rate and temperature of conversion using the different solvents. The thermodynamically unstable form I was kinetically favored in isobutanol and nitromethane where traces of this polymorph were observed below 10 degrees C. In contrast, the transformation of form II and subsequent growth of form III were inhibited in 2-propanol and nitromethane solutions. Aqueous solutions produced hydrate forms of piracetam which are different from the reported monohydrate; this crystallization evolved through successive generation of transient structures which transformed upon exchange of intramolecular water between the liquid and crystalline phases. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:1069-1078, 2007.

An fMRI study of parietal cortex involvement in the visual guidance of locomotion

Locomoting through the environment typically involves anticipating impending changes in heading trajectory in addition to maintaining the current direction of travel. We explored the neural systems involved in the “far road” and “near road” mechanisms proposed by Land and Horwood (1995) using simulated forward or backward travel where participants were required to gauge their current direction of travel (rather than directly control it). During forward egomotion, the distant road edges provided future path information, which participants used to improve their heading judgments. During backward egomotion, the road edges did not enhance performance because they no longer provided prospective information. This behavioral dissociation was reflected at the neural level, where only simulated forward travel increased activation in a region of the superior parietal lobe and the medial intraparietal sulcus. Providing only near road information during a forward heading judgment task resulted in activation in the motion complex. We propose a complementary role for the posterior parietal cortex and motion complex in detecting future path information and maintaining current lane positioning, respectively. (PsycINFO Database Record (c) 2010 APA, all rights reserved)

Altered expression of cell cycle proteins and prolonged duration of cardiac myocyte hyperplasia in p27KIP1 knockout mice

The precise role of cell cycle-dependent molecules in controlling the switch from cardiac myocyte hyperplasia to hypertrophy remains to be determined. We report that loss of p27(KIP1) in the mouse results in a significant increase in heart size and in the total number of cardiac myocytes. In comparison to p27(KIP1)+/+ myocytes, the percentage of neonatal p27(KIP1)-/- myocytes in S phase was increased significantly, concomitant with a significant decrease in the percentage of G(0)/G(1) cells. The expressions of proliferating cell nuclear antigen, G(1)/S and G(2)/M phase-acting cyclins, and cyclin-dependent kinases (CDKs) were upregulated significantly in ventricular tissue obtained from early neonatal p27(KIP1)-/- mice, concomitant with a substantial decrease in the expressions of G(1) phase-acting cyclins and CDKs. Furthermore, mRNA expressions of the embryonic genes atrial natriuretic factor and alpha-skeletal actin were detectable at significant levels in neonatal and adult p27(KIP1)-/- mouse hearts but were undetectable in p27(KIP1)+/+ hearts. In addition, loss of p27(KIP1) was not compensated for by the upregulation of other CDK inhibitors. Thus, the loss of p27(KIP1) results in prolonged proliferation of the mouse cardiac myocyte and perturbation of myocyte hypertrophy.

Acquisition of automatic imitation is sensitive to sensorimotor contingency

The associative sequence learning model proposes that the development of the mirror system depends on the same mechanisms of associative learning that mediate Pavlovian and instrumental conditioning. To test this model, two experiments used the reduction of automatic imitation through incompatible sensorimotor training to assess whether mirror system plasticity is sensitive to contingency (i.e., the extent to which activation of one representation predicts activation of another). In Experiment 1, residual automatic imitation was measured following incompatible training in which the action stimulus was a perfect predictor of the response (contingent) or not at all predictive of the response (noncontingent). A contingency effect was observed: There was less automatic imitation indicative of more learning in the contingent group. Experiment 2 replicated this contingency effect and showed that, as predicted by associative learning theory, it can be abolished by signaling trials in which the response occurs in the absence of an action stimulus. These findings support the view that mirror system development depends on associative learning and indicate that this learning is not purely Hebbian. If this is correct, associative learning theory could be used to explain, predict, and intervene in mirror system development.

Serum vitamin D concentration does not predict insulin action or secretion in European subjects with the metabolic syndrome

OBJECTIVE To investigate the relation between serum concentration of 25-hydroxyvitamin D [25(OH)D] and insulin action and secretion. RESEARCH DESIGN AND METHODS In a cross-sectional study of 446 Pan-European subjects with the metabolic syndrome, insulin action and secretion were assessed by homeostasis model assessment (HOMA) indexes and intravenous glucose tolerance test to calculate acute insulin response, insulin sensitivity, and disposition index. Serum 25(OH)D was measured by high-performance liquid chromatography/mass spectrometry. RESULTS The 25(OH)D3 concentration was 57.1 ± 26.0 nmol/l (mean ± SD), and only 20% of the subjects had 25(OH)D3 levels ≥75 nmol/l. In multiple linear analyses, 25(OH)D3 concentrations were not associated with parameters of insulin action or secretion after adjustment for BMI and other covariates. CONCLUSIONS In a large sample of subjects with the metabolic syndrome, serum concentrations of 25(OH)D3 did not predict insulin action or secretion. Clear evidence that D vitamin status directly influences insulin secretion or action is still lacking.

Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response

OBJECTIVE: The anticipation of adverse outcomes, or worry, is a cardinal symptom of generalized anxiety disorder. Prior work with healthy subjects has shown that anticipating aversive events recruits a network of brain regions, including the amygdala and anterior cingulate cortex. This study tested whether patients with generalized anxiety disorder have alterations in anticipatory amygdala function and whether anticipatory activity in the anterior cingulate cortex predicts treatment response. METHOD: Functional magnetic resonance imaging (fMRI) was employed with 14 generalized anxiety disorder patients and 12 healthy comparison subjects matched for age, sex, and education. The event-related fMRI paradigm was composed of one warning cue that preceded aversive pictures and a second cue that preceded neutral pictures. Following the fMRI session, patients received 8 weeks of treatment with extended-release venlafaxine. RESULTS: Patients with generalized anxiety disorder showed greater anticipatory activity than healthy comparison subjects in the bilateral dorsal amygdala preceding both aversive and neutral pictures. Building on prior reports of pretreatment anterior cingulate cortex activity predicting treatment response, anticipatory activity in that area was associated with clinical outcome 8 weeks later following treatment with venlafaxine. Higher levels of pretreatment anterior cingulate cortex activity in anticipation of both aversive and neutral pictures were associated with greater reductions in anxiety and worry symptoms. CONCLUSIONS: These findings of heightened and indiscriminate amygdala responses to anticipatory signals in generalized anxiety disorder and of anterior cingulate cortex associations with treatment response provide neurobiological support for the role of anticipatory processes in the pathophysiology of generalized anxiety disorder.

The risk-taking and self-harm inventory for adolescents: Development and psychometric evaluation

In this study, we report on the development and psychometric evaluation of the Risk-Taking (RT) and Self-Harm (SH) Inventory for Adolescents (RTSHIA), a self-report measure designed to assess adolescent RT and SH in community and clinical settings. 651 young people from secondary schools in England ranging in age from 11.6 years to 18.7 years and 71 young people referred to mental health services for SH behavior in London between the ages of 11.9 years and 17.5 years completed the RTSHIA along with standardized measures of adolescent psychopathology. Two factors emerged from the principal axis factoring, and RT and SH were further validated by a confirmatory factor analysis as related, but different, constructs, rather than elements of a single continuum. Inter-item and test–retest reliabilities were high for both components (Cronbach's α = .85, rtt = .90; Cronbach's α .93, rtt = .87), and considerable evidence emerged in support of the measure's convergent, concurrent, and divergent validity. The findings are discussed with regard to potential usefulness of the RTSHIA for research and clinical purposes with adolescents.

Polymorphisms in dopamine system genes are associated with individual differences in attention in infancy

Knowledge about the functional status of the frontal cortex in infancy is limited. This study investigated the effects of polymorphisms in four dopamine system genes on performance in a task developed to assess such functioning, the Freeze-Frame task, at 9 months of age. Polymorphisms in the catechol-O-methyltransferase (COMT) and the dopamine D4 receptor (DRD4) genes are likely to impact directly on the functioning of the frontal cortex, whereas polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes might influence frontal cortex functioning indirectly via strong frontostriatal connections. A significant effect of the COMT valine158methionine (Val158Met) polymorphism was found. Infants with the Met/Met genotype were significantly less distractible than infants with the Val/Val genotype in Freeze-Frame trials presenting an engaging central stimulus. In addition, there was an interaction with the DAT1 3′ variable number of tandem repeats polymorphism; the COMT effect was present only in infants who did not have two copies of the DAT1 10-repeat allele. These findings indicate that dopaminergic polymorphisms affect selective aspects of attention as early as infancy and further validate the Freeze-Frame task as a frontal cortex task.

The potential for bias in reporting of industry-sponsored clinical trials

Concerns about potentially misleading reporting of pharmaceutical industry research have surfaced many times. The potential for duality (and thereby conflict) of interest is only too clear when you consider the sums of money required for the discovery, development and commercialization of new medicines. As the ability of major, mid-size and small pharmaceutical companies to innovate has waned, as evidenced by the seemingly relentless decline in the numbers of new medicines approved by Food and Drug Administration and European Medicines Agency year-on-year, not only has the cost per new approved medicine risen: so too has the public and media concern about the extent to which the pharmaceutical industry is open and honest about the efficacy, safety and quality of the drugs we manufacture and sell. In 2005 an Editorial in Journal of the American Medical Association made clear that, so great was their concern about misleading reporting of industry-sponsored studies, henceforth no article would be published that was not also guaranteed by independent statistical analysis. We examine the precursors to this Editorial, as well as its immediate and lasting effects for statisticians, for the manner in which statistical analysis is carried out, and for the industry more generally.