Psychologic factors are related to some sensory pain thresholds but not nociceptive flexion reflex threshold in chronic whiplash

OBJECTIVES: Sensory hypersensitivity, central hyperexcitability [lowered nociceptive flexion reflex (NFR) thresholds], and psychologic distress are features of chronic whiplash. However, relationships between these substrates are not clear. This study tested the hypothesis that psychologic distress and catastrophization are correlated with sensory hypersensitivity and NFR responses in chronic whiplash. METHODS: Pressure and thermal pain thresholds (mean values across 3 body sites), NFR threshold, and pain at threshold Visual Analog Scale were measured in 30 participants with chronic whiplash and 30 asymptomatic controls. Pain and disability levels Neck Disability Index, psychologic distress (GHQ-28), and catastrophization (PCS) were also measured in the whiplash group. RESULTS: Whiplash injured participants demonstrated lowered pain thresholds to pressure and cold (P<0.05); lowered NFR thresholds (P=0.003), and demonstrated above threshold levels of psychologic distress (GHQ-28) and levels of catastrophization comparable with other musculoskeletal conditions. There were no group differences for heat pain thresholds or pain at NFR threshold. In the whiplash group, PCS scores correlated moderately with cold pain threshold (r=0.51, P=0.01). In contrast, there were no significant correlations between GHQ-28 scores and pain threshold measures or between psychologic factors and NFR responses in whiplash participants. There were no significant correlations between psychologic factors and pain thresholds or NFR responses in controls. DISCUSSION: We have demonstrated that psychologic factors have some association with sensory hypersensitivity (cold pain threshold measures) in chronic whiplash but do not seem to influence spinal cord excitability. This suggests that psychologic disorders are important, but not the only, determinants of central hypersensitivity in whiplash patients.

A semi-structured interview to assess visual hallucinations in older people

OBJECTIVE: Visual hallucinations are under-reported by patients and are often undiscovered by health professionals. There is no gold standard available to assess hallucinations. Our objective was to develop a reliable, valid, semi-structured interview for identifying and assessing visual hallucinations in older people with eye disease and cognitive impairment. METHODS: We piloted the North-East Visual Hallucinations Interview (NEVHI) in 80 older people with visual and/or cognitive impairment (patient group) and 34 older people without known risks of hallucinations (control group). The informants of 11 patients were interviewed separately. We established face validity, content validity, criterion validity, inter-rater agreement and the internal consistency of the NEVHI, and assessed the factor structure for questions evaluating emotions, cognitions, and behaviours associated with hallucinations. RESULTS: Recurrent visual hallucinations were common in the patient group (68.8%) and absent in controls (0%). The criterion, face and content validities were good and the internal consistency of screening questions for hallucinations was high (Cronbach alpha: 0.71). The inter-rater agreements for simple and complex hallucinations were good (Kappa 0.72 and 0.83, respectively). Four factors associated with experiencing hallucinations (perceived control, pleasantness, distress and awareness) were identified and explained a total variance of 73%. Informants gave more 'don't know answers' than patients throughout the interview (p = 0.008), especially to questions evaluating cognitions and emotions associated with hallucinations (p = 0.02). CONCLUSIONS: NEVHI is a comprehensive assessment tool, helpful to identify the presence of visual hallucinations and to quantify cognitions, emotions and behaviours associated with hallucinations.

Selective pharmacological targeting of a DEAD box RNA helicase

RNA helicases represent a large family of proteins implicated in many biological processes including ribosome biogenesis, splicing, translation and mRNA degradation. However, these proteins have little substrate specificity, making inhibition of selected helicases a challenging problem. The prototypical DEAD box RNA helicase, eIF4A, works in conjunction with other translation factors to prepare mRNA templates for ribosome recruitment during translation initiation. Herein, we provide insight into the selectivity of a small molecule inhibitor of eIF4A, hippuristanol. This coral-derived natural product binds to amino acids adjacent to, and overlapping with, two conserved motifs present in the carboxy-terminal domain of eIF4A. Mutagenesis of amino acids within this region allowed us to alter the hippuristanol-sensitivity of eIF4A and undertake structure/function studies. Our results provide an understanding into how selective targeting of RNA helicases for pharmacological intervention can be achieved.

Zidovudine impairs immunological recovery on first-line antiretroviral therapy: collaborative analysis of cohort studies in southern Africa

OBJECTIVES Zidovudine (ZDV) is recommended for first-line antiretroviral therapy (ART) in resource-limited settings. ZDV may, however, lead to anemia and impaired immunological response. We compared CD4+ cell counts over 5 years between patients starting ART with and without ZDV in southern Africa. DESIGN Cohort study. METHODS Patients aged at least 16 years who started first-line ART in South Africa, Botswana, Zambia, or Lesotho were included. We used linear mixed-effect models to compare CD4+ cell count trajectories between patients on ZDV-containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4+ cell count below 100 cells/μl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4+ cell count and hemoglobin level, age, sex, type of regimen, viral load monitoring, and calendar year. RESULTS A total of 72,597 patients starting ART, including 19,758 (27.2%) on ZDV, were analyzed. Patients on ZDV had higher CD4+ cell counts (150 vs.128 cells/μl) and hemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be women than those on other regimens. Adjusted differences in CD4+ cell counts between regimens containing and not containing ZDV were -16 cells/μl [95% confidence interval (CI) -18 to -14] at 1 year and -56 cells/μl (95% CI -59 to -52) at 5 years. Impaired immunological recovery was more likely with ZDV compared to other regimens (odds ratio 1.40, 95% CI 1.22-1.61). CONCLUSION In southern Africa, ZDV is associated with inferior immunological recovery compared to other backbones. Replacing ZDV with another nucleoside reverse transcriptase inhibitor could avoid unnecessary switches to second-line ART.

The ecological consequences of megafaunal loss: giant tortoises and wetland biodiversity

The giant tortoises of the Galapagos have become greatly depleted since European discovery of the islands in the 16th Century, with populations declining from an estimated 250000 to between 8000 and 14000 in the 1970s. Successful tortoise conservation efforts have focused on species recovery, but ecosystem conservation and restoration requires a better understanding of the wider ecological consequences of this drastic reduction in the archipelago's only large native herbivore. We report the first evidence from palaeoecological records of coprophilous fungal spores of the formerly more extensive geographical range of giant tortoises in the highlands of Santa Cruz Island. Upland tortoise populations on Santa Cruz declined 500-700years ago, likely the result of human impact or possible climatic change. Former freshwater wetlands, a now limited habitat-type, were found to have converted to Sphagnum bogs concomitant with tortoise loss, subsequently leading to the decline of several now-rare or extinct plant species.

Beyond words: Sensory properties of depressive thoughts

Verbal thoughts (such as negative cognitions) and sensory phenomena (such as visual mental imagery) are usually conceptualised as distinct mental experiences. The present study examined to what extent depressive thoughts are accompanied by sensory experiences and how this is associated with symptom severity, insight of illness and quality of life. A large sample of mildly to moderately depressed patients (N = 356) was recruited from multiple sources and asked about sensory properties of their depressive thoughts in an online study. Diagnostic status and symptom severity were established over a telephone interview with trained raters. Sensory properties of negative thoughts were reported by 56.5% of the sample (i.e., sensation in at least one sensory modality). The highest prevalence was seen for bodily (39.6%) followed by auditory (30.6%) and visual (27.2%) sensations. Patients reporting sensory properties of thoughts showed more severe psychopathological symptoms than those who did not. The degree of perceptuality was marginally associated with quality of life. The findings support the notion that depressive thoughts are not only verbal but commonly accompanied by sensory experiences. The perceptuality of depressive thoughts and the resulting sense of authenticity may contribute to the emotional impact and pervasiveness of such thoughts, making them difficult to dismiss for their holder.

Ezrin/Radixin/Moesin proteins and flotillins cooperate to promote uropod formation in T cells

T cell uropods are enriched in specific proteins including adhesion receptors such as P-selectin glycoprotein ligand-1 (PSGL-1), lipid raft-associated proteins such as flotillins and ezrin/radixin/moesin (ERM) proteins which associate with cholesterol-rich raft domains and anchor adhesion receptors to the actin cytoskeleton. Using dominant mutants and siRNA technology we have tested the interactions among these proteins and their role in shaping the T cell uropod. Expression of wild type (WT) ezrin-EGFP failed to affect the morphology of human T cells or chemokine-induced uropod recruitment of PSGL-1 and flotillin-1 and -2. In contrast, expression of constitutively active T567D ezrin-EGFP induced a motile, polarized phenotype in some of the transfected T cells, even in the absence of chemokine. These cells featured F-actin-rich ruffles in the front and uropod enrichment of PSGL-1 and flotillins. T567D ezrin-EGFP was itself strongly enriched in the rear of the polarized T cells. Uropod formation induced by T567D ezrin-EGFP was actin-dependent as it was attenuated by inhibition of Rho-kinase or myosin II, and abolished by disruption of actin filaments. While expression of constitutively active ezrin enhanced cell polarity, expression of a dominant-negative deletion mutant of ezrin, 1-310 ezrin-EGFP, markedly reduced uropod formation induced by the chemokine SDF-1, T cell front-tail polarity, and capping of PSGL-1 and flotillins. Transfection of T cells with WT or T567D ezrin did not affect chemokine-mediated chemotaxis whereas 1-310 ezrin significantly impaired spontaneous 2D migration and chemotaxis. siRNA-mediated downregulation of flotillins in murine T cells attenuated moesin capping and uropod formation, indicating that ERM proteins and flotillins cooperate in uropod formation. In summary, our results indicate that activated ERM proteins function together with flotillins to promote efficient chemotaxis of T cells by structuring the uropod of migrating T cells.

Blocking brain-derived neurotrophic factor inhibits injury-induced hyperexcitability of hippocampal CA3 neurons

Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin-related kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF-mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury-induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB-Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB-Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two-fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB-Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB-Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury-induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post-traumatic epilepsy. Therefore, our data suggest that blocking the BDNF-TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post-traumatic epilepsy.

Variation in precursor lesions of pancreatic cancer among high-risk groups

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are currently offered to high-risk individuals aiming to detect precursor lesions or PDAC at an early stage. We assessed differences in frequency and behavior of precursor lesions and PDAC between two high-risk groups. EXPERIMENTAL DESIGN Individuals with a p16-Leiden germline mutation (N = 116; median age 54 years) and individuals from familial pancreatic cancer (FPC) families (N = 125; median age 47 years) were offered annual surveillance by MRI and magnetic resonance cholangiopancreatography (MRCP) with or without endoscopic ultrasound (EUS) for a median surveillance period of 34 months (0-127 months) or 36 months (0-110 months), respectively. Detailed information was collected on pancreatic cystic lesions detected on MRCP and precursor lesions in surgical specimens of patients who underwent pancreatic surgery. RESULTS Cystic lesions were more common in the FPC cohort (42% vs. 16% in p16-Leiden cohort), whereas PDAC was more common in the p16-Leiden cohort (7% vs. 0.8% in FPC cohort). Intraductal papillary mucinous neoplasm (IPMN) was a common finding in surgical specimens of FPC-individuals, and was only found in two patients of the p16-Leiden cohort. In the p16-Leiden cohort, a substantial proportion of cystic lesions showed growth or malignant transformation during follow-up, whereas in FPC individuals most cystic lesions remain stable. CONCLUSION In p16-Leiden mutation carriers, cystic lesions have a higher malignant potential than in FPC-individuals. On the basis of these findings, a more intensive surveillance program may be considered in this high-risk group.