Quantitation of cannabinoid CB1 receptors in healthy human brain using positron emission tomography and an inverse agonist radioligand

[¹¹C]MePPEP is a high affinity, CB₁ receptor-selective, inverse agonist that has been studied in rodents and monkeys. We examined the ability of [¹¹C]MePPEP to quantify CB₁ receptors in human brain as distribution volume calculated with the “gold standard” method of compartmental modeling and compared results with the simple measure of brain uptake. A total of 17 healthy subjects participated in 26 positron emission tomography (PET) scans, with 8 having two PET scans to assess retest variability. After injection of [¹¹C]MePPEP, brain uptake of radioactivity was high (e.g., 3.6 SUV in putamen at  60 min) and washed out very slowly. A two-tissue compartment model yielded values of distribution volume (which is proportional to receptor density) that were both well identified (SE 5%) and stable between 60 and 210 min. The simple measure of brain uptake (average concentration of radioactivity between 40 and 80 min) had good retest variability ( 8%) and moderate intersubject variability (16%, coefficient of variation). In contrast, distribution volume had two-fold greater retest variability ( 15%) and, thus, less precision. In addition, distribution volume had three-fold greater intersubject variability ( 52%). The decreased precision of distribution volume compared to brain uptake was likely due to the slow washout of radioactivity from brain and to noise in measurements of the low concentrations of [¹¹C]MePPEP in plasma. These results suggest that brain uptake can be used for within subject studies (e.g., to measure receptor occupancy by medications) but that distribution volume remains the gold standard for accurate measurements between groups.     

Genetic dissection of the mouse brain using high-field magnetic resonance microscopy

Magnetic resonance (MR) imaging has demonstrated that variation in brain structure is associated with differences in behavior and disease state. However, it has rarely been practical to prospectively test causal models that link anatomical and functional differences in humans. In the present study we have combined classical mouse genetics with high-field MR to systematically explore and test such structure–functional relations across multiple brain regions. We segmented 33 regions in two parental strains–C57BL/6J (B) and DBA/2J (D)–and in nine BXD recombinant inbred strains. All strains have been studied extensively for more than 20 years using a battery of genetic, functional, anatomical, and behavioral assays. We compared levels of variation within and between strains and sexes, by region, and by system. Average within-strain variation had a coefficient of variation (CV) of 1.6% for the whole brain; while the CV ranged from 2.3 to 3.6% for olfactory bulbs, cortex and cerebellum, and up to  18% for septum and laterodorsal thalamic nucleus. Variation among strain averages ranged from 6.7% for cerebellum, 7.6% for whole brain, 9.0% for cortex, up to  26% for the ventricles, laterodorsal thalamic nucleus, and the interpeduncular nucleus. Heritabilities averaged 0.60 ± 0.18. Sex differences were not significant with the possible (and unexpected) exception of the pons ( 20% larger in males). A correlation matrix of regional volumes revealed high correlations among functionally related parts of the CNS (e.g., components of the limbic system), and several high correlations between regions that are not anatomically connected, but that may nonetheless be functionally or genetically coupled.     

Dextrin–rhEGF conjugates as bioresponsive nanomedicines for wound repair

Growth factors are known to act in concert to promote wound repair, but their topical application rarely leads to a significant clinical improvement of chronic wounds due to premature inactivation in wound environment. The aim of this study was to synthesise a polymer–growth factor conjugate and investigate whether the novel concept called Polymer-masking-UnMasking-Protein Therapy (PUMPT) might be used to generate bioresponsive polymer therapeutics as nanomedicines able to promote tissue repair. Succinoylated dextrin ( 85,000 g/mol;  19 mol% succinoylation), and rhEGF were chosen as a first model combination. The conjugate synthesised contained  16%wt rhEGF and < 1% free protein. It exhibited increased stability towards proteolytic degradation by trypsin and the clinically relevant enzyme neutrophil elastase. The dextrin component was degraded on addition of α-amylase leading to sustained release of free rhEGF over time (52.7% release after 168 h). When biological activity was assessed (± α-amylase) in proliferation assays using epidermoid carcinoma (HEp2) cells and HaCaT keratinocytes, as anticipated, polymer conjugation reduced rhEGF bioactivity (p = 0.0035). However, exposure to physiological concentrations of α-amylase triggered dextrin degradation and this led to protein unmasking with restoration of bioactivity to the level seen for unmodified rhEGF. Indeed, prolongation of HEp2 proliferation was observed over 8 days. The inability of dextrin, succinoylated dextrin or α-amylase alone to induce proliferative effects, and the ability of α-amylase-exposed dextrin–rhEGF to induce phosphorylation of the epidermal growth factor receptor (EGFR) in HEp2 cells confirmed a mechanism of action by stimulation of classical signal transduction pathways. These observations suggest that this dextrin–rhEGF, and other dextrin-growth factor conjugates have potential for further development as bioresponsive nanomedicines for tissue repair.     

Evaluation of two real-time PCR chemistries for the detection of Chlamydophila pneumoniae in clinical specimens

Chlamydophila pneumoniae is an atypical bacterial respiratory pathogen that is responsible for 3–10% of community-acquired pneumonia cases. We report the evaluation of two distinct real-time PCR assays for rapid and specific detection of C. pneumoniae. We tested 401 clinical specimens, finding 5.7% positive, and confirmed a localized outbreak.     

BOLD fMRI using a modified HASTE sequence

For more than a decade, turbo spin echo (TSE) pulse sequences have been suggested as an alternative to echo planar imaging (EPI) sequences for fMRI studies. Recent development in parallel imaging has renewed the interest in developing more robust TSE sequences for fMRI. In this study, a modified half Fourier acquisition single-shot TSE (mHASTE) sequence has been developed with a three-fold GRAPPA to improve temporal resolution as well as a preparation time to enhance BOLD sensitivity. Using a classical flashing checkerboard block design, the BOLD signal characteristics of this novel method have been systematically analyzed as a function of several sequence parameters and compared to those of gradient-echo and spin-echo EPI sequences. Experimental studies on visual cortex of five volunteers have provided evidence suggesting that mHASTE can be more sensitive to extra-vascular BOLD effects around microvascular networks, which leads to more accurate function localization. The studies also show that the activation cluster size in mHASTE increases with the refocusing RF flip angle and TE while decreasing with the echo number (n_center) used to sample the k-space center. Compared to spin-echo EPI, mHASTE incurs an  50% reduction in activation cluster size and an  20% decrease in BOLD contrast. However a higher signal-to-noise ratio and a spatially more uniform temporal stability have been observed in mHASTE as compared to the EPI sequences when the scan times are held constant. With further refinement and optimization, mHASTE can become a viable alternative for fMRI in situations where the conventional EPI sequences are limited or prohibitive.     

fMRI investigation of the effect of local and systemic lidocaine on noxious electrical stimulation-induced activation in spinal cord

Spinal cord fMRI offers an excellent opportunity to quantify nociception using neuronal activation induced by painful stimuli. Measurement of the magnitude of stimulation-induced activation, and its suppression with analgesics can provide objective measures of pain and efficacy of analgesics. This study investigates the feasibility of using spinal cord fMRI in anesthetized rats as a pain assay to test the analgesic effect of locally and systemically administered lidocaine. Blood volume (BV)-weighted fMRI signal acquired after intravenous injection of ultrasmall superparamagnetic iron oxide (USPIO) particles was used as an indirect readout of the neuronal activity. Transcutaneous noxious electrical stimulation was used as the pain model. BV-weighted fMRI signal could be robustly quantified on a run-by-run basis, opening the possibility of measuring pharmacodynamics (PD) of the analgesics with a temporal resolution of 2 min. Local administration of lidocaine was shown to ablate all stimulation-induced fMRI signals by the total blockage of peripheral nerve transmission, while the analgesic effect of systemically administered lidocaine was robustly detected after intravenous infusion of 3 mg/kg, which is similar to clinical dosage for human. This study establishes spinal cord fMRI as a viable assay for analgesics. With respect to the mode of action of lidocaine, this study suggests that systemic lidocaine, which is clinically used for the treatment of neuropathic pain, and believed to only block the peripheral nerve transmission of abnormal neural activity (ectopic discharge) originating from the damaged peripheral nerves, also blocks the peripheral nerve transmission of normal neural activity induced by transcutaneous noxious electrical stimulation.     

fMRI at 1.5, 3 and 7 T: Characterising BOLD signal changes

Blood oxygenation level dependent (BOLD) signal changes occurring during execution of a simple motor task were measured at field strengths of 1.5, 3 and 7 T using multi-slice, single-shot, gradient echo EPI at a resolution of 1 × 1 × 3 mm³, to quantify the benefits offered by ultra-high magnetic field for functional MRI. Using four different echo times at each field strength allowed quantification of the relaxation rate, R₂ and the change in relaxation rate on activation, ΔR₂. This work adds to previous studies of the field strength dependence of BOLD signal characteristics, through its: (i) focus on motor rather than visual cortex; (ii) use of single-shot, multi-slice, gradient echo EPI for data acquisition; (iii) co-registration of images acquired at different field strengths to allow assessment of the BOLD signal changes in the same region at each field strength. ΔR₂ was found to increase linearly with field strength (0.51 ± 0.06 s^− 1 at 1.5 T; 0.98 ± 0.08 s^− 1 at 3 T; 2.55 ± 0.22 s^− 1 at 7 T), while the ratio of ΔR₂/R₂, which dictates the accessible BOLD contrast was also found to increase (0.042 ± 0.002 at 1.5 T; 0.054 ± 0.002 at 3 T; 0.084 ± 0.003 at 7 T). The number of pixels classified as active, the t-value calculated over a common region of interest and the percentage signal change in the same region were all found to peak at TE   T₂ and increase significantly with field strength. An earlier onset of the haemodynamic response at higher field provides some evidence for a reduced venous contribution to the BOLD signal at 7 T.     

A life-threatening paediatric case of acute autoimmune haemolytic anaemia (AIHA) successfully cured by plasma-exchange and combined immunosuppressive treatment

Three types of platelet concentrates (PC) are compared: PC either processed with the platelet-rich plasma (PRP) or the Buffy coat (BC) method from whole blood units and PC obtained by apheresis. Leuko-reduction (LR) pre-storage is advocated to improve quality of the PC during storage and reduce adverse reactions in recipients. Standardization of methods allow preparation of PC with comparable yields of 400 × 10⁹ platelets in pooled non-LR-PRP, 370 × 10⁹ in pooled LR–BC–PC and in LR apheresis PC the number of platelets can be targeted on 350 × 10⁹ or more with devices of various manufacturers. While viral transmission can be prevented by outstanding laboratory tests, the risk of bacterial contamination should be reduced by improved arm disinfection, deviation of the first 20–30 ml of blood and culture or rapid detection assays of the PC pre-issue. In a large prospective multicenter trial no significant difference was observed between cultures of apheresis PC (n = 15,198): 0.09% confirmed positive units versus 0.06% in pooled BC–PC (n = 37,045), respectively.Though platelet activation as measured by CD62 expression may differ in vitro in PC obtained with various apheresis equipment, and also between PC processed with the two whole blood methods there is scarce literature about the clinical impact of these findings.In conclusion the final products of LR–PC derived from whole blood or obtained by apheresis can be comparable, provided the critical steps of the processing method are identified and covered and the process is in control.     

A MEG investigation of somatosensory processing in the rhesus monkey

The use of minimally and non-invasive neuroimaging methods in animal models has sharply increased over the past decade. Such studies have enhanced understanding of the neural basis of the physical signals quantified by these tools, and have addressed an assortment of fundamental and otherwise intractable questions in neurobiology. To date, these studies have almost exclusively utilized positron-emission tomography or variants of magnetic resonance based imaging. These methods provide largely indirect measures of brain activity and are strongly reliant on intact vasculature and normal blood-flow, which is known to be compromised in many clinical conditions. The current study provides the first demonstration of whole-head magnetoencephalography (MEG), a non-invasive and direct measure of neuronal activity, in a rhesus monkey, and in the process supplies the initial data on systems-level dynamics in somatosensory cortices. An adult rhesus monkey underwent three separate studies of tactile stimulation on the pad of the right second or fifth digit as whole-head MEG data were acquired. The neural generators of the primary neuromagnetic components were localized using an equivalent-current-dipole model. Second digit stimulation produced an initial cortical response peaking  16 ms after stimulus onset in the contralateral somatosensory cortices, with a later response at  96 ms in an overlapping or nearby neural area with a roughly orthogonal orientation. Stimulation of the fifth digit produced similar results, the main exception being a substantially weaker later response. We believe the 16 ms response is likely the monkey homologue of the human M50 response, as both are the earliest cortical response and localize to the contralateral primary somatosensory area. Thus, these data suggest that mechanoreception in nonhuman primates operates substantially faster than that in adult humans. More broadly, these results demonstrate that it is feasible to use current human whole-head MEG instrumentation to record neuromagnetic responses in adult rhesus monkeys. Nonhuman primate models of human disease provide the closest phylogenetic link to humans. The present, non-invasive imaging study could promote exciting translational integration of invasive animal studies and non-invasive human studies, allowing experimentally induced deficits and pharmacological treatments to be interpreted in light of resulting brain network interactions.     

No 4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects

The effect of ApoE genotype on grey matter (GM) atrophy was studied on a cohort of 750 healthy elderly volunteers (age range 63–75 years). High-resolution T1-weighted MR images were processed using both voxel-based morphometry and region of interest analysis for hippocampal volume estimation. Significant decrease of grey matter in ₄ homozygous subjects (n = 12), as compared both to ₄ heterozygous subjects (n = 175) and to noncarrier (n = 563) subjects, was found bilaterally in the medial temporal lobe, including the hippocampus, and extending over the superior temporal gyrus. By contrast, no significant difference was observed between ₄ heterozygous subjects and noncarriers at the level of the medial temporal lobe. Follow-up of the cohort cognitive performances over 4 years after their MRI exam revealed that, as compared to noncarrier subjects, the relative risk of cognitive impairment was 5.9 for ₄ homozygous subjects (P = 0.03), while it was not different from 1 for ₄ heterozygous subjects (P = 0.92). These findings indicate that, in the age range of this cohort, ApoE-4 effects on cortical atrophy and cognitive performances of healthy elderly are limited to ₄ homozygous subjects.     

Susceptibility contrast in high field MRI of human brain as a function of tissue iron content

Magnetic susceptibility provides an important contrast mechanism for MRI. Increasingly, susceptibility-based contrast is being exploited to investigate brain tissue microstructure and to detect abnormal levels of brain iron as these have been implicated in a variety of neuro-degenerative diseases. However, it remains unclear to what extent magnetic susceptibility-related contrast at high field relates to actual brain iron concentrations. In this study, we performed susceptibility weighted imaging as a function of field strength on healthy brains in vivo and post-mortem brain tissues at 1.5 T, 3 T and 7 T. Iron histology was performed on the tissue samples for comparison. The calculated susceptibility-related parameters R₂ and signal frequency shift in four iron-rich regions (putamen, globus pallidus, caudate, and thalamus) showed an almost linear dependence (r ≥ 0.90 for R₂; r ≥ 0.83 for phase, p < 0.01) on field strength, suggesting that potential ferritin saturation effects are not relevant to susceptibility-weighted contrast for field strengths up to 7 T. The R₂ dependence on the putative (literature-based) iron concentration was 0.048 Hz/T/ppm. The histological data from brain samples confirmed the linear dependence of R₂ on field strength and showed a slope against iron concentration of 0.0099 Hz/T/ppm dry-weight, which is equivalent to 0.05 Hz/T/ppm wet-weight and closely matched the calculated value in vivo. These results confirm the validity of using susceptibility-weighted contrast as an indicator of iron content in iron-rich brain regions. The absence of saturation effects opens the way to exploit the benefits of MRI at high field strengths for the detection of iron distributions with high sensitivity and resolution.     

The distribution of D2/D3 receptor binding in the adolescent rhesus monkey using small animal PET imaging

PET imaging of the neuroreceptor systems in the brain has earned a prominent role in studying normal development, neuropsychiatric illness and developing targeted drugs. The dopaminergic system is of particular interest due to its role in the development of cognitive function and mood as well as its suspected involvement in neuropsychiatric illness. Nonhuman primate animal models provide a valuable resource for relating neurochemical changes to behavior. To facilitate comparison within and between primate models, we report in vivo D2/D3 binding in a large cohort of adolescent rhesus monkeys. Methods: In this work, the in vivo D2/D3 dopamine receptor availability was measured in a cohort of 33 rhesus monkeys in the adolescent stage of development (3.2–5.3 years). Both striatal and extrastriatal D2/D3 binding were measured using [F-18]fallypride with a high resolution small animal PET scanner. The distribution volume ratio (DVR) was measured for all subjects and group comparisons of D2/D3 binding among the cohort were made based on age and sex. Because two sequential studies were acquired from a single [F-18]fallypride batch, the effect of competing (unlabeled) ligand mass was also investigated. Results: Among this cohort, the rank order of regional D2/D3 receptor binding did not vary from previous studies with adult rhesus monkeys, with: putamen > caudate > ventral striatum > amygdala  substantia nigra > medial dorsal thalamus > lateral temporal cortex  frontal cortex. The DVR coefficient of variation ranged from 14%–26%, with the greatest variance seen in the head of the caudate. There were significant sex differences in [F-18]fallypride kinetics in the pituitary gland, but this was not observed for regions within the blood-brain barrier. Furthermore, no regions in the brain showed significant sex or age related differences in DVR within this small age range. Based on a wide range of injected fallypride mass across the cohort, significant competition effects could only be detected in the substantia nigra, thalamus, and frontal cortex, and were not evident above intersubject variability in all other regions. Conclusion: These data represent the first report of large cohort in vivo D2/D3 dopamine whole brain binding in the adolescent brain and will serve as a valuable comparison for understanding dopamine changes during this critical time of development and provide a framework for creating a dopaminergic biochemical atlas for the rhesus monkey.     

The impact of hunger on food cue processing: An event-related brain potential study

The present study used event-related brain potentials to examine deprivation effects on visual attention to food stimuli at the level of distinct processing stages. Thirty-two healthy volunteers (16 females) were tested twice 1 week apart, either after 24 h of food deprivation or after normal food intake. Participants viewed a continuous stream of food and flower images while dense sensor ERPs were recorded. As revealed by distinct ERP modulations in relatively earlier and later time windows, deprivation affected the processing of food and flower pictures. Between 300 and 360 ms, food pictures were associated with enlarged occipito-temporal negativity and centro-parietal positivity in deprived compared to satiated state. Of main interest, in a later time window ( 450–600 ms), deprivation increased amplitudes of the late positive potential elicited by food pictures. Conversely, flower processing varied by motivational state with decreased positive potentials in the deprived state. Minimum-Norm analyses provided further evidence that deprivation enhanced visual attention to food cues in later processing stages. From the perspective of motivated attention, hunger may induce a heightened state of attention for food stimuli in a processing stage related to stimulus recognition and focused attention.     

Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain

Chronic pain is often associated with reduced tactile acuity. A relationship exists between pain intensity, tactile acuity and cortical reorganisation. When pain resolves, tactile function improves and cortical organisation normalises. Tactile acuity can be improved in healthy controls when tactile stimulation is associated with a behavioural objective. We hypothesised that, in patients with chronic limb pain and decreased tactile acuity, discriminating between tactile stimuli would decrease pain and increase tactile acuity, but tactile stimulation alone would not. Thirteen patients with complex regional pain syndrome (CRPS) of one limb underwent a waiting period and then 2 weeks of tactile stimulation under two conditions: stimulation alone or discrimination between stimuli according to their diameter and location. There was no change in pain (100 mm VAS) or two-point discrimination (TPD) during a no-treatment waiting period, nor during the stimulation phase (p > 0.32 for both). Pain and TPD were lower after the discrimination phase [mean (95% CI) effect size for pain VAS = 27 mm (14–40 mm) and for TPD = 5.7 mm (2.9–8.5 mm), p < 0.015 for both]. These gains were maintained at three-month follow-up. We conclude that tactile stimulation can decrease pain and increase tactile acuity when patients are required to discriminate between the type and location of tactile stimuli.     

Correlation of epidermal nerve fiber density with pain-related evoked potentials in HIV neuropathy

HIV associated sensory neuropathy is a common neurological disorder with reported prevalence of 53%. When only small fibers are involved, the diagnosis of neuropathy remains difficult since standard nerve conduction studies generally are unremarkable. We assessed a method to identify small-fiber neuropathy using electrically evoked pain-related potentials and correlated the electrophysiological results with intraepidermal nerve fiber density in patients with HIV associated sensory neuropathy. Nineteen HIV positive patients were investigated for clinically diagnosed peripheral neuropathy with Neuropathy Symptoms Score (NSS)  3 and Neuropathy Disability Score (NDS)  5. Nine healthy HIV negative control subjects were recruited. We performed standard nerve conduction testing, electrically evoked pain-related potentials and skin biopsy in all participants. Pain-related evoked potentials revealed abnormalities in all HIV positive neuropathy patients, while standard nerve conduction testing was abnormal in eight patients only. Pain-related evoked potential latencies and amplitudes strongly correlated with intraepidermal nerve fiber density. The method of pain-related evoked potential conduction appears to be a sensitive, fast, non-invasive technique for the detection of small-fiber neuropathy and may prove to become a valuable diagnostic asset.     

Biomarkers of oxidative stress and endothelial dysfunction in glucose intolerance and diabetes mellitus

Objectives

To evaluate biomarkers of endothelial dysfunction and oxidative stress in glucose intolerance (GI) compared to overt diabetes (DM2).

Design and methods

140 volunteers including 96 with DM2, 32 with GI and 12 controls (C) were studied. NO metabolites, NO synthase inhibitors, thiols and N-acetyl-β-glucosaminidase (NAGase) activity were analyzed by chemiluminescence, capillary electrophoresis, ELISA and colorimetric assay, respectively.

Results

NO metabolites were higher in GI (NOx: p = 0.03; S-nitrosothiols: p = 0.001) and DM2 (p = 0.006; p = 0.0006) groups in relation to group C, while nitrotyrosine was higher only in the DM2 group in comparison to the other groups. NAGase activity was elevated in GI (p = 0.003) and DM2 (p = 0.0004) groups in relation to group C, as well as, ADMA (p = 0.01; p = 0.003) and GSSG (p = 0.01; p = 0.002).

Conclusions

NO metabolites, NO synthase inhibitors, thiols and NAGase are biomarkers suitable to indicate endothelial dysfunction and oxidative stress in the early stages of impaired response to insulin.     

Group analyses of connectivity-based cortical parcellation using repeated k-means clustering

K-means clustering has become a popular tool for connectivity-based cortical segmentation using Diffusion Weighted Imaging (DWI) data. A sometimes ignored issue is, however, that the output of the algorithm depends on the initial placement of starting points, and that different sets of starting points therefore could lead to different solutions. In this study we explore this issue. We apply k-means clustering a thousand times to the same DWI dataset collected in 10 individuals to segment two brain regions: the SMA–preSMA on the medial wall, and the insula. At the level of single subjects, we found that in both brain regions, repeatedly applying k-means indeed often leads to a variety of rather different cortical based parcellations. By assessing the similarity and frequency of these different solutions, we show that  256 k-means repetitions are needed to accurately estimate the distribution of possible solutions. Using nonparametric group statistics, we then propose a method to employ the variability of clustering solutions to assess the reliability with which certain voxels can be attributed to a particular cluster. In addition, we show that the proportion of voxels that can be attributed significantly to either cluster in the SMA and preSMA is relatively higher than in the insula and discuss how this difference may relate to differences in the anatomy of these regions.     

Sequencing analysis of RHD intron 7 and 9

Whole length of RHD introns 7 and 9 of one normal Rh D-positive individual and 2 DEL samples, carrying RHD1227A allele, were sequenced and aligned. Thirty-three and 27 nucleotide variants were totally observed in intron 7 and intron 9, respectively (EMBL/GenBank/DDBJ EU3729402). Among them, 8 variants in intron 7 and 7 in intron 9 were observed commonly in all 3 samples, whereas 2 variants in intron 7 and one in intron 9 were only found in 2 DEL samples, but not in the normal D-positive. The variants observed in intron 7 in DEL cannot explain enough for that DEL mRNA has one segment of 170 base pairs sequence from intron 7. But the nucleotides AG–GT at both sides of the segment may be related to this molecular even as AG–GT may cut intron 7 with its normal splicing site (GT–AG) into two “new introns” although the mechanisms are complicated in fact. We also have not found any suspicious splicing-affecting variants in intron 9 of DEL allele. However, this may make out further that the reason of whole exon 9 spliced out in DEL mRNAs may be no more than the 1227A>G mutation in DEL allele.     

Contribution of individual, workplace, psychosocial and physiological factors to neck pain in female office workers

This study investigated the relative contribution of individual, workplace, psychosocial and physiological features associated with neck pain in female office workers towards developing appropriate intervention programs. Workers without disability (Neck Disability Index (NDI) score  8, n = 33); workers with neck pain and disability (NDI  9/100, n = 52) and 22 controls (women who did not work and without neck pain) participated in this study. Two logistic regression models were constructed to test the association between various measures in (1) workers with and without disability, and (2) workers without disability and controls. Measures included those found to be significantly associated with higher NDI in our previous studies: psychosocial domains; individual factors; task demands; quantitative sensory measures and measures of motor function. In the final model, higher score on negative affectivity scale (OR = 4.47), greater activity in the neck flexors during cranio-cervical flexion (OR = 1.44), cold hyperalgesia (OR = 1.27) and longer duration of symptoms (OR = 1.19) remained significantly associated with neck pain in workers. Workers without disability and controls could only be differentiated by greater muscle activity in the cervical flexors and extensors during a typing task. No psychosocial domains remained in either regression model. These results suggest that impairments in the sensory and motor system should be considered in any assessment of the office worker with neck pain and may have stronger influences on the presenting symptoms than workplace and psychosocial features.     

Higher serum total cholesterol levels in late middle age are associated with glucose hypometabolism in brain regions affected by Alzheimer's disease and normal aging

Epidemiological studies suggest that higher midlife serum total cholesterol levels are associated with an increased risk of Alzheimer's disease (AD). Using fluorodeoxyglucose positron emission tomography (PET) in the study of cognitively normal late middle-aged people, we demonstrated an association between apolipoprotein E (APOE) 4 gene dose, the major genetic risk factor for late-onset AD, and lower measurements of the cerebral metabolic rate for glucose (CMRgl) in AD-affected brain regions, we proposed using PET as a pre-symptomatic endophenotype to evaluate other putative AD risk modifiers, and we then used it to support an aggregate cholesterol-related genetic risk score in the risk of AD. In the present study, we used PET to investigate the association between serum total cholesterol levels and cerebral metabolic rate for glucose metabolism (CMRgl) in 117 cognitively normal late middle-aged APOE 4 homozygotes, heterozygotes and non-carriers. Higher serum total cholesterol levels were associated with lower CMRgl bilaterally in precuneus, parietotemporal and prefrontal regions previously found to be preferentially affected by AD, and in additional frontal regions previously found to be preferentially affected by normal aging. The associations were greater in APOE 4 carriers than non-carriers in some of the AD-affected brain regions. We postulate that higher midlife serum total cholesterol levels accelerate brain processes associated with normal aging and conspire with other risk factors in the predisposition to AD. We propose using PET in proof-of-concept randomized controlled trials to rapidly evaluate the effects of midlife cholesterol-lowering treatments on the brain changes associated with normal aging and AD.