Tracking the Migraine Cycle Using Visual Tasks.

There are a number of reports that perceptual, electrophysiological and imaging measures can track migraine periodicity. As the electrophysiological and imaging research requires specialist equipment, it has few practical applications. This study sought to track changes in performance on four visual tasks over the migraine cycle. Coherence thresholds were measured for two motion and two orientation tasks. The first part of the study confirmed that the data obtained from an online study produced comparable results to those obtained under controlled laboratory conditions. Thirteen migraine with aura, 12 without aura, and 12 healthy controls participated. The second part of the study showed that thresholds for discriminating vertical coherent motion varied with the migraine cycle for a majority of the participants who tested themselves multiple times (four with aura, seven without). Performance improved two days prior to a migraine attack and remained improved for two days afterwards. This outcome is as expected from an extrapolation of earlier electrophysiological research. This research points to the possibility of developing sensitive visual tests that patients can use at home to predict an impending migraine attack and so take steps to try to abort it or, if it is inevitable, to plan their lives around it.

Parathyroid hormone-related peptide activates and modulates TRPV1 channel in human DRG neurons.

Parathyroid hormone-related peptide (PTHrP) is associated with advanced tumor growth and metastasis, especially in breast, prostate and myeloma cancers that metastasize to bones, resulting in debilitating chronic pain conditions. Our recent studies revealed that the receptor for PTHrP, PTH1R, is expressed in mouse DRG sensory neurons, and its activation leads to flow-activation and modulation of TRPV1 channel function, resulting in peripheral heat and mechanical hypersensitivity. In order to verify the translatability of our findings in rodents to humans, we explored whether this signalling axis operates in primary human DRG sensory neurons. Analysis of gene expression data from recently reported RNA deep sequencing experiments performed on mouse and human DRGs reveals that PTH1R is expressed in DRG and tibial nerve. Furthermore, exposure of cultured human DRG neurons to PTHrP leads to slow-sustained activation of TRPV1 and modulation of capsaicin-induced channel activation. Both activation and modulation of TRPV1 by PTHrP were dependent on PKC activity. Our findings suggest that functional PTHrP/PTH1R-TRPV1 signalling exists in human DRG neurons, which could contribute to local nociceptor excitation in the vicinity of metastatic bone tumor microenvironment.

Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.

Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post-synaptic density 95 (PSD-95). Here, we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number and PSD size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.

Treatment for older men with fractures.

UNLABELLED: Less than 10% of men receive osteoporosis treatment, even after a fracture. A study of 17,683 men revealed that older men, those with spinal fractures, and those taking steroids or antidepressants are more likely to receive treatment after a fracture. Seeing a primary care physician also increases osteoporosis treatment rates. INTRODUCTION: In 2000, the FDA approved bisphosphonates for the treatment of osteoporosis in men. The purpose of this study is to estimate the frequency of bisphosphonate therapy within 12 months following a fracture and describe patient/physician factors associated with treatment. METHODS: Health insurance claims for 17,683 men ≥ 65 years of age, who had a claim for an incident fracture from 2000 to 2005, were followed for at least 6 months post-fracture for the initiation of treatment with a bisphosphonate. Patient characteristics, diagnostic procedures, therapies, co-morbidities, and provider characteristics were compared for men who received treatment with those who did not. RESULTS: Eight percent of men (n = 1,434) received bisphosphonate therapy. Overall treatment increased from 7% in 2001 to 9% in 2005 (p < 0.001). Treatment for hip fractures remained at 7% (p = 0.747). Treatment increased with age: 6% in men aged 65-69 compared to 11.6% in men aged 85-89 (p < 0.001). Factors associated with treatment included: diagnosis of osteoporosis (OR = 8.8; 95% CI, 7.7, 10.4), glucocorticoid therapy (OR = 3.2; 95% CI, 2.4, 4.3), bone mineral density measurement (OR = 3.4; 95% CI, 2.9, 4.0), and antidepressant therapy with tricyclics (OR = 2.0; 95% CI, 1.2, 3.5) or selective serotonin reuptake inhibitors (OR = 1.7; 95% CI, 1.3, 2.4). Men with vertebral fractures (OR = 2.2; 95% CI, 1.8, 2.6) and men seen by primary physicians (OR = 2.6; 95% CI, 2.3, 3.1) were more likely to receive treatment. CONCLUSIONS: Less than 10% of men received bisphosphonate therapy following a low-impact fracture. Men with a primary physician were more likely to receive bisphosphonate therapy; however, <25% of men were seen by a primary physician.

Intrafamilial Genotyping of Helicobacter pylori from Faecal DNA.

Helicobacter pylori infection, often acquired in early childhood, is a global cause of undernutrition, gastritis, peptic ulcer disease and gastric carcinoma. This study tested the feasibility of using H. pylori shed in the faeces as a source of DNA for non-invasive epidemiological studies. H. pylori DNA was chemically recovered and isolated using a specific biotinylated oligonucleotide probe with magnetic capture from 28 H. pylori positive faecal samples obtained from children attending hospital for the investigation of suspected H. pylori infection, together with close family members. Random amplification of polymorphic DNA (RAPD) was subsequently used to discriminate each isolate. 93% of stool samples selected were typeable. Parent, child and sibling samples were compared and similarities determined. Phylogenetic analysis showed that H. pylori DNA obtained from the faeces can be used to genotype individual strains, offering a means of studying intrafamilial transfer of this microorganism.

Changes in induced hues at low luminance and following dark adaptation suggest rod-cone interactions may differ for luminance increments and decrements.

Color contrast describes the influence of one color on the perception of colors in neighboring areas. This study addressed two issues: (1) the accurate representation of the color changes; (ii) the underlying visual mechanisms. Observers matched the hue that was induced in a neutral square when it was set in one of four standard colored surrounds: "red" (+L(-M) relative to neutral), "green" (-L(+M)), "purple" (+S), and "yellow" (-S). The standard and matching displays were viewed haploscopically. The standard neutral square was either a luminance increment, or decrement, both of which appeared the complementary color to the surrounds in which they were inset. In Experiment 1, the surround luminance in each eye's display was either equal, at 18 cd x m(-2), or the match surround luminance was reduced to 2.5 cd x m(-2). The matches with equal surround luminances could be represented as vector shifts in a logarithmic MacLeod-Boynton (r, b) chromaticity diagram, as described previously (Shepherd, 1997, 1999). The low luminance matches were, however, displaced further from neutral, as if larger chromatic differences were needed. The precise direction of the displacements differed for luminance increments and decrements: the red, green and yellow decrement matches were also displaced vertically downwards in the MacLeod-Boynton diagram. In Experiment 2, dark-adapting before setting repeat color matches displaced the decrement matches vertically, but did not affect the increment matches. Thus, rod intrusion in S-cone pathways may have boosted the S-cone signal for the lowest luminance decrement matches in Experiment 1 and account for the vertical shift in MacLeod-Boynton co-ordinates. The distinct pattern of displacements for low luminance increments and decrements may be explained if the match is set at a cone-opponent, rather than a cone contrast, site and if rod signals have an input only to S-cone decrement, perhaps S-OFF, pathways.

A visual skills inventory for children with neurological impairments.

Children with neurological impairments often have visual deficits that are difficult to quantify. We have compared visual skills evaluated by carers with results of a comprehensive visual assessment. Participants were 76 children with mild to profound intellectual and/or motor impairment (33 males, 43 females; age range 7mo-16y; mean age 5y 1mo [SD 4y 2mo]) who completed a visual skills inventory before attending a special vision clinic. The inventory included 16 questions about visual skills and responses to familiar situations. Responses were augmented by taking a structured clinical history, compared with visual evoked potential (VEP) and/or acuity card measures of visual acuity, and examined using exploratory factor analysis. Acuity ranged from normal to no light perception, and was positively associated with responses to individual questions. After excluding four uninformative questions, an association between the remaining questions and two significant independent factors was found. Factor 1 was associated with questions about visual recognition (e.g. 'Does your child see a small silent toy?') and these items were correlated with both the VEP and acuity card thresholds. Factor 2 was associated primarily with questions about visually mediated social interactions (e.g. 'Does he/she return your silent smile?'). Evaluation of visual skills in children with neurological impairment can provide valid information about the quality of children's vision. Questions with the highest validity for predicting vision are identified.

Local and global motion after-effects are both enhanced in migraine, and the underlying mechanisms differ across cortical areas.

Visual after-effects are illusions that occur after prolonged viewing of visual displays (pattern adaptation). The motion after-effect (MAE), for example, is an illusory impression of motion that is seen after viewing moving displays. After-effects have been used extensively in basic vision research as well as in clinical settings, and have been reported to be enhanced in migraine. Pattern adaptation is a cortical phenomenon that reflects both cellular mechanisms acting within individual neurons and specific interactions between groups of neurons activated by the adapting display. A remarkable feature of the MAE is that its duration is only slightly reduced if a delay is inserted between the end of the adaptation and the test display ('storage'). The reduction is consistent with recovery of the cellular component, and the residual with network changes that are maintained during the delay. This study aimed (i) to assess explanations for prolonged MAEs in migraine by teasing apart the proposed cellular and network components of adaptation using storage; (ii) to determine the extent of cortical abnormality in migraine using local and global MAEs, which reflect adaptation at different stages of the visual system. Fifty migraine (22 with, 28 without aura) and 50 control participants adapted to motion before viewing a stationary or dynamic (random motion) test, which consequently appeared to move in the opposite direction (local and global MAEs, respectively). Half of the trials included a delay between the adapting and test displays. The results extend those reported previously, as both local and global MAEs lasted longer in migraine compared with the control group. Global MAEs survived delays almost completely for both groups, whereas local MAEs were reduced to a greater extent in migraine. There were no significant differences between migraine subgroups classified according to the presence or absence of visual aura. These results suggest that cellular recovery is slowed in migraine for early but not later visual cortical areas. Sustained network changes following adaptation are implicated across cortical areas. Differences between people with and without migraine on various measures of visual perception have been attributed to abnormal cortical processing in migraine, variously described by hyperexcitability, heightened responsiveness and/or a lack of intra-cortical inhibition. The results are not consistent with hyperexcitability resulting from a lack of inhibition in migraine, but are consistent with extended suppression of intra-cortical excitation. The implications of these results for alternative models of hyperexcitability are discussed.

Colour vision in migraine: selective deficits for S-cone discriminations.

Three studies are reported that explore colour perception in migraine. In each, sensitivity for colours detected selectively by the S-cones and the L- and M-cones was assessed separately. The first study assessed the discrimination of small colour differences using the Farnsworth-Munsell 100-hue test. The second assessed threshold detection for purple, yellow, red and green targets on five equiluminant background colours. The third examined supra-threshold colour scaling using two colour series, purple-yellow and red-green. Each study indicated that differences in colour perception between migraine and control groups were restricted to colours detected by the S-cones, there were no differences in performance for colours detected by the L- and M-cones. The results are discussed in terms of possible pathologies in the early visual pathways.

Incorrect use of walking aids in patients with hip pathology.

A study was performed to assess if patients with hip pathology are using their walking aids in the correct hand. From the literature it has been concluded that the contralateral hand to the hip pathology should be used with a walking aid. A questionnaire was given to patients attending orthopaedic clinics with solely hip pathology. Four questions were asked. Firstly, are you left or right handed? Secondly, which hip is the worst /most painful? Thirdly, in which hand do you hold your stick? Finally, has a doctor or physiotherapist ever told you which hand to use? Ninety-four correctly completed questionnaires were returned. Forty-seven per cent of patients were using the aid in the incorrect hand and of this group 64% were using their dominant hand. Sixty-six per cent claimed they had never been told which hand to use. This study shows that a large percentage of patients use walking aids incorrectly, mainly with their dominant hand. This may be due to poor education. Changing hands may be a simple measure to reduce symptoms from the hip with little or no complications. (Hip International 2005; 15: 52-4).

Childhood H. pylori: disappearing disease or chronic infection?

Helicobacter pylori is one of the commonest chronic bacterial infections worldwide. It is acquired during childhood and its persistence has implications for health in later life. In adults, it is the principle cause of duodenal ulcer disease and there is evidence of an association between H. pylori and gastric cancer. However, most colonized people are asymptomatic. The prevalence of H. pylori increases with age but there is a striking difference between the rates in developed and developing countries. As no significant non-human or environmental source for this infection has been identified, person to person spread is almost certainly the main mode of transmission. Community nurses should be aware of this micro-organism as a potential cause of illness in children, and that they can play a role in promoting hygiene practices and educating families so that the risk of acquisition may be reduced. This review discusses the clinical features, prevalence, risk factors for transmission, diagnosis and treatment of H. pylori.

Characterisation of endogenous retrovirus in rodent cell lines used for production of biologicals.

Rodent cells are used widely to manufacture recombinant proteins for pharmaceutical use in humans and animals. However, all rodent cell lines express endogenous retroviruses that require appropriate testing regimes for identification and characterisation. In this communication we report the results of transmission electron microscopy, reverse transcriptase assay and infectious virus assays for retrovirus in 185 manufacturer cell banks of mouse, rat or hamster origin. The results indicated considerable variability of retroviral expression levels by transmission electron microscopy and reverse transcriptase assay, but nevertheless characteristic features of each cell type were observed. Infectious retrovirus was detected in mouse myeloma and hybridoma cell lines, but not in cell lines of hamster or rat origin. There was no evidence of contamination of cell banks with exogenous retrovirus. The results of retroviral characterisation of the parental mouse cell lines NS0, NS-1 and Sp2/0Ag14 by the above assays were consistent with the results of the survey. Co-cultivation of the above parental mouse cell lines with mouse and human cell lines suggested that the ability to infect human cells was related to threshold susceptibility of cell types and the levels of expression of infectious xenotropic retrovirus by mouse cells.

Evaluation of protocol using gene capture and PCR for detection of Helicobacter pylori DNA in feces.

The route of transmission of Helicobacter pylori, which is usually acquired in childhood and is one of the most common bacterial infections in humans, remains undetermined. Mapping the distribution of H. pylori genotypes within families could help to determine the routes of transmission and risk factors. Here we describe a noninvasive method for obtaining H. pylori DNA isolates from the feces of children. Children presenting with gastrointestinal symptoms at the Royal Hospital for Sick Children were tested for gastric H. pylori colonization by using the 13C-urea breath test (UBT) and were asked to provide fecal samples, which were tested for H. pylori by using the HpSA fecal antigen test. DNA was purified from fecal samples by using a novel method of gene capture with subsequent H. pylori PCR analysis. Fifteen UBT-positive and 15 UBT-negative children participated in the study. The positive and negative predictive values for the assay were 80 and 100%, respectively. Fecal DNA purification followed by H. pylori PCR analysis is an effective tool for harvesting H. pylori DNA isolates from the feces of children. This technique may be developed to allow the diagnosis and noninvasive genotyping of H. pylori in children and their families.

Comparison of electron microscopic techniques for enumeration of endogenous retrovirus in mouse and Chinese hamster cell lines used for production of biologics.

Murine myeloma and Chinese hamster ovary cells are used widely in the manufacture of recombinant proteins for biopharmaceuticals. However, rodent cell lines express endogenous retrovirus, which necessitates appropriate design of purification processes to remove virus in excess of the calculated maximum retroviral load. Currently, electron microscopy is the method of choice for determination of retroviral titre in bulk harvest. In this study we compared three electron microscopy techniques to determine retroviral titre in bulk harvest. These were direct negative stain, negative stain after sucrose-density purification and thin section electron microscopy of pelleted supernatant. The study demonstrated that the level of C-type retrovirus associated with cells was predictive of the viral load in cell culture supernatants. The most accurate method for quantifying viral load was direct counting, followed by thin section of pelleted supernatant and negative stain after sucrose concentration. The most practical method was thin section of resuspended pelleted supernatant, which gave improved detection limits.

Emmetropisation following preterm birth.

BACKGROUND/AIMS: Even in the absence of retinopathy of prematurity (ROP), premature birth signals increased risk for abnormal refractive development. The present study examined the relation between clinical risk factors and refractive development among preterm infants without ROP. METHODS: Cycloplegic refraction was measured at birth, term, 6, 12, and 48 months corrected age in a cohort of 59 preterm infants. Detailed perinatal history and cranial ultrasound data were collected. 40 full term (plus or minus 2 weeks) subjects were tested at birth, 6, and 12 months old. RESULTS: Myopia and anisometropia were associated with prematurity (p<0.05). More variation in astigmatic axis was found among preterm infants (p<0.05) and a trend for more astigmatism (p<0.1). Emmetropisation occurred in the preterm infants so that at term age they did not differ from the fullterm group in astigmatism or anisometropia. However, preterm infants remained more myopic (less hyperopic) than the fullterm group at term (p<0.05) and those infants born <1500 g remained more anisometropic than their peers until 6 months (p<0.05). Infants with abnormal cranial ultrasound were at risk for higher hyperopia (p<0.05). Other clinical risk factors were not associated with differences in refractive development. At 4 years of age 19% of the preterm group had clinically significant refractive errors. CONCLUSION: Preterm infants without ROP had high rates of refractive error. The early emmetropisation process differed from that of the fullterm group but neither clinical risk factors nor measures of early refractive error were predictive of refractive outcome at 4 years.

Pattern-reversal visual evoked potentials in infants: gender differences during early visual maturation.

This paper investigates gender differences in the peak latency and amplitude of the P1 component of the pattern-reversal visual evoked potential (pattern-reversal VEP) recorded in healthy term infants. Pattern-reversal VEPs in response to a series of high contrast black and white checks (check widths 120', 60', 30', 24', 12', 6') were recorded in 50 infants (20 males, 30 females) at 50 weeks post-conceptional age (PCA) and in 49 infants (22 males, 27 females) at 66 weeks PCA. Peak latency of the major component, P1, was considerably shorter in female compared with male infants. Differences in head circumference do not entirely account for the gender differences in peak latency reported here. A gender difference in P1 amplitude was not detected. These findings stress the importance of considering gender norms as well as age-matched norms when utilizing the pattern-reversal VEP in clinical investigations. Studies including a wider range of ages are clearly necessary in order to establish whether the earlier peak latencies in female infants represents a difference in the onset or rate of visual maturation.

Increased visual after-effects in migraine following pattern adaptation extend to simultaneous tilt illusion.

Much previous research into visual processing in migraine supports a model of abnormal cortical processing, in between the headache attacks, that is characterised by hyperexcitability, heightened responsiveness, a lack of habituation and/or a lack of intra-cortical inhibition. Shepherd (2001) reported two adaptation studies that challenged this view, one using the tilt after-effect, the second using the motion after-effect. Models of cortical function in migraine based on hyperexcitability and a lack of inhibition lead to specific predictions in an adaptation study: there should have been smaller after-effects in people with migraine than in people without. Both experiments, however, revealed larger after-effects in the migraine group than in the control group. Here, these results are extended to the simultaneous tilt illusion and an identical pattern of results was obtained: there were consistently larger effects in the migraine group than in the control group. The results from the three experiments are not consistent with a lack of inhibition in migraine. The results are discussed in terms of alternative models of cortical function, including a lack of excitation and reduced central energy reserves.

Increased visual after-effects following pattern adaptation in migraine: a lack of intracortical excitation?

Much research on visual function in migraine has examined early aspects of visual processing, often using detection or discrimination measures and stimuli reported to trigger an attack, e.g. striped patterns or flickering lights. Differences between people with and without migraine have been attributed to abnormal cortical processing in migraine, variously described by interictal hyperexcitability, heightened responsiveness, a lack of habituation and/or a lack of intra-cortical inhibition. Here, two experiments are presented that explore a uniquely cortical phenomenon, pattern or contrast adaptation, one using the motion after-effect, one the tilt after-effect. Pattern adaptation reflects specific interactions between groups of neurones and is therefore ideally suited to address proposed models of cortical function in migraine. These models lead to specific predictions in an adaptation study: there should be smaller effects in people with migraine than in people without. The results from both adaptation experiments, however, revealed larger effects in migraine sufferers than in headache-free control subjects. There were no differences between migraine subgroups classified according to the presence or absence of aura. These results are discussed in terms of models of cortical function in migraine.

VIDA: a virus database system for the organization of animal virus genome open reading frames.

VIDA is a new virus database that organizes open reading frames (ORFs) from partial and complete genomic sequences from animal viruses. Currently VIDA includes all sequences from GenBank for Herpesviridae, Coronaviridae and Arteriviridae. The ORFs are organized into homologous protein families, which are identified on the basis of sequence similarity relationships. Conserved sequence regions of potential functional importance are identified and can be retrieved as sequence alignments. We use a controlled taxonomical and functional classification for all the proteins and protein families in the database. When available, protein structures that are related to the families have also been included. The database is available for online search and sequence information retrieval at http://www.biochem.ucl.ac.uk/bsm/virus_database/ VIDA.html.