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1.  Multivariate spatial covariance analysis of 99mTc-exametazime SPECT images in dementia with Lewy bodies and Alzheimer's disease: utility in differential diagnosis 
We examined 99mTc-exametazime brain blood flow single-photon emission computed tomography (SPECT) images using a spatial covariance analysis (SCA) approach to assess its diagnostic value in distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Voxel SCA was simultaneously applied to a set of preprocessed images (AD, n=40; DLB, n=26), generating a series of eigenimages representing common intercorrelated voxels in AD and DLB. Linear regression derived a spatial covariance pattern (SCP) that discriminated DLB from AD. To investigate the diagnostic value of the model SCP, the SCP was validated by applying it to a second, independent, AD and DLB cohort (AD, n=34; DLB, n=29). Mean SCP expressions differed between AD and DLB (F1,64=36.2, P<0.001) with good diagnostic accuracy (receiver operating characteristic (ROC) curve area 0.87, sensitivity 81%, specificity 88%). Forward application of the model SCP to the independent cohort revealed similar differences between groups (F1,61=38.4, P<0.001), also with good diagnostic accuracy (ROC 0.86, sensitivity 80%, specificity 80%). Multivariate analysis of blood flow SPECT data appears to be robust and shows good diagnostic accuracy in two independent cohorts for distinguishing DLB from AD.
doi:10.1038/jcbfm.2013.2
PMCID: PMC3618400  PMID: 23361395
Alzheimer's disease; differential diagnosis; dementia with Lewy bodies; perfusion; spatial covariance; SPECT
2.  Optimized heterologous transfection of viable adult organotypic brain slices using an enhanced gene gun 
BMC Research Notes  2013;6:544.
Background
Organotypic brain slices (OTBS) are an excellent experimental compromise between the facility of working with cell cultures and the biological relevance of using animal models where anatomical, morphological, and cellular function of specific brain regions can be maintained. The biological characteristics of OTBS can subsequently be examined under well-defined conditions. They do, however, have a number of limitations; most brain slices are derived from neonatal animals, as it is difficult to properly prepare and maintain adult OTBS. There are ample problems with tissue integrity as OTBS are delicate and frequently become damaged during the preparative stages. Notwithstanding these obstacles, the introduced exogenous proteins into both neuronal cells, and cells imbedded within tissues, have been consistently difficult to achieve.
Results
Following the ex vivo extraction of adult mouse brains, mounted inside a medium-agarose matrix, we have exploited a precise slicing procedure using a custom built vibroslicer. To transfect these slices we used an improved biolistic transfection method using a custom made low-pressure barrel and novel DNA-coated nanoparticles (40 nm), which are drastically smaller than traditional microparticles. These nanoparticles also minimize tissue damage as seen by a significant reduction in lactate dehydrogenase activity as well as propidium iodide (PI) and dUTP labelling compared to larger traditional gold particles used on these OTBS. Furthermore, following EYFP exogene delivery by gene gun, the 40 nm treated OTBS displayed a significantly larger number of viable NeuN and EYFP positive cells. These OTBS expressed the exogenous proteins for many weeks.
Conclusions
Our described methodology of producing OTBS, which results in better reproducibility with less tissue damage, permits the exploitation of mature fully formed adult brains for advanced neurobiological studies. The novel 40 nm particles are ideal for the viable biolistic transfection of OTBS by reducing tissue stress while maintaining long term exogene expression.
doi:10.1186/1756-0500-6-544
PMCID: PMC3878247  PMID: 24354851
Organotypic brain slices; Vibroslicer; Gene gun; Biolistic transfection; Nanoparticles; Tissue slicer
3.  Intracellular Magnesium-Dependent Modulation of Gap Junction Channels Formed by Neuronal Connexin36 
Gap junction (GJ) channels composed of Connexin36 (Cx36) are widely expressed in the mammalian CNS and form electrical synapses between neurons. Here we described a novel modulatory mechanism of Cx36 GJ channels that is dependent on intracellular free magnesium ([Mg2+]i). We examined junctional conductance (gj) and its dependence on transjunctional voltage (Vj) at different [Mg2+]i in cultures of HeLa or N2A cells expressing Cx36. We found that Cx36 GJs are partially inhibited at resting [Mg2+]i, thus, gj can be augmented or reduced by lowering or increasing [Mg2+]i, respectively. Similar changes in gj and Vj-gating were observed using MgATP or K2ATP in pipette solutions, which increases or decreases [Mg2+]i, respectively. Changes in phosphorylation of Cx36 or in [Ca2+]i were not involved in the observed Mg2+-dependent modulation of gj. Magnesium ions permeate the channel and transjunctional asymmetry in [Mg2+]i resulted in asymmetric Vj-gating. The gj of GJs formed of Cxs 26, 32, 43, 45 and 47 was also reduced by increasing [Mg2+]i, but was not increased by lowering [Mg2+]i; single channel conductance did not change. We showed that [Mg2+]i affects both open probability and the number of functional channels, likely through binding in the channel lumen. Finally, we showed that Cx36-containing electrical synapses between neurons of the trigeminal mesencephalic nucleus in rat brain slices are similarly affected by changes in [Mg2+]i. Thus, this novel modulatory mechanism could underlie changes in neuronal synchronization under conditions in which ATP levels, and consequently [Mg2+]i, are modified.
doi:10.1523/JNEUROSCI.2825-12.2013
PMCID: PMC3635812  PMID: 23486946
4.  Adenosine and dopamine receptors co-regulate photoreceptor coupling via gap junction phosphorylation in mouse retina 
Gap junctions in retinal photoreceptors suppress voltage noise and facilitate input of rod signals into the cone pathway during mesopic vision. These synapses are highly plastic and regulated by light and circadian clocks. Recent studies have revealed an important role for connexin36 (Cx36) phosphorylation by protein kinase A (PKA) in regulating cell-cell coupling. Dopamine is a light-adaptive signal in the retina, causing uncoupling of photoreceptors via D4 receptors (D4R), which inhibits adenylyl cyclase (AC) and reduces PKA activity. We hypothesized that adenosine, with its extracellular levels increasing in darkness, may serve as a dark signal to co-regulate photoreceptor coupling through modulation of gap junction phosphorylation. Both D4R and A2a receptor (A2aR) mRNAs were present in photoreceptors, inner nuclear layer neurons, and ganglion cells in C57BL/6 mouse retina, and showed cyclic expression with partially overlapping rhythms. Pharmacologically activating A2aR or inhibiting D4R in light-adapted daytime retina increased photoreceptor coupling. Cx36 among photoreceptor terminals, representing predominantly rod-cone gap junctions but possibly including some rod-rod and cone-cone gap junctions, was phosphorylated in a PKA-dependent manner by the same treatments. Conversely, inhibiting A2aR or activating D4R in daytime dark-adapted retina decreased Cx36 phosphorylation with similar PKA dependence. A2a-deficient mouse retina showed defective regulation of photoreceptor gap junction phosphorylation, fairly regular dopamine release, and moderately down-regulated expression of D4R and AC type I mRNA. We conclude that adenosine and dopamine co-regulate photoreceptor coupling through opposite action on the PKA pathway and Cx36 phosphorylation. In addition, loss of the A2aR hampered D4R gene expression and function.
doi:10.1523/JNEUROSCI.2807-12.2013
PMCID: PMC3711184  PMID: 23407968
5.  EptC of Campylobacter jejuni Mediates Phenotypes Involved in Host Interactions and Virulence 
Infection and Immunity  2013;81(2):430-440.
Campylobacter jejuni is a natural commensal of the avian intestinal tract. However, the bacterium is also the leading cause of acute bacterial diarrhea worldwide and is implicated in development of Guillain-Barré syndrome. Like many bacterial pathogens, C. jejuni assembles complex surface structures that interface with the surrounding environment and are involved in pathogenesis. Recent work in C. jejuni identified a gene encoding a novel phosphoethanolamine (pEtN) transferase, EptC (Cj0256), that plays a promiscuous role in modifying the flagellar rod protein, FlgG; the lipid A domain of lipooligosaccharide (LOS); and several N-linked glycans. In this work, we report that EptC catalyzes the addition of pEtN to the first heptose sugar of the inner core oligosaccharide of LOS, a fourth enzymatic target. We also examine the role pEtN modification plays in circumventing detection and/or killing by host defenses. Specifically, we show that modification of C. jejuni lipid A with pEtN results in increased recognition by the human Toll-like receptor 4–myeloid differentiation factor 2 (hTLR4-MD2) complex, along with providing resistance to relevant mammalian and avian antimicrobial peptides (i.e., defensins). We also confirm the inability of aberrant forms of LOS to activate Toll-like receptor 2 (TLR2). Most exciting, we demonstrate that strains lacking eptC show decreased commensal colonization of chick ceca and reduced colonization of BALB/cByJ mice compared to wild-type strains. Our results indicate that modification of surface structures with pEtN by EptC is key to its ability to promote commensalism in an avian host and to survive in the mammalian gastrointestinal environment.
doi:10.1128/IAI.01046-12
PMCID: PMC3553815  PMID: 23184526
6.  Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration 
Lancet Neurology  2013;12(8):822-838.
Summary
Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).
doi:10.1016/S1474-4422(13)70124-8
PMCID: PMC3714437  PMID: 23867200
7.  The spectrum of nonmotor symptoms in early Parkinson disease 
Neurology  2013;80(3):276-281.
Objective:
Nonmotor symptoms (NMS) are common in patients with established Parkinson disease (PD) but their frequency in early PD has not been extensively studied. Our aim was to determine the frequency of NMS in a cohort of patients with newly diagnosed PD.
Methods:
A total of 159 patients with early PD and 99 healthy controls participated in this study. NMS were screened for using the Nonmotor Symptom Questionnaire. Other assessments included measures of motor disability (Movement Disorders Society–revised Unified Parkinson's Disease Rating Scale [MDS-UPDRS]), disease severity (Hoehn & Yahr staging), depression (Geriatric Depression Scale), and global cognitive function (Mini-Mental State Examination and Montreal Cognitive Assessment).
Results:
The PD group reported a significantly greater number of NMS compared with controls (8.4 [4.3] vs 2.8 [2.6]). In the PD group, the most commonly experienced NMS were excessive saliva, forgetfulness, urinary urgency, hyposmia, and constipation. Patients with higher MDS-UPDRS III scores and those with the postural instability gait subtype experienced a greater number of NMS.
Conclusion:
NMS are common in early PD and reflect the multisystem nature of the disorder. Even in the earliest stages of PD, NMS may be detrimental to patients' functional status and sense of well-being.
doi:10.1212/WNL.0b013e31827deb74
PMCID: PMC3589180  PMID: 23319473
8.  Calcium/Calmodulin Stimulates the Autophosphorylation of Elongation Factor 2 Kinase on Thr-348 and Ser-500 to Regulate its Activity and Calcium Dependence 
Biochemistry  2012;51(11):2232-2245.
Eukaryotic elongation factor 2 kinase (eEF-2K) is an atypical protein kinase regulated by Ca2+ and calmodulin (CaM). Its only known substrate is eukaryotic elongation factor 2 (eEF-2), whose phosphorylation by eEF-2K impedes global protein synthesis. To date, the mechanism of eEF-2K autophosphorylation has not been fully elucidated. To investigate the mechanism of autophosphorylation, human eEF-2K was co-expressed with λ-phosphatase, and purified from bacteria in a three-step protocol using a calmodulin-affinity column. Purified eEF-2K was induced to autophosphorylate by incubation with Ca2+/CaM in the presence of MgATP. Analyzing tryptic or chymotryptic peptides by mass spectrometry monitored the autophosphorylation over 0–180 minutes. The following five major autophosphorylation sites were identified, Thr-348, Thr-353, Ser-445, Ser-474 and Ser-500. In the presence of Ca2+/CaM, robust phosphorylation of Thr-348 occurs within seconds of adding MgATP. Mutagenesis studies suggest that phosphorylation of Thr-348 is required for substrate (eEF-2 or a peptide substrate) phosphorylation, but not self-phosphorylation. Phosphorylation of Ser-500 lags behind the phosphorylation of Thr-348, and is associated with calcium-independent activity of eEF-2K. Mutation of Ser-500 to Asp, but not Ala, renders eEF-2K calcium-independent. Surprisingly, this calcium-independent activity requires the presence of calmodulin.
doi:10.1021/bi201788e
PMCID: PMC3401519  PMID: 22329831
9.  Efficient Depletion of Host DNA Contamination in Malaria Clinical Sequencing 
Journal of Clinical Microbiology  2013;51(3):745-751.
The cost of whole-genome sequencing (WGS) is decreasing rapidly as next-generation sequencing technology continues to advance, and the prospect of making WGS available for public health applications is becoming a reality. So far, a number of studies have demonstrated the use of WGS as an epidemiological tool for typing and controlling outbreaks of microbial pathogens. Success of these applications is hugely dependent on efficient generation of clean genetic material that is free from host DNA contamination for rapid preparation of sequencing libraries. The presence of large amounts of host DNA severely affects the efficiency of characterizing pathogens using WGS and is therefore a serious impediment to clinical and epidemiological sequencing for health care and public health applications. We have developed a simple enzymatic treatment method that takes advantage of the methylation of human DNA to selectively deplete host contamination from clinical samples prior to sequencing. Using malaria clinical samples with over 80% human host DNA contamination, we show that the enzymatic treatment enriches Plasmodium falciparum DNA up to ∼9-fold and generates high-quality, nonbiased sequence reads covering >98% of 86,158 catalogued typeable single-nucleotide polymorphism loci.
doi:10.1128/JCM.02507-12
PMCID: PMC3592063  PMID: 23224084
10.  Characterizing dementia with Lewy bodies by means of diffusion tensor imaging 
Neurology  2012;79(9):906-914.
Objective:
To investigate patterns of in vivo white matter tract change using diffusion tensor imaging (DTI), we conducted a cross-sectional study of dementia with Lewy bodies (DLB) in comparison with Alzheimer disease (AD) and normal aging.
Methods:
The study included 106 subjects (35 with DLB, 36 with AD, and 35 elderly controls) who underwent clinical and neuropsychological assessment and diffusion tensor MRI. We used tract-based spatial statistics to investigate patterns of reduced fractional anisotropy (FA) and increased mean diffusivity (MD) across the entire white matter tract skeleton and also investigated correlations with clinical features.
Results:
Areas of reduced FA in subjects with DLB vs controls were found primarily in parieto-occipital white matter tracts; in AD, the changes were much more diffuse. DLB was also associated with reduced FA in the pons and left thalamus, in comparison with AD. The pattern of MD increase was diffuse in AD and DLB. We found an association between DTI parameters and impaired episodic memory, letter fluency, and severity of motor parkinsonism in DLB.
Conclusions:
Despite a similar level of dementia severity, patterns of DTI changes in AD and DLB differed significantly. The selective involvement of the visual association areas and subcortical structures and the significant clinical correlations highlight the potential importance of white matter tract change in the pathogenesis of DLB. DTI may be a useful technique to investigate early and possible preclinical changes in DLB and warrants further investigation.
doi:10.1212/WNL.0b013e318266fc51
PMCID: PMC3425843  PMID: 22895591
11.  Histamine Receptors of Cones and Horizontal Cells in Old World Monkey Retinas 
In primates the retina receives input from histaminergic neurons in the posterior hypothalamus that are active during the day. In order to understand how this input contributes to information processing in Old World monkey retinas, we have been localizing histamine receptors (HR) and studying the effects of histamine on the neurons that express them. Previously, we localized HR3 to the tips of ON bipolar cell dendrites and showed that histamine hyperpolarizes the cells via this receptor. We raised antisera against synthetic peptides corresponding to an extracellular domain of HR1 between the 4th and 5th transmembrane domains and to an intracellular domain near the carboxyl terminus of HR2. Using these, we localized HR1 to horizontal cells and a small number of amacrine cells and localized HR2 to puncta closely associated with synaptic ribbons inside cone pedicles. Consistent with this, HR1 mRNA was detected in horizontal cell perikarya and primary dendrites and HR2 mRNA was found in cone inner segments. We studied the effect of 5 µM exogenous histamine on primate cones in macaque retinal slices. Histamine reduced Ih at moderately hyperpolarized potentials, but not the maximal current. This would be expected to increase the operating range of cones and conserve ATP in bright, ambient light. Thus, all three major targets of histamine are in the outer plexiform layer, but the retinopetal axons containing histamine terminate in the inner plexiform layer. Taken together, the findings in these three studies suggest that histamine acts primarily via volume transmission in primate retina.
doi:10.1002/cne.22731
PMCID: PMC3272842  PMID: 21800315
retinopetal; centrifugal; histamine receptor 1; histamine receptor 2; photoreceptor; primate
12.  Resting-State Functional Connectivity in Late-Life Depression: Higher Global Connectivity and More Long Distance Connections 
Functional magnetic resonance imaging recordings in the resting-state (RS) from the human brain are characterized by spontaneous low-frequency fluctuations in the blood oxygenation level dependent signal that reveal functional connectivity (FC) via their spatial synchronicity. This RS study applied network analysis to compare FC between late-life depression (LLD) patients and control subjects. Raw cross-correlation matrices (CM) for LLD were characterized by higher FC. We analyzed the small-world (SW) and modular organization of these networks consisting of 110 nodes each as well as the connectivity patterns of individual nodes of the basal ganglia. Topological network measures showed no significant differences between groups. The composition of top hubs was similar between LLD and control subjects, however in the LLD group posterior medial-parietal regions were more highly connected compared to controls. In LLD, a number of brain regions showed connections with more distant neighbors leading to an increase of the average Euclidean distance between connected regions compared to controls. In addition, right caudate nucleus connectivity was more diffuse in LLD. In summary, LLD was associated with overall increased FC strength and changes in the average distance between connected nodes, but did not lead to global changes in SW or modular organization.
doi:10.3389/fpsyt.2012.00116
PMCID: PMC3540775  PMID: 23316175
late-life depression; aging; resting-state; functional connectivity; default mode network; network analysis; graph theory; functional magnetic resonance
13.  VAGINAL PROGESTERONE VERSUS CERVICAL CERCLAGE FOR THE PREVENTION OF PRETERM BIRTH IN WOMEN WITH A SONOGRAPHIC SHORT CERVIX, SINGLETON GESTATION, AND PREVIOUS PRETERM BIRTH: A SYSTEMATIC REVIEW AND INDIRECT COMPARISON META-ANALYSIS 
OBJECTIVE
No randomized controlled trial has directly compared vaginal progesterone and cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix in the midtrimester, singleton gestation, and previous spontaneous preterm birth. We performed an indirect comparison of vaginal progesterone versus cerclage, using placebo/no cerclage as the common comparator.
STUDY DESIGN
Adjusted indirect meta-analysis of randomized controlled trials.
RESULTS
Four studies evaluating vaginal progesterone versus placebo (158 patients) and five evaluating cerclage versus no cerclage (504 patients) were included. Both interventions were associated with a statistically significant reduction in the risk of preterm birth <32 weeks of gestation and composite perinatal morbidity and mortality compared with placebo/no cerclage. Adjusted indirect meta-analyses did not show statistically significant differences between vaginal progesterone and cerclage in reducing preterm birth or adverse perinatal outcomes.
CONCLUSION
Based on state-of-the-art methodology for indirect comparisons, either vaginal progesterone or cerclage are equally efficacious in the prevention of preterm birth in women with a sonographic short cervix in the midtrimester, singleton gestation, and previous preterm birth. The selection of the optimal treatment may depend upon adverse events, cost and patient/clinician preferences.
doi:10.1016/j.ajog.2012.10.877
PMCID: PMC3529767  PMID: 23157855
prematurity; uterine cervix; transvaginal ultrasound; perinatal mortality; admission to neonatal intensive care unit; birth weight <1500 g; progestin
14.  My surgical heroes 
PMCID: PMC3523775  PMID: 23382619
15.  Salivary Endothelin-1 Potential for Detecting Oral Cancer in Patients with Oral Lichen Planus or Oral Cancer in Remission 
Oral oncology  2011;47(12):1122-1126.
Objectives
Endothelin-1 (ET-1) is a potent vasoconstrictor involved not only in vascular biology but also in carcinogenesis. Results of a study in 2007 suggested salivary ET-1 as a potential biomarker for oral squamous cell carcinoma (OSCC), but a later study showed conflicting results. The purpose of our pilot study was to investigate feasibility of using salivary ET-1 as a biomarker for OSCC in two groups: oral lichen planus (OLP) patients and patients with OSCC in remission.
Materials and Methods
Saliva samples were collected from five groups of subjects: patients with newly diagnosed, active OSCC (Group A); patients with OSCC in remission (Group B); patients with active OLP lesions (Group C); patients with OLP in remission (Group D); and normal controls (Group E). Salivary ET-1 levels were determined by enzyme-linked immunosorbent assay, and the results were analyzed by the Mann Whitney U test.
Results
The mean salivary ET-1 level in Group A was significantly higher than that found in Group C (p=0.001), Group D (p=0.015) or Group E (p=0.004). There were no significant differences (p>0.05) in the mean salivary ET-1 levels between Groups A and B; Groups B and C; Groups B and D; Groups B and E; Groups C and D; Groups C and E; or Groups D and E.
Conclusion
Salivary ET-1 could be a good biomarker for OSCC development in OLP patients regardless of the degree of OLP disease activity. However, it appeared not to be a good biomarker for detecting recurrence of OSCC in patients in remission.
doi:10.1016/j.oraloncology.2011.07.032
PMCID: PMC3225505  PMID: 21868280
Oral cancer; oral squamous cell carcinoma; saliva; endothelin; ET-1; lichen planus; biomarker
16.  Nonsynaptic NMDA receptors mediate activity-dependent plasticity of gap junctional coupling in the AII amacrine cell network 
The Journal of Neuroscience  2012;32(20):6747-6759.
Many neurons are coupled by electrical synapses into networks that have emergent properties. In the retina, coupling in these networks is dynamically regulated by changes in background illumination, optimizing signal integration for the visual environment. However, the mechanisms that control this plasticity are poorly understood. We have investigated these mechanisms in the rabbit AII amacrine cell, a multifunctional retinal neuron that forms an electrically coupled network via Cx36 gap junctions. We find that presynaptic activity of glutamatergic ON bipolar cells drives increased phosphorylation of Cx36, indicative of increased coupling in the AII network. The phosphorylation is dependent on activation of nonsynaptic NMDA receptors that colocalize with Cx36 on AII amacrine cells, and is mediated by CaMKII. This activity-dependent increase in Cx36 phosphorylation works in opposition to dopamine-driven reduction of phosphorylation, establishing a local dynamic regulatory mechanism, and accounting for the non-linear control of AII coupling by background illumination.
doi:10.1523/JNEUROSCI.5087-11.2012
PMCID: PMC3367513  PMID: 22593045
NMDA receptor; gap junction; Cx36; plasticity; CaMKII; phosphorylation
17.  Photoreceptor Coupling mediated by Connexin 36 in the Primate Retina 
The Journal of Neuroscience  2012;32(13):4675-4687.
Photoreceptors are coupled via gap junctions in many mammalian species. Cone-to-cone coupling is thought to improve sensitivity and signal-to-noise ratio while rod-to-cone coupling provides an alternative rod pathway active under twilight or mesopic conditions (Smith et al., 1986; DeVries et al., 2002; Hornstein et al., 2005). Gap junctions are composed of connexins and Cx36, the dominant neuronal connexin, is expressed in the outer plexiform layer. Primate (Macaca mulatta) cone pedicles, labeled with an antibody against cone arrestin (7G6) were connected by a network of fine processes called telodendria and, in double-labeled material, Cx36 plaques were located precisely at telodendrial contacts between cones, suggesting strongly they are Cx36 gap junctions. Each red/green cone made non-selective connections with neighboring red/green cones. In contrast, blue cone pedicles were smaller with relatively few short telodendria and they made only rare or equivocal Cx36 contacts with adjacent cones. There were also many smaller Cx36 plaques around the periphery of every cone pedicle and along a series of very fine telodendria that were too short to reach adjacent members of the cone pedicle mosaic. These small Cx36 plaques were closely aligned with nearly every rod spherule and may identify sites of rod-to-cone coupling, even though the identity of the rod connexin has not been established. We conclude that the matrix of cone telodendria is the substrate for photoreceptor coupling. Red/green cones were coupled indiscriminately but blue cones were rarely connected with other cones. All cone types, including blue cones, made gap junctions with surrounding rod spherules.
doi:10.1523/JNEUROSCI.4749-11.2012
PMCID: PMC3335500  PMID: 22457514
cones; rods; gap junctions; connexin 36; telodendria; confocal microscopy
18.  VAGINAL PROGESTERONE IN WOMEN WITH AN ASYMPTOMATIC SONOGRAPHIC SHORT CERVIX IN THE MIDTRIMESTER DECREASES PRETERM DELIVERY AND NEONATAL MORBIDITY: A SYSTEMATIC REVIEW AND META-ANALYSIS OF INDIVIDUAL PATIENT DATA 
OBJECTIVE
To determine whether the use of vaginal progesterone in asymptomatic women with a sonographic short cervix in the mid-trimester reduces the risk of preterm birth and improves neonatal morbidity and mortality.
STUDY DESIGN
Individual patient data meta-analysis of randomized controlled trials.
RESULTS
Five trials of high quality were included with a total of 775 women and 827 infants. Treatment with vaginal progesterone was associated with a significant reduction in the rate of preterm birth <33 weeks (RR 0.58, 95% CI 0.42–0.80), <35 weeks (RR 0.69, 95% CI 0.55–0.88) and <28 weeks (RR 0.50, 95% CI 0.30–0.81), respiratory distress syndrome (RR 0.48, 95% CI 0.30–0.76), composite neonatal morbidity and mortality (RR 0.57, 95% CI 0.40–0.81), birth weight <1500 g (RR 0.55, 95% CI 0.38–0.80), admission to NICU (RR 0.75, 95% CI 0.59–0.94), and requirement for mechanical ventilation (RR 0.66, 95% CI 0.44–0.98). There were no significant differences between the vaginal progesterone and placebo groups in the rate of adverse maternal events or congenital anomalies.
CONCLUSION
Vaginal progesterone administration to asymptomatic women with a sonographic short cervix reduces the risk of preterm birth and neonatal morbidity and mortality.
doi:10.1016/j.ajog.2011.12.003
PMCID: PMC3437773  PMID: 22284156
prematurity; uterine cervix; transvaginal ultrasound; respiratory distress syndrome; admission to neonatal intensive care unit; mechanical ventilation; birth weight <1500 g; preterm birth; progestin; 17OHP-C; 17OHP; 17-alpha hydroxyprogesterone caproate
19.  Congenital sacrococcygeal PNET and chemotherapy 
We present the case of a congenital localised sacrococcygeal primitive neuroectodermal tumor treated aggressively with surgical resection and modified age-appropriate adjuvant chemotherapy. The conventional combination chemotherapy of vincristine, adriamycin, cyclophosphamide, ifosfamide and etoposide was modified to a regimen including vincristine, adriamicin, cyclophosphamide and actinomycin in order to minimise the predicted toxicity in this age group. Adjuvant “induction” chemotherapy commenced at 4 weeks of age and consisted of four cycles of vincristine, adriamycin and cyclophosphamide at 50%, 75%, 75% and 100% of recommended doses (vincristine 0.05 mg/kg, adriamycin 0.83 mg/kg daily × 2, cyclophosphamide 40 mg/kg) at 3-weekly intervals. This was followed by four cycles of “maintenance” chemotherapy with vincristine (0.025 mg/kg), actinomycin (0.025 mg/kg) and cyclophosphamide (36 mg/kg) at full recommended doses. Cardioxane at a dose of 16.6 mg/kg was infused immediately prior to the adriamycin. Our patient is thriving at 19 months out from end of treatment.
doi:10.4103/0971-5851.103151
PMCID: PMC3523479  PMID: 23248428
Chemotherapy; neonatal; peripheral primitive neuroectodermal tumor; primitive neuroectodermal tumor
20.  Visual cortex in dementia with Lewy bodies: magnetic resonance imaging study 
The British Journal of Psychiatry  2012;200(6):491-498.
Background
Visual hallucinations and visuoperceptual deficits are common in dementia with Lewy bodies, suggesting that cortical visual function may be abnormal.
Aims
To investigate: (1) cortical visual function using functional magnetic resonance imaging (fMRI); and (2) the nature and severity of perfusion deficits in visual areas using arterial spin labelling (ASL)-MRI.
Method
In total, 17 participants with dementia with Lewy bodies (DLB group) and 19 similarly aged controls were presented with simple visual stimuli (checkerboard, moving dots, and objects) during fMRI and subsequently underwent ASL-MRI (DLB group n = 15, control group n = 19).
Results
Functional activations were evident in visual areas in both the DLB and control groups in response to checkerboard and objects stimuli but reduced visual area V5/MT (middle temporal) activation occurred in the DLB group in response to motion stimuli. Posterior cortical perfusion deficits occurred in the DLB group, particularly in higher visual areas.
Conclusions
Higher visual areas, particularly occipito-parietal, appear abnormal in dementia with Lewy bodies, while there is a preservation of function in lower visual areas (V1 and V2/3).
doi:10.1192/bjp.bp.111.099432
PMCID: PMC3365275  PMID: 22500014
21.  Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer's disease: a cohort study 
BMJ Open  2012;2(1):e000380.
Objectives
Dementia with Lewy bodies (DLB) accounts for 10%–15% of dementia cases at autopsy and has distinct clinical features associated with earlier institutionalisation and a higher level of carer distress than are seen in Alzheimer's disease (AD). At present, there is on-going debate as to whether DLB is associated with a more rapid cognitive decline than AD. An understanding of the rate of decline of cognitive and non-cognitive symptoms in DLB may help patients and carers to plan for the future.
Design
In this cohort study, the authors compared 100 AD and 58 DLB subjects at baseline and at 12-month follow-up on cognitive and neuropsychiatric measures.
Setting
Patients were recruited from 40 European centres.
Participants
Subjects with mild–moderate dementia. Diagnosis of DLB or AD required agreement between consensus panel clinical diagnosis and visual rating of 123I-FP-CIT (dopamine transporter) single photon emission computed tomography neuroimaging.
Outcome measures
The Cambridge Cognitive Examination including Mini-Mental State Examination and Neuropsychiatric Inventory (NPI).
Results
The AD and DLB groups did not differ at baseline in terms of age, gender, Clinical Dementia Rating score and use of cholinesterase inhibitors or memantine. NPI and NPI carer distress scores were statistically significantly higher for DLB subjects at baseline and at follow-up, and there were no differences between AD and DLB in cognitive scores at baseline or at follow-up. There was no significant difference in rate of progression of any of the variables analysed.
Conclusions
DLB subjects had more neuropsychiatric features at baseline and at follow-up than AD, but the authors did not find any statistically significant difference in rate of progression between the mild–moderate AD and DLB groups on cognitive or neuropsychiatric measures over a 12-month follow-up period.
Article summary
Article focus
Dementia with Lewy bodies (DLB) has distinct neuropsychiatric features.
At present, we do not know whether the poorer prognosis of DLB is due to a more rapid cognitive decline compared with Alzheimer's disease (AD).
Key messages
In this fairly large cohort of patients with DLB and AD, while there was no difference in level of cognitive impairment (Cambridge Cognitive Examination (CAMCOG) score) at baseline and at 12-month follow-up, DLB patients had significantly higher Neuropsychiatric Inventory (NPI) and NPI carer distress scores both at baseline and at 12-month follow-up.
Therefore, the worse prognosis of DLB is likely to be mediated by neuropsychiatric or other symptoms and not only by cognitive decline.
Strengths and limitations of this study
Inclusion of high number of subjects from 40 European clinical centres.
Well-characterised cases with both consensus panel clinical diagnosis (three clinical experts) and dopaminergic transporter single photon emission computed tomography imaging.
No autopsy data were available and therefore it is possible that more rapid cognitive decline may be present in pure DLB.
Only 1 year of follow-up.
There was higher attrition rate (no-follow-up assessment) in the DLB group, and DLB patients that did not return for follow-up were more impaired than AD patients.
doi:10.1136/bmjopen-2011-000380
PMCID: PMC3330257  PMID: 22318660
22.  Functional connectivity in cortical regions in dementia with Lewy bodies and Alzheimer's disease 
Brain  2011;135(2):569-581.
Using resting-state functional magnetic resonance imaging, spontaneous low-frequency fluctuations in the blood oxygenation level-dependent signal were measured to investigate connectivity between key brain regions hypothesized to be differentially affected in dementia with Lewy bodies compared with Alzheimer's disease and healthy controls. These included connections of the hippocampus, because of its role in learning, and parietal and occipital areas involved in memory, attention and visual processing. Connectivity was investigated in 47 subjects aged 60 years and over: 15 subjects with dementia with Lewy bodies, 16 subjects with Alzheimer's disease and 16 control subjects. Subjects were scanned using a 3 Tesla magnetic resonance imaging system. The mean blood oxygenation level-dependent signal time series was extracted from seed regions in the hippocampus, posterior cingulate cortex, precuneus and primary visual cortex and correlated with all other brain voxels to determine functional connectivity. Both subjects with dementia with Lewy bodies and Alzheimer's disease showed greater connectivity than control subjects. Compared with controls, the dementia with Lewy bodies group had greater connectivity between the right posterior cingulate cortex and other brain areas. In dementia with Lewy bodies, there were no significant differences in hippocampal connectivity compared with controls, but in Alzheimer's disease left hippocampal connectivity was greater compared with controls. There were no significant differences between groups for precuneus or primary visual cortex connectivity. No seed regions showed significantly less connectivity in subjects with dementia with Lewy bodies or Alzheimer's disease compared with controls. We found greater connectivity with the posterior cingulate in dementia with Lewy bodies and with the hippocampus in Alzheimer's disease. Consistent with the known relative preservation of memory in dementia with Lewy bodies compared with Alzheimer's disease, hippocampal connectivity was not found to be greater in dementia with Lewy bodies. Importantly, while metabolic imaging shows functional change in primary visual cortex in dementia with Lewy bodies, which is hypothesized to account for visual hallucinations, we found connectivity with this region to be unaffected. This implicates areas beyond visual sensory input level in the visual symptoms and visual–perceptual dysfunction seen in dementia with Lewy bodies.
doi:10.1093/brain/awr327
PMCID: PMC3708629  PMID: 22189566
dementia with Lewy bodies; functional magnetic resonance imaging; resting-state; functional connectivity
23.  Long term incidence of dementia, predictors of mortality and pathological diagnosis in older stroke survivors 
Brain  2011;134(12):3713-3724.
Greater understanding of the risk factors and mechanisms of incident dementia in stroke survivors is needed for prevention and management. There is limited information on the long-term consequences and forms of incident dementia in older stroke survivors. We recruited 355 patients aged >75 years from hospital-based stroke registers into a longitudinal study 3 months after stroke. At baseline none of the patients had dementia. Patients were genotyped for apolipoprotein E and assessed annually for cognition and development of incident dementia over up to 8 years of follow-up. The effect of baseline vascular risk factors upon incidence of dementia and mortality were estimated by Cox proportional regression analyses adjusted for age and gender. Standard neuropathological examination was performed to diagnose the first 50 cases that came to autopsy. We found that the median survival from the date of the index stroke was 6.72 years (95% confidence intervals: 6.38–7.05). During the follow-up of a mean time of 3.79 years, 23.9% of subjects were known to have developed dementia and 76.1% remained alive without dementia or died without dementia. The incidence of delayed dementia was calculated to be 6.32 cases per 100 person years whereas that for death or dementia was 8.62. Univariate and multivariate regression analyses showed that the most robust predictors of dementia included low (1.5 standard deviations below age-matched control group) baseline Cambridge Cognitive Examination executive function and memory scores, Geriatric Depression Scale score and three or more cardiovascular risk factors. Autopsy findings suggested that remarkably ≥75% of the demented stroke survivors met the current criteria for vascular dementia. Demented subjects tended to exhibit marginally greater neurofibrillary pathology including tauopathy and Lewy bodies and microinfarcts than non-demented survivors. Despite initial improvements in cognition following stroke in older stroke survivors, risk of progression to delayed dementia after stroke is substantial, but is related to the presence of vascular risk factors. Careful monitoring and treatment of modifiable vascular risk factors may be of benefit in preventing post-stroke dementia in the general population.
doi:10.1093/brain/awr273
PMCID: PMC3235558  PMID: 22171356
Alzheimer's disease; diagnosis; post-stroke dementia; stroke; vascular dementia
24.  Visual hallucinations in dementia with Lewy bodies: transcranial magnetic stimulation study 
The British Journal of Psychiatry  2011;199(6):492-500.
Background
The aetiology of visual hallucinations is poorly understood in dementia with Lewy bodies. Pathological alterations in visual cortical excitability may be one contributory mechanism.
Aims
To determine visual cortical excitability in people with dementia with Lewy bodies compared with aged-matched controls and also the relationship between visual cortical excitability and visual hallucinations in dementia with Lewy bodies.
Method
Visual cortical excitability was determined by using transcranial magnetic stimulation (TMS) applied to the occiput to elicit phosphenes (transient subjective visual responses) in 21 patients with dementia with Lewy bodies and 19 age-matched controls.
Results
Phosphene parameters were similar between both groups. However, in the patients with dementia with Lewy bodies, TMS measures of visual cortical excitability correlated strongly with the severity of visual hallucinations (P = 0.005). Six patients with dementia with Lewy bodies experienced visual hallucination-like phosphenes (for example, seeing people or figures on stimulation) compared with none of the controls (P = 0.02).
Conclusions
Increased visual cortical excitability in dementia with Lewy bodies does not appear to explain visual hallucinations but it may be a marker for their severity.
doi:10.1192/bjp.bp.110.090373
PMCID: PMC3227808  PMID: 22016436
25.  Neuroimaging predictors of death and dementia in a cohort of older stroke survivors 
Background
Stroke is a risk factor for subsequent death and dementia. Being able to identify subjects at particular risk would be beneficial to inform treatment and patient management.
Methods
Subjects aged over 75 years with incident stroke were recruited. Subjects had a cognitive assessment at 3 months post stroke to exclude dementia, and had an MRI scan (n=106) at that time. Subjects were then followed longitudinally for incident dementia and/or death.
Results
Independent neuroimaging predictors of survival to dementia were medial temporal atrophy (MTA; p=0.013) and the presence of thalamic infarcts (p=0.002). After inclusion of cognitive score in the model, the significance of MTA (p=0.049) and thalamic infarcts (p=0.04) was reduced, with survival being best predicted by baseline cognitive score (p=0.004). The only independent significant predictor of survival to death was MTA. Apart from thalamic infarcts, the NINDS/AIREN neuroimaging criteria did not independently predict survival to death or dementia.
Conclusions
MTA was associated with shorter time to dementia, suggesting a role for Alzheimer pathology in the development of post stroke dementia.
doi:10.1136/jnnp-2011-300873
PMCID: PMC3289833  PMID: 22114300

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