A first English translation of the original work is provided in the Supplementary Materials.Bajada  Anatomie des centres nerveux; volume 2 was published in 1901. In a major section of this tome (vol. 1 pp. 749–80), Joseph Dejerine and his wife and long-term collaborator, Augusta Dejerine-Klumpke, produced a treatise on the white matter pathways of the brain, composed of anatomical descriptions of meticulous detail and beautiful illustration (drawn by H. Gillet) that reflected a combination of the most advanced methodologies of the day and a review of leading neuroscientific research. We have selected and focused this specific output . Dejerine passed away in 1917 after suffering from Bright’s disease (nephritis)  .Anatomie des centres nerveux  regions associated with specific cognitive functions dynamically interacted with one another to produce a more complex function; and (ii) resultantly, higher cognitive impairment resulted not only from damage to cortical regions but also to the connections between them. This concept was expanded upon by Dejerine in his view on pure alexia, which he conceptualized as a disconnection syndrome . It is wWith the relatively recent emergence of diffusion MRI and related tractography techniques, modern neuroscience has been reconnecting with the work of the 19th century masters. A search of current literature will reveal a rapidly increasing interest in the association of specific cognitive functions to the white matter tracts of the brain. Despite the plethora of functional association studies, there remain many controversies surrounding the origin, course, termination and even sometimes the very existence of these tracts .Anatomie des centres nerveux is made available in the online With this in mind, and at such a poignant time as the 100th anniversary of the passing of Joseph Dejerine, we highlight the legacy of two pioneers in the subject and revive their descriptions of the long association fasciculi of the cerebral cortex. These descriptions were based on an in-depth study of the white matter of the human brain, based on a convergence of methodologies available at the time including gross dissection, histological preparations, animal experimentation and a thorough contemporary review of known findings. A full translation  of the section regarding the Long Association Fasciculi from The first section explores the concept of a multi-component tract; the conglomeration of fibres that underlie different functional networks.The second section focuses on regions of white matter tracts outlined by the Dejerines but subsequently lost to the literature, either in the 19th or 20th century, and some current conceptualizations of these.The third section highlights the Dejerines’ contributions to long-standing debates, some of which are still unresolved in the contemporary literature.Looking with a modern eye (and with modern methods) at the historical anatomical tract descriptions provided by the Dejerines, it is clear that some are incomplete and others inaccurate. However, such assertions could be argued to ring true for some modern anatomical studies of the brain’s major white matter tracts, and much of Dejerine’s work still holds true today. In addition, their descriptions offer an insight into the thoughts of two 19th century experts on topics that are still discussed and debated today.The Dejerines described five long association fasciculi, all of which are still discussed in the modern literature, namely the cingulum, uncinate fasciculus, superior longitudinal/arcuate fasciculus, occipito-frontal fasciculus, and the inferior longitudinal fasciculus. While we leave the reader to examine the full translation for an in-depth description of the tracts, we explore three key discussion points.Tracts can be conceptualized in one of two different ways, each of which can be likened to the wiring within a house. The first conceptualization posits that a tract is composed primarily of fibres that emerge from the same subregion, continue together along a single path and then terminate in the same destination. This is very much like the power cord of an electrical appliance through which positive, negative and earth wires travel together, therein providing the conduit from the power supply to the appliance. The second conceptualization, and the one promoted by the Dejerines in their anatomical descriptions , views a tract as a collection of fibres, from different sources and potentially carrying different information, which have been amalgamated together within a confined, shared neuroanatomical envelope (i.e. the tract). Under this view, a neural fibre may enter and exit a tract at any point along its trajectory. Accordingly, not only is a tract composed of long fibres that directly connect beginning and end points , but also of shorter fibres that connect the different regions that the tract passes along its trajectory. This second conceptualization is akin to a duct or trunk within a house in which wiring from the kitchen, bathroom, living room, etc. may be bundled together within a small space so they can be made to pass efficiently throughout the house. If one accepts this conception, then single tracts may be involved in very different functional networks. Hence, uncovering tract subcomponents, in addition to the major tract body, is an important step in understanding the functional associations of each tract. Furthermore, from a clinical neuroscience perspective, this second conceptualization would imply that the exact sequelae of tract damage may vary according to its position along each tract.‘Dissections show that the cingulum is not formed of fibres that extend the full length of the fasciculus, but of relatively short fibres. These short fibres are curved at both ends to penetrate white matter of the surrounding gyri and, for part of their trajectory, constitute the cingulum of Burdach.’Likewise, the Dejerines’ conceptualization of the occipitofrontal fasciculus, the arcuate fasciculus and the inferior longitudinal fasciculus reinforces the idea of a tract as a multi-component shared conduit. For example, they describe the occipitofrontal fasciculus as one that ‘like all long association fasciculi, it is formed of fibres of unequal length that only belong to the occipito-frontal fasciculus for part of their trajectory’. The Dejerines described the arcuate fasciculus as a tract that is almost entirely composed of short fibres that connect nearby gyri, none of which traverse the entire course of the tract. Once again, although current evidence points to long range fibres being present within the arcuate fasciculus, the concept of multiple components remains.Examples of conceiving the tract as a shared neural wiring conduit occur frequently in the Dejerines’ descriptions. For example, they describe the cingulum as an arched fasciculus on the medial aspect of the brain, yet note that it is composed of smaller bundles of fibres:‘Like all long association fasciculi, the inferior longitudinal fasciculus comprises a complex system of fibres of unequal lengths. However, secondary degeneration, resulting from localised cortical lesions of the occipital lobe, has shown us that this fasciculus contains a large number of long fibres whose degeneration can be seen in the white matter of the temporal lobe.’Although the exact descriptions of many of the association fasciculi have been challenged by later evidence , the concept of a tract comprising fibres of multiple lengths remains firm.Finally, in their description of the inferior longitudinal fasciculus, the Dejerines inculcate the concept that tracts are made up of fibres of differing lengths including long-range connections:In the 19th century, anatomists primarily performed dissections and microscopic sections on post-mortem human brains. In contrast, much late 20th century neuroanatomical work used axonal tracer studies in non-human primates, or more advanced neuroimaging techniques. This difference in both methodology and/or species has contributed to discrepancies and disagreements in the literature regarding the composition of some of the main association tracts. This has led to key fibre bundle components delineated by the Dejerines’ historical work being lost and rediscovered by modern neuroscience, as well as components overlooked by the Dejerines being found.in vivo diffusion MRI tractography techniques, contemporary neuroscientists have re-examined many of the tracts originally discussed in both the 19th century dissection and the 20th century tract tracing literature, rediscovering the multi-element nature of key association tracts. For example, the Dejerines conceptualized the cingulum as being composed of a series of comparatively short-range tract subcomponents. Using modern The inferior longitudinal fasciculus provides another example of modern tractography revisiting questions from the 19th and 20th century. The tract has a complex history and has, at various times, been conceptualized as either a single long tract or an occipitotemporal stream of short fibres connecting nearby gyri. During the 19th century, the great anatomists such as Charcot and Meynert believed that the inferior longitudinal fasciculus only had a projection fibre component . More recently, ‘the innermost fibres of this fasciculus are as arced as the U-fibres that line the bottom of sulci; it is this pronounced curvature that earned it the name uncinate fasciculus. However, it is only the innermost fibres that possess such a pronounced curvature. The further away the fibres are from the anterior perforated substance , the less curved they become, so much so that the very end fibres are not only straight but are curved in the opposite direction.’Recently, In the spirit of tracts being lost and found, most descriptions of the uncinate faciculus note a narrow U-shaped tract that connects the temporal pole to the orbitofrontal cortex. While this is one aspect of the uncinate that was described by the Dejerines, their uncinate fasciculus was a tract of greater complexity:‘[the occipito-frontal fasciculus] becomes closely associated with the most compact portion of the uncinate fasciculus, the two forming a double fan. The fasciulus occipito-frontalis inferior can thus be envisaged as representing a dorsal extension of the fronto-temporal associational system that forms the uncinate fasciculus.’Indeed, more than one possibility may be correct: it may be that the posterior component of the uncinate may be both a curving of uncinate fibres as well as part of the inferior fronto-occipital fasciculus, as highlighted in the description provided by Anatomie des centres nerveux will be familiar to the modern reader, many are steeped in controversy. The following section is devoted to the tracts that have stirred up debate in both the modern and the historical literature. Many of the tracts already described have been debated, discussed and redefined throughout history. However, some remain more controversial than others.While some descriptions of the white matter anatomy found in The occipito-frontal fasciculus  is a traThe brain is a complex structure and to date there has been no way to provide a truly objective, error-free description of its structure. Thus, anatomists of different eras may decide to give alternative names for the same structure, or may decide that the distinction is important. For example, the Dejerines used the terms arcuate fasciculus and superior longitudinal fasciculus interchangeably while modern neuroscientists make a distinction.‘The arcuate fasciculus appears to be composed of short association fibres that connect together two neighbouring gyri. Its deep layers, particularly those in contact with the external capsule, only contain a few longer fibres which, skipping over a gyrus, connect together two gyri a little further apart. But the arcuate fasciculus does not appear to contain fibres, of any length, that connect two distant lobes. In fact, we have seen several times, using a series of microscopic sections, that when the arcuate fasciculus or superior longitudinal fasciculus of Burdach is included in an old cortical lesion, there is hardly any degeneration of fibres beyond the immediate vicinity of the original source.’This description of the arcuate fasciculus as a collection of very short association fibres is in stark contrast to the modern view of the tract as a long-range connective pathway , differs from modern conceptualizations that have brought together complementary evidence from a range of sources including tract tracer, electrophysiology, modern blunt dissections and tractography experiments. According to the Dejerines description: pathway . While iAside from contending with archaic and occasionally cumbersome sentence structure, reading through the chapter on the long association fasciculi by Joseph and Augusta Dejerine feels almost modern, with some aspects being very familiar: they approached the subject by examining it through multimodal and convergent methodologies, and anatomy was often discussed in the context of the function that it underpins.in vivo study of human white matter, since we are now free from a reliance on the availability of post-mortem specimens. However, rarely does any advance come without its own challenges and limitations. Indeed, the easy availability of data can come at the cost of increasing abstraction and the validity of the tractography model is hard to verify. Furthermore, it is rare to find contemporary researchers who have investigated brain structures so thoroughly and systematically as did the Dejerines. Due to the relative dominance of the English language in the modern scientific literature and the relative lack of interest in historical sources, many researchers may not have access to the works of Dejerine  (The MRI revolution in human neuroscience has opened the possibility of the widespread, repeated, While modern explorations of the white matter architecture have evolved from a traditional mapping of the large fibre tracts and their cortical origin/terminations to a more fine-grained delineation of their subdivisions, the focus has still been on the long-range association fibres. With current knowledge and methodological advances, we are now able to begin to explore both the short and long components, as well as their relationship to higher cognitive functions and the pattern of impairments that result when these are affected by different neurological diseases (Not only for an increased neuroscientific understanding, but also for a wider, especially clinical, application, the notions of the 19th century fasciculi remain important. These are the white matter bundles that are commonly affected by stroke and other forms of full depth injuries leading to various forms of disconnection syndromes . They arAnatomie des centres nerveux is a beautiful and meticulous work which deserves appreciation. The Dejerines are one part of a long history of pioneers in neuroanatomy. In remembering them and their contribution, we can recognize that modern neuroscience is standing on the shoulders of giants.In these situations, a comprehensive understanding of tract anatomy is essential. While the descriptions made by the Dejerines do not always conform to our modern understanding of tracts, their insights, taken in conjunction with modern evidence are still valuable. At the very least, the two volume Supplementary DataClick here for additional data file.


The article reports about electric field-induced alignment of the carbon nanoparticles embedded in epoxy matrix. Optical microscopy was performed to consider the effect of the electric field magnitude and configuration, filler morphology, and aspect ratio on alignment process. Characteristic time of aligned network formation was compared with modeling predictions. Carbon nanotube and graphite nanoplatelet rotation time was estimated using an analytical model based on effective medium approach. Different depolarization factor was applied according to the geometries of the particle and electric field.Solid nanocomposites were fabricated by using AC electric field. We have investigated concentration dependence of electrical conductivity of graphite nanoplatelets/epoxy composites using two-probe technique. It was established that the electrical properties of composites with random and aligned filler distribution are differ by conductivity value at certain filler content and distinguish by a form of concentration dependence of conductivity for fillers with different morphology. These differences were explained in terms of the dynamic percolation and formation of various conductive networks: chained in case of graphite nanoplatelets and crossed framework in case of carbon nanotubes filler. Tailorable properties provide an application of conductive carbon-based composite materials in many industries as electronic and constructional components: in microelectronics, electrostatic dissipation, at electromagnetic shields fabrication, for aircraft structures, etc. –4. They 1–104) [Non-spherical particles are more favorable as composite fillers from the perspective of improving electrical conductivity of composite –7. This 1–104) , as fillRecomposing of filler and its specific spatial distribution allows obtaining composites with low percolation threshold which reduces the cost of material. The most popular methods of preparation of composites with anisotropic filler distribution are exposure of liquid composite mixture to electromagnetic field and application of mechanical stress. Among disadvantages of filler alignment method by rolling, shearing stress is possible breaking and destruction of carbon nanoparticles under such exposure . MagnetiBut the overwhelming majority of the presented works about electric field-assisted alignment are devoted to carbon nanotubes embedded in polymer matrix –18. The Based on epoxy resin Larit 285 , composite materials were fabricated and investigated in this study. In the initial state, this polymer is two-component and consists of liquid epoxy and appropriate hardener H 285. Low viscosity of the used resin (600 ÷ 900 mPa × s at 25 °С) and hardener (50 ÷ 100 mPa × s at 25 °С) allows using the impact of an external electric field for the manufacture of composite materials on their basis.Multiwall carbon nanotubes (MWCNTs) ;Graphite nanoplatelets (GNPs).The following materials were used as fillers for the fabricated composite systems:GNPs were obtained by ultrasonic dispersing (in acetone medium for 3 h) of thermally exfoliated graphite which is a resulting product of deep thermo-chemical treatment of dispersed graphite. The process of GNP manufacturing is described in detail in .ρ(MWCNT) = 1.8 g/cm3 [ρ(GNPs) = 2.23 g/cm3, as the density of monocrystalline graphite.Table .8 g/cm3 , ρ(GNPs)Composite samples that were prepared contained different concentrations of GNPs as a filler . One type of samples had random distribution of the filler, and in another one, GNPs were aligned by external electric field.Method of composite systems preparation was as follows. At first, required amount of carbon filler was poured into pre-dissolved polymer matrix and mixed mechanically. After that, the mixture was exposed to ultrasonic dispersing for a better distribution of filler in epoxy matrix. Dispersion was carried out in ultrasonic bath Вaku-9050 with frequency of 40 kHz and maximum output electric power of 50 W. The composite mixture was exposed to ultrasonic action for 30 min at 50 W, after that hardener Н 285 was added to the resulting composite mixture in 100/40 ratio by mass to the weight of Larit 285.Eventually, for composites with aligned filler distribution fabrication, a part of obtained composite mixture was poured into plastic mold which was placed between the plates of capacitor. AC voltage with frequency of 15 kHz and magnitude of 2000 V was applied to the plates. High-voltage source with the ability to generate AC voltage at 15 kHz frequency and magnitude in the range up to 2000 V or DC voltage with magnitude in the range up to 2000 V was used as a source of electric field. The value of the magnitude of electric field was controlled by universal voltmeter В7-16А.Under choosing the AC electric field frequency, we kept in mind two points: (1) the frequency should be high enough that the carbon nanoparticles alignment time would be the time of epoxy hardening; (2) the frequency should be low enough to observe the dynamics of nanoparticles alignment in electric field. Keeping in mind these considerations, we have carried out composites formation at the frequency of 15 kHz.The other part of the composite mixture was left without the influence of an external electric field.After holding at room temperature, molds with composite samples were subjected to heat treatment at stepwise increasing temperature from 40 to 80 °C, which increased on 10 °C hourly. This was done to complete polymerization process of composites.Investigation of the character of carbon fillers distribution in epoxy matrix under electric field treatment was performed for composites with the content of carbon filler of 0.05 wt%. This was done with a stereoscopic optical microscope МBS-1 equipped with digital camera Etrek DCM-510. This setup provided the opportunity of observation online of the liquid epoxy with dispersed carbon nanoparticles under electric field influence. The configuration of experiment is described in detail in , 27. A s10 ohm. Higher than 1010 ohm, resistances were measured using teraommetr Е6–13. Samples for measurements were prepared in the form of regular parallelepipeds with the dimensions 5.0 × 4.0 × 4.0 mm3.Electrical conductivity of the investigated composites was measured by standard two-probe method in DC mode at room temperature with a limit of measurement of electrical resistance of 10Equations by which characteristic time of carbon particle rotation under electric field action was estimated were solved using a mathematical package Maple 13.The following figures show optical photos of the surface of composite materials GNPs/Larit 285 Figs.  and 2 anProcessed with AC electric field, composites became more transparent with increasing time of electric field action due to filler movement in the direction of power lines of an external electric field. It was also observed that with increasing time of electric field action, the aligned structures of carbon filler broaden and some clearances emerge between them. This may be due to Van der Waals interactions of carbon nanoparticles. In this manner, chains of nanocarbon filler of specified distribution are forming in composite.As seen in Fig. In case the of MWCNTs/Larit 285 composites treatment with AC electric field, a formation of elongation in the direction of the electric field chains was observed as well. Distinct chains become thicker when time of AC field exposure increases. But characteristic time of aligned chain formation in MWCNTs/epoxy composite is minutes while in GNPs/epoxy composite is seconds in embedded electrodes configuration. Moreover, due to GNP shape and size, aligned filler distribution in GNPs/epoxy composites can be formed at less magnitudes of AC electric field than in MWCNTs/epoxy composites. But on the other hand due to GNPs mobility because of its shape and size in comparison with MWCNTs, the formation of bulk composites with GNP filler is complicated. Aligned network of GNPs tends to destroy shortly after switching off the electric field if the composite has not polymerized completely.When considering all optical images of aligned network under AC electric field formation in GNPs/− and MWCNTs/epoxy composites, we can conclude that under equal conditions when changing only the type of carbon filler, the aligned network is formed faster in the GNPs/epoxy composite. In the case of MWCNTs, their tendency to agglomeration prevents effective alignment in the direction of the applied electric field. It should be noted that DC field is not effective for formation of aligned network in composite .To explain the observation by optical microscopy peculiarities of electric field-assisted alignment of the filler of different morphology, a characteristic time of carbon nanoparticle rotation in epoxy matrix under AC electric field action was theoretically estimated.I is the moment of inertia of carbon nanoparticle; Θ is the angle between the particle and the electric field direction; Tη is a damping torque; ε) and conductivity  of nanoparticle and matrix; v = f is the volume of carbon nanoparticle which depends on its weight (m) and dimensions .The mechanism of composite with a specified spatial distribution of filler formation method is that every carbon nanoparticle which is embedded in dielectric matrix undergoes polarization under AC electric field action due to the polarization of the interface between the polymer and the particle. Generally, polarizing moment and the electric field vector are noncollinear due to anisotropy of the nanoparticles. Therefore, when the electric field is activated, a torque which leads to carbon nanoparticle rotation in the direction of the field occurs. It is known that the rotational motion of a particle in this case is described by the following equation :1\documeν and is determined by the formula [ε0 is the permittivity of free space, εm is a dielectric constant of the matrix, β is a dimensionless parameter which, in particular, depends on the shape of inclusion. In [β for an ideal conductive disc and cylinder are given:Generally, polarizing moment  formula :\documension. In , formulaII means codirection of the long axis of the particle and of the field direction, ⊥—perpendicularity). Thus, for GNPs and MWCNTs, It follows from these dependencies that Θ(t = 0) = Θ0, εm , p , σm , p are dielectric constant and conductivity of the medium and particle, ω = 2πf, f—electric field frequency.To evaluate the characteristic time of carbon particle rotation under electric field action and its alignment by the direction of the field Eq.  with therding to , terms iTo determine the depolarization factor of carbon nanotube and graphite nanoplatelet, they must be considered as the particles of certain shape Fig. . MWCNT cing form .Fig. 5ScFor the ellipsoid:For the spheroid:Lx is a depolarization factor if the external field is applied along the x-axis =34.3, and for MWCNT, εp(CNT)=62.2 was taken.are given, in our calculations for GNP ε0=8.85 × 10−12 F/m, η = 0.75 Pa × s, f = 15 kHz, εm=2.8ε0 [σm=10−6 Sm/m [σp(CNT)=105 Sm/m [σp(GNP)=105 Sm/m [.Geometrical parameters of the particles were taken from Table m=2.8ε0 , σm=10−0−6 Sm/m . Conduct105 Sm/m , σp = π/2.05).Figure  by Eqs.  and 3)..Lx was  by Eqs. а and 36 min). For GNPmax and CNTmax, alignment time is almost equal, and equal time of alignment is for GNPaver and CNTmin.There has been a clear correlation between the aspect ratio of the particles and the time of alignment by the electric field. Namely, maximum time for alignment is for particles with the lowest aspect ratio  = π/2.05). For comparison, the results of calculations of the angle dependence for MWCNTs  = π/2.05).Figure x-axis of GNP, the rotation time increases significantly compared with the calculation in case of the field axis and GNP radius codirection. And this behavior is irrespective of the GNPs aspect ratio. Secondly, the course of the dependence is minimally different for the particles with different aspect ratios, and at a certain point of process time, more aligned particle is the particle with minimum aspect ratio GNPmin while GNPaver and GNPmax angles coincide. This behavior is due to the value of depolarizing factor which is close to 1 for the above cases.From the analysis presented in Fig. Thus, the estimation have shown that the rotation time of carbon particles under AC electric field action depends on their morphology and aspect ratio. Note that the model considers one particle embedded in polymer matrix while in composite, we have an ensemble of particles with different initial angles of inclination. That is one of the reasons why real characteristic time of the whole network formation may be very different from the estimated time.Besides, it is complicated to achieve such a distribution of MWCNTs in composite mixture where each individual tube is entangled. It is known that carbon nanotubes tend to tangle due to the interaction of their surfaces. Therefore, the real time of MWCNTs in composite mixture alignment is significantly higher than it was theoretically estimated. Besides, the viscosity of composite mixture with the same content of MWCNTs is higher than the viscosity of composite mixture with GNPs. All these factors prevent such a rapid alignment of MWCNTs in composite as it was estimated.Within the study, values of resistivity of the prepared GNPs/Larit 285 composites with aligned and with random filler distribution in epoxy matrix were experimentally found. Figure σ correspond to the samples of epoxy resin without filler (conductivity of 10−11 Sm/m). With GNPs adding to the composite, its conductivity increases and reaches the value of σ = 10−6 Sm/m  at GNPs content с in composite of φс = 2 wt% for the composites with random filler distribution. For the GNPs/Larit 285 composites with aligned filler distribution, percolation concentration is of φс = 0.84 wt%. Thus, materials of the identical composition are characterized by different values of percolation threshold depending on the method of preparation and filler distribution in the polymer matrix .The lowest values of the conductivity Conductivity of GNPs/Larit 285 composites smoothly increases with the increment of GNPs content for both types of the samples while the shape of the dependence is completely different for the MWCNTs/Larit 285 composites obtained by the same method  see Fig. ConcentStatistical percolation model operates with probabilities of particles in composite to create a conductive chain at their certain content. As it was shown in our paper, manufactured with electric field treatment, composites become conductive at lower content of carbon filler due to activation of dynamic percolation which is a phenomenon when conductive chain formation is stimulated by external influences at such a content of conductive particles in composite which is not enough for statistical percolation.It should be noted that the existence of two types of percolation transitions is a characteristic feature of composite materials which are in low-viscosity state during the manufacture . The higNanocarbon-polymer composite material with aligned distribution of graphite nanoparticles in epoxy matrix has been produced by exposing to a high-voltage AC electric field. The influence of electric field treatment time, strength, and configuration of electric field on formation of aligned GNPs network in liquid polymer medium was investigated by optical microscopy.σ = f(c) dependence and the critical concentration of both dynamic and statistical percolation thresholds.It was shown that the influence of AC electric field at composite fabrication process leads to the manifestation of two types of percolation transitions: statistical and dynamic ones. In addition, the aspect ratio of the filler particles and the character of the formation of the conducting cluster, depending on the shape of the particles, determine the shape of the The effects of the morphology of the filler particles on the process of nanocarbon alignment in polymer matrix under AC electric field have been investigated by estimating of carbon nanotube and graphite nanoplatelet rotation time using an analytical model based on effective medium approach. The theoretical evaluation of characteristic time of carbon nanoparticle of different morphology rotation under AC electric field action have shown that rotation time of carbon nanoparticle is determined by its depolarization factor which in turn depends directly on the aspect ratio of particle.ϕc = 2 wt% for composites with random filler distribution of GNPs to ϕc = 0.84 wt% for the obtained under AC electric field action GNPs/Larit 285 composites.The investigation of concentration dependences of conductivity of composites GNPs/Larit 285 with aligned by AC electric field action filler distribution and random filler distribution in epoxy matrix have shown that under AC electric field action composites, percolation threshold decreases essentially from


Preterm birth is a major perinatal health problem, but factors leading to it are still not completely understood.Our goal was to identify the relation between acute increase in ambient air pollution in a few hours before onset of labor and the risk of preterm birth.We collected registered birth outcome data and hourly ambient air pollution measurements during 2009‒2013 in Brisbane, Australia. Using a time-stratified case-crossover design and conditional logistic regression models with natural cubic splines, we assessed the shape of air pollution-preterm birth curve, after controlling for potential confounders. We also examined the effect modification of other factors.The association between air pollution  and preterm birth was nonlinear. Threshold concentrations for the mean of 0‒24 hr NO2, 24‒48 hr SO2, and 24‒48 hr CO before onset of labor were 7.6 parts per billion (ppb), 3.8 ppb, and 162.5 ppb, respectively. Increases in air pollution concentrations above thresholds were associated with increased risks of preterm birth. The odds ratios of preterm birth at the 95th percentile of NO2, SO2, and CO against the thresholds were 1.17 , 1.01 , and 1.18 , respectively. The associations were modified by demographic factors, such as maternal smoking and socioeconomic status.Acute increases in ambient air pollution concentrations above certain levels before onset of labor may stimulate preterm birth.Li S, Guo Y, Williams G. 2016. Acute impact of hourly ambient air pollution on preterm birth. Environ Health Perspect 124:1623–1629; http://dx.doi.org/10.1289/EHP200 Preterm birth is a major perinatal health problem associated with neonatal mortality and morbidity and can cause long-term adverse health consequences in life . It was The aim of the present study was to identify the relation between maternal exposures to ambient air pollutants a few hours before onset of labor and preterm birth in Brisbane, Australia, from 2009 through 2013. We hypothesized that a short-term increase in ambient air pollution closely before onset of labor contributes to the risk of preterm birth and that this effect would be modified by demographic factors such as maternal age, maternal existing medical conditions, number of previous pregnancies, smoking status, multiple birth, infant sex, and socioeconomic levels.We collected birth outcome data from the Queensland Health Perinatal Data Collection Unit for births during 1 January 2009‒31 December 2013 in the Brisbane metropolitan area, Australia. This registered database covers births from all public and private hospitals and voluntarily reported homebirths in Brisbane. Information used in this study includes birth status (live born or stillbirth), gestational age in weeks, date and time of birth, method of birth, length of labor, number of births, infant sex, maternal age, prepregnancy medical conditions, number of previous pregnancies, maternal smoking status, and an index of socioeconomic status (SES) linked to the living area during pregnancy. The definition of preterm birth is birth before a gestational age of 37 weeks . Thus, w10), particulate matter ≤ 2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), carbon monoxide (CO), ambient temperature, and relative humidity were obtained from the Queensland Government Department of Environment and Heritage Protection for five monitoring sites across Brisbane. PM2.5 and PM10 were measured by either a high- or low-volume air sampler or a tapered element oscillating microbalance (TEOM). NO2 was measured with chemiluminescence, which is a chemical reaction that emits energy in the form of light. SO2 was measured by a differential optical absorbance spectroscopy (DOAS) instrument. O3 concentrations were monitored through the principle of absorption of ultraviolet (UV) light. CO was measured by gas filter correlation.Hourly data on particulate matter ≤ 10 μm in diameter  for the periods of 0‒24 hr, 24‒48 hr, 48‒72 hr, 0‒48 hr, and 0‒72 hr preceding the time of labor onset were examined separately in single-pollutant models. To fully adjust for the potential time-variant confounders, we used natural cubic splines with 4 degrees of freedom (df) for the 0‒72 hr mean values of ambient temperature and relative humidity in all models.We used conditional logistic regression models to fit the time-stratified case-crossover design, which successfully controlled for time-invariant individual level confounders , because comparisons between case and control periods were made within individuals. Mean values of the air pollutants . For each air pollutant, model with the lowest AIC value indicated the best df and exposure time frame. In case of linear relationship between air pollution and preterm birth, we calculated the odds ratios (OR) and the 95% confidence intervals (CI) of preterm birth at 75th and 95th percentiles of air pollution against the median concentration of air pollution. Otherwise, in case of nonlinear relationship, we calculated the OR and 95% CI of preterm birth at 75th and 95th percentiles of air pollution against the minimum preterm birth concentration of air pollution (threshold).To determine the threshold of air pollutant, we first plotted the graph of the relationship between air pollutant and preterm birth, and then visually checked the possible range of the threshold. Afterward, we iteratively estimated the AIC values for conditional logistic regression models by 0.1-unit increments in air pollutant within the identified range of threshold from visual inspection using the segment spline model. The concentrations of air pollutants corresponding to the lowest AIC values were chosen as the thresholds (minimum preterm birth concentrations of air pollutants). This method has been widely used to test the threshold for nonlinear temperature effect on mortality .To evaluate the potential confounding effects of other air pollutants on the association between an air pollutant and preterm birth, we ran two-pollutant and multiple-pollutant models, and compared the OR and 95% CI of preterm birth associated with a pollutant from the single-pollutant model with those from the two-pollutant or multiple-pollutant model. To assess the possible modification effects of demographic factors on the air pollution–preterm birth association, we conducted stratification analyses for different groups: maternal age (< 35 years vs. ≥ 35 years), prepregnancy medical conditions (yes vs. no), number of previous pregnancies (0 vs. ≥ 1), maternal smoking status [smokers (self-reported any smoking during pregnancy) vs. nonsmokers (self-reported no smoking during pregnancy)], number of births (single birth vs. multiple births), infant sex (girls vs. boys), and SES index [1‒5 (indicating low level) vs. 6‒10 (indicating high level)]. The statistical significance of difference between effect estimates for the above subgroups , was examined byQˆ1 and Qˆ2 are the effect estimates for the two categories , and SÊ1 and SÊ2 are their respective standard errors (where d errors . PlannedWe added temperature variability (standard deviation of 0‒72 hr temperatures) to the models, to check whether the effects of air pollutants on preterm birth would be changed or not, because studies have reported that large temperature change increased risk of health events . We used2.5, PM10, NO2, SO2, O3, CO, ambient temperature, and relative humidity were 6.32 μg/m3, 17.27 μg/m3, 6.52 ppb, 1.95 ppb, 17.27 ppb, 219.30 ppb, 21.97°C, and 70.82%, respectively. The summary statistics for daily air pollution and meteorological factors are similar to the hourly data (see Table S1). Hourly values of air pollutants and weather conditions were positively correlated with each other (see Table S2).2, SO2, and CO—that is, the threshold effect (a minimum preterm birth concentration of the air pollutant) was indicated. There were no statistically significant relationships among PM2.5, PM10, and O3 and preterm births in single-pollutant models. Natural cubic splines with 3 df for the mean values of 0‒24 hr NO2, 24‒48 hr SO2, and 24‒48 hr CO preceding the time of labor onset, respectively, produced the best model fits for each air pollutant. Thus, we chose these three air pollutants with certain exposure time frames to estimate the risk of preterm birth at the 75th and 95th percentiles of pollutant against the threshold in all following analyses.Our preliminary analyses  showed that the associations between air pollutants and preterm birth were generally U-shaped for NO2, 3.8 ppb for the mean of antepartum 24‒48 hr SO2, and 162.5 ppb for the mean of antepartum 24‒48 hr CO, respectively. 2, SO2, and CO above thresholds shortly before onset of labor were positively associated with increased risks of preterm birth. ORs for preterm birth at the 75th percentile of NO2, SO2, and CO against the thresholds were 1.01 , 1.04 , and 1.10 , respectively; ORs for preterm birth at the 95th percentile of NO2, SO2, and CO against the thresholds were 1.17 , 1.01 , and 1.18 , respectively .The effects of air pollutants on preterm birth did not change when we put temperature variability to the models . When we used 0‒12 hr average concentrations of air pollutants, the model fit was not improved.2, SO2, and CO on preterm birth. Increased risks of preterm birth were associated with increases in the mean concentrations of NO2, SO2 and CO above thresholds in 24 or 48 hr before birth. The effect of each pollutant appeared independent of the others. We did not discover effect modification with maternal age or maternal health history. The associations of air pollutants with preterm birth risk were stronger among smokers and women from areas with relatively lower SES, and the risks associated with NO2 and CO were slightly greater among previously pregnant women, multiple births, and female babies.In this study, we found the threshold effect (concentration of the air pollutant corresponding to minimum preterm birth) of NO3 for PM2.5. A Spanish study  and OR = 1.26 , respectively. This indicates that PM and O3 might not have short-term effects on preterm birth, but have long-term (cumulative) effects  air pollution exposure and the risk of preterm birth. The time-stratified case-crossover design ensured unbiased conditional logistic regression estimates and avoided time trend bias of the exposure . We ran Our study does have several limitations. First, we assigned mean pollutant concentrations of the specific hours preceding onset of labor to each preterm birth, ignoring pregnant women’s time spent indoors and outdoors. This may lead to exposure measurement error for the true exposure. However, we deducted the labor length when defining the time of labor onset to minimize this error. Moreover, this exposure measurement error can only underestimate the risk of preterm birth associated with increases in ambient air pollution concentrations . Second,2, SO2, and CO above the threshold levels in 24 or 48 hr immediately before onset of labor stimulated preterm birth. This study provides the latest evidence that reducing air pollution to a certain level or lower could greatly benefit perinatal health, and that the influence may be quickly effective. Some maternal demographic characteristics such as smoking and socioeconomic levels may modify the air pollution effects. We have proposed some biologic mechanisms underlying these associations.In conclusion, we found that sudden increases in the mean concentrations of ambient NO(431 KB) PDFClick here for additional data file.


The study uses geographic information science (GIS) and statistics to find out if there are statistical differences between full term and preterm births to non-Hispanic white, non-Hispanic Black, and Hispanic mothers in their exposure to air pollution and access to environmental amenities  in the second largest city in New England, Worcester, Massachusetts. Proximity to a Toxic Release Inventory site has a statistically significant effect on preterm birth regardless of race. The air-pollution hazard score from the Risk Screening Environmental Indicators Model is also a statistically significant factor when preterm births are categorized into three groups based on the degree of prematurity. Proximity to green space and to a healthy food vendor did not have an effect on preterm births. The study also used cluster analysis and found statistically significant spatial clusters of high preterm birth volume for non-Hispanic white, non-Hispanic Black, and Hispanic mothers. Preterm birth (PTB) shortens in utero fetal development and has been linked to numerous adverse health outcomes including learning disabilities, respiratory problems, visual issues hearing loss, as well as immediate hospitalization following birth and others Biologic associations and risk factors for PTB are well documented, and many studies have been performed to test correlations between social and environmental stressors potentially leading to PTB mechanisms, but the exact etiology of PTB is unknown. Biology of stress theories have led scientists to focus on the social determinants that contribute to the incidence of PTB. These can be divided into the two categories: socioeconomic status and environmental exposure. Mothers living in poverty can experience a number of related socio-environmental stressors that may increase the risk of delivering babies preterm or at LBW Environmental stressors, such as air pollution, landfills, and industrial polluting sites, have been linked to PTB and LBW as well. A literature review found that living in proximity to the aforementioned areas confers an increased risk of adverse health outcomes in general It is possible that some of the effects of pollution exposure will be mitigated by proximity and access to green space. For instance, an increase in birth weight was associated with an increase in distance to major highways and increase in percent open space Most studies on adverse birth outcomes that use GIS technology are usually limited to mapping maternal addresses and calculating their distances to polluting facilities or major roads. Studies that use methods of spatial cluster analysis and mapping to explore the spatial distribution and pattern of adverse birth outcomes are still limited Multiple studies have concluded that environmental factors are important contributors to birth outcomes, along with social and host factors 2.2.1.Worcester's population of 182,669 makes it the second-largest city in New England after Boston As a former manufacturing base Worcester is home to a number of brownfields, or abandoned but desirable building sites with unknown levels of pollutants that are part of the EPA's National Priorities List Worcester is also home to dense “triple-decker” housing, living units built during the industrial era that typically house a family on each floor 2.2.Birth data for residents of the city of Worcester delivered between 4/1/2006 and 3/31/2011 were provided by UMASS Memorial Health Care  after approval by the Institutional Review Board of its academic partner, the University of Massachusetts Medical School and the Institutional Review Board of Clark University. UMASS Memorial Health Care delivers on average about 50 percent of all births in Worcester County .The data included mother's residential address and race/ethnicity, baby's birth date, gender, estimated gestational age (EGA) in weeks, birth weight, singleton or multiple birth, and if it was a live birth. We used the address database from the GIS Office of Worcester to geocode and map birth data. This database consists of about 48,000 points corresponding to individual buildings and allows identifying each birth's location with a high degree of spatial accuracy. The geocoding success rate was 99.8% (only 16 addresses of 7377 were unmatched). We selected only singleton births (7217 records), and from them further selected only live births (7136 records). We then separated singleton live births into two groups for each race/ethnicity—full term (≥ 37 weeks EGA) and preterm (<37 weeks EGA). There were 613 PTB total see . It shouTo examine PTB in more details we divided them into three groups based on the degree of prematurity: late preterm ; early preterm , and extremely preterm . The thresholds for the groups were selected based on what has been reported in the literature To explore socio-economic context of PTB we used Environmental Justice map obtained from MassGIS All environmental variables were obtained from public sources. We downloaded relevant data not only for the City of Worcester, but also for the surrounding areas within 5 km of the City. This allowed accounting for nearest points of interest  that are outside the city border to be included in the calculations of distances .Distance to nearest major roads for each birth was calculated using Massachusetts Department of Transportation roads data available from MassGIS http://www.referenceusa.com/), a commercial database of all businesses in the country, to which we had access as patrons of Worcester public library. We selected the following vendor types based on the North American Industry Classification System (NAICS) codes: supermarkets and other grocery stores, except convenience stores (code 445110), fruit and vegetable market (code 445230), department stores except discount stores (code 45211101) and warehouse clubs and supermarkets (code 45291001). These categories include large chain supermarket such as Stop and Shop, Shaw's, Price Chopper, smaller non-chain ethnic supermarkets, such as Compare Foods, small markets that exclusively sell fruits and vegetables, and department and warehouse stores, such as Wal-Mart Supercenter, Sam's Club, and BJ's Club. There were a total of 59 vendors in Worcester and the surrounding towns; their addresses were geocoded using the Worcester address database.To find vendors of healthy foods we used Reference USA . We downloaded data for 2005-2010 and linked each birth to the corresponding year of the TRI release. For babies born before April 15 of each year we used TRI data from the previous year to account for the exposure during the first half of the pregnancy. The number of TRI facilities that reported HAP releases ranged between 64 and 96 for the six years we examined.The main source of air pollution data are regional monitoring stations that provide continuous measurements over 24-hour periods on a variety of air pollutants, most commonly including Ozone, Carbon Monoxide, Sulfur Dioxide, Nitric Oxide, Nitrogen Dioxide, Total Reactive Oxides of Nitrogen, Lead, Particulate Matter or PM10 , and Fine Particles or PM2.5 . Unfortunately, stations are often located far from each other, so their data is most suitable for a regional level assessment rather than individual-level exposure. For example, there are only three air-monitoring stations in Worcester, MA making the data unsuitable for individual-level exposure analyses. An alternative approach to modeling air pollution exposure is to use emissions data from polluting facilities. For example, the Environmental Protection Agency (EPA) collects data for the Toxic Release Inventory (TRI) every year from more than 20,000 U.S. industrial facilities We used two approaches to model maternal exposure to these pollutants. First, we calculated straight-line distance to the nearest TRI facility for each birth using spatial join in GIS. The second approach used a modeled hazard score and was based on the amount of release and its toxicity. The data for the second approach came from the EPA's Risk-Screening Environmental Indicators (RSEI) Model 2.3.As the first step, to visually represent the spatial distribution of PTB we created kernel density maps for each race separately. This technique shows general patterns of distribution while masking the exact location of the points and thus preserving confidentiality of the data. We used Spatial Analyst in ArcGIS 10.1 with a quadratic kernel function 2.3.1.While most research on birth outcomes uses birth data aggregated to census block group, tract, city block, town, zip code or county, some researchers used mother's residence address and geocoding tools to create maps depicting locations of births. These studies then used point locations on the map as inputs for distance and buffer operations in GIS to calculate exposure to air pollution from traffic To answer these questions we used two spatial clustering methods—Nearest Neighbor Hierarchical (NNH) Clustering and Risk-Adjusted Nearest Neighbor Hierarchical (RNNH) Clustering in CrimeStat software The NNH technique uses two criteria for grouping points into clusters—the threshold distance and the minimum number of points per cluster. The threshold distance is related to the probability level for selecting any two points as a pair by chance. The smaller the threshold distance, the lower is the probability of identifying a cluster by chance  and the choice of kernel bandwidth (fixed distance or adaptive). We used a normal density function (most commonly used setting) and an adaptive bandwidth with a minimum of 25 points.Monte-Carlo simulation was used to test statistical significance of clusters produced by each NNH and RNHH run. This simulation assigns the same number of observations to random locations within a rectangular area of the same size as the study area (38.44 sq. miles for Worcester), and evaluates the number of clusters according to the parameters previously set by the researcher. The simulation is repeated multiple times, and for each simulation, the number of clusters generated from a random distribution is compared to the number of observed clusters.2.3.2.To analyze associations with environmental factors we first ran a t-test to compare the means for the two groups (PTB and full-term) for all races together for the following variables: distance to major roads, distance to vendors of healthy foods, distance to the nearest green space, distance to the nearest TRI facility, and modeled hazard score for RSEI. Then we repeated the analysis for each race separately. We used Welch's t-test because of unequal variances within the samples. We also used ANOVA to compare the means of these variables for three PTB groups based on the degree of prematurity. All tests were done in SPSS software (version 20.0) and statistical significance of the tests was assessed at p = 0.05.3.3.1.There were 136 PTB to non-Hispanic Black mothers, and NNH clustering produced two spatial clusters of high volume of PTB: one cluster with 12 and the other with 9 PTBs. There were 265 preterm births to non-Hispanic white mothers, 37 of them formed 4 spatial NNH clusters, containing between 8 and 11 births each . All of There were 212 PTB to Hispanics mothers, and 71 of those formed 9 spatial clusters, with 7 to 13 PTB each . As with3.2.A closer examination of the preterm births stratified into three groups by EGA reveals  that the4.We found statistically significant clusters of high PTB volume for all three racial/ethnic groups. They represent high concentrations of incidents that did not happen due to a random chance. All of these clusters were located in areas designated as environmental justice areas, meaning that people who live in these locations are more vulnerable to potential exposure to harmful effects of environmental pollution. When overlaid on top of the PTB density maps –4 these When risk-adjusted NNH routine was applied to the data, only one cluster of high PTB risk among non-Hispanic Black women was found, with all PTBs located at one particular address. Further exploration of our data in GIS revealed that this cluster is located in close proximity to the top air polluter in Worcester (largest number of pounds of HAP released each year between 2006 and 2010). This facility, KT Acquisition LLC, specializes in iron and steel forging and emits chromium compounds, cobalt compounds, lead and nickel compounds. According to the EPA, “exposure to chromium (VI) may result in complications during pregnancy and childbirth Our results are consistent with the findings of previous studies that industrial air pollution exposure has an effect on PTB. We modeled exposure to air pollution using two different measures—proximity of the polluting facility and its modeled hazard score. The first measure was significant when all PTB were compared to full term births. This indicates that proximity to TRI sites has an effect on PTB outcome regardless of race. When PTB were analyzed by maternal race, the second measure proved significant for non-Hispanic Black PTB as compared to full term non-Hispanic Black births. The hazard score was also a statistically significant factor when PTB were split into three groups based on the degree of prematurity: the hazard score was much higher for the extremely preterm group, both when PTB were considered all together  and when split by race (for Hispanic and non-Hispanic white mothers only).A major strength of this study was the use of the novel air pollution data set from RSEI. A majority of the birth outcomes studies use government monitoring station data to assess exposure. However, dense networks of air pollution monitors exist only in large urban centers, and medium-size cities like Worcester do not have enough stations to be useful in spatial analysis. RSEI data provides several advantages. First, it combines source-specific data on release amount, stacks height and exit gas velocities and uses a fate-and-transport model to estimate ambient concentrations around each facility. Second, RSEI weighs chemicals by their toxicity thus improving the measure of the potential health effect due to air pollution. Additional studies utilizing source-specific information on pollutants, such as RSEI, could provide further evidence on pollutants impact on pregnancy outcomes and may help inform public health policy decisions.Another study strength is that exposure to air pollution and access to environmental amenities were estimated at the individual level. Very few studies examine the relationship between birth outcomes and “positive” elements of the environment, and our study attempted to address this gap in the literature. However, we found no association between proximity to major roads, proximity to healthy food vendors, and proximity to green space and PTB. Our findings illustrate that even sophisticated distance calculation methods (street network-based vs. a straight line) have difficulty explaining the variation of birth outcomes because other important individual-level factors are not included in the analysis.The unavailability of individual maternal data on behavior , health issues , socio-demographic factors , psychological factors  and neighborhood conditions is the major limitation of our study. All of these factors play an important role in pregnancy outcomes, including PTB, but they were not available to us.A second limitation is that the birth data we used accounts for about a half of all births in the city, thus leading to a potential selection bias, smaller sample size and small clusters of outcomes. Our findings could have been different if we had access to data on all births in the city. There are several reasons why we chose to use birth data from the UMass Memorial Health Care (UMMHC). Of relevance, the impetus to this study was a noted public health trend of significant disparities in infant mortality rates to black and Hispanic residents of the city in which UMMHC is located . This notable difference was especially prominent regarding mortality at peri-viable gestations and thus prompted our focus on preterm birth. UMMHC is a tertiary care referral center for the region and thus we were confident that these high risk gestations and early deliveries would be captured utilizing our health system data. This study focused on piloting and refining spatial clustering methods prompted by this public health issue and hence we used readily available records that we knew would capture the deliveries of greatest interest. Future studies would seek to validate these methods in larger datasets and would require access to birth certificate data for the entire city.A third limitation is related to the fact that we based our assessment on self-reported maternal addresses; we assumed that the mothers lived at the reported birth address during the entire pregnancy and that their air pollution exposure was constant. Their exposure to pollution could have been different at earlier stages of pregnancy if they moved to this address soon before the birth. In the study conducted by Brauer et al. An additional limitation is related to the uncertainty associated with the modeled hazard score, due to the subjective nature of the parameters in the kernel density technique. While we acknowledge that the resulting raster density surface may look somewhat different if the input parameters were modified, we are confident that the surface we used represents the general spatial pattern of the hazards score accurately.Despite the limitations discussed above, we believe that our study provides useful results and makes a unique contribution to the existing body of literature. It is the first study to apply two hierarchical nearest neighbor clustering techniques in the context of birth outcomes. Our findings illustrate the usefulness of these two techniques and their complimentary nature. When used in concert they allow the identification of two characteristics of spatial distribution—the high volume and high-risk areas of PTB. We hope that in the future these approaches are used more in public health studies in general, and in birth outcome studies in particular. Furthermore, our study is methodologically unique because it used RSEI to estimate the potential hazard from exposure to industrial air pollution. RSEI is a complex and rich model that has been peer-reviewed GIS and spatial statistics are useful tools for studying birth outcomes. The study's result indicated that there are statistically significant spatial clusters of preterm births in Worcester for non-Hispanic Black, non-Hispanic white and Hispanic mothers. These clusters were located in areas with low income and/or a high percent of linguistically isolated population. Preterm births are located closer to polluting facilities and have higher hazard score than full term births. However, there was no evidence of associations between PTB and proximity to the nearest major road, to parks and to vendors of healthy foods. Information about traffic density and individual maternal nutritional and exercise habits would be necessary to make these associations more meaningful.


To compare the cyto- and chemokine profiles in the aqueous humor of PEXS eyes in the absence or presence of secondary glaucoma with or without luxation of the intraocular lens (IOL).n = 33), those with a late form of PEX-syndrome and glaucoma , and those with a late form of PEX-syndrome with luxation of the IOL that required surgery . The samples were analyzed in parallel after storage at -80°C. The levels of 40 cytokines were simultaneously quantified using the Bio-Plex® multiplex beads system. The inter-group data were statistically compared using the Kruskal-Wallis test (p ≤ 0.01).Samples of aqueous humor were collected intraoperatively from 20 healthy controls and from 73 eyes with PEX-syndrome, which was manifested in the absence of any other local or systemic desease. The latter group was sub-devided into eyes with an early form of PEX-syndrome in the absence of complications . This latter finding is indicative of a non-specific inflammatory reaction in the context of IOL-luxation. The concentrations of 6 cytokines lay below the detection limit in all groups.PEX and PEXG were comparable in their cytokine profiles for all 40 cytokines, whereas the cytokine profile in PEXL-eyes revealed higher levels of all but 5 cytokines (CXCL13, CCL27, IL-2, CCL3, CCL20; The local up-regulation of 85% of the detectable cytokines in the aqueous humor of PEXL-eyes may be linked either with a progression of the disease or a breakdown of the antero-posterior barrier in the context of IOL-luxation. Pseudoexfoliation syndrome (PEXS) is a clinically late-manifesting generalized fibrillopathy, which is characterized by a pathological accumulation of abnormal extracellular material in intra- and extraocular tissues. Although many factors are known to influence the development of the PEX-syndrome the exact aetiology of the disease remains elusive . ChangesAge, race and gender, as well as free radicals and oxidative damage, contribute to the development of the PEX-syndrome ,6.The deposition of PEX-material along the inner surfaces of the anterior segment is associated with progressive atrophy of the iris, weakness of the zonular fibres and an increase in the outflow resistance of the trabecular meshwork. In the long term, these changes almost inevitably lead to luxations of the natural or an implanted lens, a rise in intraocular pressure and the development of secondary glaucoma .Clinically, PEX-syndrome usually begins unilaterally. In 24–52% of the cases, the fellow eye is also implicated at a later stage . In the 10. Pathophysiologically, an elevation of the intraocular pressure appears to be the result of a local production and deposition of PEX-material by cells of the trabecular meshwork and by those of Schlemm's canal resulting in degenerative changes in Schlemm's canal and in the juxtacanalicular tissues [Secondary glaucoma does not necessarily develop in association with the PEX-syndrome. However, in 25% of all cases of glaucoma, PEXS is manifested tissues ,7. Furth tissues .Pro-inflammatory cytokines have been implicated in the onset and the progression of various fibrotic disorders and in the pathophysiology of glaucoma, as well as of PEXS –15. HoweIn the present study, wecompared the concentrations of 40 cyto- and chemokines in the aqueous humor in eyes in which an early form of the PEX-syndrome was manifested in the absence of complications (PEX), of those with a late form of PEX-syndrome and glaucoma (PEXG), and of those with a late form of PEX-syndrome, glaucoma and luxation of the intraocular lens (IOL) that required surgery (PEXL). The purpose of this analysis was to ascertain whether the progression of the PEX-syndrome is associated with changes in the intraocular cytokine environment.This prospective study of a case-series of patients with PEX, PEXG and PEXL was approved by the local Institutional Ethics Board of the University of Bern, Switzerland (registration number: 152/08). It was undertaken with the informed written consent of each of the participants and was fully compliant with the tenets of the Declaration of Helsinki.A total of 73 eyes with PEX-syndrome in as many patients, who were otherwise healthy, were enrolled. Twenty healthy eyes that were undergoing phacoemulsification surgery served as controls. The patients in the control group were not suffering from or being treated for any other systematic disease.Individuals with a history of any intraocular disorder other than PEX-syndrome, including diabetes with or without diabetic retinopathy, and those who had undergone uncomplicated phacoemulsification up to 6 months prior to the time of enrollment, were excluded from the analysis.Samples of aqueous humor were collected at the onset of phacoemulsification surgery. They were maintained at ambient temperature for up to 6 hours prior to storage at -20°C for maximally 3 months and thereafter (January 2014 to January 2016) at -80°C until the time of the analysis at the Berner Augenklinik am Lindenhof, Bern, Switzerland.The cytokine analyses were performed using the Bio-Plex® multiplex beads system . With this system, it is possible to quantify in parallel the concentration of numerous cytokines and chemokines in a single sample with small volume. In the present study, the levels of 40 pro- and anti-inflammatory chemo- and cytokines were quantified in each sample of aqueous humor. To this end, fluorescently-labelled magnetic microspheres were coupled to specific capture antibodies and mixed with the samples in which the cytokine concentrations were unknown. Biotinylated detection antibodies and streptavidin R-phycoerythrin were introduced into the mixture, which was then analyzed by flow cytometry. Two lasers identified the microsphere type and quantified the amount of the bound antigen. The readings were compared with the values on a standard curve, which represented the average of triplicate standard dilutions of the corresponding cytokines that were run on the same plates. All measurements were performed in a blinded manner by a laboratory technician who was experienced in executing the technique.Numerical data are presented as mean values ± standard deviation (SD). The concentrations of several of the cytokines in some of the samples lay below the curve fit of the standards. To avoid the bias that would have been introduced by excluding these data, the concentrations of the implicated cytokines were set at half of the lower cut off of the test system, which was usually about 1 pg/ml. Outliers at the other end of the spectrum (higher than the mean ± 2 SD) were identified via boxplots and were excluded from the statistical analysis.p ≤ 0.01. Total Protein Concentration, IgG and Albumin measurements were statistically evaluated using Student’s t-test, with the level for statistical significance being set at p < 0.05. Correlations between cytokine concentrations and patient`s age and IOP were calculated using Spearman`s correlation test. The statistical analysis was performed using SPSS .The Shapiro-Wilk test was implemented to ascertain whether the data were or were not normally distributed. Since the criteria for a normal distribution were not fulfilled, the non-parametric Kruskal-Wallis test was used for the inter-group comparisons, with the level for statistical significance being set at Three groups of PEX patients were composed of individuals of comparable age and gender at the time of inclusion . The heaRegarding the correlation of age and IOP cytokines, no consistent or systematic correlations were identified. Nevertheless, we observed positive correlations for four cytokines  in the healthy group and for three cytokines  in the early PEX group. In the PEXG-group we found an association of seven cytokines with age , whereas no significant correlation for any of the 40 cytokines for the PEXL group were detected  in the samples of aqueous humor are displayed numerically in The concentration profiles of the 40 cytokines were quantitatively distinct in each of the four groups . The levels were notably higher in the PEXL-group than in the other categories .p ≤ 0.01 in each category; p ≤ 0.01 in each category; CXCL5, IL-10 and CCL2 were detected in each of the three groups of eyes with PEX-syndrome . Hence, these cytokines seem to play no role in healthy and in PEX eyes.p≤0.01; p≤0.01; Compared to the controls, CCL25 was down-regulated in PEX-, PEXG- and PEXL-groups p≤0.01;  Tables. p≤0.01, each; Compared to the controls, the levels of CXCL13, CCL24, IL-16, IL-4, CCL13, CCL22, CCL15 and CXCL16 were higher in late PEX and late PEX with IOL-luxation, but not in early PEX when compared to healthy controls  over green (low levels) reveals that the aqueous humor cytokine concentrations in the PEXL group were higher than in the other groups .Total protein and albumin concentrations in the aqueous humor of all 4 groups were similar, whereas the IgG levels were increased in the PEXL group  in the AH have been demonstrated . Our own3. Previously PEX has been linked solely to TGF-beta 1 [The aqueous humor levels of CXCL13, CCL24, IL-16, IL-4, CCL13, CCL22, CCL15 and CXCL16 were higher in the PEXG—and the PEXL-groups than in the control and the early PEX eyes. All of these cytokines share in common chemoattractant properties and, with the exception of IL-4, they are pro-inflammatory. Since IL-4 can induce CCL2 (MCP-1) it contributes indirectly to inflammatory processes , 23, 24,F-beta 1 , later aF-beta 1 . RecentlF-beta 1 . Takai eF-beta 1 , whereasWe are obviously still far from pinpointing the impact of single factors on the environmental changes that occur in the anterior segment of eyes with PEX-syndrome ,12. SincS1 Tablep-values for each cytokine and for each group are calculated by Spearman’s correlation test. * p<0.05, ** p<0.01.The correlation coefficient (ρ) and (DOCX)Click here for additional data file.S2 TableP values for each cytokine and for each group are calculated by Spearman’s correlation test. * p<0.05, ** p<0.01.The correlation coefficient (ρ) and (DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10−8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose  and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci ( S1The basic characteristics of study participants in the EGG Consortium discovery, EGG follow-up and UK Biobank GWAS analyses are presented in P < 5 × 10−8  were identified in UK Biobank data only, and the index SNPs were unavailable in the EGG Consortium data. Consideration of results for proxy SNPs at these three loci from the EGG meta-analysis is in the next section. For the index SNPs at the other seven loci, we observed no strong evidence of heterogeneity in allelic effects between the EGG Consortium and UK Biobank components of the meta-analysis (r2 < 0.95), but the index SNP in SH2B3, rs3184504, is a non-synonymous coding variant (R262W). Approximate conditional analysis  showed no evidence of secondary signals at any locus at P < 5 × 10−8. In combination, the 10 loci explained 1.4% [standard error (SE) = 1.2%] of variance in birth weight, whereas the variance in birth weight captured by all autosomal genotyped variants on the UK Biobank array was considerably greater: 11.1% (SE = 0.6%).We identified 10 autosomal loci that were associated with offspring birth weight at 5 × 10−8 . The lin5 × 10−8  from theanalysis . The majKCNAB1, EBF1 and CYP3A7 resulted from analysis of UK Biobank data only, and index SNPs were unavailable in the EGG Consortium meta-analysis (imputed to HapMap Phase 2). To investigate further the evidence for association at these loci, we identified proxy SNPs (r2 = 1) for KCNAB1 (rs9872556) and EBF1 (rs2964484) that were available in HapMap Phase 2 (no proxy SNP was available at r2 > 0.5 at the CYP3A7 locus). Meta-analysis of the EGG Consortium and UK Biobank data showed weaker evidence of association overall, with some evidence of heterogeneity between the EGG meta-analysis and UK Biobank  and KCNAB1 , mapped >2 Mb away from, and were statistically independent of any index SNPs previously associated with birth weight at P < 5x10−8 in a fetal GWAS (r2 < 0.05) , and the directions of association were consistent, suggesting that they were tagging the same causal variant. At the L3MBTL3 locus, the maternal and fetal directions of association were consistent, but the index SNPs were weakly correlated (r2 = 0.13), and conditional analyses in UK Biobank suggested weakening of the association when the L3MBTL3 SNP identified in the fetal GWAS was accounted for  to allow comparison of data across studies. We excluded multiple births, stillbirths, congenital anomalies (where known) and births before 37 weeks of gestation (where known). We assessed the association between each SNP and offspring birth weight using linear regression of the birth weight z-score against maternal genotype (additive genetic model), with sex and gestational duration as covariables . Ancestry principal components were included as covariables where necessary in the individual studies. Genome-wide association analyses were conducted using PLINK  to a ng PLINK , SNPTESTng PLINK , Mach2qtng PLINK  or Beaglng PLINK  . Data annotation, exchange and storage were facilitated by the SIMBioMS platform  < 0.01 and poorly imputed SNPs  were excluded. To adjust for inflation in test statistics generated in each cohort, genomic control  was applplatform . Qualityplatform . We obtaP-value threshold of P < 1 × 10−5 for follow-up in additional, independent studies. Of these, one SNP (rs11020124) was in LD  with SNP rs10830963 at the MTNR1B locus known to be associated with fasting glucose and Type 2 diabetes (P < 5 × 10−8) of association with other phenotypes, and therefore higher prior odds of association with birth weight: rs2971669 near GCK (r2 = 0.73 with rs4607517 associated with fasting glucose) (LMO1 (r2 = 0.90 with rs110419 associated with neuroblastoma) (RAD51AP1 (r2 = 0.27 with rs2970818 associated with serum phosphorus concentration) (We selected 15 SNPs that surpassed a diabetes . We assulastoma)  and rs79n = 18 319 individuals), 9 studies (n = 15 288) provided custom genotyping of between 4 and 18 SNPs, whereas 4 studies  had in silico genome-wide or exome-wide SNP genotypes available. Where SNPs were imputed, we included only those with quality scores (r2hat or proper_info) >0.8. We excluded directly genotyped SNPs showing evidence of deviation from Hardy–Weinberg Equilibrium at P < 0.0028 (Bonferroni corrected for 18 tests). Where genotypes were unavailable for the index SNP, we used r2 > 0.8 proxies  were excluded from the analysis along with those reporting offspring birth weights of <2.5 or > 4.5 kg (n = 5479). ‘British descent’ was defined as individuals who both self-identified as white British and were confirmed as ancestrally Caucasian using principal components analyses . A total of 1976 of the women were asked to repeat the questionnaire at a follow-up assessment and therefore had two reports of birth weight of first child. Those with values differing by ≥1 lb (0.45 kg) were excluded (n = 280). This resulted in n = 48 632 women with both genotype data and a valid offspring birth weight value, which was z-score transformed for analysis (P < 1 × 10−6), MAF < 0.01 or overall missing rate > 0.015, resulting in 17 352 SNPs for analysis in PLINK v.1.07, with the first 5 ancestry principal components as covariates.UK Biobank data were available for 502 655 participants, of whom 273 463 were women , and of analysis  to accouanalysis . We addiIn both the full UK Biobank sample and our refined sample, birth weight of first child was associated with mother’s smoking status, maternal BMI and maternal height in the expected directions  using METAL  using a sample of 10 000 individuals selected at random from the UK Biobank to approximate patterns of LD between variants in these regions.At each of the identified loci, we looked for the presence of multiple distinct association signals in the region 1 Mb up- and down-stream from the lead SNP through approximate conditional analysis. Conditional and joint analysis in the analysis program, genome-wide complex trait analysis  was applr2 > 0.8) reported from GTEx v4, GEUVADIS, and 11 other studies using Haploreg v4.1 .To search for candidate genes at the four loci not already covered by the previous fetal GWAS of birth weight , we idenBecause of the small number of cohorts with both maternal and offspring genotype data available to conduct conditional analysis, we developed a novel method using SEM to estimate the conditional maternal and fetal genetic effects on birth weight, which we subsequently applied to the maternal and offspring birth weight data in the UK Biobank. SEM is a flexible multivariable statistical approach that allows investigators to model the covariance between an observed set of variables  as a function of several latent unobserved variables . The full details of the SEM method for estimating the conditional fetal and maternal effects are described elsewhere . BrieflyP-value for the fetal and maternal paths was calculated using a Wald test. We fitted a second SEM without the child and maternal path to conduct a 2 degree of freedom test for the effect of the SNP on birth weight.To fit the SEM, we used OpenMx  in R ve with thez-scores for analysis.Genotype data from the UK Biobank May 2015 release was used for analysis. We included 57 711 participants who reported their own birth weight and 45 436 women who reported the birth weight of their first child, giving a total of 78 674 unique individuals in the analysis (24 473 women had both their own and their offspring’s birth weight). Individuals who were not of ‘British descent’ (as defined earlier), or were related to others in the sample, or who were part of multiple births, were excluded. The birth weight of offspring phenotype was prepared as described earlier, whereas own birth weight was prepared as described previously , becausez-score and maternal genotype conditional on fetal genotype and vice versa . We combined the results from the individual studies using inverse variance meta-analysis with fixed effects. We performed a further meta-analysis to combine the overall estimates with those from the SEM using UK Biobank data.We analysed up to 8705 mother–child pairs from 4 studies with both maternal and fetal genotypes available . We used linear regression to test the association between birth weight KCNAB1, EBF1 and CYP3A7 were unavailable, we used proxies . Because GWAS summary statistics for blood pressure were not publicly available, we used the UK Biobank May 2015 genetic data release and tested associations between the SNPs and systolic and diastolic blood pressure (SBP and DBP) in 127 968 and 127 776 British descent participants, respectively. Two blood pressure readings were taken approximately 5 min apart using an automated Omron blood pressure monitor. Two valid measurements were available for most participants, and the average was taken. Individuals were excluded if the two readings differed by more than 4.56 SD , and blood pressure measurements more than 4.56 SD away from the mean were excluded. We accounted for blood pressure medication use by adding 15 mmHg to the SBP measure and 10 mmHg to the DBP measure in those reporting regular use of any antihypertensive. Blood pressure was adjusted for age, sex and centre location and then inverse normalized before analysis.We looked up associations between the 10 identified loci and various anthropometric and cardiometabolic traits in available GWAS result sets. The traits and sources are presented in http://www.ebi.ac.uk/gwas/home, last accessed 2 August 2017) for associations P < 5 × 10−8 between any additional traits or diseases and SNPs within 500 kb of, and in LD with, the index SNP at each locus.We additionally queried the NHGRI-EBI catalog of published GWAS  was corrected for confounding factors such as gene size, SNP density and LD-related properties in a regression model. Genes within the HLA-region were excluded. Genes were then ranked by their adjusted gene scores. The observed number of gene scores in a given pathway with a ranked score above a given threshold (95th and 75th percentiles) was calculated and this statistic was compared with 1 000 000 randomly permuted pathways of the same size. This generated an empirical P value for each pathway, and we considered pathways reaching FDR < 0.05 to be of interest. The 3230 biological pathways tested were from the BIOCARTA, Gene Ontology, Ingenuity, KEGG, PANTHER and REACTOME databases, with a small number of additional custom pathway.We used MAGENTA to test for pathway-based associations using summary statistics from the overall meta-analysis . The sofHMG online. Summary statistics from the meta-analysis are available at http://egg-consortium.org/.Supplementary InformationClick here for additional data file.Supplementary TablesClick here for additional data file.


Lumbar facet cysts are frequently found in patients with facet degeneration and segmental instability. When the facet cyst is localized in the neural foramina and lateral recess or becomes large, it can cause radiculopathy or neurogenic claudication. These symptomatic cysts are typically treated interventionally with drainage and a corticosteroid injection or attempts via overinflation to rupture the cyst; however, these procedures have a significant recurrence rate (up to 50%) and often need to be repeated or lead to lumbar surgery if unsuccessful.  This is the first report of using targeted radiofrequency (RF) current as an adjunct to cyst drainage. Although RF has been used for years to treat facet pain indirectly by targeting the medial facet nerve branches, with this technique, under image guidance, the actual cyst is percutaneously drained and then cauterized along with the associated facet capsule, where the original cyst developed. This has improved overall results with less cyst recurrence than previous percutaneous methods and was documented with both intermediate and long-term followup clinically and with magnetic resonance imaging (MRI) scans. This report reviews the underlying anatomy and pathology of the facet joint relating to the development of facet cysts and how current percutaneous treatments for lumbar facet cysts can be supplemented and improved by adding targeted RF ablation to the percutaneous options available to treat a lumbar facet cyst. The lumbar facet joints are true synovial joints with hyaline cartilage and a highly innervated fibrous capsule. The joints have the capacity to hold 1.0-1.5 mL of fluid . ChronicRadiofrequency (RF) rhizotomy has been used in and around the facet joint for pain control by targeting the external branches of the recurrent sensory nerve innervating the facet joint. There are recent reports of using RF heat safely within the epidural space to reduce ligamentous spinal stenosis . This isWe performed a retrospective chart review of all patients identified with facet cysts on MRI scans within a 36-month period and reviewed their treatments. Patients were evaluated with a combination of imaging techniques, mainly MRIs in conjunction with computerized tomography (CT) scans and flexion/extension radiographs. Radiologic studies determined if the cyst was an isolated finding or part of more extensive lumbar degenerative spondylosis including segmental instability or stenosis.Combined with physical examination, it was possible to determine if the identified cyst was the main cause of symptoms of low back pain and especially radicular pain or neurogenic claudication. There were a total of 37 patients identified who had lumbar facet cysts on radiologic studies. The decision to treat the cyst either with drainage alone or combined with RF ablation of the cyst, facet joint, and capsule, or open surgery was based on the location and size of the cyst, concurrent lumbar degenerative disease and stenosis, and comorbidities. Associated medical comorbidities such as age, obesity, diabetes, pulmonary and cardiac restrictions, and the use of anticoagulants were all factors in considering the more minimal RF approach versus lumbar surgery. Twenty-four patients had either small facet cysts or cysts associated with more severe stenosis or spondylolisthesis and were not treated with drainage and RF ablation. A subgroup of 13 patients within the total group had either facet cysts or dorsal epidural cysts that were treated with cyst drainage combined with RF ablation of the cyst, facet joint, and capsule.The procedure is performed at an outpatient surgical center under local anesthetic with intra-operative fluoroscopy and minimal sedation as needed. Preoperative antibiotics including either one gram of cephalexin or 600 mg clindamycin is administered intravenously before the procedure. The patient is then placed prone on the procedure table. The skin is sterily cleansed and draped. Lidocaine 1% is used for skin anesthesia. A 20 gauge spinal needle is placed in the intrathecal space to perform a spinal tap, either above or below the targeted level, and a myelogram using 4 to 8 cc of water soluble contrast is performed as the first step of the procedure. The contrast provides precise localization by outlining the cyst corresponding to that seen on the MRI scan. This step allows real-time delineation of the target for RF lesioning  was 6.8/10. Post-procedure average VAS at one month was 2/10 and at six months 1.5/10. One patient with a L5-S1 foraminal facet cyst had a repeat procedure within six weeks after a followup MRI demonstrated the same cyst; however, after the second treatment when the facet joint capsule was added to the RF targets, the patient lost the radicular leg pain. No patient developed a recurrent cyst or had later open surgery.There were six patients who had dorsal cysts with or without interspinous fluid clefts on MRI. Distinct hyperintense T2 signal fluid clefts between the spinous processes were seen on 50% of the MRI scans. The average age was 71.5 and there were five males and only one female. The cysts were located at L4-5 in five of six cases, and two patients had cysts at two levels, both L3-4 and L4-5. There was associated degenerative spondylolisthesis at L4-5 in four cases and there was associated canal stenosis at one or more levels in five of six. One early case had repeat RF because of decreased but persistent symptoms, and the facet capsule and joint were included in the second procedure with further reduction in leg pain. None of the patients with dorsal cysts required open surgery.Followup: The followup period for the patients undergoing drainage plus RF ranged from a minimum of six months to 36 months. Two patients (15%) had repeat procedures but none required open surgery for cyst removal. VAS scores for patients with facet cysts averaged 6.8/10 before the procedure to 1.5/10 at the six-month followup. VAS scores for dorsal cysts averaged 6/10 before and 1.2/10 at the six-month followup. Five patients had a VAS of 0 and a return to full activity. MRI scans were obtained in followup at least one time in nine cases.In summary, of the total group of 37 patients identified with symptomatic lumbar facet cysts, 10 patients had surgery, including cyst resection as their primary procedure. Fourteen patients underwent only cyst drainage and in five (or 36%) cases the cyst recurred. Of the recurrent cysts, three (or 21%) of the total drainage-only group underwent later surgery. Of the 13 patients that had cyst drainage plus RF ablation of the cyst, facet joint, and capsule, only two (or 15%) had repeat procedures but without any later cyst recurrence after the second procedure. In both patients who needed a second RF procedure, the facet capsule and joint space were not originally targeted with RF. No patient in the RF group, including the two patients who had repeat procedures, underwent later lumbar surgery. A 79-year-old female with a history of low-grade lumbar pain for three years subsequently developed, over a period of eight months, increasingly severe and constant left leg pain. This was aggravated by extension and left lateral bending, and it was associated with intermittent left leg numbness. There was no relief with a combination of anti-inflammatory medications and physical therapy. An MRI scan showed a left L5-S1 foraminal cyst. She underwent percutaneous drainage and RF ablation of the cyst and left L5-S1 facet capsule. Pre-procedure VAS was 8/10. Post-procedure she had complete relief of her leg pain and return of full spinal motion. In followup after 18 months, she has continued pain-free with VAS score of 0/10 with a full range of motion Figure .Repetitive stress/trauma results in osteoarthritis that causes inflammation and joint fluid . This chInterventional approaches include intra-articular steroid injections with or without cyst aspiration, medial branch blocks, and epidural blocks with or without attempting to rupture the cyst . SurgeriIn the past, RF facet rhizotomy has been used mainly for pain control without direct targeting of the facet capsule or the facet cyst. In RF rhizotomy, the target is the recurrent medial branch of the sensory nerve innervating the facet capsule. Radiofrequency was used at multiple levels to treat both axial lumbar pain secondary to degenerated facets and referred pain secondary to segmental degeneration, but this does nothing to address the cyst itself or facet joint membrane and capsule .This report describes the use of direct cyst drainage combined with radiofrequency ablation of the facet cyst, the facet capsule, and facet joint. This additional step addresses the original cause of the cyst: the synovial lining of the abnormal facet joint. This approach immediately reduces the cyst and prevents re-accumulation of cyst fluid over a period of time, well beyond the common recurrences within six to 12 months. Clinical response and long-term followup with sequential MRI scans demonstrate the lasting effect of this approach clinically and radiographically over 36 months Figure .The key underlying pathologic cause of either foraminal or dorsal lumbar facet cysts is the reaction of the facet joint synovial membrane producing inflammatory fluid with accumulation in the joint  and ultimately cyst development. It was apparent after two of the early cases needed to be repeated that it was important to treat the cyst, the synovium of the facet capsule, and the facet joint to reduce the chance of recurrence. The approach to the cyst and the synovium with RF has not been addressed before this report. Recent studies have shown that RF current can safely be used intra-spinally, around the lumbar nerve roots, and within the contiguous vertebrae as long as the patient can undergo motor and sensory testing , 25. In The safety and position of the electrode for RF facet ablation is intraoperatively testable with the patients under local anesthesia. This allows for appropriate patient feedback to avoid any injury to nerve roots as the RF lesion is made. Procedures that only drain or rupture symptomatic synovial cysts have a high recurrence rate, since the synovium is capable of regenerating or re-accumulating fluid within any residual facet cyst. Cysts treated with drainage and RF ablation in the proper locations should have a much lower recurrence rate. Symptomatic lumbar synovial cysts are often effectively treated interventionally with drainage and a corticosteroid injection or overinflation to rupture the cyst; however, this often fails. Cyst drainage and rupture have a significant recurrence rate close to 50% and often need to be repeated. If unsuccessful, the patient usually has open surgery with cyst resection or decompression with or without segmental stabilization. Pathologic studies demonstrate that the underlying cause of cyst formation and the likely reason for frequent recurrence is progressive facet degeneration. This degeneration leads to reactive fluid formation from the synovium of the facet joint and later associated facet joint hypertrophy secondary to segmental instability. Combining cyst drainage with cauterizing the facet cyst and joint capsule with RF ablation directly targets one of the primary causes of cyst formation. Use of targeted RF current directly into the cyst as well as the connected facet capsule and joint space is safe with proper intra-procedural testing. In our series of 13 patients, none have had further surgery for removal of the cyst. Serial followup MRI scans in patients have demonstrated lasting reduction in cyst size when comparing them to pre-treatment scans. The average followup was 15 months and the longest followup was 36 months. Clinically, there was a persistent loss of radicular complaints and claudication. There was a marked reduction in post-procedure VAS scores at six months' (or greater) followup. This study demonstrates that combining cyst drainage/rupture with the use of RF current for cauterization/ablation of the facet cyst, its wall, and synovial joint capsule serves as an additional step that can reduce the frequency of cyst recurrence.