Every consecutive brain injured adult patient, who required a brain CT and TCS monitoring were included. The V3 diameter was blindly measured by TCS and CT. Intraclass correlation coefficient (ICC) and Bland–Altman plot were used to assess the reliability and agreement between TCS and CT V3 measurements. Diagnosis performance of the V3 diameter using TCS to detect hydrocephalus was measured. Absolute difference between V3 measurement by residents and experts was measured consecutively to assess the learning curve.Transcranial sonography is a point-of-care tool recommended in intensive care units (ICU) to monitor brain injured patients. Objectives of the study was to assess feasibility and reliability of the third ventricle (V3) diameter measurement using transcranial sonography (TCS) compared to brain computed-tomography (CT), the gold standard measurement, and to measure the TCS learning curve. DesignAmong the 100 patients included in the study, V3 diameter could be assessed in 87 patients (87%) from at least one side of the skull. Both temporal windows were available in 70 patients (70%). The ICC between V3 diameter measured by TCS and CT was 0.90 [95% CI 0.84–0.93] on the right side, and 0.92 [0.88–0.95] on the left side. In Bland–Altman analysis, mean difference, standard deviation, 95% limits of agreement were 0.36, 1.52, − 2.7 to 3.3 mm, respectively, on the right side; 0.25, 1.47, − 2.7 to 3.1 mm, respectively, on the left side. Among the 35 patients with hydrocephalus, V3 diameters could be measured by TCS in 31 patients (89%) from at least one side. Hydrocephalus was, respectively, excluded, confirmed, or inconclusive using TCS in 35 (40%), 25 (29%) and 27 (31%) of the 87 assessable patients. After 5 measurements, every resident reached a satisfactory measurement compared to the expert operator.TCS allows rapid, simple and reliable V3 diameter measurement compared with the gold standard in neuro-ICU patients. Aside from sparing irradiating procedures and transfers to the radiology department, it may especially increase close patient monitoring to detect clinically occult hydrocephalus earlier. Further studies are needed to measure the potential clinical benefit of this method.Trial registration: ClinicalTrials.gov ID: NCT02830269.The online version contains supplementary material available at 10.1186/s13613-021-00857-x. Transcranial sonography (TCS) is an important point-of-care diagnostic tool , 2 recomObstructive hydrocephalus can occur in subarachnoid haemorrhage patient and in patient with external ventricular drain. V3 study can detect this pathological issue. A retrospective study reported a good correlation between TCS and CT in 15 patients with traumatic brain injury for the measurement of V3 diameter . FeasibiThe study protocol was approved by the Ethics committee of “Comité de Protection des Personnes Sud-Méditerranée I” , ClinicalTrials.gov ID: NCT02830269. Because the trial used non-invasive procedures along with standard care provided in French ICUs . AdditioThe study took place in the 16-bed neuro-ICU of the tertiary University Hospital of Montpellier Gui de Chauliac, France. All consecutive neuro-ICU patients ≥ 18 years old, admitted to the neuro-ICU with a brain injury, were eligible for enrolment if they underwent a brain CT planned by the bedside physicians, as well as TCS monitoring. Exclusion criteria were: a sonographic assessment of the third ventricle impossible to perform within one hour around a brain CT, or consent disclaimed.2), age, gender, type of brain injury, Glasgow Coma Scale, Simplified Acute Physiology Score 2 (SAPS2) ) mm from the right side, and 6.3 (IQR [4.6–9.6]) mm from the left side. V3 diameters measured by TCS were 5.8 (IQR [4.6–8.4]) mm for the right side, and 5.8 (IQR 4.4–8.6]) mm for the left side.The ICC between TCS and CT were 0.90 (95% CI 0.84 to 0.93) for the right side and 0.92 (CI 0.88 to 0.95) for the left side   patients among the 35 patients with hydrocephalus diagnosed using the CT. The median V3 diameter measured by TCS was significantly greater in the hydrocephalus group (8.8 (IQR 6.8 to 11.7) mm) compared to the non-hydrocephalus group (5.0 (IQR 3.8 to 6.1) mm, The V3 measurement from the right side was included for these analyses because right side was the most frequently assessable side. The left side was included when V3 was not assessable from right side.Figure Feasibility was good, with 87 (87%) of patients amenable to TCS measurements, and the reliability was high compared to the gold standard (brain CT). TCS was effective to exclude or confirm hydrocephalus in two-thirds of patients at bedside. Moreover, the learning curve is steep, with only 5 procedures necessary to acquire a satisfactory skill.. described similar V3 diameters than us in patients with a mean age of 56 years after a decompressive craniectomy [Our findings are consistent with the existing literature concerning non-ICU patients. Regarding the feasibility of TCS to identify the V3, Bogdahn et al.  describeniectomy .n = 15).V3 diameter measurement by TCS compared to CT, is consistent with the findings of the recent retrospective study by Oliveira et al.  that shoTCS has a pivotal role in the ICU: it is a non-invasive, reproducible and bedside available tool, with a low cost. In patients with an adequate acoustic window , it allows for a non-irradiating assessment of the brain parenchyma and cerebral blood flow  without The V3 diameter was measurable in 87 (87%) of our patients and, compared to the CT, was conclusive in 60/87 patients (69%) for a V3 diameter < 5.2 or > 7.7 mm for diagnosing hydrocephalus Fig. . TherefoTCS could be helpful to monitor EVD management and weaning at the bedside, or to detect clinically occult hydrocephalus. EVD management impacts the ICU and hospital lengths of stay in patients with aneurysmal subarachnoid haemorrhage . In 2016Every anaesthesiologist-intensivist resident with previous TCS Doppler experience but without V3 sonography experience could reach satisfactory skill after only five measurements. Four residents out of 9 made a substantial error on the third measurement. Therefore, even if the second measure is close to that of the expert operator, five measurements seem necessary to reach satisfactory skill. Measuring the V3 diameter by TCS appears to be an easy skill to learn. This tool could become widespread over ICUs after a short training by expert TCS operators. If the relevance of V3 monitoring is confirmed, it could be implemented as a first line strategy and interest centres where brain CT is not quickly available.Strengths of this study are that it is the first prospective study, in a large population of neuro-ICU patients with diverse brain illnesses, which compared TCS and CT on V3 measurements, each investigator blinded to one other, with standardised measurements for both TCS and CT. Furthermore, the study had a high inclusion rate of consecutively admitted patients within a short period of time (8 months). This suggests the feasibility of TCS in routine.Our study has several limitations. First, we were unable to measure V3 diameter with TCS in 13 patients (13%) because of the impossibility to recognise the V3 using echography. The risk of failure using echography in critically ill patients is one of the main issues related to this technique, as also describe for other indications such as cardiac (1% of failure ) or pneuIn conclusion, TCS is a feasible, simple, reliable and non-invasive tool for measuring V3 diameters in neuro-ICU patients at the bedside and is associated with a short learning curve. Monitoring V3 diameters by TCS could be a point-of-care tool to facilitate the early diagnosis of hydrocephalus. The role of TCS for the measurement of the V3 diameter in the management and weaning of EVD requires further studies.Additional file1: Table S1: Patient characteristics, Table S2: CT and TCS findings for the 100 patients included for analysis, Figure S1: Study design, Figure S2: Study flow chart, Figure S3: Right and left sides V3 diameters measured by TCS compared with CT, Figure S4: Comparison of V3 diameters measured by TCS, according to the hydrocephalus status, Figure S5: V3 diameters measured by TCS compared with the other side


MYO7A, USH1C, CDH23, PCDH15, and USH1G (SANS) for Usher type 1; USH2A, ADGRV1, and WHRN for Usher type 2; CLRN1 for Usher type 3. USH is inherited in an autosomal recessive pattern. Digenic, bi-allelic, and polygenic forms have also been reported, in addition to dominant or nonsyndromic forms of genetic mutations. This narrative review reports the causative forms, diagnosis, prognosis, epidemiology, rehabilitation, research, and new treatments of USH.Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are also observed in some cases. The syndrome was first described by Albrecht von Graefe in 1858, but later named by Charles Usher, who presented a large number of cases with hearing loss and retinopathy in 1914. USH has been grouped into three main clinical types: 1, 2, and 3, which are caused by mutations in different genes and are further divided into different subtypes. To date, nine causative genes have been identified and confirmed as responsible for the syndrome when mutated:  Human communication is, to a large extent, based on our “far senses”: hearing and vision . The useMYO7A, USH1C, CDH23, PCDH15, and SANS for Usher type 1; USH2A, ADGRV1, and WHRN for Usher type 2; CLRN1 for Usher type 3.Usher syndrome (USH) is the most common deaf–blind syndrome, with 50% of deaf-blindness in persons younger than 65 years of age. It is a genetic condition that includes hearing loss, retinopathy (retinitis pigmentosa), and vestibular areflexia with different entities and onset ,3,4. It CIB2 (USH1J) is no longer considered responsible for Usher syndrome and was recently excluded from Usher genes by Booth et al., 2018 (https://www.usher-syndrome.org/ accessed on 21 December 2021) [er 2021) .ESPN (USH1M), HARS (USH3), CEP78 , CEP250 , ABDH12 (USH3), and ARSG , and three loci, namely, USH1E, USH1H, and USH1K. In addition, PDZD7, a modifier gene, is considered responsible for Usher type 2 when associated with mutations in other Usher genes, such as USH2A, ADGRV1, and WHRN. Nonsyndromic recessive and dominant hearing loss without retinopathy caused by USH genes has also been reported [Other genes and loci have been related to the disease; however, their roles are not clear and must be confirmed in further studies: reported .CIB2 is also being questioned by Booth et al., 2018 [USH is the most common cause of syndromic hearing loss after Pendred syndrome ,11,12 anl., 2018 , even thFor the purpose of this review, it is important to consider that the syndrome is divided into three clinical subtypes , identified by clinical investigation, and that different subtypes correspond to different responsible genes, identified by genetic investigation. However, genetic investigations are essential to confirm or reject the clinical diagnosis. The introduction of next-generation sequencing has improved the identification of new genes and mutations ,18. NeveUSH can be considered a ciliopathy ,21 becauThe terminology might be quite confusing because the structures of inner ear cells have been called stereocilia (sing. stereocilium) and kinocilia (sing. kinocilium) . HistoloUSH belongs to a group of ciliopathies affecting nonmotile or sensory cilia, which include Bardet–Biedl syndrome, Alström syndrome, Meckel syndrome, Joubert syndrome, and Leber congenital amaurosis (primary nonmotile ciliopathies). Despite sharing overlapping features, these syndromes are very different, and it is rare for the same gene to be involved in two different conditions. This suggests a strong specific causative relationship between the genotype and phenotype.Even if both microtubules and actin filaments are involved in different ciliopathies, USH seems to interfere exclusively with sensory cells that express actin filaments in specific segments ,32,33,34Despite symptoms following the distribution and expression of different proteins in different organs, the variability in expression of similar dysfunctions can be remarkable, even among siblings . PenetraThe scope of this narrative review is to provide an overview of the current clinical and genetic knowledge concerning the epidemiology, diagnosis, prognosis, rehabilitation, and treatment of USH. It intends to provide clinical features and genetical understanding, helpful to several specialists, to sustain a multidisciplinary approach and successful management of the syndrome. It is targeted to professionals, researchers, and students with interest in the field of otology, audiology, and genetics. Reported variants should be intended as examples and they do not refer to the prevalence of the variants. Unless otherwise specified in the text, they were selected from the literature for teaching purposes and to clarify what is eventually reported in the text. Figures and tables should be also intended as explicative, simplified, and helpful for readers in understanding the genetics, clinical aspects, and pathophysiology of USH. Genotype/phenotype correlations have been described following the most common accepted criteria available in the literature; however, exceptions are possible and partially reported in the text, even if they do not necessarily reflect the direct experience of the authors. Finally, the authors herein provide available solutions for the most effective rehabilitative approach in the management of USH following national guidelines, personal experience, and scientific literature; however, rehabilitation may be influenced by local laws, national guidelines, and health institutions with different approaches to the management of the syndrome. To the best of our knowledge, an international consensus statement on diagnosis, treatment, rehabilitation, and follow-up of USH has not been published to date.A literature search was carried out in medical databases, such as “PubMed.” The keywords “Usher”, “syndromic hearing loss”, “blindness”, “retinitis pigmentosa”, “retinal dystrophy”, “ciliopathies”, and “deafness” were used, and 450 English articles from 1988 to 2021 were selected and analyzed. It is important to emphasize that this report is not a systematic literature review. The text has been formatted based on the following main categories: genetics, epidemiology, diagnosis, rehabilitation, treatment, and some future perspectives. Of the 450 articles, 128 full texts, best suited to our purposes, were selected and included in this review.Even if kinocilium may present a motile structure (9 + 2), it is considered a nonmotile cilium, lacking inner dynein arms . DegenerIn the eye, mutations in Usher genes are responsible for affecting light-sensing rods and cones, thus leading to the degeneration of the retina with pigment deposits, a condition named retinitis pigmentosa (RP). In RP, the retina’s light-sensing rods and cones slowly lose their properties and functions, starting at the outer edges.Compromised photoreceptors, retinal pigment epithelium cells, and Müller cells are thought to be the cellular basis underlying the pathogenesis of RP ,44,45.Usher proteins are widely expressed in the retina and particularly in the connecting cilium, periciliary membrane, calyceal process, inner and outer segment, basal body, and synapse. Mutations are responsible for progressive degeneration and loss of functions of those structures. In particular, the rods are first involved in the process, thus leading to difficulties in seeing in darkness. Degeneration of cones often starts at the outer edges, causing a “tunnel view”, and subsequent degeneration causes loss of central vision .ABHD12, ADGRV1, ARSG, CDH23, CEP250, CEP78, CIB2, CLRN1, DFNB31, ESPN, HARS, MYO7A, PCDH15, USH1C, USH1G, and USH2A. In addition, one modifier gene (PDZD7) was identified in 2015. Three new loci, USH1E [https://sph.uth.edu/retnet/sum-dis.htm#Agenes accessed on: 21 December 2021). Thus, genetic heterogeneity of this syndrome and some of the genes can also be found in nonsyndromic hearing and nonsyndromic RP forms. The large heterogeneity and rarity of USH often results in late or incorrect diagnosis in subjects with a mild phenotype [To date, USH has been associated with 16 genes : ABHD12,i, USH1E , USH1H [i, USH1E ,33, and i, USH1E , have beMYO7A, USH1C, CDH23, PCDH15, and SANS for Usher type 1; USH2A, ADGRV1, and WHRN for Usher type 2; CLRN1 for Usher type 3.To date, nine of the aforementioned genes have been identified and confirmed as causative genes: MYO7A alleles associated with differing phenotypes, (2) alleles responsible across different genes, or (3) phenotypic heterogeneity due to variable degrees of penetrance and expressivity. However, penetrance in USH type 1 and 2 is considered almost complete (99–100%).Genetic heterogeneity can also arise from (1) various mutations in the same gene in different individuals, such as USH1C, USH1G/SANS, PCDH15, CDH23, and MYO7A) and Usher protein complex 2 . These complexes are involved in tip links, lateral links, top connectors, and ankle links  seem to be involved in hearing loss when mutated, while only MYO7A has been associated with USH. Structural proteins play important roles in the functions and movements of actin cilia. In the inner ear motor, some Usher proteins are hypothesized to be part of an Usher protein network constituted by USH1C, USH1G, CDH23, and MYO7A, which mediate mechano-transduction in cochlear hair cells, vestibular hair cells, and photoreceptors (primarily the rods). Furthermore, mutated MYO7A causes USH1B, the most common form of USH1. Mutations in this gene can also be found in rare cases of nonsyndromic hearing loss (DFNA11 and DFNB2). Myosins are mechano-chemical proteins characterized by the presence of domains that interact with other proteins, with structural properties that allow ciliary movements in actin filaments.This gene is one of the most common and is frequently involved in Usher syndrome. It belongs to a superfamily of motor genes that encodes large proteins, the so-called myosins. They are known to play a role in many motile functions in mammals. Different myosins have different functions in many organs and they may interact with actin filaments to provide specific and specialized functions in hearing and vision. Some myosins .Lastly, l myosin ,49,50,51no acids . InteresReported pathological variants are p.R150X (USH 1B), p.Q234X (USH 1B), p.R212H (USH1B), p.R212C (USH1B), C168X (USH1B), p.G214R (USH1B), p.A397D (USH1B), p.R244P (DFNB2), p.M599I (DFNB2), p.R395H (DFNB2), C31X (USH1B), C628X (USH1B), and 9-BP DEL exon 22 (DFNA11) ,54,55. IMYO7A mutations among Usher patients are responsible for congenital severe-to-profound hearing loss, equilibrium disorders, and early onset of RP. Exceptions are reported where the most of pathological variants are usually responsible for profound congenital hearing loss with the absence of vestibular function. RP is also severe and rapidly progressive, with early onset [As widely reported in the literature, ly onset ,57. Bilaly onset ,59,60. Ily onset .This gene encodes a structural protein called protocadherin and is a member of the cadherin superfamily. Protocadherin belongs to the family of integral membrane proteins that mediate calcium-dependent cell–cell adhesion. It plays an essential role in the maintenance of normal retinal and cochlear functions. It is a crucial part of the tip link structure (tip link complex) and interacts with cadherin-23 to form tip links that are extracellular filaments that connect stereovilli in the inner ear. The tip link complex is located in the apical part of the hair cells. Mutated proteins cause defective tip links and affect the functions of the stereocilia, particularly the mechanoelectrical transduction . FurtherPCDH15 encodes for 33 exons and 1995 amino acids. R245X is considered a founder mutation responsible for approximatively 50–60% of USH1 in the Ashkenazi Jewish population [pulation . Other rpulation , c.del14pulation , p.K808Xpulation , p.R134Qpulation , and S64PCDH15 mutations were associated with poor CI performances and should be screened through next-generation sequencing for prognostic purposes to explore cochlear implantation outcomes [Chen ci Wu, in 2015, reported that children with outcomes .PCDH15 is widely expressed in the brain and nerves, and it is thought that mutations in PCDH15 also involve the neural partition of the cochlea. In 2021, Nisenbaum et al. included PCDH15 mutations among children that had no successful outcome post CI. This would be a strong recommendation for genomic screening among CI candidates with USH before surgery [PCDH15 mutations. surgery . These pThis gene encodes harmonin, an anchoring scaffold protein that is also hypothesized to be a part of the Usher protein network. The gene was identified in the short arm of chromosome 11 ,69,70. MLocalized on the long arm of chromosome 17, this gene is responsible for the transcription and encoding of a small protein named USH type-1G protein. The encoded protein is an anchoring/scaffolding protein that interacts with harmonin and is also a part of the Usher protein network in hair cells. The gene is found in the USH1G subtype ,73,74.CDH23 is located in 10q21–q22, a region containing the human deafness loci DFNB12 and USH1D. CDH23 contains 69 exons and encodes for 3354 amino acids. CDH23 is required for proper organization development of stereocilia in the cochlea and vestibule. It is also part of the Usher protein network, USH1D, which is the second most common genetic type of USH1.This gene is a member of the cadherin superfamily, whose genes encode calcium-dependent cell–cell adhesion glycoproteins. These are transmembrane proteins that are thought to be involved in stereocilia organization and hair bundle formation. It is involved in tip links, top connectors, and lateral links, and when mutated, is responsible for USH1. The gene Pathological variants responsible for USH1D are p.Q1496H, p.R1746Q, p.E1006K, p.E2520K, c.2289 + 1G > A, and p.Q492X .The following variants are responsible for DFNB12: p.D1243N, p.D1400N, p.D2148N, p.D1341N, p.V586M, p.R301Q, and p.P240L. Cochlear implantation has provided successful outcomes worldwide.This gene is located on chromosome 15q25.1 and encodes a calcium-binding regulatory protein. These proteins are involved in intracellular calcium homeostasis. It is also involved in the maintenance of photoreceptor and hair cells. Mutations in this gene are responsible for DFNB48 and USH1J. It was previously reported to be responsible for USH1H but was subsequently identified as a different gene and therefore named USH1J, with the gene in the locus USH1H still unknown. The protein localizes to the stereocilia of inner ear hair cells and photoreceptors and is postulated to be a component of the Usher protein network ,75. Its This gene encodes a multifunctional actin-bundling protein called espin. It plays a major role in regulating the organization, dimensions, dynamics, and signaling capacities of actin filament-rich microvilli in mechanosensory and chemosensory cells. It is required for the assembly and stabilization of stereocilia in parallel actin bundles. Mutations in this gene are associated with autosomal recessive sensorineural deafness (DFNB36) with or without vestibular involvement and USH1M ,76. HoweThree new loci were identified in different families, after mutations in known genes for USH were excluded. They were named USH1 E, H, and K, and cryptogenic studies have revealed that these three loci map to chromosomes 21, 15, and 10, respectively . To dateUSH2A, which is localized to the long arm of chromosome 1. It is a structural protein expressed in the basement membranes of the cochlea and retina. Usherin potentially plays an important role in the homeostasis of eye and ear functions. It is also thought to be a part of other genes in the Usher protein network. Furthermore, Usherin is necessary for the function and organization of the periciliary membrane complex in photoreceptors by regulating intracellular protein transport. The USH2 protein network consists of USH2A, GPR98 (ADGRV1), WHRN, and PDZD7 [USH2A are usually responsible for moderate-to-severe hearing loss and because of the absence of progression, bilateral hearing aids are usually beneficial. USH2A mutations are the most frequent worldwide. Reported variants are p.Cys934Trp, p.(Thr65Ilefs*80), p.R34X, p.R63X, p.W3955X, and p.R4608X [Usherin is a protein encoded by nd PDZD7 . The prop.R4608X ,79,80,81p.R4608X .ADGRV1, also known as GPR98 or VLGR1, encodes a calcium-binding G protein-coupled receptor. The encoded protein contains a 7-transmembrane receptor domain, binds calcium, and is widely expressed in the central nervous system, eye, and ear. It has an essential role in the development of hearing and vision. The protein is required for the formation of the ankle link complex in the hair cells (The gene ir cells . In addiWHRN) is a protein-coding gene. Diseases associated with WHRN include deafness, autosomal recessive hearing loss (DFNB31), and USH2D [WHRN is important for the maintenance of a periciliary membrane complex that seems to play a role in regulating intracellular protein transport in photoreceptors [EPS8 encodes an epidermal growth factor protein that is also reported to be responsible for DFNB102 and syndromic hearing loss  [This gene is thought to function in the organization and stabilization of stereocilia (stereovilli) elongation and actin cystoskeletal assembly. Mutations in this gene have been associated with autosomal recessive nonsyndromic deafness and USH. Whirlin  ,45,85,86This gene encodes a ciliary protein homologous to proteins that are mutated in patients with USH, and mutations and translocations involving this gene have been proposed to be associated with USH2A and DFNB57 . It is cCLRN1 mutations have also been reported in a potential digenic deafness associated with MYO7A [This gene encodes a protein (clarin) that may be important in the development and homeostasis of the inner ear and retina. It is thought to play a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina. It acts as a modulator of transduction activity. The gene was found to be connected to the USH3A subtype ,96,97,98th MYO7A ,101,102.th MYO7A .HARS is located on chromosome 5q31 and encodes an aminoacyl-tRNA synthetase. Mutations in this gene have been hypothesized to be linked to USH3B and Charcot–Marie–Tooth Disease . The protein encoded by this gene is a cytoplasmic enzyme that belongs to the class II family of aminoacyl-tRNA synthetases. The enzyme is localized in the cytoplasm, and it is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins [proteins .HARS mutations. In 2012, Puffenberger et al. reported partial restoration with hearing aids or cochlear implant [Few data are available in the literature on cochlear implantation outcomes among patients with  implant . Its rolABHD12 gene encodes an enzyme that is involved in the hydrolysis of 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. It was originally localized in Norwegian families, and in 2012, a homozygous ABHD12 mutation was identified and reported in a Lebanese family with USH3-like findings and cataracts [This gene is located on the short arm of chromosome 20 and is an acronym for polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract due to an inborn error in endocannabinoid metabolism. The ataracts . Its rolCEP250 gene (chr. 20q) encodes a core centrosomal protein required for centriole–centriole cohesion, thus playing an important role during the interphase of the cell cycle.New forms of a potential “atypical USH,” with mild sensorineural hearing loss and different retinal degeneration, have recently been found in some families. Centrosomal proteins are proteins that are localized in the centrosome or centriolar satellites. Centrosomes and centriolar satellites seem to play important roles in the cellular cycle and are responsible for the correct matching of chromosomes during mitosis and meiosis. However, they are also involved in the maintenance of regular function and organization of primary or motile cilia, which are located in the basal body of cilia and microtubules. These proteins may be considered structural proteins and their role can explain their involvement in several ciliopathies ,106, affCEP250 mutations include cone–rod dystrophy, hearing loss 2, and USH. Its possible role in USH is not yet fully understood [Diseases associated with derstood .This gene encodes a centrosomal protein of 78 kDa that is required for the regulation of centrosome-related events during the cell cycle and is required for ciliogenesis. Naturally occurring mutations in this gene cause defects in primary cilia that result in retinal degeneration and sensorineural hearing loss. This can be associated with photoreceptor degeneration hearing loss and may be a new form of USH ,109,110.ARSG encodes the protein arylsulfatase G, which hydrolyzes sulfate esters from sulfated steroids, carbohydrates, proteoglycans, and glycolipids. They are involved in hormone biosynthesis, modulation of cell signaling, and degradation of macromolecules. This protein is localized in the lysosomes. In 2018, Khateb et al. reported mutations in this gene in a family with “atypical” Usher [l” Usher . Subsequl” Usher ,113,114.USH2A gene accounting for 80–90% of cases [USH1B and USH1D) and Louisiana, USA (USH1C), where USH1 is more common than USH2. Furthermore, isolated communities and cultural causes often result in deaf-by-deaf marriages [USH is a rare condition in the general population. However, it should be considered a common condition for professionals, geneticists, ophthalmologists, otolaryngologists, and audiologists, since mutations in genes responsible for Usher are the most common cause of ciliopathies and deaf-blindness. The prevalence rate is not well described globally, and large variations in prevalence have been reported, probably due to a lack of diagnostic and rehabilitation resources. Nevertheless, the prevalence has been estimated with greater accuracy in Great Britain, Sweden, Norway, Finland, Denmark, Italy, the Netherlands, Australia, and the United States. In Asia and Africa, only a few reports have been published, but the prevalence in most countries and ethnic groups has been estimated. Considering these discrepancies, the global estimation is 1/30,000 inhabitants, which should be considered as a low average because several studies have reported a wide range of prevalence that varies from 1 to 17 per 100,000 inhabitants . A Swediof cases . In USH1arriages . USH3 isarriages . Sweden arriages . This isarriages . An overClinical USH diagnosis is essentially based on the association between hearing loss and RP, where hearing loss is congenital, and RP is apparent in childhood or young adulthood . To dateA neonatal audiological diagnosis should include otoacoustic emission (OAE), auditory brainstem response (ABR) with threshold measurements, auditory steady-state response (ASSR), and stapedial reflexes to determine the degree of hearing loss and rule out auditory neuropathy. The localization of hearing loss in USH is cochlear, with loss of both outer and inner hair cells. Later in childhood and during the life course, the addition of pure tone audiometry and speech audiometry should be included. The differences between USH1, USH2, and USH3 are as follows :USH1: Congenital profound bilateral deafness.USH2: Congenital moderate-to-severe bilateral hearing loss. In most cases, stable hearing loss occurs during the first 3–4 decades. Hearing loss has a sloping pattern: in most cases mild to moderate in the low frequencies and severe to profound at higher frequencies.USH3: Congenital hearing loss, which is usually mild during childhood with a typical sloping pattern. The hearing loss is more variable, which differs from USH2 in that it is progressive with acquired severe-to-profound hearing loss usually in the third decade.USH1: Vestibular investigation is an essential part of the diagnosis since all children suffer from bilateral vestibular areflexia. In small children, a rotatory test in an office chair using video Frenzel goggles reveals absent horizontal nystagmus during rotation. Assessment of motor milestone development shows delayed gross motor development with hypotonia as neonates; the children show delays in sitting and crawling and usually have a walking age of >18 months. Later, during childhood, they present difficulties in walking balance beams and difficulties in learning to ride a bicycle.USH2: Vestibular function is normal with normal motor milestones.USH3: Balance function is usually normal during childhood and early adulthood and is decreased later.Vision loss is caused by a degenerative retinal disorder called “retinitis pigmentosa.” This name goes back to the time at which the findings in the retina were thought to be related to inflammation. Today, we know that RP in USH is a slow retinal degeneration that initially affects the rods. RP in USH should not be compared with other forms of RP since the progression in USH is much slower than in other RPs. There are essentially two known types of photoreceptor cells (rods and cones), and ganglion cells involved in RP, thus resulting in progressive vision impairment. Rods are primarily responsible for nighttime vision, so-called scotopic conditions. The contribution of ganglion cells in RP remains unclear. The rods are located in the periphery of the retina and are also responsible for peripheral vision, while cones contribute to daytime and central vision (photopic conditions). Cones are also responsible for the color vision. RP is quite similar in all Usher types, and individual variation is usually greater than the variation between types. Vision loss in childhood is mild and may go undetected during the first 10 years. The slow degeneration of rods results in minor problems with contrast vision and light sensitivity. Progressive problems with night vision can be detected at around 8–10 years of age. Visual diagnosis should be made as early as possible. It is possible to detect dysfunction of the rods by electroretinography at an early age. Fundoscopy and testing of the visual field in small children are usually not sufficient to detect RP in USH .The next symptom to appear is the so-called scotomas, which are small blind spots where small objects might be difficult to see. This is usually not noted by younger children who obviously do not comprehend how their vision is different from others. However, later in teenage and young adulthood, the degeneration of the rods increases, resulting in large peripheral visual loss and “tunnel vision.” At this stage (20–30 years), the night vision capability is extremely poor. In most cases, cataracts develop around 30–40 years. Several people with USH have preserved some central vision throughout most of their lives, although with visual fields of only 5–10 degrees ,121.In making a correct clinical and genetic diagnosis of USH1, it is important to keep in mind that there exist rare cases characterized by a nonsyndromic deafness with “typical” USH1 mutations.USH1: To date, children with USH1 have often been misdiagnosed as having a nonsyndromic profound deafness. Today, in most industrialized countries, deafness is discovered through universal neonatal screening. Since deafness in USH is always bilateral, early cochlear implantation should be performed (6–12 months) to provide hearing and spoken speech . It is iUSH2A). It has recently been evident that the deterioration of hearing to some extent is dependent on different mutation patterns. Some older adults have shown a combination of congenital hearing loss and age-related hearing loss, which has resulted in profound deafness and cochlear implantation [USH2: The hearing loss in USH2 is so severe that it can be detected by neonatal hearing screening. The hearing loss should be treated as soon as possible after diagnosis with bilateral hearing aids (2–3 months). It is quite easy to fit children with USH2 since hearing loss during childhood and young adulthood is relatively stable. Most subjects with USH2 harbor mutations involving the Usherin gene , might result in falls and fractures. Unlike the rapid progression of hearing loss, RP does not seem to differ from USH1 and 2 .Recently published articles have suggested a new type of USH. To the best of our knowledge, the existence of a fourth type of Usher is not clear and must be confirmed. Usher type 4 has been proposed in a new study among five subjects from three families with atypical forms of Usher. However, further evidence is required to support the introduction of this new type as an atypical Usher form .Deaf-blindness, as well as USH, is the result of the progression in various combined vision and hearing impairments to such an extent that it is difficult for the impaired senses to compensate for each other. However, deaf-blindness is a distinct entity and should not be rehabilitated as a simple coexistence and summation of two single impaired senses (hearing and vision). Since USH limits activities and restricts full participation in society, it also affects social life, communication, access to information, orientation, and the ability to move around freely and safely. To compensate for this loss, the tactile sense becomes important. Furthermore, because vision loss is progressive, the mode of communication must be continuously changed. Communication will always be time-, cognitive-, and energy-consuming. Impaired vision and hearing function increases the need to make use of other sensory stimuli . It limits access to distance information and creates a need to rely on information within the near surroundings. Extensive research in gene therapy is at hand; however, to date, there is no effective treatment beyond clinical trials in preventing or treating hearing, vision, or vestibular loss. Correct and early rehabilitation can prevent many other physical and psychological co-morbidities following progressive deaf-blindness.Most children with USH1 in developed countries are offered cochlear implants (CIs) with high efficacy. In Sweden, the majority of subjects with USH3 are offered CI, usually around 30–40 years . Some peThe hearing loss in USH2 is stable in most cases, and the linguistic outcome is good when hearing aid fitting and audiological rehabilitation start early. The difference in audiological rehabilitation between people with deaf-blindness and people with nonsyndromic hearing loss is that humans always use a combination of hearing and vision, as symbolically illustrated by “One hears with the eye and sees with the ear.” The authors believe that children with USH should obtain sign language as a second language, to have an alternative mode of communication if blindness should occur and tactile sign language has to be used in compliment with hearing.Early diagnosis using electrophysiology will ensure correct and early rehabilitation. Once the diagnosis is obtained, yearly visual examinations should be performed, and pediatric ophthalmologists and optometrists should pay attention to contrast sensitivity, light sensitivity, and scotomas. This will make it easier for schools and families to use correct lighting conditions and contrast. Strong sunlight is often problematic, and sunglasses should be encouraged.Bilateral vestibular areflexia in USH1 results in impaired and delayed motor milestones. Thus, early rehabilitation has to focus on making use of somatosensory and visual signals to compensate for vestibular loss. This can be done in preschools and schools by having extra physical training under the guidance of a physiotherapist.Rehabilitation will benefit from close cooperation between ENT/audiology and ophthalmology/low-vision clinics. Adjustments, especially with special light conditions, must be executed in the home, schools, and later in life, at workplaces.Recent research in Sweden has shown that adults with USH generally have poor physical health compared with a cross section of the Swedish population. The most prominent physical symptoms were fatigue, headache, as well as neck and shoulder pain. Psychological health was also impaired, with the inability to manage problems and lack of social trust. The USH group showed a statistical over-representation of suicidal behaviors ,128.Thus, rehabilitation in USH must focus not only on vision and hearing, but also on the psychosocial consequences of deaf-blindness. Rehabilitation must be multidisciplinary and involve family, school, employer, etc. Rehabilitation is lifelong and increases with age.It must be noted that the epidemiology presented in Gene therapy in USH has undergone significant achievements during the last 5 years. Several different approaches are currently used in different stages of animal and human clinical trials. Most research has focused on the retina and preserving vision. The reasons for this are that CI has been shown to both allow hearing in USH1 and restore hearing in USH2 and 3. Moreover, the retina is easier to access than the cochlea. Nevertheless, gene therapy studies are ongoing and directed towards the retina, cochlea, and vestibular apparatus.Mice and zebrafish are often used as in vivo animal models. Translating results from animal models is often difficult, but the results from current clinical trials will hopefully result in new treatments. Different approaches have been used, such as adeno-associated viral vectors, for in vivo gene transfer. It has the advantage of using a DNA virus that is nonpathogenic to humans. It appears to enable long-term transduction after a single vector administration and has a good safety profile in humans. Some of the USH genes are quite large, and a potential disadvantage can be limited cargo capacity. Clinical trials using dual AAV vectors have been conducted. Another approach is to use antisense oligonucleotides, with clinical application becoming a reality and several drugs already in trials. Nonsense mutations are common in USH, and the drug Ataluren creates a premature stop signal in the translation of the genetic code, which allows the cell to produce a full-length, functional protein.USH2A gene. An excellent review of the gene-, drug-, and cell-based therapies has recently been published by French et al. [The discovery of CRISPR–CAS9 that received the Nobel Prize in 2020 is another method enabling in vitro correction of the c2299delG mutation in the h et al. .USH is one of the most common autosomal recessive syndromes associated with double-sense impairment, hearing, and vision. This combination creates a unique entity of deaf-blindness. Genetics has enabled significant advances, accurate diagnosis, and improved understanding of the pathology and is expected to provide innovative treatments for gene therapy. Next-generation sequencing has also helped in new conceptions and knowledge of the field.The rehabilitation of these patients is complicated and requires specific knowledge and education. Even if bioengineering provides continuous progression in retinal support, the best treatment option remains hearing rehabilitation with hearing aids and CIs. Bilateral devices can partially restore spatial orientation and support residual visual function. Encouraging results have been published on gene therapy in experimental animal models, but this approach has not been translated into current clinical management. Nevertheless, further studies are necessary to develop new strategies and collect information on USH.


Previous studies have shown that the minor allele  for Cry 1 rs2287161, may be associated with increased risk of cardiovascular diseases (CVDs). Low resting metabolic rate (RMR) caused by the diet has been shown to have, potentially, unfavorable effects on obesity. This study sought to investigate the interactions between the Cry 1 Gene and fat intake on RMR in women with overweight of obesity.This comparative cross-sectional study was conducted on 377 Iranian women with overweight of obesity. A food frequency questionnaire (FFQ), with 147 items, was used to assess dietary intake. Individuals were categorized into two groups based on the rs2287161 genotype. Body composition, dietary intake, and RMR were assessed for all participants.P = 0.04), fat free mass (FFM) (P = 0.0009), RMR per FFM (P = 0.05), RMR per body mass index (BMI) (P = 0.02), and RMR deviation (P = 0.01). Our findings also showed significant interactions between total fat and C allele carrier group on RMR per kg body weight, RMR per body surface area (BSA), RMR per FFM, and RMR deviation (P for interaction < 0.1), in addition to a significant interaction between CC + CG group genotype and polyunsaturated fatty acids (PUFA) intake on RMR per BMI (P for interaction =0.00) and RMR per kg (P for interaction = 0.02) and RMR per BSA (P = 0.07), compared to the GG group, after control for confounder factors.There was a significant difference between genotypes for fasting blood sugar (FBS) (These results highlight that dietary compositions, gene variants, and their interaction, should be acutely considered in lower RMR. The prevalence of overweight and obesity has increased such that almost one-third of the global population is now categorized as overweight or obese , 2. GlobIt has been theoretically demonstrated that individuals with low resting metabolic rate (RMR) are at increased risk of developing obesity-related disorders, since a larger portion of their daily food intake is stored as fat , 15. RMRThe human circadian clock is responsible for the coordination between energy intake and metabolism based on changes in external factors including sunset/sunrise, physical activity, and dietary intake –25. ReceSome studies have reported that RMR rate have depends on genetic factor and diet especially fat. Overall, some recent research, diet such as high-fat diet can have an interaction with CRY1 gene polymorphism , 36, 37.To our knowledge, there is currently no study that has investigated the association between Cry1, diet, and energy expenditure. Thus, given the potential future importance to clinical practice, we sought to assess the interaction of Cry1 and high-fat diet with RMR in women with overweight of obesity.2. The exclusion criteria were; history of diabetes mellitus, hypertension, CVDs or fatty liver, taken all types of medicine including an oral contraceptive pill, smoking, intake of alcohol, pregnancy, currently lactating, and post menopause. We also excluded participants if chronic disease affected their diet, were following an arbitrary special dietary regimen, had weight fluctuations in the past 1 year, and if they were on a specific diet or if their daily energy intake was < 800 kcal or > 4200 kcal /22.5.n = 270) versus homozygous non-risk allele GG genotype (n = 107). Comparisons between groups were made using the independent t-test for continuous variables and chi-square test for categorical variables. Moreover, age, BMI, IPAQ, and energy intake-adjusted analyses were performed using general linear models (ANCOVA). Moreover, to analyze the potential interactions between genotype and diet intake, and the genotype and fat, PUFA or SFA, an interaction term of genotype x fat, SFA or PUFA dietary intake on types of RMR was included in the binary logestic regression. For this analysis, the GG genotype and categories of lower intake of total fat, PUFA, SFA were considered as reference groups. Data were analyzed using IBM SPSS version 23 . P-values for all variables were reported before the adjustment in the crude model by by independent T-test and after adjustment with potential confounders as age, BMI, physical activity, and energy intake using analysis of covariance (ANCOVA). P < 0.05 was considered statistically significant, but for interactions, P < 0.1 was considered significant.The Hardy-Weinberg equilibrium and comparison of categorical variables were assessed with the χ2 test. Descriptive statistics, including the mean (standard deviation) and frequency summaries, were used to describe the study population. A total of 377 Iranian women with overweight of obesity were categorized based on rs2287161genotypes and divided into two groups according to dominant genetic model , RMR deviation (− 8.00), RMR per BMI (50.90), and RMR per FFM (33.73), and for RMR per kg body weight was [The present study was conducted on 377 obese and overweight Iranian women, of which, 70.8% were married, 36.2% occupied, 86.6% had a college education, and 45.8% had good economic status. The mean age, weight, BMI, WHR, WC, body fat mass (BFM), FFM were 36.67 ± 9.10 years, 81.29 ± 12.43 kg, 31.26 ± 4.29 kg/might was , respectP = 0.03), FFM (P = 0.00), BMI (P = 0.06), RMR per BMI (P = 0.02), RMR per FFM (P = 0.05) RMR deviation (P = 0.01), FBS (P = 0.04), marriage status (P = 0.07), economic status (P = 0.01), and physical activity (P = 0.04).Comparison of participant’s variables based on rs2287161 genotypes was shown in Table P = 0.07) with a higher mean in the group with risk allele group (CC + CG), and in education status (P = 0.01). For all other variables, no significant association was observed , and polyunsaturated fatty acid (PUFA) intake, are presented in Table P = 0.04), WC (P = 0.02), and in biochemical variables; TG (P = < 0.001). Among SFA categories, there was a significant mean difference for marriage status (P = 0.02). After adjusting for potential confounders, women with higher intake of SFA had significantly higher mean HOMA-IR (P = 0.02), and LDL(P = 0.02), all other variables were no longer significant after adjustment. Regarding other variables related to general characteristics, there were no significant differences noted .In the crude model, in body composition variables there were significant mean differences for BFM (P = 0.05), but after controlling for confounders, this association was not present. There were no significant differences in terms of other biochemical assessments, body composition, RMR measurement, education level, economic status, marital status, rs2287161 genotypes, physical activity, and job-status  (Table There was a significant difference in cholesterol between lower and higher PUFA intake categories before adjustment (P = 0.05), TG (P = 0.05), height (P = 0.02), and marriage status (P = 0.02) between lower and higher total fat intake categories in the crude model, but after controlling for confounders , these variables were no longer significant(P > 0.05). There were no significant differences for the remaining variables before and after adjustment (P > 0.05) . Table SFA intake was significantly lower in the GG genotype group compared to the CC + CG group  but in Model 1, after adjusting for potential confounders, such as education level, BMI, marriage status, age, history of weight loss in past year, total energy intake, economic status, respiratory quotient (RQ), and physical activity, the association changed to a significant interaction . The RMR per BSA variable in the crude model did not yield a significant interaction , yet, after controlling for confounders, a significant interaction was found . In addition, RMR per FFM was not significant in the crude model , but, in the adjusted model, a significant interaction was found . Moreover, in the crude model, there was no significant interaction between the allele risk group (CC + CG) in comparison with the reference group (GG) on RMR deviation from normal , however, after controlling for confounders, a significant interaction was found  , after controlling for confounders, this association remained significant , such that in participants with increased intake of PUFA in the risk alleles group had 81% lower odds for higher RMR per kg compared to participants with no allele risk (GG) and a lower intake of PUFA. Also, for RMR per BSA, there was no significant association in the crude model , but after adjustment, there we found a significant interaction between CC + CG group with higher intake of PUFA, compared to GG group   genotype group (CC + CG) in comparison with the reference group (GG) on RMR per kg body weight , and this remained significant after adjustment for potential confounders and lead to decreased odds . Accordingly, this equated to an 87% reduction in the odds of higher RMR per BMI in individuals in the risk allele group (CC + CG) and with higher intake of PUFA intake, compared to participants with no allele risk (GG) and a lower intake of PUFA (Table P = 0.09), which ameliorated after adjustment for confounding variables (P = 0.11). No other significant associations were found between PUFA and RMRs  genotype group (CC + CG) on RMR per MBI in the crude model , however, after controlling for confounders, this association was attenuated   genotype group (CC + CG), in comparison with the reference group (GG), on RMR per kg  of action.


Aging is associated with a broad range of visual impairments that can have dramatic consequences on the quality of life of those impacted. These changes are driven by a complex series of alterations affecting interactions between multiple cellular and extracellular elements. The resilience of many of these interactions may be key to minimal loss of visual function in aging; yet many of them remain poorly understood. In this review, we focus on the relation between retinal neurons and their respective mass transport systems. These metabolite delivery systems include the retinal vasculature, which lies within the inner portion of the retina, and the choroidal vasculature located externally to the retinal tissue. A framework for investigation is proposed and applied to identify the structures and processes determining retinal mass transport at the cellular and tissue levels. Spatial variability in the structure of the retina and changes observed in aging are then harnessed to explore the relation between variations in neuron populations and those seen among retinal metabolite delivery systems. Existing data demonstrate that the relation between inner retinal neurons and their mass transport systems is different in nature from that observed between the outer retina and choroid. The most prominent structural changes observed across the eye and in aging are seen in Bruch’s membrane, which forms a selective barrier to mass transfers at the interface between the choroidal vasculature and the outer retina. Increasing age is associated with a broad range of visual impairments that include loss of spatial contrast sensitivity, decreased light and wavelength sensitivities, deficits in the processing of temporal information and slowing of visual processing speed . These cEvery part of the eye undergoes changes as we age . The humWhile many age-related vision impairments are driven by transmission losses in the optical media of the eye , cellulaThe purpose of this review is to assess how documented spatial and age-related variations in retinal neuron populations relate to changes observed in the structure and function of the mass transport systems to the retina. Homeostasis, metabolism, and survival of retinal cells rely on the adequate supply of metabolism substrates and clearance of metabolic waste products from the retina. These processes are supported by a dual circulatory system formed by the choroidal and retinal vasculatures see . The choAn underlying hypothesis to this work is that age-related changes in the structure and function of the mass transport systems sustaining the retina correlate with variations in retinal cell populations observed in aging. This would support the idea that the transport of material that is key to healthy cell metabolism is adjusted in aging, so that correlated changes in the retina and its metabolite delivery system are adaptive. Departure from this correlated behavior may then put the eye at a higher risk of vision impairments and disease. The first step in testing this hypothesis is to determine the nature of the relation between retinal neuron populations and mass transport systems in health. The human eye offers an ideal template to explore this relationship. Spatial variations in the structure of the retina and choroid are well-documented and, within an adequate framework, may be harnessed to identify correlated patterns of change. Aging can provide valuable insights into the resilience of correlated behaviors to perturbations occurring over large timescales. Changes in the relation between retinal neurons and their respective metabolite delivery system in aging are therefore also explored.This review investigates biological systems – retinal neurons and their respective metabolite delivery systems – often considered in isolation. An important factor to consider when assessing relations between any biological systems is the characteristic length- and timescales associated with the elements, systems, and processes at play .Many interactions between retinal cells and the retinal and choroidal vasculatures occur through a movement of molecules. For instance, the movement of oxygen, nutrients, metabolism byproducts, signaling proteins and growth factors between vasculatures and neurons partly determines the metabolism of these cells, their function, and their ability to survive and adapt to changes in their microenvironment. Exchange between neurons and the retinal and choroidal vasculatures may be studied at the scale of cells, tissue or even organs see . PhenomeAdvances in molecular techniques have made it possible to explore variations in genome, epigenome, transcriptome, metabolism and immune response in the retina of human donor eyes . These mTo ensure that most of the information relevant to interactions between retinal neurons and their respective metabolite delivery systems is captured, this review focuses on structures and processes at the cellular and tissue scales.in vitro models have been used to attempt to address this limitation , filtration and osmosis see . The traThe movement of molecules across capillaries is partly determined by the physical characteristics of structures composing them such as the thickness of their basement membranes and the diameter and spatial distribution of inter-endothelial junctions. The molecular composition of the extravascular space, the structure of cells consuming or delivering transported material and their distance from vascular compartments also influence molecular transfers significantly. At a basic tissue scale (∼1 mm), the movement of material is generally described using average statistics based on mean squared displacements of molecules. Within this framework, the effect of structures influencing the movement of material – such as the geometry of capillaries and composition of the extravascular space – is described using averaged characteristics, such as diffusivity, permeability and cellular density. These measures translate the underlying small-scale structure of molecules, cells and media across which transfers occur; they may vary in space and time and are often determined experimentally. Within frameworks using averaged statistics (in tissue level models for instance), the transfer of diffusive molecules between the vasculature and tissue is mainly a function of blood flow, the geometry of capillaries, the concentration of a specific compound in blood and its consumption in tissue  and the resistance of the capillary wall, extravascular space and cells to diffusion . The topIn the retina, the transfer of metabolism substrates and by-products to and from blood must be adequately controlled and regulated. This is the main function of the blood-retinal barrier (BRB), which involves several cellular and extracellular structures regulating transfers between retinal capillaries and the inner part of the retina  and between the choriocapillaris and the outer part of the retina  . MovemenThe extracellular structures involved in the regulation of transfers between blood and tissue are the glycocalyx and extracellular matrix. The glycocalyx consists of a coat of macromolecules bound to the apical and luminal plasma membrane of epithelia and endothelial cells . ThroughIn vivo imaging techniques include optical coherence tomography (OCT), optical coherence tomography angiography (OCTA) and adaptive optics (AO). OCT uses low-coherence interferometry to generate cross-sectional images (B-scans) of optical scattering from retinal structures with a longitudinal and lateral spatial resolution of a few micrometers  that arise from the ophthalmic artery . Each ofThe structure of choroidal vessels differs markedly from those forming the retinal vasculature. Smooth muscle cells and pericytes are present along choroidal arteries and veins, respectively; however, their function and subtypes remain poorly characterized in man . PericytThe large diameter of choriocapillaris vessels  demonstrCAV1 (caveolin), TSPO (cholesterol) and TFRC (transferring receptor) (PLVAP). The Plvap protein is present in fenestrations, caveolae and transendothelial channels, and therefore plays a key role in the regulation of transendothelial transport , they do not allow for the free transport of macromolecules from plasma to the extravascular space as is often assumed . In facteceptor) . One of ransport . Our undransport .Molecules reaching the choroidal extravascular space must cross Bruch’s membrane, which occupies the space between the choriocapillaris and the RPE, to reach photoreceptor outer segments see . Bruch’sin vitro    and pigms (Vegf) . Vegf exs (Vegf) , partly s (Vegf) .Tissue-level analyses of the movement of molecules between retina and choriocapillaris, which describe the combination of phenomena occurring at the level of choroidal endothelial cells, Bruch’s membrane and the RPE, are scarce. Salient features of the transfer of small passively transported molecules may be inferred from theoretical and experimental analyses of oxygen concentration profiles . These sBlood enters and leaves the choriocapillaris through a set of arterioles and venules connected to the surface furthest from the retina approximately perpendicularly to the plane of the capillaries. Because of this arrangement, the blood flow is decomposed into contiguous functional vascular segments separated by separation surfaces across which there is no flow . Groups A0 is the surface area of the lobule, h the local thickness of the choriocapillaris, Qa is the flow rate in the arteriole feeding the lobule, Φ is the vascular volume fraction of the choriocapillaris (the volume of tissue occupied by capillaries) and 1/τ is a transfer coefficient specific to the compound considered  follows a similar pattern, varying between about 3 and 18 μm in diameter at the posterior pole  .In vitro experiments indicate that the hydraulic conductivity of Bruch’s membrane is higher in the retinal periphery as compared to the submacular region  is maximal close to the optic nerve head, where the concentration of ganglion and bipolar cells is highest. It decreases toward the periphery, where the density of retinal neurons is comparatively reduced. The amplitude of differences in vascular density displayed by the choriocapillaris across the choroid seem almost marginal when compared to those seen among photoreceptors. Variations in the thickness and hydraulic conductivity of Bruch’s membrane indicate that this structure forms a greater impediment to mass exchange in the submacular area as compared to the periphery. Therefore, barriers to transport appear to be more selective in regions where the density of photoreceptors is highest.Aging can provide valuable insights into the relation between retinal neuron populations and mass transport systems, including information about its resilience to perturbations occurring over large timescales. Many structural changes have been observed in the aging retina see . Some reIn vivo methods have found that the vascular density of deep and superficial retinal capillary layers decreases by 0.55–0.86% per decade on average (While this is disputed  due to m average . This va average  and a de average . The eff average ; howeverThe amplitude of changes observed in the outer retina and choroid appears larger in magnitude than those documented in the inner retina. Displacement and patchy loss of nuclei in cone outer segments have been observed in the macular retina . Analysein vivo using OCTA (In vitro experiments have demonstrated a 45–65% linear decrease of the transport of amino-acids across Bruch’s membrane over a lifespan (Analyses of OCT volume scans suggest that the total choroidal and mean choroidal luminal areas decrease with age . Choroiding OCTA . The effing OCTA . Mathemaing OCTA , but is ing OCTA . A reducing OCTA  is yet ting OCTA , a loss ing OCTA . Increasing OCTA  are alsoing OCTA  and alteing OCTA . This vaing OCTA , which fing OCTA . In vitrlifespan . The diflifespan . The maxlifespan .2/year, respectively (At the temporal equator, the density of cones is reduced by 23% on average by the ninth decade ; see Figectively . Some haectively  whereas ectively . This laectively . Age-relectively  includinectively  are not ectively , and macectively .The extension of dendritic fibers of a subtype of bipolar cells beyond the outer plexiform layer and into the outer nuclear layer has been observed in aged peripheral retinas . WidesprIt is beyond the scope of this review to describe systemic changes associated with aging; however, their effect on retinal mass transport systems should not be overlooked. It has long been known that cardiac output decreases with age while blood pressure increases . Plasma The effect of aging on the retina is spatially heterogeneous; it is more prominent in the region with the highest energy requirements, the macula, and in the outer retina and choroid as compared to the inner retina. Direct and indirect evidence point to a progressive breakdown of mass transfers between retinal neurons and their respective metabolite delivery systems. However, the contribution of this breakdown to retinal aging and its correlation with cellular alterations and potential loss of function remains to be fully elucidated. The 30% loss in rod density in the macula appears to concord with the 34% decrease in choriocapillaris density observed with age see . Howeversymbiotic relationships. It is now thought that photoreceptors are at the center of a metabolic landscape involving RPE and Müller cells (Our ability to fully assess correlations between variations in retinal neuron populations and changes in their respective mass transport systems using published data is limited by the fact that the key components to consider – neurons, vasculatures, extravascular and extracellular elements – have predominantly been studied in isolation. The retina involves many cellular elements that function through er cells . These fOur assessment of the relation between retinal neuron populations and mass transport systems in aging is considerably limited by the lack of models or frameworks developed to differentiate between structural and functional changes caused by aging and those driven by disease. This limitation is more broadly a significant impediment to the study of retinal aging. A large part of our understanding in this regard comes from samples selected based on the absence of phenotypes traditionally associated with vitreoretinal disorders. But many  have shoFuture studies may benefit from considering variations in mass exchange within the retina and their effect at the molecular, cellular and tissue levels. Models developed within frameworks centered around basic physical principles can provide extremely valuable insights into processes driving alterations and help generate hypotheses to be experimentally tested. A benefit of these approaches is the ability to link phenomenon occurring at distinct scales. Biological systems such as the retina are intrinsically multiscale, and cells themselves must integrate several scales to functions . IntegraLaying down a framework capable of assessing the effect of variations in retinal neuron populations and their respective mass transport systems on visual function is incredibly challenging, in part because of the broad range of scales associated with the processes and structure at play. Such a framework is however necessary to determine the nature of the relation between cellular and tissue-level changes and vision. Alterations in the selective permeability of Bruch’s membrane restrict the movement of many molecules essential to the visual cycle; however, their effect on visual function is presently impossible to assess directly. Some have proposed that rod visual function is unlikely to be affected by rod losses observed in aging . This woMAZ performed all literature searches, wrote and revised the review and generated all figures.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Based on this translational package of data, a gepotidacin 1,500-mg oral dose twice daily for 5 days was selected for two ongoing, randomized, multicenter, parallel-group, double-blind, double-dummy, active-comparator phase III clinical studies evaluating the safety and efficacy of gepotidacin in adolescent and adult female participants with uUTIs .Antibiotics are the current standard-of-care treatment for uncomplicated urinary tract infections (uUTIs). However, increasing rates of bacterial antibiotic resistance necessitate novel therapeutic options. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interaction with the bacterial subunits of DNA gyrase (GyrA) and topoisomerase IV (ParC). Gepotidacin is currently in clinical development for the treatment of uUTIs and other infections. In this article, we review data for gepotidacin from nonclinical studies, including  Urinary tract infections (UTIs) and their recurrence are associated with substantial health care burdens and morbidity globally, including impacts on the daily activities and quality of life of sufferers , 2. UTIsThe standard-of-care antibiotic treatment for uUTIs is one of several recommended agents: nitrofurantoin, trimethoprim, fosfomycin, or pivmecillinam , as first-choice agents, with fluoroquinolones or β-lactams as second choices . SelectiEscherichia coli is the most common causative uropathogen of uUTIs  to maximize the likelihood of antimicrobial success and resolution of infection . A regimE. coli  is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by inhibiting DNA gyrase and topoisomerase IV by unique and balanced interactions on the GyrA subunit of bacterial DNA gyrase and the ParC subunit of bacterial topoisomerase IV in E. coli , 14. ThiE. coli , 14 confinolones , 15, 16.inolones . GEP is inolones , 18. TheIn this review, we summarize how the results of these studies and analyses were used to select dosage regimens for the two ongoing GEP phase III studies in participants with uUTI.in vitro activity of GEP was evaluated against a global collection of 1,010 E. coli isolates  of the tested isolates had GEP MIC values of ≤4 μg/mL  and increased to 4 μg/mL for ESBL-producing isolates (n = 179) and also for isolates not susceptible to nitrofurantoin (n = 55), fosfomycin (n = 11), or levofloxacin (n = 278)  .in vitro activity of antimicrobial agents do not always directly translate to the clinic, as such test systems are not able to fully simulate in vivo environments  and kidneys (cUTIs) (in vivo efficacy of GEP against E. coli (Results from studies measuring the ronments . The in  (cUTIs) . Althoug (cUTIs) , uUTI an (cUTIs) , 24. As  E. coli . Althoug E. coli , and intE. coli (fAUC]) determined from previous in vivo efficacy studies . Overall, treatment with both GEP exposures led to a reduced bacterial burden (log10 reduction in CFU per milliliter) compared with the baseline (nontreated) controls in the kidney (0–12) values of GEP were 21 and 51 μg · h/mL  in rat blood for the recreated human plasma PK 800-mg and 1,500-mg q12h oral doses, respectively. The mean GEP systemic exposure profiles in the rats were similar to the mean human exposure profiles for these doses  in healthy participants  , was exaE. coli . The foue kidney  25). Th. ThE. coe kidney . SimilarE. coli following GEP exposure  using a one-compartment in vitro PK/PD model mimicking human free-drug plasma-concentration profiles. E. coli NCTC 13441 (GEP MIC of 2 μg/mL) was chosen based on its result reproducibility and representation of the ST-131 clonal group (in vitro dose fractionation study demonstrated that the ratio of the area under the unbound drug concentration-time curve over 24 h at steady state to the MIC (fAUC0–24/MIC ratio) was the PK/PD index most predictive of GEP efficacy against E. coli  , the fAUC0–24/MIC values resulting in net bacterial stasis, a 1-log10 reduction, and a 2-log10 reduction in the bacterial burden from the baseline were 34.5, 41.3, and 49.7, respectively  . Of noteectively . Since aE. coli strain NCTC 13441 was used to determine the fAUC0–24/MIC exposure of GEP required to prevent the amplification of a resistant subpopulation. Using this approach, fAUC0–24 values of ≥549 μg · h/mL prevented resistance amplification to GEP for 10 days, equating to an fAUC0–24/MIC ratio of ≥275 when applying the GEP broth microdilution MIC of 2 μg/mL for E. coli NCTC 13441 . Th. ThE. coin vitro studies to further support GEP dosing regimen selection for phase III clinical trials. A summary of the urine PK findings from the phase I and II studies is shown in Tmax) ranging from 1.25 to 2.5 h on day 1, and had an elimination half-life ranging from 11.2 to 14.7 h across all dose levels. Following 14 days of repeat BID or TID doses, the mean effective half-life values ranged from 6.12 to 8.96 h across all dose levels. The AUC0–∞ and Cmax values increased in a greater-than-dose-proportional manner following single or repeat doses ranging from 400 to 2,300 mg . Minimal to moderate accumulation was observed after repeat BID or TID dosing, and accumulation tended to be higher with TID dosing (accumulation ratios ranging between 1.27 and 1.52 for BID dosing and between 1.69 and 1.72 for TID dosing).The pharmacological activity of a drug depends on its adequate levels at the effect site. Plasma drug concentrations are often used as surrogate markers because access to effect sites for sampling can be limited . However35–0–24 and AUC0–48 values in urine than those of adults.The study under ClinicalTrials.gov identifier NCT04079790  was condGEP exposure in the urine was also examined in a phase I study  in participants with hepatic impairment . Values GEP exposure in urine was also examined in a phase I study  in participants with renal impairment  37). Ov. Ov37). Furthermore, an absorption, distribution, metabolism, and excretion study for GEP describing GEP PK in healthy subjects indicated that when administered as a single i.v. dose, approximately 60% of GEP was recovered in urine . In addi0–12 on day 4 was 15.2 μg · h/mL  (Cτ [plasma predose concentrations]/day 3 free-drug plasma Cτ) in urine than the free-drug concentration in the plasma at steady state, demonstrating increased exposures at the target infection site (urine/bladder)  to evaluate plasma and urine PK, safety, and exploratory efficacy endpoints, participants with uUTIs received oral GEP at 1,500 mg BID for 5 days in the clinic  and returned to the clinic for test-of-cure (days 10 to 13) and follow-up (day 28 ± 3) visits  that were qualifying uropathogens  and thus were included in the microbiological intent-to-treat population , 8 had baseline isolates (5 N = 22) and in the microbiological intent-to-treat population (n = 8) (3 CFU/mL]) of the baseline uropathogen, was also achieved in 7/8 (88%) participants at the test of cure , with 6/8 (75%) with success at follow-up . Cli. CliN = in vitro models (90 for fluoroquinolone-resistant and ESBL-producing E. coli in a large MIC study (0–24/MIC ratio (urine exposures are not adjusted for protein binding) of 403 exceeded the target for delivering efficacy at the site of infection  (in vitro PK/PD hollow-fiber model) by approximately 1.5-fold . Fo. Foin vin vitro)  by appropression  by approEnterobacterales uropathogen. For these participants, plasma fAUC0–24/MIC ratios ranged from 6.99 to 90.5, and urine AUC0–24/MIC ratios ranged from 1,292 to 121,698 , six had both available PK and a qualifying in vitro activity against over 1,010 E. coli isolates identified an MIC90 for GEP of 2 μg/mL . Additional data derived from these studies will allow the further study of the GEP dose regimen and a greater understanding of GEP’s PK variability in larger participant cohorts.In the GEP phase III clinical studies, urine levels of GEP observed following a 1,500-mg BID oral dose are anticipated to exceed the


This is probably because NF155 coexists in the PNS and CNS. Such cases showing demyelinating lesions in both the CNS and PNS are now termed combined central and peripheral demyelination (CCPD). NF155+ CIDP/CCPD commonly presents hypertrophy of spinal nerve roots and cranial nerves, such as trigeminal and oculomotor nerves, and extremely high levels of cerebrospinal fluid (CSF) protein, which indicates nerve root inflammation. In the CSF, the CXCL8/IL8, IL13, TNFα, CCL11/eotaxin, CCL2/MCP1, and IFNγ levels are significantly higher and the IL1β, IL1ra, and GCSF levels are significantly lower in NF155+ CIDP than in non-inflammatory neurological diseases. Even compared with anti-NF155 antibody-negative (NF155−) CIDP, the CXCL8/IL8 and IL13 levels are significantly higher and the IL1β and IL1ra levels are significantly lower than those in NF155+ CIDP. Canonical discriminant analysis revealed NF155+ and NF155− CIDP to be separable with IL4, IL10, and IL13, the three most significant discriminators, all of which are required for IgG4 class switching. Therefore, upregulation of both Th2 and Th1 cytokines and downregulation of macrophage-related cytokines are characteristic of NF155+ CIDP, which explains spinal root inflammation and the lack of macrophage infiltration in the sural nerves. All Japanese patients with NF155+ CIDP/CCPD have one of two specific human leukocyte antigen (HLA) haplotypes, which results in a significantly higher prevalence of HLA-DRB1*15:01-DQB1*06:02 compared with healthy Japanese controls. This indicates an involvement of specific HLA class II molecules and relevant T cells in addition to IgG4 anti-NF155 antibodies in the mechanism underlying IgG4 NF155+ CIDP/CCPD.Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated demyelinating disease of the peripheral nervous system (PNS). A small number of CIDP patients harbors autoantibodies against nodal/paranodal proteins, such as neurofascin 155 (NF155), contactin 1, and contactin-associated protein 1. In most cases, the predominant immunoglobulin (IgG) subclass is IgG4. Node/paranode antibody-positive CIDP demonstrates distinct features compared with antibody-negative CIDP, including a poor response to intravenous immunoglobulin. The neuropathology of biopsied sural nerve shows Schwann cell terminal loop detachment from axons without macrophage infiltration or inflammation. This is partly attributable to IgG4, which blocks protein–protein interactions without inducing inflammation. Anti-NF155 antibody-positive (NF155 CIDP is etiologically heterogeneous, which results in variable responses to immunotherapies. Accumulating evidence indicates that a fraction of CIDP patients carries autoantibodies against nodal or paranodal proteins , such ase matter , 13. NF1e matter , 15. Thun (CCPD) . In thisNF is crucial in constructing and maintaining the nodes of Ranvier. Four major NF polypeptides are produced by alternative splicing: NF186, NF180, NF166, and NF155 [v1.1) toward the nodal region (v) from juxtaparanodal potassium channels (Kv). The loss of NF155 and CNTN1 in genetically engineered mice results in the disruption of septate-like junctions, which produces a large gap between the axolemma and Schwann cell terminal loops. This leads to a decreased nerve conduction velocity  revealed low positivity rates for human NF155 of 2.5% , while arm NF186 . Recentlrm NF186 . Conversrm NF186  and 3%  had IgG1 subclass . It seemAs for other nodal/paranodal antibodies, anti-CNTN1 antibodies were detected in 6% of CIDP patients in whom advanced age, predominant motor involvement, aggressive symptom onset, and early axonal involvement were commonly observed –10. A reIn summary, the prevalence of antibodies against nodal/paranodal proteins, such as NF155, CNTN1, and CASPR1, in CIDP is very low, except for the relatively high percentages of Japanese and Chinese CIDP patients who have anti-NF155 antibodies .+ CIDP patients have young onset ages and high frequencies of tremors, distal-dominant sensory and motor impairments, ataxia, and gait disturbance irrespective of ethnicity. In a Japanese cohort, IgG4 NF155+ CIDP mostly showed a chronic progressive course after onset (92.3%), with no patients showing acute onset  CIDP (+ than in NF155− CIDP (46.2 vs. 4.9%); however, the clinical subtype of NF155+ CIDP was not only confined to the DADS phenotype but was also associated with proximal nerve involvement presenting as the typical CIDP phenotype. Devaux et al.  electrodiagnostic criteria for definite CIDP. In particular, NF155+ CIDP showed more pronounced prolongation of distal (7.7 ± 1.4 vs. 6.7 ± 3.3 ms) and F-wave (53.7 ± 16.3 vs. 42.4 ± 11.4 ms) latencies in the median nerve compared with NF155− CIDP  is anatomically absent or loose.NF155plitudes , these f+ CIDP patients we examined showed blink reflex abnormalities, including absent and/or delayed R1 in 91.7% (11/12) and absent and/or delayed R2 in 83.3% (10/12)   . Given t% (8/15)  and 62.1% (8/15)  of Cauca% (8/15) , althoug% (8/15) , 29, 36 % (8/15) , it is cn Asians  than in n Asians , 29, 36 n Asians  comparedn Asians , 34.r = 0.9184; left; r = 0.9217)  , which s 0.9217) , which i 0.9217) . The fac 0.9217) .+ CIDP patient cohort, absent and/or prolonged visual-evoked potentials (VEPs) were observed in 10 of 13 (76.9%) patients and in 17 of 26 (65.4%) eyes  compared with the abnormal VEP frequencies reported in the total CIDP patients (47–50%). The latter mostly reflects NF155− CIDP cases because the frequency of NF155+ CIDP was very low in Caucasians  eyes , althoug4%) eyes –39. In t4%) eyes , 50% (9/4%) eyes , and 50%ucasians , 29, 36.and CIDP . Collect+ CIDP patients had significantly greater values than did NF155− CIDP patients (7.7 ± 1.3 vs. 4.9 ± 2.0 mm) (+ CIDP (r = 0.739)   patients had trigeminal nerve hypertrophy , a new MRI neurography method to visualize spinal roots and plexuses , all 13  2.0 mm) , 41. The (+ CIDP . In our  (+ CIDP . The int 0.7857) , as showertrophy . Furtherertrophy , which sertrophy .+ CIDP patients also occasionally develop white matter lesions, suggestive of demyelination in the CNS, which is designated CCPD  (+ CIDP (4.0 ± 3.1) compared with NF155− CIDP (2.1 ± 2.3) and other non-inflammatory neurological disease (NIND) patients (1.8 ± 1.9)  . Even th8 ± 1.9) . These o+ CIDP patients (n = 35) and compared them with those of NF155− CIDP (n = 36) and NIND patients (n = 28) , IL13, tumor necrosis factor alpha (TNFα), CCL11/eotaxin, CCL2/MCP1, and IFNγ were significantly higher and the levels of IL1β, IL1ra, and GCSF were significantly lower compared to those in NIND. Compared with NF155− CIDP, the levels of CXCL8/IL8 and IL13 were significantly higher and the levels of IL1β, IL1ra, and IL6 were significantly lower in NF155+ CIDP. Importantly, the CXCL8/IL8, IL13, CCL11/eotaxin, CXCL10/IP10, CCL3/MIP1α, CCL4/MIP1β, and TNFα levels were positively correlated with the markedly elevated CSF protein levels, and the IL13, CCL11/eotaxin, and IL17 levels were positively correlated with the increased CSF cell counts. Conversely, NF155− CIDP had significantly increased IFNγ levels compared with NIND and exhibited positive correlations of the IFNγ, CXCL10/IP10, and CXCL8/IL8 levels with the CSF protein levels. According to the canonical discriminant analysis of cytokines/chemokines, NF155+ and NF155− CIDP were separable, with IL4, IL10, and IL13 the three most significant discriminators  . In NF15+ CIDP, a significantly depressed IL1β was recovered to the normal range after immunotherapy  antibody-positive myasthenia gravis  than in the general Spanish population (+ CIDP had either of two specific HLA haplotypes: HLA-DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or HLA-(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01. Consequently, the HLA-DRB1*15, HLA-DRB1*15:01, HLA-DQB1*06:01/06:02, HLA-DQB1*06:02, and HLA-DRB1*15:01-DQB1*06:02 frequencies were significantly greater in NF155+ CIDP patients than in healthy Japanese controls  shared by DQA1*01:03-DQB1*06:01 and DQA1*01:02-DQB1*06:02  may be a good candidate for a T cell epitope on NF155.Certain human leukocyte antigen (HLA) class II alleles are strongly associated with IgG4 autoantibody-mediated diseases: phalitis , HLA-DR1a gravis , 49, HLAreceptor , and HLAember 13 . It was pulation . Surpriscontrols . These fulations , 29 may ucasians . DQA1*01g groove , 57. Theanalysis . Of noteB1*06:02 . TherefoCCPD is an extremely rare disease involving both CNS and PNS. According to the nationwide survey of CCPD in Japan , CCPD pr+ CCPD patients demonstrate: (i) sequential or simultaneous CNS and PNS involvement; (ii) diffuse conduction slowing with focal conduction failure indistinguishable from that in CIDP in nerve conduction studies; (iii) CNS involvement mostly typical for MS, in which spinal cord lesions and gadolinium-enhanced lesions could develop, but occasionally atypical involvement, with diffuse cerebral white matter lesions; (iv) negative CSF oligoclonal IgG bands; and (v) beneficial effects of combined immunotherapies including corticosteroids, IVIg, and plasma exchange on both CNS and PNS lesions   . Accordil nerves , 46.+ CIDP, long-term immunosuppression by daily oral corticosteroids and/or immunosuppressants is more efficacious for sustained improvement than repeated IVIg administrations. Notably, in a long-term observational study, the anti-NF155 antibody levels varied in parallel with clinical and electrophysiological changes, or even preceded these changes . Hypertrophy of nerve roots and cranial nerves as well as VEP and blink reflex test abnormalities are also suggestive of NF155+ CIDP. Anti-NF155 antibodies should also be examined in patients with CCPD manifestations. As IVIg alone is not sufficient to treat NF155+ CIDP and nerve hypertrophy responds poorly to immunotherapy after long disease duration (Awareness of IgG4 nodal antibody-positive CIPD is important in clinical practice because IgG4 autoantibody-related neurological diseases are often refractory to conventional immunotherapies, such as IVIg. In NF155duration .+ CIDP is strongly associated with certain HLA class II alleles (The mechanism by which IgG4 anti-NF155 antibodies cause peripheral nerve demyelination by Schwann cell terminal loop detachment from axons has been well-characterized clinically and experimentally, while the mechanisms of severe nerve root and cranial nerve hypertrophy, as well as frequent involvement of CNS tissues, such as optic nerves, remain to be elucidated. In particular, as NF155 alleles , 53, furAnother important issue is to elucidate the mechanism by which IgG4 antibodies against nodal/paranodal proteins emerge. IgG4 class switching requires help from Tfh2 cells producing IL4, IL10, and IL13. Given that IgG4 antibodies act as blocking antibodies to alleviate allergic inflammation by interfering with the binding of allergen-specific IgE to allergens, environmental antigens that cross-react with nodal/paranodal proteins may be important for future investigations.+ CIDP patients (+ CIDP affects young adults and may cause severe disability, unless appropriate combined immunotherapy is introduced in the early course of the disease. Considering the long-term side effects of the corticosteroids and immunosuppressants currently used to suppress relapse in NF155+ CIDP patients, more efficacious and safer drugs for NF155+ CIDP treatment need to be developed.Concerning treatment, clinical trials of an anti-B cell monoclonal antibody therapy are currently being undertaken in NF155patients . NF155+ J-iK contributed to the study conception and design, obtained funding and did the acquisition, analysis, and interpretation of data and the drafting of the manuscript.J-iK received research funds from Dainippon Sumitomo Pharma, Daiichi Sankyo, Mitsubishi Tanabe Pharma, and Kyowa Kensetsukougyo, and consultancy fees, speaking fees and/or honoraria from Novartis Pharma, Mitsubishi Tanabe Pharma, CSL Behring, Biogen Japan, Teijin Health Care, the Takeda Pharmaceutical Company, Kyowa Kirin, Ono Pharmaceutical Co. Ltd., Alexion Pharmaceuticals Inc., Tsumura, Ricoh, EMC, and Eisai.


Akita inu male dog presented with a red penile neoformation. It was further referred for a specialist andrological examination. During the visit, ultrasonography of genital apparatus and cytology of the penile lesion were performed. A suspected neoformation of vascular origin was observed on ultrasonography. Cytology was inconclusive as composition of the sample revealed blood elements only. The neoformation was surgically removed and the excised sample was submitted for the histological examination, which revealed an anomalous varicose dilatation of the venous vascular structures. In human medicine, varicose veins are part of the spectrum of chronic venous disease and include spider telangiectasia, reticular veins, and true varicosities. Reports of penile localization of varicose veins is rare in human medicine and, to the best of our knowledge, it has never been reported in veterinary medicine.Penile varicose veins are a rare lesion described in human medicine. A seven-year-old intact  Varicose veins represent a chronic pathology of the venous vessels  due to rIn human medicine, the pathology is well-known and well-studied: varicose veins belong to the group of the chronic venous diseases. Generally, it is more common in older women with venous insufficiency and high concentrations of estrogen in the blood. Varicose vein transformation is a minor phenomenon of undifferentiated connective tissue dysplasia (UCTD) leading to failure of contractability of their walls due to abnormalities in the fibrous structures and extracellular matrix . In animals, varicose veins are rare, with few case reports that described an ocular localization in dog ,4.In the genital organs, varicose veins have been described in some cases of vaginal changes in mares, and never in males .The aim of this study was to report the clinical and pathological findings of a penile varicose vein in a dog.Akita inu male dog was presented because of an unusual swelling which appeared on the glans penis, particularly evident during moments of excitement. The pet was not used for breeding purposes. The swelling, slightly detected on the surface of the organ on the ventrolateral left side, appeared ovoidal in shape, 0.9 × 0.6 cm, with irregular margins blurring into the surrounding tissue, and with a hollow center. The swelling was not painful and showed the tendency to engorge with blood when a slight pressure was applied on the organ  of the lesion was performed and the smears were stained with May–Grunwald–Giemsa Quick, revealing only a blood-filled background without any cellular details; hence, it was inconclusive. Ultrasonography of the genital apparatus was performed using a linear 12 MHz probe .Based on the obtained results, anesthesia for excisional biopsy and orchiectomy were performed. The anesthetic protocol provided intramuscular premedication with dexmetedomidine  and methadone . Induction was performed with propofol  and maintained with 2% isoflurane inhalation anaesthesia . Orchiectomy was performed by prescrotal approach, and the penile lesion was excised for excisional biopsy b; carefuPost-operative follow-up did not reveal any complications. The surgical wound healed uneventfully c. The teThe excised penile tissue and both testes were fixed in 10% buffered formalin and sent to the laboratory for histological examination. In the left testicle there were no pathological findings. In the right testicle, the parenchyma was entirely composed of seminiferous tubules in which the absence of mature germ cells was observed. Seminiferous tubules were covered by Sertoli cells, often vacuolized (degeneration), mixed with occasional germ cells, such as spermatogonia and spermatocytes, in the early stages of maturation (compatible with spermatogenic arrest). The histopathological picture was suggestive of diffuse testicular tubular atrophy. In the tissue sample from the glans penis (size of 2 × 1 × 0.5 cm), multifocal vascular structures were observed, coalescing, some of which contain red blood cells, markedly dilated, covered by flattened well-differentiated endothelial cells without any pathological alteration a. In theImmunohistochemistry for ER (estrogen receptor) was performed on formalin-fixed paraffine-embedded tissue sections of the testicles. Antigen retrieval was obtained with citrate buffer pH 6.0 for 10 min at 750 W in microwave. Primary antibody  was incubated overnight at 4 °C. ABC kit (Vector) was used to amplify the reaction. Two normal testicles and a normal canine uterus were used as positive control.A moderate intense diffuse nuclear positive staining was observed in both Sertoli cells and Leydig cells, but not in the germ cells of all the examined testicles b. No difThis case report is the first case of a penile varicose vein in dog, which has not been described previously in veterinary medicine literature. Varicose veins are most frequently described in human medicine, where they are part of the spectrum of chronic venous disease. Generally, it is more common in women and in the older age group with venous insufficiency, including venous ulceration . The risGlans localization, to the best our knowledge, has never been described before in veterinary medicine. In men, this is also a rare event, frequently correlated with other pathologies of hormonal dysfunction. A case report of syndromes of functional hypogonadotropic hypogonadism and sterility in males with elevated serum estradiol  has been described. A 36-year-old male was a genotypic male, but phenotypically, he exhibited signs of long-standing estrogen excess, such as a feminine body build, gynecomastia, and varicose veins. In that case, a significantly elevated serum estradiol level was reported and considered the most likely cause of a concurrent functional suppression of gonadotropin secretion . The cliIn humans, a strong relationship has been assessed between hyperestrogenism and varicose veins . The effERα immunoreactivity in the cryptorchid testis was significantly increased compared to the control testis . MultiplIn our case, ER immunohistochemical expression was comparable between the testicle of the affected subject and the control testicles. This does not allow definitive correlation of hyperestrogenism to the varicose veins in this case. The case described represents, to our knowledge, the first case described in Veterinary Medicine to date, and specifically for the canine species. The present case report offers information regarding the incidence of varicose veins in dogs, their location, evolution, and related etiopathogenetic aspects. The varicose vein is a pathological process that does not predispose neoplastic evolution, therefore the possibility of monitoring the lesion without surgery may be a therapeutic option.