The presence of telocytes (TCs) as distinct interstitial cells was previously documented in human dermis. TCs are interstitial cells completely different than dermal fibroblasts. TCs are interconnected in normal dermis in a 3D network and may be involved in skin homeostasis, remodelling, regeneration and repair. The number, distribution and ultrastructure of TCs were recently shown to be affected in systemic scleroderma. Psoriasis is a common inflammatory skin condition (estimated to affect about 0.1–11.8% of population), a keratinization disorder on a genetic background. In psoriasis, the dermis contribution to pathogenesis is frequently eclipsed by remarkable epidermal phenomena. Because of the particular distribution of TCs around blood vessels, we have investigated TCs in the dermis of patients with psoriasis vulgaris using immunohistochemistry (IHC), immunofluorescence (IF), and transmission electron microscopy (TEM). IHC and IF revealed that CD34/PDGFRα-positive TCs are present in human papillary dermis. More TCs were present in the dermis of uninvolved skin and treated skin than in psoriatic dermis. In uninvolved skin, TEM revealed TCs with typical ultrastructural features being involved in a 3D interstitial network in close vicinity to blood vessels in contact with immunoreactive cells in normal and treated skin. In contrast, the number of TCs was significantly decreased in psoriatic plaque. The remaining TCs demonstrated multiple degenerative features: apoptosis, membrane disintegration, cytoplasm fragmentation and nuclear extrusion. We also found changes in the phenotype of vascular smooth muscle cells in small blood vessels that lost the protective envelope formed by TCs. Therefore, impaired TCs could be a ‘missed’ trigger for the characteristic vascular pathology in psoriasis. Our data explain the mechanism of Auspitz’s sign, the most pathognomonic clinical sign of psoriasis vulgaris. This study offers new insights on the cellularity of psoriatic lesions and we suggest that TCs should be considered new cellular targets in forthcoming therapies. We also assessed whether psoriatic skin TCs exhibit (ultra)structural changes. TCs distribution and the pattern of cellular interaction in psoriasis patients could offer new insights into the pathogenesis and progression of this disease.n = 8) or metabolic (n = 2). The skin samples were biopsied three times: from the mature psoriatic lesion, non-lesional skin (40 cm distance from any lesion), and after the clearance induced by local treatment. The treatment followed by the patients was entirely topical: keratolytic  and cytoreductor , followed by calcipotriol and steroid ointments. This study was approved by the Bioethics Committee of the ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest, according to generally accepted international standards. All subjects provided signed informed consent.We studied skin samples from 10 patients  with fully developed (mature) plaques of psoriasis vulgaris. Three of the patients were diagnosed with psoriasis vulgaris type II, and seven were diagnosed with psoriasis vulgaris type I. The triggers of psoriasis were psychological  using a 1 ml syringe until a bleb approximately 5 mm diameter formed under the skin. After testing for numbness, the biopsy was performed with a sterile 6 mm skin punch. After the skin was cored and excess blood cleared the fragment of skin, the biopsy was removed using a scalpel and forceps. The post-biopsy lesion was ligated with two stitches of Ethicon Polyglactin 910 . To prevent infection, the wound was dressed with bacitracin Zn and neomycin sulphate powder  and carefully bandaged.Each of the skin biopsies were divided into two equal fragments, each fragment following the protocol for paraffin embedding for histology, immunohistochemistry (IHC) and immunofluorescence (IF) or Epon embedding for transmission electron microscopy (TEM).Histology and IHC were performed on formalin-fixed, paraffin-embedded, 3-μm-thick tissue sections made from the tissue samples collected from all patients. For histology, standard haematoxylin and eosin staining was performed. For IHC, samples were incubated with primary antibodies Table overnighFor IF we used formalin-fixed paraffin-embedded 3-μm-thick tissue sections. After deparaffinization, the samples were buffered at 97°C with Epitope Retrieval Solution  at pH 6 for PDGFRα and pH 9 for CD34. The samples were washed in PBS with glycine (2 mg/ml) and then blocked with 2% BSA for 1 hr. Samples were incubated with primary antibodies overnight at room temperature with a cocktail consisting of mouse monoclonal CD34  and rabbit polyclonal PDGFRα . After washing three times in EnVisionTM Flex Wash Buffer (Dako) the sections were incubated with anti-mouse Alexa Fluor 488  or anti-rabbit rhodamine  secondary antibodies for another 2 hrs. The nuclei were stained with 4′,6-diamidino-2-phenylindole . Immunofluorescence studies were performed with a Zeiss Axio Imager Z1 microscope (Carl Zeiss MicroImaging GmbH) using 10×, 20×, 40×, and 63× objectives with the appropriate fluorescence filters. Digital images were acquired with a CV-M4+CL CCD camera  linked to a computer running the Isis software .2. The summation of the surfaces of known magnification images was used to obtain this surface area. Data were processed and statistically analysed using Microsoft Excel software.Cell counting was performed on calibrated IF images of known magnification using the NIH ImageJ software 3) tissue fragments processed according to a routine Epon embedding procedure as described previously Transmission electron microscopy was performed on small  had decreased inflammatory infiltrate, and the mild oedema was slightly persistent. Eosinophils and neutrophils were absent from the inflammatory infiltrate. In contrast, the distant uninvolved skin and treated lesion had fewer normally maturated keratinocyte layers and similar rete ridge lengths.CD31 expressed Fig. in the hEndothelial cells were also CD34-positive  in small blood vessels in psoriatic skin Fig.. In addis in smalThe pathogenesis of psoriasis is not fully understood despite efforts to focus on cellular types and signalling molecules We found a decreased number of TCs in psoriatic papillary dermis and observed their recovery after local corticoid therapy. Immunofluorescence showed that the density of TCs identified as CD34/PDGFRα-positive cells was comparable in the dermis of uninvolved and treated skin but decreased in the lesional papillary dermis. Electron microscopy showed that TCs undergo apoptosis and dystrophic changes in psoriatic plaques. Also, IHC showed that CD34-positive cells are not present near dilated capillaries in the dermis of psoriatic plaques. Notably, the interstitial expression of CD34 was slightly increased in the proximity of blood vessels in treated lesional skin. These data suggest TC recovery after topic corticoid therapy despite the residual inflammatory microenvironment We found that TCs usually surround blood vessels in normal skin The 3D reconstruction of dermal TCs by FIB-SEM tomography revealed various conformations of Tps: long, flattened irregular veils (ribbon-like segments) and tubular structures (podomers) with uneven calibre because of irregular dilations (podoms) Vasodilatation tests indicated that arterioles in psoriatic plaques are not normally maximally dilated but have a basal constrictor tone We previously showed that, within the dermis, TCs form an interstitial network based on homocellular (TC-TC junctions) and heterocellular  interactions, suggesting an essential role of TCs in intercellular signalling required for skin homeostasis In conclusion, damaged TCs could be an important step in the pathophysiology of psoriasis. This study offers new insights into the cellularity of psoriatic lesions and we suggest considering TCs as new cellular targets for forthcoming therapies. Because pustular psoriasis is not characterized by Auspitz’s sign, clarifying the involvement of TCs in other forms of psoriasis would be attractive. In the future, we propose extending the research to the pustular and erythrodermic forms of psoriasis.


To assess the functional connectivity in the remodeled, light-insensitive outer rd1 retina, we recorded spontaneous population activity in retinal wholemounts using Ca2+ imaging and identified the participating cell types. Focusing on cones, RBCs and horizontal cells (HCs), we found that these cell types display spontaneous oscillatory activity and form synchronously active clusters. Overall activity was modulated by GABAergic inhibition from interneurons such as HCs and/or possibly interplexiform cells. Many of the activity clusters comprised both cones and RBCs. Opposite to what is expected from the intact (wild-type) cone-ON bipolar cell pathway, cone and RBC activity was positively correlated and, at least partially, mediated by glutamate transporters expressed on RBCs. Deletion of gap junctional coupling between cones reduced the number of clusters, indicating that electrical cone coupling plays a crucial role for generating the observed synchronized oscillations. In conclusion, degeneration-induced synaptic remodeling of the rd1 retina results in a complex self-sustained outer retinal oscillatory network, that complements  the recently described inner retinal oscillatory network consisting of amacrine, bipolar and ganglion cells.During neuronal degenerative diseases, neuronal microcircuits undergo severe structural alterations, leading to remodeling of synaptic connectivity. The functional consequences of such remodeling are mostly unknown. For instance, in mutant  All procedures were performed in accordance with the law on animal protection (Tierschutzgesetz) issued by the German Federal Government.We used adult mice (both genders) at postnatal days (P) 30–60 crossbred from the transgenic 2, 1 MgCl2, 1.25 NaH2PO4, 26 NaHCO3, and 20 glucose, and was maintained at pH 7.4 using carboxygen (95% CO2/5% O2). All chemicals were purchased from Sigma-Aldrich (Germany) and Merck (Germany). Since rd1 degeneration progresses with age and retinal eccentricity, recorded fields (146 × 110 μm) were consistently taken within a ~800 μm radius from the optic disk. Retinas were incubated in extracellular solution containing 0.27 μM Fura-2-AM and 0.1% Pluronic acid  for 35′ at room temperature (RT), washed, mounted on filter membranes  outer retina side up, and transferred to the recording chamber, where the tissue was perfused with carboxygenated medium at 32°C.Eyes were enucleated and the retina was isolated in extracellular solution containing (in mM): 125 NaCl, 2.5 KCl, 2 CaClrd1 mouse retina at P30 , which is consistent with earlier reports . Because ratiometric measurements are much less sensitive to experimental artifacts , we selected the Ca2+ indicator Fura-2 . No differences in activity were detected between cones that contained only Fura-2  and those containing both Fura-2 and TN-XL , therefore we consider it unlikely that the presence of two Ca2+ buffers critically affected our results.To record Ca2+ imaging, we used an upright fluorescence microscope  equipped with a 40x water immersion objective , a polychromator  and a CCD camera  with a resolution of 640 × 480 pixels , corresponding to a retinal area of 0.25 × 0.25 μm per pixel when using the 40x objective. For all experiments a 2 × 2 pixel binning was used. Single-plane two-channel image stacks of the Fura-2 fluorescence in the outer retina were acquired at 10 Hz  using the TillVision software .For Fura-2 CaF340/380). Cells that generated transient Ca2+ events (“active cells”) were identified by calculating the standard deviation (SD) image of each stack using ImageJ (http://rsbweb.nih.gov/ij). The SD images also confirmed that the observed activity was almost exclusively restricted to clearly delineated areas of 5–15 μm in diameter , pointing at active cells and arguing against substantial contributions from the surrounding neuropil.For offline analysis, ratio image stacks were generated by dividing the fluorescence images recorded at the two excitation wavelengths (F340/380 (ratio) response trace. We used F340/380 as a proxy for changes in Ca2+ concentration. Because we were mainly interested in Ca2+ spiking activity (see below) and not in absolute Ca2+ levels, we refrained from calibrating the system. The baseline was determined by averaging F340/380 trace sections between events across the cells of each recorded field. Only cells with signal-to-noise ratios ≥ 10  were included in the analysis. From the ratio traces we then determined the mean Ca2+ event frequency (Fmean) for each cell using a peak detection routine (based on MATLAB's findpeaks routine). In addition, the pair-wise Pearson's correlation coefficient index (Ci) was calculated for all cell pairs (using the corrcoef MATLAB routine). Higher event frequencies, for instance as a result of pharmacologically blocking inhibitory feedback , could, in principle, result in Ci values purely by chance. Therefore, we tested for dependence between Fmean and Ci (using linear regression) but did not find any substantial correlations . This indicates that Ci can indeed be used as a measure for changes in correlated activity between cells. Cell position and type, as well as Fmean and Ci were then compiled to activity maps of each recorded region. The Wilcoxon signed-rank test and the student's t-test were used to evaluate drug effects; statistical significance is indicated as *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, and all parameters are given as mean ± s.e.m.For the subsequent analysis we used custom scripts . Active cells were manually encircled by regions of interest (ROIs) to retrieve their HR2.1:TN-XL “wild-type” mice (our unpublished data). This is consistent with the observation of Borowska et al. .Note that we did not detect comparable spontaneous events in cones in retinal whole mounts of a et al.  that bipC receptor antagonist; 1,2,5,6-Tetrahydropyridin-4-yl)met hylphosphinic acid), 10 Gabazine -1(6H)-pyridazine-butanoic acid hydrobromide), 75 DL-TBOA  and 100 CPPG -α-Cyclopropyl-4-phosphonophenylglycine) were purchased from Tocris Bioscience; 1 strychnine (glycine receptor antagonist), 100 Verapamil  and 100 carbenoxolone -3-(3-Carboxy-1-oxopropoxy)-11-oxoolean-12-en-29-oic acid disodium) were purchased from Sigma-Aldrich; 100 L-AP4  and 20 NBQX  were purchased from Bio Trend. For some experiments, glutamate (250 μM) was directly puffed with a glass pipette for 750 ms onto recorded outer retina neurons using a VC3−8 perfusion system .Drugs were bath applied for 10′ and washed out for 20′. We used (in μM): 50 TPMPA  in extracellular solution for 15′ at RT and washed twice for 20′ in 0.1 M phosphate buffered saline  at 4°C. Retinas were then incubated overnight at 4°C in blocking solution containing 0.3% Triton X-100, 1% BSA and 10% corresponding normal serum from the host animals used for generating the respective secondary antibodies. Subsequently, retinas were incubated for 1–3 days in primary antibodies . The pattern of TN-XL-positive cones was then used as landmark to find the recorded region on the immunostained retina and to determine active cell types by overlaying Fura-2 image, TN-XL image, and the images of the immunostained retina. We observed little shrinkage of the retinal tissue (5–7% compared to the living retina); in any case, because that shrinkage was homogenous we were able to register pictures from live-imaging and immunostained material reliably . In the rd1 x HR2.1:TN-XL line, TN-XL labeling in cones was intensified using antibodies against GFP . In experiments using the C3H/rd1 and rd1 x Cx36−/− lines we identified cones using recoverin staining . In adult rd1 mice, up to 35% of all Fura-2 loaded cells in the outer retina were spontaneously active and displayed transient Ca2+ events . While the mean frequency (Fmean) for individual cells reached up to 3 Hz, the studied types/groups of cells were typically dominated by frequencies below 1 Hz , which are present in cones . Additionally, multi-electrode recordings in the rd1 retina , we used a more “conservative” threshold of 0.75 to focus on the strong interactions between cells.Calcium transients were often synchronized in neighboring cells, forming clusters of correlated oscillatory activity Figure . Such cord1 retinas a total of 144 clusters, including 92 cone-RBC clusters (5.5 ± 3.4 cells/cluster), 31 cone-only clusters .Most activity clusters comprised both cones and RBCs. Under control conditions, we detected in 22 rd1 retina was therefore surprising. It suggests that previously described ectopic synapses between the bulb-like neurites sprouting from cones and RBC somata , likely due to a reduction of inhibition by HCs , as rd1 cones  and of TPMPA+Gz  increased spontaneous activity in RBCs , indicating that there is no direct (GABAergic) excitatory drive from HCs to RBCs. Thus, our data indicate that correlated cone-RBC activity is based on sign-conserving ectopic synapses between cones and RBCs and mediated, at least partially, by glutamate transporters (likely EAAT5).The results so far predict that activation of glutamate transporters on  Figures . Puffing Figures  or verap Figures  failed trd1? To test this, we bath-applied the group III mGluR agonist L-AP4 and antagonist CPPG and measured spontaneous activity. We found that L-AP4 decreased RBC activity, whereas CPPG led to an increase in RBC activity  rd1 RBCs still express functional mGluR6, although the transmission from the cones appears to be dominantly mediated by glutamate transporters, as we find cone-RBC activity to be positively and not negatively correlated (see previous section). (ii) Hyperpolarizing or depolarizing the rd1 RBCs by modulation of the TRPM1 channels via the activation or blockade of mGluR6, respectively, appears to “clamp” the cells' membrane potential and thereby effectively “decouples” RBCs from cone input—restricting synchronous activity largely to cone-only clusters.Is there a role for mGluR6, which mediates transmission from rods to RBCs in wild-type mammalian retina  increased with CPPG  but decreased with L-AP4 , consistent with mGluR8 auto-receptors modulating the cone's basal Ca2+ level  and RBCs , nevertheless, transmission from cones to RBCs appears to be dominated by sign-conserving glutamate transporter activation.Taken together, glutamate released from rd1 retina, neuritic protrusions of remnant cones express Cx36    Figure , in whica Figure , Table 2a Figure  and the a Figure , Table 3rd1 retina, HC neurites sprout vertically toward the outer and inner retina  play a role in  Figures  and the  Figures , Table 3 Figures , suggesti) Some cones and RBCs that were not spontaneously active under control condition started to generate Ca2+ transients and (ii) activity increased in already active cones and RBCs  New activity clusters formed  the cluster composition changed, with the cone/RBC ratio in cone-RBC clusters increasing from 0.8 to 1.3  reduced the number and size of cone-only and cone-RBC clusters but did not significantly affect Fmean in cones and RBCs , we did not investigate this aspect of rd1 remodeling in detail.In addition to the cone network, also HCs form an electrical network. Fura-2 loaded HCs were easily identified because of their regularly spaced large somata, as confirmed by subsequent immunostaining with antibodies against calbindin Figures . In stro Figures . It is u2+ transients and determined Fmean of consecutively identified HCs and cones  coincided with cone Ca2+ transients (0.53 ± 0.42 Hz), whereas not every cone transient was accompanied by a HC transient  Cones make functional synapses onto RBCs and (ii) signal transmission from cones to RBCs is predominantly mediated by glutamate transporters (likely EAAT5) rather than by mGluR6. (iii) This activity is attenuated by HC feedback, primarily via GABAA/C receptors on cones rather than via a complex mechanism that involves GABA auto-receptors on HCs . Sign-inverting mGluR6, which mediate sign-inverting input from rods to RBCs in the wild-type retina, appears to play a minor role, an observation that is in agreement with a previous study showing that rd1 RBCs are much less sensitive for mGluR6 agonists  than that of the Ca2+ signals in outer retina neurons (<3 Hz) observed in this study. This argues against the outer retina as the sole source of inner retina activity, but it does not exclude a contribution of outer retinal activity, i.e., via RBCs and possibly other bipolar cell types. Taken together, oscillatory activity in the rd1 retina is likely generated independently by electrically coupled networks consisting of cones in the outer and AIIs/ON-cone bipolar cells in the inner retina. An important difference, however, may be that the activity in the outer rd1 retina results from synaptic remodeling, whereas for the inner retina a correlation between aberrant activity and structural changes has not (yet) been described.How does the spontaneous activity in cones and RBCs relate to the oscillations described earlier in the inner rd1 mouse also exists in retinal degeneration patients, potentially manifesting as photopsia. Moreover, photopsia poses a severe problem for the development of therapeutic strategies, such as electrical retinal implants (Klauke et al., rd1 outer retinal neurons. Similar effects of gap junction blockers were reported for the spontaneous activity in the inner retina (Borowska et al., Spontaneous activity in the retina of blind human patients has not yet been directly recorded. Nevertheless, patients with retinal degenerative disorders, such as Retinitis Pigmentosa or age-related macular degeneration, often report a discomforting “misperception” of bright, light-independent flashes, a phenomenon described as photopsia (Bittner et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The temporal signature of the IHC Ca2+ AP is modified through an efferent cholinergic feedback from the medial olivocochlear bundle (MOC) and drives the IHC pre- and post-synapse phenotype towards low spontaneous (spike) rate (SR), high-threshold characteristics. With sensory experience, the IHC pre- and post-synapse phenotype matures towards the instruction of low-SR, high-threshold and of high-SR, low-threshold auditory fiber characteristics. Corticosteroid feedback together with local brain-derived nerve growth factor (BDNF) and catecholaminergic neurotransmitters (dopamine) might be essential for this developmental step. In this review, we address the question of whether the control of low-SR and high-SR fiber characteristics is linked to various degrees of vulnerability of auditory fibers in the mature system. In particular, we examine several IHC synaptopathies in the context of various hearing disorders and exemplified shortfalls before and after hearing onset.Before hearing onset, inner hair cell (IHC) maturation proceeds under the influence of spontaneous Ca Accompanied by spontaneous IHC CaMaturation continues with sensory experience under the control of central feedback loops. Within the scope of this review, we summarize the way that feedback circuits from the central nervous system to the IHC synapse might stepwise improve the temporal and frequency resolution of the mature auditory system. We examine the driving forces behind the various auditory fibers of different sensitivities and discuss them in the context of the different degrees of vulnerability of the IHC pre- and post-synapse possibly leading to diverse hearing disorders.2+ APs of IHCs are the result of ATP that is released from the organ of Kölliker and that drives small voltage input in IHCs after birth , a key enzyme in the generation of phosphatidylinositol 4,5-bisphosphate , where they “wait” under the IHC region before targeting the outer hair cells  K+ channels  on time  develop only over time  and the first sound-driven brainstem responses  develop and probably represent the highly synchronous fusion of many vesicles  what is the trigger of this crucial process and (2) how are these final pre- and post-synaptic IHC maturation events interconnected? The following sections provide some currently discussed ideas cocnerning the central feedback control of the IHC maturation steps with sensory experience.On the pre-synaptic side of the IHC synapse, after hearing onset, CaThe IHC pre- and post-synaptic maturation that occurs after hearing onset and that leads to the establishment of lower threshold sound responses has to be seen as a critical, behaviorally relevant step for any individual species. Accordingly, high-SR AN fibers define the lowest thresholds and narrowest dynamic ranges at their characteristic frequency (CF) as shown in many species, including rats, mice and gerbils  can mimic, accelerate, or improve cortical and sub-cortical maturation steps occurring with sensory experience. This is shown in the auditory system in the improved directional sensitivity of primary auditory cortical neurons by EE  leading to BDNF deletion in preferentially the cochlea, dorsal cochlear nucleus and IC induces significantly reduced exocytosis activity in the high-frequency cochlear turns . The failure to improve hearing thresholds in the absence of BDNF goes hand in hand with the prevention of the loss of sound sensitivity after acoustic trauma  possibly comprises low-SR, high-threshold and high-SR, low-threshold fibers. We discuss, in the following section, the possibility of a differential loss of these fiber types in hearing disorders such as tinnitus and hyperacusis.A differential AN fiber loss has previously been hypothesized to be linked in various ways to the central responsiveness related to diverse auditory disorders such as tinnitus and hyperacusis  permits central mobilization of the activity-related gene Arc/Arg3.1 linked with restored supra-threshold ABR waves in No-tinnitus animals. A higher degree of deafferentation  obstructs compensation of central network activity in tinnitus animals  receptors, which are predominantly located on the modiolar side of IHCs, should also be considered  the temporal signature of these spontaneous IHC bursts might serve as the driving force for the segregation of binaural cues; (3) TH eliminates cholinergic input to IHCs and terminates spontaneous APs carried by Ca2+ APs, a prerequisite for the subsequent maturation of efficient Ca2+-dependent exocytosis and/or efficient Ca2+-dependent coupling of exocytosis and endocytosis; (4) CRH-, BDNF- and dopamine-dependent steps influence the properties of high-SR auditory fibers with low-thresholds  before hearing onset, the temporal signature of a defined cholinergic feedback control on IHC Ca


There have been few studies of how personal and instrumental activities of daily living (P-ADL and I-ADL) develop over time in older people receiving domiciliary care. This study aimed at assessing variables associated with the development of P-ADL and I-ADL functioning over a 36-month follow-up period, with a particular focus on cognitive functioning.In all, 1001 older people (≥70 years) receiving domiciliary care were included in a longitudinal study with three assessments of P-ADL and I-ADL functioning during 36 months. P-ADL and I-ADL were assessed using the Lawton and Brody’s Physical Self-Maintenance Scale and Instrumental Activities of Daily Living Scale, respectively. Mini Mental State Examination (MMSE), diagnosis of dementia and MCI, neuropsychiatric symptoms and use of psychotropic medication were also evaluated during the three assessments. Baseline demographic and general medical health information and information of being a nursing home resident at follow-up were recorded. Linear mixed models were estimated.There was a significant decline in P-ADL and I-ADL functioning throughout the follow-up. A lower MMSE sum-score, diagnosed MCI and dementia, a higher level of neuropsychiatric symptoms and the use of antipsychotics and antidepressants recorded at each assessment were associated with a decline in both P-ADL and I-ADL functioning. Furthermore, a decline in P-ADL and I-ADL functioning at follow-ups was associated with being male, a higher baseline age and in poorer medical health as well as residing in a nursing home at follow-up.P-ADL and I-ADL functioning in older people worsened over time. The worsening was associated with lower MMSE sum-score, diagnosed MCI and dementia, poorer medical health, neuropsychiatric symptoms, use of psychotropic medication and being transferred to nursing home care. Clinicians should pay close attention to the assessment and treatment of these factors to help older people maintain their level of functioning for as long as possible. In older people, cognitive state and activities of daily living (ADL) functioning are important for mortality, institutionalization, and quality of life -3. ADL dThe association between cognitive decline and decline in ADL functioning in older people is well-known from numerous of studies covering a wide range of countries -11 that Cognitive functioning is one of several factors important in the decline in ADL functioning . Other mWe conducted a study to examine the association between cognitive functioning, both at the baseline and at two follow-ups over a 36-month period, and to examine the development in P-ADL and I-ADL functioning assessed by the Physical Self-Maintenance Scale (P-ADL sum-score) and the Instrumental Activities of Daily Living Scale (I-ADL sum-score) , respectThis was a 36-month prospective study with three assessments. The baseline assessment took place between August 2008 and December 2010. The two follow-up assessments took place after 18 and 36 months.A representative sample of older people (≥70 years) receiving domiciliary care was recruited from 19 municipalities in five counties in the eastern part of Norway. Both rural and urban municipalities of various sizes were invited to participate in the study. A random selection of older recipients of domiciliary care with a next of kin who saw them at least once a week was made, regardless of the amount and kind of service received. Of 1,796 eligible people, 795 declined to participate . Those wThe levels of personal and instrumental functioning (the dependent variables) were reported by the next of kin at all assessments and classified using Lawton and Brody’s Physical Self-Maintenance Scale (P-ADL) and Instrumental Activities of Daily Living Scale (I-ADL) . The P-ACognitive functioning was evaluated at each assessment by the Mini-Mental State Examination (MMSE) , InformaThe severity of the dementia was evaluated at each assessment by the Clinical Dementia Rating Scale . The CDTwo physicians (SB & GS) with extensive experience in research and clinical old age psychiatry independently diagnosed dementia according to the ICD-10 criteria and mild cognitive impairment (MCI) according to the Winblad criteria  using alPsychotropic medications were grouped according to the ATC code, as antipsychotics (N05A except lithium), antidepressants (N06A), anxiolytics (N05B), hypnotics/sedatives (N05C), and anti-dementia medication (N06D) (yes versus no). The information was collected from the medical record of each individual at the initial assessment.The General Medical Health Rating Scale was used at the baseline to evaluate comorbidity. This is a four-point global scale for scoring the degree of somatic illness from very good (1) to very poor (4). The scale considers each patient’s number of general medical conditions, the severity of these conditions, and the use of medication due to the conditions .Demographic information including age, gender, marital status at inclusion, and municipality of residence, was collected as a part of the general baseline examination.Formal level of care over time was recorded as living at home with domiciliary care, or living in a nursing home.A research nurse coordinated the project and cooperated with the health workers, who were assessors in each of the municipalities. The assessors, mostly nurses, social educators, and occupational therapists, interviewed participants and their next of kin in the 19 municipalities. Before the baseline data collection, all assessors went through a two-day course with training in how to use the assessment scales. Interviews with each participant and their next of kin were performed simultaneously in their own homes by two separate assessors. A one-day training program was conducted prior to each follow-up assessment.Both written and oral study information was given to the participants and their next of kin. Written informed consent was obtained from both the participant and their next of kin before the interviews were conducted. In those lacking the capacity to give consent, the closest family proxy gave informed consent on behalf of their next of kin. The project was approved by the Regional Committee for Medical and Health Research Ethics for Eastern Norway (S-08111b), the Norwegian Social Science Data Services (NSD) (07–2008SI), and the Directorate for Health and Social Affairs (08/2984).Continuous socio-demographic and clinical characteristics were presented as means and standard deviations (SD), while frequencies and proportions were used for categorical characteristics. An intra-class correlation coefficient (ICC) was calculated for both outcomes, P-ADL and I-ADL, to quantify a proportion of intra-municipality variation. There was a significant cluster effect on the municipality level found in both variables, confirming a hierarchical structure in the data. Moreover, the data were collected at three times, comprising repeated measurements for each patient. Therefore, a linear mixed model with random intercepts for patients and nursing homes was estimated (SAS MIXED procedure). Fixed effects for both linear and second-order time components were included. The second-order time component was only left in the model if it was significant. Trend estimates were further adjusted for the (main) independent variable, the degree of cognitive functioning (MMSE sum-score). An interaction term between the degree of cognitive functioning (MMSE) and time was included into the model. For each outcome (P-ADL and I-ADL sum-score), two different models with respect to adjustments were estimated. In both models, adjustment variables included demographic characteristics , dementia, general somatic health, neuropsychiatric symptoms, and use of psychotropic medications. The first model contained adjustment variables that were assessed at the baseline. The second model included demographic characteristics and general somatic health, also assessed at the baseline, while dementia, neuropsychiatric symptoms, and use of psychotropic medications were entered as longitudinal variables. Changes in level of care from domiciliary care to nursing home care were also included in the second model. The results of the regression analysis were tabulated as coefficients with the corresponding 95% confidence intervals (CI) and p-values. The P-ADL and I-ADL sum-scores at each assessment, which were estimated as the average value of the MMSE sum-score from the baseline assessment, were illustrated graphically.Analyses were performed in SAS v9.3 and SPSS v22. P-values below 0.05 were considered statistically significant. All tests were two-sided.At the baseline, the mean (SD) age was 83.4 (5.7) years , a higher psychosis sub-syndrome score and affective sub-syndrome score, as well as using antipsychotic, antidepressants, anxiolytics, and anti-dementia medication were associated with lower I-ADL functioning. Being a nursing home resident at the time of the second and third assessments was associated with significantly poorer I-ADL functioning at the same assessments compared to those living at home at the same assessments.Figure This follow-up study of 1,001 older community-dwelling people (≥70 years) receiving domiciliary care found that reduced cognitive functioning at the baseline and the course of cognitive functioning assessed with MMSE during follow-up were associated with significantly lower P-ADL and I-ADL functioning. Independently of the adjustments made, there was a decline in P-ADL and I-ADL functioning over time. In addition, the rate of decline in I-ADL functioning, but not P-ADL functioning, flattened during the time of follow-up.Numerous other authors have pointed to a relationship between reduced cognitive functioning and worsening P-ADL in older community-dwelling people -9,14-19,In the present study, we assessed P-ADL and I-ADL functioning separately and at all assessments. We found a decline in I-ADL functioning by time and cognitive functioning, as we did for P-ADL functioning, but we also found that the slope of decline in I-ADL functioning flattened at the third assessment. The I-ADL assessment covers more complex activities of daily living than the P-ADL assessment . ImpairmIndependent of the assessed ADL functioning outcome (I-ADL or P-ADL functioning), we found that lower age and better general somatic health at the baseline were associated with better functioning throughout the assessment period. These results are in accordance with findings from other community studies assessing risk factors for the decline of ADL functioning over time . In the In population-based studies, men often reported higher P-ADL and I-ADL functioning than women . In the In the adjusted analyses, we found that participants with dementia had worse P-ADL and I-ADL functioning at each time point compared to participants without dementia. Furthermore, we found that those with MCI had worse I-ADL functioning, but not P-ADL functioning at the same assessments as those without dementia. This was expected since previous research has found MCI to affect complex ADL (I-ADL) functioning, but not basic self-care (P-ADL) functioning , while dInterestingly, we found that worsening ADL functioning at each assessment was associated with higher levels of neuropsychiatric symptoms at the same assessment. Higher agitation and affective sub-syndromes scores were associated with worsening P-ADL functioning, while higher psychosis and affective sub-syndromes scores were associated with worsening I-ADL functioning. To our knowledge, no previous studies have explored neuropsychiatric symptoms in relation to ADL functioning in community-dwelling older people. However, a recent study of decline in P-ADL functioning with four assessments in nursing home residents are in line with the present study in reporting that higher neuropsychiatric symptoms were associated with worsening P-ADL functioning . MoreoveCommunity-dwelling older people receiving domiciliary care represent a vulnerable group, and at assessments two and three, 86 (14.4%) and 114 (25.2%) participants had become nursing home residents, respectively. Being a receiver of nursing home care at assessment two and three was associated with worsening ADL functioning at the same assessments compared to those receiving care at home. Other studies have also reported that a decline in ADL is associated with nursing home admission ,59. In aWhile the study has a number of advantages, such as using well-known, internationally accepted P-ADL and I-ADL assessment scales, a high number of baseline participants, use of a direct measure of cognitive functioning, and adjustments for a high number of variables of potential importance to the outcome, such as medical health, demographic variables, and diagnosed MCI and dementia, it nevertheless has some limitations that need to be addressed.First, the associations found in our study should be interpreted with caution since our design does not allow for inferences about causality.Secondly, participants differed in mean age and gender distribution from the original population, many of whom refused participation at the baseline . Even thThirdly, assessments of P-ADL and I-ADL functioning in older people in a longitudinal study with three follow-ups over a three years period are statistically challenging. Repeated measurements of the same individuals imply dependency in data. Having a large number of drop-outs due to death and other reasons, leads to a varying number of observations per individual and generates data imbalances. Furthermore, a number of the independent variables in the adjusted models vary with time. However, the linear mixed model handles any degree of imbalance in data by including all available data . It alsoFourthly, even if information about the use psychotropic medications were available, we did not have information about the dosages or length of the use of the psychotropic medications. We also used a very rough assessment of level of care, i.e. domiciliary care or nursing home care at the second and third assessment time point. We did not have detailed information about the degree of domiciliary care that was provided at any assessment time point, but we expect that individuals whose ADL functions decline a great deal will have received more care compared with those who performed better. Lastly, since I-ADL function is often related to mobility , it woulIn a large-scale longitudinal study among older people who receive domiciliary care that included three assessments over a 36-month period, we found that P-ADL and I-ADL functioning declined over time. Furthermore, the worsening of P-ADL and I-ADL functioning was associated with lower baseline cognitive functioning and with a decline in cognitive functioning during follow-up. The degree of decline in I-ADL functioning explained by cognitive functioning decreased during follow-up. Clinicians should pay attention to the associates of P-ADL and I-ADL functioning identified in this study so they can better tailor care, and thus, help older people maintain their level of functioning as long as possible.


Visual working memory (VWM) is the ability to hold in mind visual information for brief periods of time. The current study investigated VWM precision development longitudinally. Participants  completed delayed reproduction sequential VWM tasks at baseline and two years later. Results show age-related improvement in recall precision on both 1-item and 3-item VWM tasks, suggesting development during childhood and early adolescence in the resolution with which both single and multiple items are stored in VWM. Probabilistic modelling of response distribution data suggests age-related improvement in precision is attributable to a specific decrease in the variability (noisiness) of stored feature representations. This highlights a novel developmental mechanism which may underlie longitudinal improvement in VWM performance, crucially without invoking improvement in the number of items that can be stored. VWM precision provides a sensitive metric with which to track developmental changes longitudinally, shedding light on underlying cognitive mechanisms. This abnumber of items that can be remembered, e.g. using tasks that measure recall span or change detection. These reports rely on the classical concept that VWM is limited to holding only a very small number of items, as little as 3 or 4 in adults, arguing in favour of a ‘quantal’ memory mechanism limited to 3–4 memory ‘slots’ is erroneously linked with the feature (e.g. orientation) of a different object stored in memory  in response. After controlling for developmental changes in sensorimotor performance, we predicted longitudinal increases in recall precision on both the 1-item and 3-item VWM tasks. In addition, we predicted mixture modelling of recall data from the 3-item VWM task would provide evidence that effects of age are attributable specifically to a decrease in variability in the representation of target stimuli, and not to any changes in random guessing or misbinding. That is, the mixture modelling would shed further light on more fundamental cognitive mechanisms underlying memory development—whether changes in VWM performance are due to developmental increases in continuous memory resource, or to some other process such as reduced frequency of misbinding or guessing.22.1t1 and t2). Participant age at t1 ranged from 7.9 to 11.7 years, with mean 10.2 and standard deviation (SD) 1.02 (see N = 90) cross-sectional cohort  preparatory school in Oxfordshire and tested on the same protocol twice, two years apart (1.02 see . Particil cohort . The cur2.2www.gl-assessment.co.uk) were provided by the school for each participant at t1 and transformed into estimated full-scale IQ  was presented against a grey background. After 500 ms following the presentation of the bar, a probe bar of the same colour surrounded by a black circle appeared below the target. Participants were asked to adjust the orientation of the probe bar using a rotating dial to match the orientation of the target which remained on screen until response. The black circle surrounding the probe item disappeared upon rotating the dial.Bar colour was selected so as to be easily distinguishable—as in the colour-naming task. The orientation of the target and probe were independently randomized. The inter-trial interval (ITI) was 500 ms.2.3.3Directly after completion of the sensorimotor control task, participants completed 30 trials of a 1-item VWM task. On each trial, participants were presented with a single coloured oriented bar at the centre of the screen for 500 ms. Following a blank 500 ms delay, a probe bar of the same colour appeared at the centre of the screen surrounded by a black circle. Participants were asked to adjust the probe bar’s orientation to match the orientation of the probed (‘target’) bar using the dial B.Participants completed 30 trials of this task divided into 2 blocks of 15 trials each with a short break in between blocks. During the break participants were encouraged to focus on a far point in the room, to minimise ocular fatigue. The ITI was 500 ms.2.3.4Directly after completion of the 1-item VWM task, participants completed 90 trials of a 3-item VWM task. A schematic presentation of this task is shown in 2.42.4.1We calculated recall precision as the reciprocal of the circular standard deviation of response error (where response error is the difference between response and target angles) . Precisit-tests) were conducted comparing t1 vs. t2 corrected 1- and 3-item VWM precision values  as well as sensorimotor precision. Statistical significance was p < 0.05. Non-parametric statistics were used since in our data precision is not normally distributed. Finally, to investigate differential trajectories of development for 3-item relative to 1-item VWM tasks, Wilcoxon signed-rank tests were conducted comparing t1 vs. t2 3-item VWM precision values, corrected for 1-item VWM performance by subtracting 1-item VWM recall error from overall 3-item VWM recall error and recalculating precision accordingly (i.e. 1/sqrt(difference in error variance)).To evaluate developmental changes in precision, Wilcoxon signed-rank tests . This model is described by the following equation:In order to identify mechanisms underlying developmental changes in precision on the 3-item VWM task, we fit a probabilistic model that dissociates different sources of error in memory previously introduced by combination of orientation and colour. Therefore, changes in performance on the 3-item VWM task could arise as a result of changes in the proportion of responses arising as a result of an incorrect conjunction of colour and orientation (misbinding errors). In such trials participants make an error centred on the orientation of other (non-probed) items in the sequence . κ is a measure of variability, where higher κ corresponds to lower variability in memory representations A. Successequence B. In cledel by γ C, where t-tests to compare t1 vs. t2 measures of κ and the proportion of target, non-target and random responses.Maximum likelihood parameters of κ, α, β and γ were obtained for each task using an expectation maximization procedure for each participant . Using t33.1t1 and t2 . Thus, precision of recall for even a single item maintained in memory increased after 2 years in childhood and early adolescence.Mean precision on the 1-item VWM task improved significantly after 2 years after correcting for developmental change in sensorimotor precision  with no significant difference for the third item  orientation. As shown in sources of error, and how these alter with age. That is, overall performance does not shed light on whether improved VWM performance is due to decreased variability in response for the target feature (kappa), changes in proportion of target (p(T)) or non-target responses (p(NT)), or increased random responses (p(U)). We therefore fit a probabilistic model  = 3.3, p = 0.002), crucially with no change in other model parameters: t(39) = 1.6, p = 0.12 for p(T), t(39) = 1.4, p = 0.18 for p(NT and t(39) = 0.3, p = 0.73 for p(U) (Results show that kappa (inverse of variability in response around probed or target orientation) increased significantly with age (for p(U) C. Thus v4t1 completed a VWM precision task battery twice, two years apart. Results demonstrate firstly that recall precision increased with age on both 1-item and 3-item sequential VWM precision tasks. These increases remained significant after controlling for age-related improvement in performance on a sensorimotor control task. Second, the longitudinal effects of age were attributable to a specific decrease in variability in the representation of target stimuli, and not due to changes in random responding or to misbinding, i.e. corruption by features of other items retained in memory. We discuss implications in terms of developmental mechanisms underlying observed improvements in VWM performance with age.The current study investigated longitudinal development of VWM precision during childhood and early adolescence. Forty participants aged 7–11 years at 4.1A number of studies have shown improvement across childhood in performance on standard tests of VWM . In the These conclusions align with those from cross-sectional studies showing age-associated development during childhood and adolescence in VWM performance . The cur4.2Continuous VWM tasks provide a means to examine the sources of error in recall. We applied a probabilistic model  to respoIn future, delayed reproduction VWM tasks accompanied by probabilistic modelling of response data could also provide a useful tool for characterising more fully neural changes associated with VWM across the lifespan. Several studies have shown that it is possible to track development of the functional neural substrates of VWM during childhood and adolescence . Using p4.3difference in recall precision between 1-item and 3-item tasks, conceptually equivalent to an age by task interaction. That is, whereas we demonstrate significant improvement with age on both VWM tasks, improvement on the harder 3-item task was more substantial. Further empirical studies are needed to explore the developmental cognitive mechanisms underlying this result. Possibilities include development of attention (The current study showed effects of age on the ttention  or even ttention .5precision of VWM for individually and multiply-encoded items develops throughout middle childhood and early adolescence. This development is attributable to a specific decrease in variability – noisiness – of stored feature representations. This highlights a mechanism that may underlie longitudinal improvement in VWM performance, without invoking improvement in the number of items that can be stored.We present longitudinal evidence that the These findings demonstrate protracted development in VWM performance and shed light on the potential mechanisms which could underpin this development longitudinally. Currently, there is much interest in modifying cognition as a means of addressing suboptimal developmental trajectories . VWM rec


Noise induced hearing loss (NIHL) remains as a severe health problem worldwide. Existing noise metrics and modeling for evaluation of NIHL are limited on prediction of gradually developing NIHL (GDHL) caused by high-level occupational noise. In this study, we proposed two auditory fatigue based models, including equal velocity level (EVL) and complex velocity level (CVL), which combine the high-cycle fatigue theory with the mammalian auditory model, to predict GDHL. The mammalian auditory model is introduced by combining the transfer function of the external-middle ear and the triple-path nonlinear (TRNL) filter to obtain velocities of basilar membrane (BM) in cochlea. The high-cycle fatigue theory is based on the assumption that GDHL can be considered as a process of long-cycle mechanical fatigue failure of organ of Corti. Furthermore, a series of chinchilla experimental data are used to validate the effectiveness of the proposed fatigue models. The regression analysis results show that both proposed fatigue models have high corrections with four hearing loss indices. It indicates that the proposed models can accurately predict hearing loss in chinchilla. Results suggest that the CVL model is more accurate compared to the EVL model on prediction of the auditory risk of exposure to hazardous occupational noise. Noise induced hearing loss (NIHL) is a serious problem that affects many people worldwide. According to the World Health Organization (WHO), exposure to excessive noise is the major avoidable cause of permanent hearing loss . It is eLAeq) [To estimate NIHL, various standards and regulations have been developed over years, for example, ISO 1999:2013 , ANSI-S3LAeq) . These nIn recent years, the mammalian auditory model has been utilized to develop more advanced models for assessment and prediction of NIHL. Price  developeNumerous auditory models (AMs) have been developed in the past decades –22. ThesFor NIHL study, the key consideration for choosing an AM is how to accurately quantify the flow of acoustic power from the environment into the inner ear . In addiIn functional auditory models, three families of auditory filters have been developed, including the rounded exponential (roex) family, the gammatone family , and the filter cascades  . The roeIn material science, fatigue is a progressive and localized structural damage of a material caused by repeatedly applied loads. There are two kinds of material fatigues, low-cycle and high-cycle fatigues . For lowAssuming that the hearing loss intrinsically is a mechanical failure of the auditory system  –32, NIHLIn addition, instead of using the displacement of BM as the loads in , the velS-N) curve and the Miner rule in the high-cycle fatigue theory, the EVL and CVL fatigue based models are developed, respectively. In addition, a series of chinchilla noise exposure data are applied to validate the effectiveness of our developed models for prediction of NIHL in this paper.In this study, two BM velocities based fatigue models, equivalent velocity level (EVL) and complex velocity level (CVL), are proposed to predict the GDHL caused by occupational noise. The auditory model combining the external-middle ear model and the TRNL filter is applied to obtain the BM velocities at different partitions of cochlea ). Based on the stress against cycles to failure  as shown in VS and sound pressure near the TM in the ear canal PTM (SVTF = VS/PTM) [VS can be obtained through dividing volume velocity US by average area of the footplate  , where t = 2 mm2 ).One can assume that cochlea is a two-chambered, fluid-filled box with rigid side walls , and theVS and the output represents the BM velocity of a particular location along the cochlea partition. Each individual site is represented as a tuned system including three parallel signal-processes paths: one linear (left), one nonlinear (middle), and one low-gain linear (right). The first linear path consists of a bandpass function, a low pass function, and a gain/attenuation factor, g, in a cascade. The nonlinear path is a cascade combination of a bandpass function, a compression function, a second bandpass function, and a low pass function. The third linear path includes a linear, low-gain, all-pass filter. The output of the system is the sum of outputs of the three signal-processing paths.In this study, the TRNL filter introduced in  has beenx(t) is the output of the first filter in the nonlinear path. a, b, and c are parameters of the model. The values for these parameters are summarized in Each individual bandpass function is a cascade of two or more gammatone filters  with uniS-N curve based EVL model and the Miner rule based CVL model, are proposed to calculate noise induced cumulative hazard, denoted by the number of fatigue cycles.In this study, two fatigue models, the S-N curve. In this model, the BM velocities, which are regarded as stresses (“S”), correspond to the hearing damage, which can be quantitatively denoted by numbers of cycles (“N”) that cause the functional failure of hair cells. Assuming that hearing loss level of a deaf ear is 1 and the hearing loss level of a normal ear is 0, we can quantitatively describe the degree of hearing loss in Δt asV(t) and N(t) are the velocity and corresponding failure cycles at time t, respectively. Considering that it takes long time to produce GDHL, the S-N curve used in this study can be considered as a linear approximation. Accordingly, H0 = V0N0 represents the total hearing loss and can be normalized as 1. Furthermore, supposing that the hearing damage is calculated in unit time period, which means that dN(t) = 1, and assuming that the negative velocity produces the same level hazard as the positive velocity, HV(t),Δt in  refers to the velocity of the ith ERB band of BM at time j. The constant V0 is the BM velocity located at the ERB with 1 kHz center frequency. To characterize the auditory system, ERB based frequency band physically corresponds to the space ERB distance of BM [Li,EVL reflects the integration of hearing loss level at the ith ERB temporally. Comparatively, LI,EVL is the hearing loss level in frequency band I, in which several ERBs might be included. Based on the EVL model, the concept described in  = 5 and v(t + 1) = −6, they will only be characterized according to their amplitudes as 5 and 6 under the S-N circumstance. In contrast, in the Miner rule, they can be characterized according to both the amplitude and the mean value of the two loads, regarded as |(v(t) + v(t + 1))/2|, which will be applied to assess the corresponding damage. In order to obtain the amplitude and mean value distribution of the input, rainflow counting algorithm is developed, which is used to reduce a spectrum of varying stress into a set of simple stress reversals [The CVL model is designed based on the Miner rule, which has been commonly used to predict high-cycle fatigue life. In the EVL model, the transition of adjacent stimulus is not accounted for because the loads in the eversals . The conith ERB in certain time duration and can be described asB is a constant and can be treated as unit. vk is the number of cycles of load in kth category with a Vk failure cycles. The number of categories is defined as K = NAmplitude∗NMean, where NAmplitude and NMean are the length of the x-axis and y-axis in Hi,CVL is the integration of different types of inputs along time axis as follows:A is the amplitude of velocity and M is the mean value of the adjacent velocities. Based on the ith ERB hearing loss Hi,CVL, CVL can be obtained:H0 is the hearing loss at the ERB with 1 kHz CF. Similar to the EVL model, Li,CVL and LI,CVL are the log scale metrics of hearing loss at ith ERB and I frequency band.As shown in A series of the animal experimental data were used for effectiveness validation of the proposed fatigue models. The animal data were provided by the research group at State University of New York at Plattsburgh and were used in published animal noise exposure experiments , 55. 22 1248 = (1/4)(PTS1 + PTS2 + PTS4 + PTS8), where PTS1, PTS2, PTS4, and PTS8 are the PTS values measured at the one-octave band with center frequencies 1, 2, 4, and 8 kHz, respectively. The same rule is applied to TTS to obtain TTS1248. LAeq of 22 different noise samples and OHC and IHC (at six different one-octave bands) of animals in each group corresponding to the noise sample.Detailed descriptions of the noise data and experimental protocols of animal studies are available in various publications , 55. In T-F) distributions of the BM velocities in the cochlea as the output of the TRNL filter, responding to the simulated noises. The frequency axis labeled as the locations along the BM, which refers to the partitions in the cochlea. Each partition works as a bandpass filter, which can be represented by the ERBs with different CFs. The highest CF is at the base of the cochlea, and CFs decrease from the base to the apex of the cochlea [The distribution of BM velocities is obtained by the TRNL filter (as shown in  cochlea .BM velocity responding to the simulated impulse noise (the Dirac delta function) is shown in Furthermore, two chirp noise signals in different frequency bands were simulated and applied to the TRNL filter to validate the BM motion responding to different frequency components. Figures T-F domain as the output of the developed chinchilla auditory model. The noise sample G63, as shown in the insert figure in Two experimental noise samples  were used as inputs to validate the developed chinchilla auditory model, including the consecutive external-middle ear and the inner ear. As shown in the front views in Figures As shown in Figures LEVL and LCVL) and NIHL (hearing loss indices) can be evaluated by applying the linear regression analysis as described in [ϵ is the error to be minimized and Lmetric refers to the proposed fatigue metrics. The expressions of other three hearing loss indices are the same as PTSLoss in  at six one-octave frequency bands has been conducted using all 22 groups of experimental data. r2 value is used to reveal the linear correlation between two variables. r2 = 1 indicates a perfect correlation and r2 = 0 indicates no correlation between the fatigue models and NIHL. The values of r2 are summarized in r2 values at 2, 4, and 8 kHz are higher than these values at 0.5 and 1 kHz. It means that both LEVL and LCVL have strong correlations with hearing loss indices at frequency bands centered at 2, 4, and 8 kHz. In contrast, the metrics demonstrate weak correlations with hearing loss indices at low frequency bands, for example, 0.5 and 1 kHz. The results are consistant with LEVL and LCVL show the highest correlations with TTS than other three hearing loss indices  at all frequency bands. TTS refers to the instant hearing loss immediately after a noise exposure, while the PTS is the permanent hearing loss after noise exposure and certain recovery time [p values of linear regressions are lower than 0.05. There are eight p values higher than 0.05, including LEVL-OHC at 0.5 kHz, LEVL-IHC at 0.5, 1, 8, and 16 kHz, LCVL-IHC at 0.5 and 1 kHz, and LEVL-PTS at 0.5 kHz. The results indicate that most of the linear regressions are statistically significant.Moreover, the ery time . TTS dir1248 loss, OHC1248 loss, TTS1248, and PTS1248, were used for the regression analysis. 1248 loss and OHC1248 loss. It can be found that OHC1248 loss is larger than IHC1248 loss, and both LEVL and LCVL have stronger correlations with OHC1248 loss than with IHC1248 loss. The scattering plots and the fitting lines of the pairs of the developed fatigue metrics and TTS1248 and PTS1248 are shown in 1248 than with PTS1248.To further evaluate the effectiveness of the proposed fatigue metrics on NIHL prediction, hearing loss indices averaged by the one-octave bands centered at 1, 2, 4, and 8 kHz, including IHCr2 values with all four effective hearing loss indices. This indicates that both developed fatigue models have high correlations with the chinchilla experimental hearing loss data. Specifically, the r2 values between the fatigue metrics and two major hearing loss indices (TTS1248 and PTS1248) are higher than 0.65, which is considerable high value in the regression analysis. Further, all the p values are lower than 0.001; consequentially the linear regressions are statistically significant. It means that the developed fatigue models can accurately predict NIHL in chinchilla.The regression analysis results of the fatigue models and four effective hearing loss indices are summarized in Moreover, one can also see that, in both Tables In this study, we developed two fatigue models , which combined the high-cycle fatigue model with the mammalian auditory model, to predict GDHL. The high-cycle fatigue theory was used because GDHL caused by occupational noise can be considered as a long-time process of physical compression and stretching of organ of Corti. The mammalian auditory model was introduced by combining the TRNL filter with the transfer function of the external-middle ear to accurately characterize the vibration of BM. A series of animal noise exposure data were used to validate the effectiveness of the developed fatigue models. The regression analysis of fatigue models and four hearing loss indices was conducted. Results showed that both fatigue models have high correlations with animal hearing loss data. It indicates that the developed models can accurately predict the NIHL in chinchilla. In addition, the CVL model demonstrated higher correlations with four hearing loss indices than the EVL model. The CVL model would be more accurate on the evaluation of the auditory risk of exposure to hazardous occupational noise. In our future work, we will develop fatigue based models for prediction of auditory risk on human exposed to high-level occupational noise.


However, evidence from human studies is scarce. Our study aims to investigate the relationship between TCS exposure and semen quality. We measured urinary TCS concentrations in 471 men recruited from a male reproductive health clinic. TCS was detected in 96.7% of urine samples, with a median concentration of 0.97 ng (mg·creatinine)−1 −1). A multiple linear regression analysis showed a negative association between natural logarithm (Ln) transformed TCS concentration (Ln-TCS) and Ln transformed number of forward moving sperms  . Furthermore, among those with the lowest tertile of TCS level, Ln-TCS was negatively associated with the number of forward moving sperms ), percentage of sperms with normal morphology ), as well as number of normal morphological sperms, sperm concentration and count. Our findings suggest that the adverse effect of TCS on semen quality is modest at the environment-relevant dose in humans. Further studies are needed to confirm our findings.Triclosan  is widely used in personal care, household, veterinary and industrial products. It was considered as a potential male reproductive toxicant in previous  Triclosan , a broad spectrum antimicrobial agent, is widely used in personal care, household as well as health care products, including toothpastes, antibacterial soaps, shampoos, deodorants, cosmetics, kitchen utensils, toys, bedding and clothes . The use−1 in 2003–2004 National Health and Nutrition Examination Surveys (NHANES) of the U.S. population [The daily contact of all types of TCS-containing products and the environment contributes to the wide spread exposure of TCS to human beings’. The derma and digestive tract are two main positions of TCS absorption ,5. TCS hpulation .In vitro studies have shown that TCS binds to androgen receptors (AR) and exhibits an anti-androgenic activity in human breast cancer cells [Despite its high occurrence across the ecosystem, the health effect of TCS has not been well studied. Recently, TCS is suspected to be a potential male reproductive toxicant. er cells . This cher cells ,11. TCS er cells . TCS haser cells . HoweverMale volunteers were recruited at a male reproductive health clinic in a university affiliated teaching hospital during November 2013–March 2014. The study was approved by the Ethics committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China (XHEC-C-2013-001). All participants signed a written informed consent. Through a face-to-face interview, a trained interviewer filled in a standardized questionnaire to obtain information on participants’ demographic characteristics, living and working environment, health-related behaviors, sexual and reproductive status, as well as medical history that may affect reproductive health. The participants were asked to provide a single spot urine sample and semen specimen as part of their clinical examination on the day of their clinic visit.Of the 526 men recruited, we excluded subjects with cryptorchidism, varicocele, male infertility and those who failed to provide urine or semen samples. Four-hundred-seventy-one men were included in the final analysis .About 50 mL urine sample was collected in a sterile polypropylene cup from each subject, aliquoted to polypropylene storage tubes  and stored at –80 °C until TCS analysis.−1, Dr. Ehrenstorfer GmbH, Augsburg, Germany) was added into a 4 mL urine sample. Then, samples were incubated in 1 mol·L−1 ammonium acetate buffer solution (pH = 5.0) with 20,000 IU·mL−1 β-glucuronidase  at 37 °C overnight to hydrolyze the conjugated TCS. Secondly, regeneration of solid phase extraction (SPE) (500 mg (3 mL)−1, Supelco, Bellefonte, PA, USA) with 3 mL 100% methanol and equilibration of SPE with 3 mL H2O were performed. Thirdly, TCS was retained and concentrated by a SPE, eluted by 9 mL acetonitrile, concentratedby speed vacuum concentrator and redissolved in 200 uL 90% methanol. After that, separation and determination of TCS were performed using high performance liquid chromatography–electrospray ionization tandem mass spectrometry (HPLC-MS/MS) . Separations were carried out on a ZORBAX RRHD Eclipse plus C18  column . The column was maintained at 40 °C. The mobile phase consisted of (A) 10 mmol/L ammonium acetate in water and (B) methanol. The gradient elution method was as follows: 60% B at 0–5 min (0.3 mL·min−1), 90% B at 6–9 min (0.3 mL·min−1), then changed gradually to 50% B and ended at 10 min (0.3 mL·min−1). The samples were injected with a 5 μL loop. Samples were analyzed in multiple reaction monitoring (MRM) mode. The optimized MS/MS parameters were as follows: electrospray ionization (ESI), ion spray voltage, 3000 V and temperature, 200 °C.Total urinary TCS (free and conjugated) concentration was measured in each urine sample using internal standard method as described previously . After t−1. Linearity was valid over the range of 0.1–50 ng·mL−1 (r2 = 0.998). Low, moderate and high concentration quality control materials were 0.8 ng·mL−1, 8 ng·mL−1 and 40 ng·mL−1, which were analyzed five times in a single day, replicating these determinations on five consecutive days. All the intra- and inter-batch precisions were less than 15%. The recovery was 91.1%. The same three quality controls of low, moderate and high concentration were also analyzed in parallel with the other 23 unknown samples in each analytical batch to assure the accuracy of determination. Analysts were blinded to all information during the test. We also measured creatinine (CR) concentration in each urine sample using enzymatic method on automatic chemical analyzer  to correct the fluctuations of TCS levels caused by urine concentration or dilution.The quality control (QC) materials were prepared with TCS standard  and a blank urine which was pooled by TCS undetectable samples obtained from several anonymous donors. The limit of detection (LOD) was 0.1 μg·L6 per ejaculate) was calculated by semen sample volume (milliliters) multiplied by the sperm concentration (106 mL−1). For speed, only the average path velocity was measured. For morphological evaluation, 10 µL semen was spread onto a glass slide and air-dried at room temperature. The smears were then stained with Giemsa stain and sperm morphology was assessed by the same two professional technicians, according to WHO criteria [Semen was collected in a private room by masturbation into a sterile polypropylene cup, and was analyzed within 60 min after collection. After liquefaction of the semen at 37 °C, semen volume was measured with a serologic pipette. Semen quality parameters including concentration, motility, and speed were analyzed by using a computer-aided semen analyzer  in accordance with the World Health Organization (WHO) guidelines . Total scriteria .−0.5, a commonly accepted practice [All data were doubly entered into the EpiData database. Urine TCS values less than LOD were imputed as LOD × 2practice ,17. The Factors that may affect the relationship between TCS exposure and semen quality biologically were chosen as potential confounders . Age, smt-test for those that were normally distributed or the Wilcoxon rank-sum test for non-normally distributed variables. The chi-square test was used to examine differences in categorical variables. General linear regression was used to examine the correlation between the urine TCS level and various semen quality parameters adjusted for potential confounders. The variables of skewed distribution were included in the model after natural logarithm transformation. Box plot and smoothing spline were applied to depict the relation of semen parameters and TCS concentration using EmpowerStats software .The continuous variables were compared with the independent sample −2. Among them, 27 (5.7%) men had sperm count below the reference (<39 million), 21 (4.5%) had low sperm concentration (<15 million·mL−1), and 126 (26.8%) had low percentage of forward moving sperms (<32% motile) according to WHO  reference values. Meanwhile, a total of 241 men had the four semen parameters at or above the reference. Box-plot diagrams show no significant difference in semen parameters among tertiles of urine TCS concentration . Table 3We found an inverse association between urine TCS concentration and the number of forward moving sperms. Among the participants with relatively low TCS burden, TCS was negatively associated with sperm concentration, sperm count, number of forward moving sperms, and percentage and number of normally morphologic sperms. This finding suggests that environmental exposure of TCS may have impact on semen quality.et al. found no relationship between TCS exposure and idiopathic male infertility [et al. found no effect of TCS on total motility count decrease either [−1, which raised the detectable rate from 48% in the previous study [−1 in Belgium [−1 in Spain [−1 in U.S. [−1 in Canada [To our best knowledge, this is the first report showing a significant association between environmental exposure of TCS and semen quality in humans. In a case-control study conducted in China, Chen ertility . Den Hone either . Two impe either . Second,us study  to 96.7% Belgium ; GM = 6.in Spain ) and Amen Canada ). This fIn the present study, the most significant associations between semen quality parameters and TCS were observed only at the lower TCS levels. These associations diminished as the TCS level rose. This “non-monotonic” dose-response relationship was also observed between TCS and BMI in NHANES from 2003–2008 , where T−1 in combination with a single dose of ethinylestrodial (EE) resulted in a significant increase in rat uterine weight while at as high as 300 mg·kg−1 without cotreatment of estrogen, TCS did not alter the uterine weight [TCS is considered as an endocrine disruptor . At a ree weight . ERs plae weight ,32. If ee weight , which se weight  where ERe weight .in vivo.In addition to co-activator of ER, some other cell-based essays revealed the interaction of TCS and androgen receptor (AR), including antiandrogenicity ,10,24,35Several limitations of our study need to be kept in mind. First, due to the variability of TCS levels in spot urine, a single urine sample may not be representative of the usual environmental exposure level of an individual. However, it has been found that triclosan concentrations in a single urine sample could be used to categorize the six-month average exposure to triclosan in 6–10 year-old children . AlthougAn association between environmental exposure to TCS and poor semen quality parameters was observed in this cross-sectional study, suggesting that TCS may affect human sperm production and normal morphology. However, the association was limited to the lowest tertile. Additional studies are needed to confirm or refute our findings.


To screen the newborn by Transient evoked Otoacoustic emission and to assess the incidence of hearing damage and associated risk factors.This longitudinal prospective observational study was conducted at a tertiary care hospital in India. A total of 415 babies were included in the study. All the newborns were evaluated with Transient evoked Otoacoustic emission (TEOAE) which was done by age of 1–3 days. Auditory brain stem response audiometry (AABR) was performed at the age of three months for confirming the hearing loss in the neonates those who failed the TEOAE screening. For infants proven to have significant hearing loss in one or both ears, were denoted to an ear, nose, and throat specialist for further evaluation & rehabilitation.Out of total 415 babies included in the study, 22 neonates showed abnormal TEOAE examination. Out of these 22 neonates, hearing loss was confirmed in 18 (82 %) subjects. by AABR. The following antenatal and post-natal risk factors were associated with hearing loss: ante-partum bleeding, history of maternal blood transfusion, fetal distress, prematurity, severe birth asphyxia, NICU admission for more than 24 h and Apgar score less than five at 5 min.Late identification of hearing loss presents a substantial public health burden. Early recognition and intervention prior to 6 months of age has a significant positive impact on development. A high incidence of hearing impairment seen in our study neonatal population warrants the urgent implementation of universal hearing screening of all the newborn infants in India. NICU infants admitted for more than 24 h are to have an auditory brainstem response (AABR) included as part of their screening so that neural hearing loss will not be missed. Hearing impairment has a devastating, and detrimental impact on the development of newborn infants . NeonateThe present study was designed to perform newborn hearing by Otoacoustic emission (TEOAE), determine the incidence of hearing damage in a population of at risk and not at risk neonates, and to determine various risk factor associations with learning impairment.We conducted a prospective observational longitudinal study in a tertiary care hospital in India, Department of Pediatrics, Sardar Patel Medical College, & Associated Group of Hospitals, Bikaner (Rajasthan). The study was approved by institutional research board (IRB) of the college.During the 8 month study period, form March, 2011 to October 2011, a total 1125 neonates were born in our hospital. We decided to enroll 415 neonates in the study. All the neonates born during the study period were divided into neonates with and without risk factors using predetermined Joint Committee statement on infant hearing screening (JCIH) criteria. Then each neonate was given a sequential number and enrolled in the study using random numbers generated by the computer for each group and enrolled till our sample size reached 415.All newborn babies born in our hospital from 3/11-10/11.Low birth weight (less than 2 lb) and/or prematurity.Assisted ventilation (to aid with breathing for more than 10 days after parturition).Low Apgar scores with severe birth asphyxia (defined as Apgar score of three or less at 1 min of age).Severe jaundice after birth requiring exchange transfusion or serum bilirubin level >20 mg/decilitre.HydrocephalusMaternal illness during pregnancy .An illness or condition requiring admission of 24 h or more to a NICU.Stigmata or other findings associated with a known syndrome to include a sensorineural and/or conductive hearing loss.Family history of permanent childhood sensorineural hearing loss.Craniofacial anomalies including those with morphological abnormalities of the pinna & ear canal.In utero infection by TORCH group of organisms.Respiratory distress;.Meningitis and sepsis with positive CSF and blood cultures respectively.Parental concern.Out of total 248 newborns having no risk factor while 167 newborn had some risk factor for hearing loss as per American Joint Committee statement on infant hearing screening (JCIH) criteria . The risTransient evoked Otoacoustic emission (TEOAE) was employed as the first stage of screening by the age of 1–3 days.Auditory brain stem response audiometry (AABR) was performed at the age of three months for confirming the hearing loss if the neonates failed the TEOAE screening.Informed written consent was obtained from the parents of all babies. Thorough Ear, nose, and throat examination done before doing Transient evoked Otoacoustic emission (TEOAE) that includes looking at the morphological abnormalities of the external ear. These newborns were screened for hearing impairment using the following test protocols.Children who had normal AABR were declared as ecologically sound & no further evaluation was suggested to these children.All neonates were screened with TEOAE testing in a quiet room adjacent to the NICU. Otoread TEOAE screeners  was used for testing. The TEOAE was done by an audiologist who was trained in doing the TEOAE and this test was done free of cost. The Quick screen mode was used with a specially designed “stop” protocol that forced discontinuation of the protocol when “pass” criteria was met. The timing window was 12.5 milliseconds, and clicks were delivered at a rate of 80 per second. Stimuli consisted of standard transient clicks at 70 to 88 dB pSPL.Otoacoustic emissions were judged to be present and an ear to have “pass” when signal-to-noise ratio was at least 3 dB in at least three of four frequency bands . A minimum of 60 successful sweeps was achieved in the test to be considered valid. Screening continued until passing criteria were met or 1000 successful sweeps were occurring, or for 10 min. If a baby failed an initial screen, it was repeated immediately after an effort to troubleshoot i.e. improve probe fit, clean probe contaminated by dust, decrease ambient noise, or change site of testing, calming baby by swaddling, rocking, and eating. An acceptable screen was done but once for each ear.Follow-up testing consisted of AABR testing that was performed under conditions of natural sleep using an Evomatic 4000 evoked potential unit , a standard Ag/AgCl electrode applied on the forehead and each mastoid, and pediatric insert earphones coupled to Etymotic ER3A stimulators . The AABR was done by a trained audiologist and was done free of cost. Stimuli consisted of 100-millisecond rarefaction clicks and tone pips presented at a rate of 25 per second for at least 1000 presentations with alternating triggering to permit both ears to be examined simultaneously. Our cutoff values of normal were 23 to 26 dB for observable wave V for clicks and 30 dB NHL for tone pips.For babies who failed the initial TEOAE screening, the mother, & relatives were contacted in person and counselled as to the significance of a broken screen . These neonates’ parents were also contacted in between for giving them a reminder for AABR and on the day of examination, they were contacted in personnel to get the test done.Auditory brain stem response audiometry was used to confirm the hearing loss if the neonates failed the TEOAE screening at the age of 3 months.For infants proven to suffer substantial hearing loss in one or both ears, were referred to an Ear, nose, and throat specialist for further evaluation & rehabilitation.t test and Chi-square test were used for data analysis. A p value less than 0.05 was considered significant.All the patient data were entered into Microsoft excel sheets. The Statistical Package for the Social Sciences (SPSS) software version 16 for Windows was used for data analysis. Student’s In the present study, we have performed the initial screening of 415 newborn by TEOAE, only 22 babies had abnormal results. These 22 babies were further evaluated by AABR at age of 3 months. AABR showed 18 babies with confirmed significant hearing loss. Out of the 22 babies with abnormal results, 16 babies were in with any risk factor group and remaining babies were in without any risk factor group.The demographic data of the study population, including gestational age, birth weight, gender stratification in with, and without risk factor groups are summarized in Table Out of the 415 newborns screened with TEOAE test 22 (5.68 %) babies had abnormal screen either in single or both ears. Out of total 22 abnormal TEOAE cases, 18 (81.82 %) cases were taking in significant hearing loss with AABR while four (18.2 %) cases had normal AABR  and for AABR was 1300 Indian rupees (21 US dollars). The parents were not billed for either of the probes.In our survey, among 415 of the total newborns screened 94.7 % (393) cases passed on TEOAE while 5.3 %  cases weNagapoornima et al. conducted a similar study in India and screened a total of 1769 infants  & reported that 10 babies were having a hearing impairment . The higJohn et al. conducted study in Christian Medical College (C.M.C.) Vellore and evaluated 500 newborns and found 32 (6.4 %) neonates with negative response. These effects are quite comparable to our study. At the second stage screening on 32 (6.4 %) cases by Distortion Product Otoacoustic Emission DPOAE, eight (25 %) were extended to sustain a negative response  and simiThomson et al. in their study of newborn screening, included 67,261 newborn from different states and 8.2 % mothers of babies were from 11–19 years age group while 23.1 % were from 20–25 years & 67.5 % mothers were a 25 + age group . In our In subject done by John et al. , they reNagapoornima et al.  recordedJohn et al.  showed tIn our study, most of the antenatal risk factor for hearing loss were found non-significant except the history of antepartum hemorrhage and history of antenatal blood transfusion in the mother. The apparent cause of these antenatal risk factors associated with hearing loss may be due to intrauterine distress to fetus followed by birth asphyxia.In our study, we concluded that the method of delivery does not play a significant role on newborn hearing impairment.p < 0.01). This could be explained because signs of fetal distress like meconium stained liquor, bradycardia, or tachycardia indicates fetal hypoxia, which may lead to damage to cochlear cells and neuronal pathway leading to more significant hearing abnormality. These findings also strengthen the view that these neonates with perinatal asphyxia need to be screened for hearing assessment.Out of the 18 neonates with significant hearing impairment nine cases where having the antenatal sign of fetal distress in the form of either meconium stained liquor, bradycardia, or tachycardia. When comparing these data, the difference was statistically significant (In the present study, 16.7 %  cases ouSimilar outcomes were likewise received in the survey performed by Thomson et al.  on newboAccording to JCIH 2000 criteria  an illneIn our experience from a developing country, we encountered few difficulties for newborn screening. The availability of a trained audiologist and the cost are important issues. However, both OAE and AABR are paid by the institution in the majority of places, hence all parents from the low income and low middle income countries will not be able to get their newborn infant screened. As both OAE and AABR were free to our patients could be one of the reason for hundred percent follow up of all infants. All these problems can be overcome if the government makes hearing screening compulsory, and free of cost, and many more audiologists are trained for performing newborn screens. Though the initial phase of screening implementation may be costly because getting new screening machines, training new audiologist, and setting up new rehabilitation centers, but in the long term these interventions will be more cost effective and will help in reducing the burden on society because of hearing impairments.In the nursery, the high risk neonates are more prone to suffer hearing problems. In the various studies done it has been shown that in these neonates AABR when compared with OAE has better sensitivity and specificity which highlights that in these neonates AABR should be a primary screening modality and in normal neonates OAE can be taken as a primary modality of screening , 23.Hence the results of our study show that all neonates having a turbulent course in nursery and various risk factors, needs to be screened for hearing assessment and neonates with the abnormal OAE need to be followed up. Universal screening of hearing should be done as neonates with no risk factors can also have abnormal hearing as seen in our study and it can delay the diagnosis of hearing impairment and also intervention for rehabilitation.The limitation of our study includes small sample size, and our inability to evaluate all the risk factors of JCIH criteria. The strong point of our study includes hundred percent follow up of all the newborns who had abnormal OAE and all these neonates had AABR done. This was possible as we educated all parents regarding the consequences of impaired hearingand maintained regular contact with them.Late identification of hearing loss presents a significant public health concern. However, without screening, children with hearing loss are usually not identified until 2 years of age, which results in significant delays in voice communication, language communication, social, cognitive, and emotional development. In contrast, early recognition, and intervention prior to 6 months of historic period has a significant positive impact on development.Hence, there is an urgent need to incorporate universal neonatal hearing screening in all the neonatal health care facilities in India. While studying the facts like infrastructure limitations of our rural area where basic needs are deficient, there is a demand to employ cost-effective behavioural observation methods using calibrated noise making toys to screen all newborn infants.Further prospective studies on a larger sample size are required to study the association of hearing impairment with various congenital syndromes and antenatal, perinatal, postnatal & demographic factors.


Maximum mouth opening (MMO) is a useful parameter to identify common temporomandibular joint (TMJ) disorders. Up to now, a few studies addressed the issue on MMO normal values in pediatric population, according to age and/or presence of generalized joint hypermobility (GJH), therefore it is difficult to use it in general medical practice.nd and 4th fingers of the right hand at the level of the lowest nail bed, to evaluate the TMJ hypermobility in children. We also analyzed the relationship between GJH and TMJ hypermobility.Aim of the study was to evaluate the MMO in a cohort of healthy schoolchildren and to propose a new parameter, the Three Middle Fingers Width (TMFW), the distance between 2We conducted a cross sectional study in a cohort of healthy schoolchildren, aged 8-13 years, by collecting information on family history of GJH and on history of TMJ involvement and performing a physical examination. This included height, weight, body surface area (BSA), body mass index (BMI), and musculoskeletal examination focused on the presence of GJH according to the Beighton criteria (BS≥4/9). TMJ evaluation included a complete gnathological visit, aimed to investigate the presence of TMJ disorders and to evaluate the MMO. The evaluation of TMFW was also performed and the Mouth Opening Ratio (MOR) was consequently calculated by the formula (MMO-TMFW)/MMOx100, adopting a 10% cut-off value to define the TMJ hypermobility.Two hundred and eighty-eight schoolchildren, 143 females and 145 males, entered the study. Mean MMO was 45.57 mm (± 5.12) for males and 44.87 mm (± 4.98) for females. Mean TMFW was 43.03 mm (± 4.09) for males and 41.71 mm (± 3.84) for females. Both MMO and TMFW correlate with growth parameters as height, weight, BMI and BSA. 89 (30.9%) subjects showed TMJ hypermobility (MOR>10%). In these subjects and in those with normal MOR MMO correlates with TMFW ; The prevalence of subjects with GJH was significantly (p < 0.001) higher in the group with TMJ hypermobility than in the other (44.8% vs 21.5%).TMFW correlates with MMO in schoolchildren and may represent a simple and reliable method to evaluate TMJ abnormalities. MOR, as an index to identify TMJ hypermobility, correlates with the presence of GJH and could be included, as an adjunctive point, to the Beighton Criteria.None declared.