pH-dependent water permeability switching and its memory in MoS2 membranes.

Intelligent transport of molecular species across different barriers is critical for various biological functions and is achieved through the unique properties of biological membranes1-4. Two essential features of intelligent transport are the ability to (1) adapt to different external and internal conditions and (2) memorize the previous state5. In biological systems, the most common form of such intelligence is expressed as hysteresis6. Despite numerous advances made over previous decades on smart membranes, it remains a challenge to create a synthetic membrane with stable hysteretic behaviour for molecular transport7-11. Here we demonstrate the memory effects and stimuli-regulated transport of molecules through an intelligent, phase-changing MoS2 membrane in response to external pH. We show that water and ion permeation through 1T' MoS2 membranes follows a pH-dependent hysteresis with a permeation rate that switches by a few orders of magnitude. We establish that this phenomenon is unique to the 1T' phase of MoS2, due to the presence of surface charge and exchangeable ions on the surface. We further demonstrate the potential application of this phenomenon in autonomous wound infection monitoring and pH-dependent nanofiltration. Our work deepens understanding of the mechanism of water transport at the nanoscale and opens an avenue for the development of intelligent membranes.

The Scottish national LifeCurve™ survey: costs of functional decline, opportunities to achieve early intervention to support well-being in later life, and meaningfulness of the LifeCurve™.

OBJECTIVES: The aim of the Scottish AHP LifeCurve™ survey was to gather a snapshot of where people are on their LifeCurve™ when receiving allied health professions (AHP) services and to understand the cost consequence of intervening 'late' in the ageing trajectory. The objectives were to promote discussion around preventing functional decline, support innovation in service delivery, and facilitate broader engagement with individuals, communities, and wider environments for improving health and well-being in later life. In addition, subsequent learning could help address the increasing resource gap between the demand and capacity across health and social care. STUDY DESIGN: The survey was paper-based in the form of a printed booklet, which contained the 15 activities of daily living (ADL) and instrumental ADL (IADL) which comprise the LifeCurve™ with additional lifestyle questions and information about the member of staff and service the participant was seen in, including their Community Health Index (CHI) number. The survey questions and booklet layout were tested over a five-month period with AHPs and people receiving AHP services. Liaison with national health literacy colleagues and lead speech and language therapists ensured that the survey material was accessible to a wide range of people. In addition, the survey could be made available in alternative formats, on request. METHODS: Agreement to undertake the national survey was obtained in November 2016 by all AHP directors and associate directors who appointed communication support leads in their area who would support implementation at all stages at a local level. All materials relating to the survey were published on a dedicated area of a community of practice to support awareness and training during the preimplementation phase. AHPs working in adult services were asked to complete a survey with a minimum of two people they would 'typically' see in their service during a two-week period in May 2017, with the exclusion of people who were too unwell to participate, children and young people under 16 years, and adults with incapacity and without a guardianship arrangement in place. Approval was gained from the Public Benefit Privacy Panel to link the survey data to participants' health service usage using their CHI number. Completed forms were returned to the University of Strathclyde for entry into an encrypted electronic database using a double data entry process and were allocated a unique identifier. The unique identifier and CHI numbers were sent to Information Services Division (ISD), and then, the CHI numbers were deleted from the encrypted database. ISD sent the linked health data to the Scottish Government Analytical Services Division, which thus produced a full encrypted and anonymised database. RESULTS: The data explain what stages on the LifeCurve™ AHPs are intervening, and the matched data provide associated healthcare costs at each stage. Due to poor or missing data in the AHP/Service section, only 60% (n = 8261) of the total completed surveys were able to be matched with health service usage records. These data show that whilst AHPs are seeing people at each of the 15 ADL/IADL stages on the LifeCurve™, interventions fell into three groups where 25% of people where seen at the 'precurve' stage, 13% of people at 'mid-curve' (stage number five), and 39% of people at 'late-curve' (stages 10 to 13). The healthcare cost usage of these participants increased the further along the LifeCurve™ a person moves, with an average annual cost of £2700 at 'precurve' rising to £12,330 at 'late-curve' in 2016-2017. The results indicate that different services and professions are represented at each of these three points. So, for example, as might be expected, outpatient (especially musculoskeletal) services were seen more often at the 'precurve' stage, and in-patient and community rehabilitation, services were seen more often at the 'late-curve' stages; diagnostic radiographers and orthoptists saw people at the 'early-curve' stages, dieticians and podiatrists saw people at the 'mid-curve' stage, whilst physiotherapists, speech and language therapists, and occupational therapists saw people at the 'late-curve' stages. Data analysis showed this pattern is different for people receiving mental health services and, so, their data were removed and will be analysed and reported separately. CONCLUSIONS: It is clear from the results that healthcare costs increased as participants moved down LifeCurve™ stages, that is, as their levels of functional decline increase. It is also clear that AHPs are intervening late in a person's functional decline with associated limitations on changing their ageing trajectory. The cost consequence of this is significant - moving someone from 'late- to mid-curve' could save £3200 per person per annum. However, those AHPs typically associated with reabling approaches and rehabilitation, which have greatest potential to change ageing trajectories, were not represented at the 'mid-curve' stage (e.g., physiotherapists, occupational therapists). Therefore, we must find places to have conversations with people to inform them that functional decline is malleable and not inevitable purely by virtue of chronological age and provide education and support to prevent or reverse functional decline and collaborate around strategic planning and commissioning to offer different options that support an optimum LifeCurve™.

Optimising perioperative care for hip and knee arthroplasty in South Africa: a Delphi consensus study.

BACKGROUND: A structured approach to perioperative patient management based on an enhanced recovery pathway protocol facilitates early recovery and reduces morbidity in high income countries. However, in low- and middle-income countries (LMICs), the feasibility of implementing enhanced recovery pathways and its influence on patient outcomes is scarcely investigated. To inform similar practice in LMICs for total hip and knee arthroplasty, it is necessary to identify potential factors for inclusion in such a programme, appropriate for LMICs. METHODS: Applying a Delphi method, 33 stakeholders (13 arthroplasty surgeons, 12 anaesthetists and 8 physiotherapists) from 10 state hospitals representing 4 South African provinces identified and prioritised i) risk factors associated with poor outcomes, ii) perioperative interventions to improve outcomes and iii) patient and clinical outcomes necessary to benchmark practice for patients scheduled for primary elective unilateral total hip and knee arthroplasty. RESULTS: Thirty of the thirty-three stakeholders completed the 3 months Delphi study. The first round yielded i) 36 suggestions to preoperative risk factors, ii) 14 (preoperative), 18 (intraoperative) and 23 (postoperative) suggestions to best practices for perioperative interventions to improve outcomes and iii) 25 suggestions to important postsurgical outcomes. These items were prioritised by the group in the consecutive rounds and consensus was reached for the top ten priorities for each category. CONCLUSION: The consensus derived risk factors, perioperative interventions and important outcomes will inform the development of a structured, perioperative multidisciplinary enhanced patient care protocol for total hip and knee arthroplasty. It is anticipated that this study will provide the construct necessary for developing pragmatic enhanced care pathways aimed at improving patient outcomes after arthroplasty in LMICs.

Rhinology Future Debates, an EUFOREA Report.

The first Rhinology Future Debates was held in Brussels in December 2016, organized by EUFOREA (European Forum for Research and Education in Allergy and Airways diseases). The purpose of these debates is to bring novel developments in the field of Rhinology to the attention of the medical, paramedical and patient community, in a highly credible and balanced context. For the first time in Rhinology, a peer to peer scientific exchange with key experts in the field of rhinology and key medical colleagues from leading industries let to a brainstorming and discussion event on a number of hot issues in Rhinology. Novel developments are presented by key experts from industry and/or key thought leaders in Rhinology, and then followed by a lively debate on the potential positioning of new developments in care pathways, the strengths and weaknesses of the novel development(s), and comparisons with existing and/or competing products, devices, and/or molecules. As all debates are recorded and distributed on-line with limited editing (www.rhinology-future.com), EUFOREA aims at maximizing the education of the target groups on novel developments, allowing a critical appraisal of the future and a more rapid implementation of promising novel tools, techniques and/or molecules in clinical practise in Europe. The next Rhinology Future debate will be held in Brussels in December 2017.

Mechanism-Based QSAR Modeling of Skin Sensitization.

Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods to give a quantitative indication of potency. Using two large published data sets of skin sensitizers, we have allocated each sensitizing chemical to one of 10 mechanistic categories and then developed good QSAR models for the seven categories that have a sufficient number of chemicals to allow modeling. Both internal and external validation checks showed that each model had good predictivity.

Abnormal osteopontin and matrix extracellular phosphoglycoprotein localization, and odontoblast differentiation, in X-linked hypophosphatemic teeth.

Mutations in phosphate-regulating gene (PHEX) lead to X-linked hypophosphatemic rickets (XLH), a genetic disease characterized by impaired mineralization in bones and teeth. In human XLH tooth dentin, calcospherites that would normally merge as part of the mineralization process are separated by unmineralized interglobular spaces where fragments of matrix proteins accumulate. Here, we immunolocalized osteopontin (OPN) in human XLH teeth, in a three-dimensional XLH human dental pulp stem cell-collagen scaffold culture model and in a rat tooth injury repair model treated with acidic serine- and aspartate-rich motif peptides (ASARM). In parallel, matrix extracellular phosphoglycoprotein (MEPE) immunolocalization and alkaline phosphatase (ALP) activity were assessed in XLH teeth. OPN was expressed by odontoblasts in the XLH models, and localized to the abnormal calcospherites of XLH tooth dentin. In addition, ALP activity and MEPE localization were abnormal in human XLH teeth, with MEPE showing an accumulation in the unmineralized interglobular spaces in dentin. Furthermore, XLH odontoblasts failed to form a well-polarized odontoblast layer. These data suggest that both MEPE and OPN are involved in impaired tooth mineralization associated with XLH, possibly through different effects on the mineralization process.

A purpose-built dynamometer to objectively measure static and dynamic knee torque.

This paper reports the development of a purpose-built knee dynamometer (PBKD) to evaluate passive range of motion (ROM) and isometric muscle strength measurements of the knee. The PBKD uses a TorqSense rotary torque transducer and objectively measures isometric knee muscle strength in a valid and reliable manner and passive resistance to motion through range. The device and all associated instrumentation underwent dynamic and static calibration to ensure consistent and accurate measurements were obtained in terms of knee joint angular position, passive torque measures, and isometric torque measures. Eleven healthy male participants performed a knee flexion and extension task designed to evaluate knee function. The validation of the PBKD entailed measuring the consistency of measurement and accuracy of measurement. Accuracy of the PBKD was determined by comparing peak isometric muscle strength measurements against a KIN-COM machine. No significant differences were observed both passively and isometrically between cycles and between trials. This device can have widespread applications within the rehabilitation and clinical environment and could be used as a functional outcome measuring tool to distinguish pathological from non-pathological knees. The presented preliminary results indicate that reliable and accurate measurements of knee ROM and muscle strength can be obtained.

Assessment of dispersion of airborne particles of oral/nasal fluid by high flow nasal cannula therapy.

BACKGROUND: Nasal High Flow (NHF) therapy delivers flows of heated humidified gases up to 60 LPM (litres per minute) via a nasal cannula. Particles of oral/nasal fluid released by patients undergoing NHF therapy may pose a cross-infection risk, which is a potential concern for treating COVID-19 patients. METHODS: Liquid particles within the exhaled breath of healthy participants were measured with two protocols: (1) high speed camera imaging and counting exhaled particles under high magnification (6 participants) and (2) measuring the deposition of a chemical marker (riboflavin-5-monophosphate) at a distance of 100 and 500 mm on filter papers through which air was drawn (10 participants). The filter papers were assayed with HPLC. Breathing conditions tested included quiet (resting) breathing and vigorous breathing (which here means nasal snorting, voluntary coughing and voluntary sneezing). Unsupported (natural) breathing and NHF at 30 and 60 LPM were compared. RESULTS: Imaging: During quiet breathing, no particles were recorded with unsupported breathing or 30 LPM NHF (detection limit for single particles 33 µm). Particles were detected from 2 of 6 participants at 60 LPM quiet breathing at approximately 10% of the rate caused by unsupported vigorous breathing. Unsupported vigorous breathing released the greatest numbers of particles. Vigorous breathing with NHF at 60 LPM, released half the number of particles compared to vigorous breathing without NHF.Chemical marker tests: No oral/nasal fluid was detected in quiet breathing without NHF (detection limit 0.28 µL/m3). In quiet breathing with NHF at 60 LPM, small quantities were detected in 4 out of 29 quiet breathing tests, not exceeding 17 µL/m3. Vigorous breathing released 200-1000 times more fluid than the quiet breathing with NHF. The quantities detected in vigorous breathing were similar whether using NHF or not. CONCLUSION: During quiet breathing, 60 LPM NHF therapy may cause oral/nasal fluid to be released as particles, at levels of tens of µL per cubic metre of air. Vigorous breathing (snort, cough or sneeze) releases 200 to 1000 times more oral/nasal fluid than quiet breathing (p < 0.001 with both imaging and chemical marker methods). During vigorous breathing, 60 LPM NHF therapy caused no statistically significant difference in the quantity of oral/nasal fluid released compared to unsupported breathing. NHF use does not increase the risk of dispersing infectious aerosols above the risk of unsupported vigorous breathing. Standard infection prevention and control measures should apply when dealing with a patient who has an acute respiratory infection, independent of which, if any, respiratory support is being used. CLINICAL TRIAL REGISTRATION: ACTRN12614000924651.

MEPE/OF45 as a new target for sensitizing human tumour cells to DNA damage inducers.

BACKGROUND: We recently identified matrix extracellular phosphoglycoprotein/osteoblast factor 45 (MEPE/OF45) as a new cofactor of CHK1 in rat cells. The aim of this study was to determine the role of human MEPE/OF45 (hMEPE/OF45 has approximately 50% homology with rat MEPE/OF45 (rMEPE/OF45)) in affecting the sensitivity of human tumour cells to DNA damage. METHODS: hMEPE/OF45 expression in different human tumour cell lines and its relevance to the resistance of cell lines to DNA damage inducers such as ionising radiation (IR) or camptothecin (CPT) were assessed. Cells lines stably expressing wild-type MEPE/OF45 or mutant MEPE/OF45 (with the CHK1 interactive key domain (amino acids 488-507) deleted) were established. Cell survival, G(2) accumulation, CHK1 half-life and the CHK1 level in ligase 3 complexes were examined. RESULTS: hMEPE/OF45 expression correlates with the resistance of cell lines to IR or CPT. Upregulating wild-type hMEPE/OF45 (but not mutant hMEPE/OF45) could stabilize CHK1 by reducing CHK1 interaction for its E3 ligases Cul1 or Cula4A; it increases the G(2) checkpoint response and increases the resistance of tumour cells to IR or CPT treatment. CONCLUSION: hMEPE/OF45 could be a new target for sensitizing tumour cells to radiotherapy or chemotherapy.

Comparison of the thermal and histopathological effects of bipolar and monopolar electrosurgical resection of the prostate in a canine model.

OBJECTIVES: To compare the thermal and histopathological effects of two commercially available bipolar systems and conventional monopolar transurethral resection of the prostate (TURP) in a canine model. Bipolar TURP is an alternative to monopolar electrosurgery for treating benign prostatic hyperplasia and has several potential clinical advantages, including the ability to use normal saline irrigation, enhanced haemostasis and less collateral thermal damage. MATERIAL AND METHODS: In all, 12 adult male beagles were studied. After midline laparotomy and exposure of the bladder and prostate, two fibre-optic thermosensors were placed to record tissue temperatures; one sensor was placed into the substance of the prostate 2 cm from the urethra and the second in the prostatic-rectal groove on the capsular surface of the prostate to measure temperatures in the region of the neurovascular bundles. Through a midline cystotomy, antegrade TURP was performed using two different bipolar systems (Gyrus PlasmaKinetic and Vista, both from Gyrus-ACMI Corporation, Maple Grove, MN, USA) or a monopolar device (Force(TM) 2, Valleylab, Boulder, CO, USA). TURP was performed in each lateral lobe using 24 F resection loops. The dogs were humanely killed acutely and the prostates excised for histopathological assessment. RESULTS: When comparing intraprostatic temperature data, the mean (sem) temperature changes recorded for the monopolar group were significantly higher than in either the Gyrus or Vista bipolar groups, at 24.2 (3.9) degrees C vs 8.1 (1.5) degrees C and 6.8 (1.8) degrees C, respectively (P < 0.001). No measurable temperature elevations were recorded near the neurovascular bundles with any of the electrosurgery devices. The depth of thermal damage was greatest in the monopolar group at 0.59 (0.27) mm compared with the Gyrus and Vista groups at 0.07 (0.08) mm and 0.15 (0.02) mm, respectively (P < 0.001). CONCLUSION: Bipolar TURP generated significantly less heat and histopathological evidence of thermal damage compared with monopolar TURP in the present canine model.

Cation-controlled wetting properties of vermiculite membranes and its promise for fouling resistant oil-water separation.

Manipulating the surface energy, and thereby the wetting properties of solids, has promise for various physical, chemical, biological and industrial processes. Typically, this is achieved by either chemical modification or by controlling the hierarchical structures of surfaces. Here we report a phenomenon whereby the wetting properties of vermiculite laminates are controlled by the hydrated cations on the surface and in the interlamellar space. We find that vermiculite laminates can be tuned from superhydrophilic to hydrophobic simply by exchanging the cations; hydrophilicity decreases with increasing cation hydration free energy, except for lithium. The lithium-exchanged vermiculite laminate is found to provide a superhydrophilic surface due to its anomalous hydrated structure at the vermiculite surface. Building on these findings, we demonstrate the potential application of superhydrophilic lithium exchanged vermiculite as a thin coating layer on microfiltration membranes to resist fouling, and thus, we address a major challenge for oil-water separation technology.

Proprioception and muscle torque deficits in children with hypermobility syndrome.

OBJECTIVES: Sensorimotor deficits such as impaired joint proprioception and muscle weakness have been found in association with hypermobility syndrome (HMS) in adults. HMS is more common in children than adults, yet such deficits have not been adequately investigated in paediatric populations. It is therefore uncertain as to what sensorimotor deficits are present in children with HMS. This study investigated knee joint proprioception and muscle torque in healthy children and those with HMS. METHODS: Thirty-seven healthy children (mean age +/- s.d. = 11.5 +/- 2.6 yrs) and 29 children with HMS (mean age +/- s.d. = 11.9 +/- 1.8 yrs) participated in this study. Knee joint kinaesthesia (JK) and joint position sense (JPS) were measured, with the absolute angular error (AAE) calculated as the absolute difference between the target and perceived angles. Knee extensor and flexor muscle torque was assessed and normalized to body mass. Mann-Whitney U-tests were performed to compare JK, JPS and muscle torque between the two groups. RESULTS: Children with HMS had significantly poorer JK and JPS compared with the controls (both P < 0.001). Knee extensor and flexor muscle torque was also significantly reduced (both P < 0.001) in children with HMS compared with their healthy counterparts. CONCLUSIONS: The findings of this study demonstrated that knee joint proprioception was impaired in children with HMS. They also had weaker knee extensor and flexor muscles than healthy controls. Clinicians should be aware of these identified deficits in children with HMS, and a programme of proprioceptive training and muscle strengthening may be indicated.

The Past and Future of Clinical Biomechanics: Time to deliver on the legacy of pioneers such as Professor John P. Paul (1927-2013).

This editorial pays tribute to the work of Professor John P. Paul and his team at the University of Strathclyde in the 1960s and '70s, and subsequently by the Strathclyde Rehabilitation Engineering Group, as featured in the journal Medical Engineering & Physics. It also includes a consideration of the nature of full biomechanical analysis of movement and how it can be mathematically modelled and physically recorded, the different approaches taken by Paul's and Winter's groups, respectively, and what a full biomechanical model should include in the future. The article also attempts to signpost the reader to future developments in the field, and how the techniques pioneered by Paul in the 1960s may influence Clinical Biomechanics and Rehabilitation in the years to come.

Between-day repeatability of knee kinematics during functional tasks recorded using flexible electrogoniometry.

The objective of this study was to assess the between-day repeatability of knee kinematics during activities of daily living recorded by electrogoniometry. One rater assessed the peak knee angles and knee excursion of 15 subjects during 13 activities twice with an average of 22 days (range 5-31) between the two assessments. The 15 subjects included four patients one year after total knee replacement (TKR) surgery, five patients before TKR surgery and six age-matched controls. Intra-class correlation coefficients and Bland and Altman coefficient of repeatability were derived to analyse the results. Only the most affected leg of the patients and the right leg of the controls were used for analysis. Different measures of repeatability showed different results. Intra-class correlation coefficients were higher than 0.75 for peak values of all functions except sitting down and rising from a standard chair. However, coefficients of repeatability ranged from 5.6 degrees for the loading response in level walking to 39.8 degrees for stepping out of a bath. Both of these values are higher than clinically significant changes seen after total knee surgery. It was concluded that for a single assessment on individual patients, the functional knee motion as performed in this study did not have sufficient repeatability. However, if the measurements are used to assess the average changes before and after surgery in a group of patients, the assessment of knee motion during activities such as level walking, and slope and stair ascending and descending were found to be sufficiently repeatable.

Gait stability in response to platform, belt, and sensory perturbations in young and older adults.

Perturbation-based gait assessment has been used to quantify gait stability in older adults. However, knowledge on which perturbation type is most suitable to identify poor gait stability is lacking. We evaluated the effects of ipsi- and contra-lateral sway, belt acceleration and deceleration, and visual and auditory perturbations on medio-lateral (ML) and anterior-posterior (AP) margins of stability (MoS) in young and older adults. We aimed to evaluate (1) which perturbation type disturbed the gait pattern substantially, (2) how participants recovered, and (3) whether recovery responses could discriminate between young and older adults. Nine young (25.1 ± 3.4 years) and nine older (70.1 ± 7.6 years) adults walked on the CAREN Extended (Motek BV, The Netherlands). The perturbation effect was quantified by deviation in MoS over six post-perturbation steps compared to baseline walking. Contra-lateral sway and deceleration perturbations resulted in the largest ML (1.9-4 times larger than other types) and AP (1.6-5.6 times larger than other types) perturbation effects, respectively. After both perturbation types, participants increased MoS by taking wider, shorter, and faster steps. No differences between young and older adults were found. We suggest to evaluate the potential of using contra-lateral sway and deceleration perturbations for fall risk identification by including both healthy and frail older adults. Graphical abstract Margins of stability during steady state (left) and perturbed (right) gait to quantify reactive gait stability in response to various perturbation types in young and older adults.

Defective Mineralization in X-Linked Hypophosphatemia Dental Pulp Cell Cultures.

X-linked hypophosphatemia (XLH) is a skeletal disease caused by inactivating mutations in the PHEX gene. Mutated or absent PHEX protein/enzyme leads to a decreased serum phosphate level, which cause mineralization defects in the skeleton and teeth (osteomalacia/odontomalacia). It is not yet altogether clear whether these manifestations are caused solely by insufficient circulating phosphate availability for mineralization or also by a direct, local intrinsic effect caused by impaired PHEX activity. Here, we evaluated the local role of PHEX in a 3-dimensional model of extracellular matrix (ECM) mineralization. Dense collagen hydrogels were seeded either with human dental pulp cells from patients with characterized PHEX mutations or with sex- and age-matched healthy controls and cultured up to 24 d using osteogenic medium with standard phosphate concentration. Calcium quantification, micro-computed tomography, and histology with von Kossa staining for mineral showed significantly lower mineralization in XLH cell-seeded scaffolds, using nonparametric statistical tests. While apatitic mineralization was observed along collagen fibrils by electron microscopy in both groups, Raman microspectrometry indicated that XLH cells harboring the PHEX mutation produced less mineralized scaffolds having impaired mineral quality with less carbonate substitution and lower crystallinity. In the XLH cultures, immunoblotting revealed more abundant osteopontin (OPN), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) than controls, as well as the presence of fragments of these proteins not found in controls, suggesting a role for PHEX in SIBLING protein degradation. Immunohistochemistry revealed altered OPN and DMP1 associated with an increased alkaline phosphatase staining in the XLH cultures. These results are consistent with impaired PHEX activity having local ECM effects in XLH. Future treatments for XLH should target both systemic and local manifestations.

EPG5-Related Vici Syndrome: A Primary Defect of Autophagic Regulation with an Emerging Phenotype Overlapping with Mitochondrial Disorders.

Vici syndrome is a rare, under-recognised, relentlessly progressive congenital multisystem disorder characterised by five principal features of callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and oculocutaneous hypopigmentation. In addition, three equally consistent features (profound developmental delay, progressive failure to thrive and acquired microcephaly) are highly supportive of the diagnosis. Since its recognition as a distinct entity in 1988, an extended phenotype with sensorineural hearing loss, skeletal myopathy and variable involvement of virtually any organ system, including the lungs, thyroid, liver and kidneys, have been described.Autosomal recessive mutations in EPG5 encoding ectopic P-granules autophagy protein 5 (EPG5), a key autophagy regulator implicated in the formation of autolysosomes, were identified as the genetic cause of Vici syndrome. The eight key features outlined above are highly predictive of EPG5 involvement, with pathogenic EPG5 mutations identified in >90% of cases where six or more of these features are present. The manifestation of all eight features has a specificity of 97% and sensitivity of 89% for EPG5-related Vici syndrome. Nevertheless, substantial clinical overlap exists with other multisystem disorders, in particular congenital disorders of glycosylation and mitochondrial disorders. Clinical and pathological findings suggest Vici syndrome as a paradigm of congenital disorders of autophagy, a novel group of inherited neurometabolic conditions linking neurodevelopment and neurodegeneration due to primary autophagy defects.Here we describe the diagnostic odyssey in a 4-year-old boy whose clinical presentation with multisystem manifestations including skeletal myopathy mimicked a mitochondrial disorder. A genetic diagnosis of Vici syndrome was made through whole genome sequencing which identified compound heterozygous variants in EPG5. We also review the myopathic presentation and morphological characterisation of previously reported cases.

Changes in levels of actin and tubulin mRNAs upon the lectin activation of lymphocytes.

The expression of beta-actin, gamma-actin, alpha-tubulin, and beta-tubulin mRNA during the lectin activation of human peripheral blood lymphocytes was examined with specific cDNA clones. The resting lymphocyte has a low level of both alpha- and beta-tubulin mRNAs, and these increase 10-fold after 72 h of lectin stimulation in which maximum cell transformation is achieved. Although there is a slight increase in tubulin mRNA during the first 6 h, most of the increase occurs between 6 and 24 h as the cells start to increase their RNA content and progress from G0 into G1. Both beta- and gamma-actin mRNAs are more abundant than the tubulin mRNAs in resting cells, with beta-actin mRNA being the major species. Upon activation, beta-actin mRNA increases threefold, whereas gamma-actin mRNA increases almost sixfold. Both beta- and gamma-actin mRNA are elevated 2.5-fold as early as 6 h, the gamma-actin mRNA level then increasing more than beta-actin between 6 and 24 h, resulting in the reduced beta-actin/gamma-actin mRNA ratio. The lectin-stimulated lymphocyte has a similar beta-actin/gamma-actin mRNA ratio as that of the human leukemic T-lymphoblast cell line CCRF-CEM. These increases are over and above the general increase in polyadenylated RNA content upon lectin activation. On returning to a noncycling state, the levels of these cytoskeletal mRNAs decrease. There were two beta-tubulin mRNAs present in lymphocyte cytoplasm, one of 1.8 kilobases and one of 2.8 kilobases in length. The nongrowing lymphocytes had relatively lower levels of the larger sized mRNA. Upon stimulation, the relative level of the larger mRNA was increased, and at 72 h the cells had approximately equal levels of both mRNAs as did the leukemic lymphoblasts.

Structure-based modelling in reproductive toxicology: (Q)SARs for the placental barrier.

The replacement of animal testing for endpoints such as reproductive toxicity is a long-term goal. This study describes the possibilities of using simple (quantitative) structure-activity relationships ((Q)SARs) to predict whether a molecule may cross the placental membrane. The concept is straightforward, if a molecule is not able to cross the placental barrier, then it will not be a reproductive toxicant. Such a model could be placed at the start of any integrated testing strategy. To develop these models the literature was reviewed to obtain data relating to the transfer of molecules across the placenta. A reasonable number of data were obtained and are suitable for the modelling of the ability of a molecule to cross the placenta. Clearance or transfer indices data were sought due to their ability to eliminate inter-placental variation by standardising drug clearance to the reference compound antipyrine. Modelling of the permeability data indicates that (Q)SARs with reasonable statistical fit can be developed for the ability of molecules to cross the placental barrier membrane. Analysis of the models indicates that molecular size, hydrophobicity and hydrogen-bonding ability are molecular properties that may govern the ability of a molecule to cross the placental barrier.