Berlin : Hirschwald, 1905.

London (Braynes-Row, Spa-Fields) : Publish'd ... by R. Pollard printseller, Jany: 30th; 1797.

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39. However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf. Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.

SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3'UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.

Source: Retema - La Comisión Europea ha aprobado un conjunto de inversiones por valor de 222 millones de euros procedentes del presupuesto de la UE para facilitar la transición de Europa hacia un futuro más sostenible e hipocarbónico en el marco del programa LIFE de medio ambiente y acción por el clima. La financiación de la UE movilizará inversiones adicionales con las que se llegará a un total de 379 millones de euros destinados a 139 nuevos proyectos en 20 Estados miembros.

Acquired widespread pain syndromes of youth are prevalent, disabling, usually unexplained, and untreatable. Small-fiber polyneuropathy causes widespread pain and multisystem complaints in older adults. Some causes are treatable. Neurodiagnostic skin biopsy, autonomic function testing, and nerve biopsy permit objective diagnosis.

It identifies definite (in 59%) and probable (in 17%) small-fiber polyneuropathy among 41 young patients with otherwise-unexplained, childhood-onset widespread pain. It characterizes this new disease’s clinical features, diagnostic, and treatment options. Some cases appeared immune mediated and responded to immunomodulatory therapies. (Read the full article)

Winners to qualify automatically for UEFA Champions League while commercial rights are fully centralised from group stage

Draws for qualifying rounds to be held at UEFA Headquarters on 24 June

041 - Draws to be held at UEFA headquarters in Nyon on 19 July

043 - Draws to be held at UEFA headquarters on 9 August

The new programme was announced last week at the International Conclave on Learning Ecosystems in Bengaluru, held to celebrate IFIM’s 25-year journey, and inaugurated by Eric Cornuel, CEO & director general of European Foundation for Management Development, and Debashis Chatterji, director, IIM Kozhikode.

ABSTRACT

Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not reflect the tempo of neuroAIDS progression in humans. Recently, we isolated a neuropathogenic clone, SIVsm804E-CL757 (CL757), obtained from an SIV-infected rhesus macaque (RM). CL757 causes a more protracted progression to disease, inducing SIVE in 50% of inoculated animals, with high cerebral spinal fluid viral loads, multinucleated giant cells (MNGCs), and perivascular lymphocytic cuffing in the central nervous system (CNS). This latter finding is reminiscent of human immunodeficiency virus (HIV) encephalitis in humans but not generally observed in rapid progressor animals with neuroAIDS. Here, we studied which subsets of cells within the CNS were targeted by CL757 in animals with neurological symptoms of SIVE. Immunohistochemistry of brain sections demonstrated infiltration of CD4⁺ T cells (CD4) and macrophages (Ms) to the site of MNGCs. Moreover, an increase in mononuclear cells isolated from the brain tissues of RMs with SIVE correlated with increased cerebrospinal fluid (CSF) viral load. Subset analysis showed a specific increase in brain CD4⁺ memory T cells (Br-mCD4), brain-Ms (Br-Ms), and brain B cells (Br-B cells). Both Br-mCD4s and Br-Ms harbored replication-competent viral DNA, as demonstrated by virus isolation by coculture. However, only in animals exhibiting SIVE/neuroAIDS was virus isolated from Br-Ms. These findings support the use of CL757 to study the pathogenesis of AIDS viruses in the central nervous system and indicate a previously unanticipated role of CD4s cells as a potential reservoir in the brain.

IMPORTANCE While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4⁺ T cells harbor replication-competent SIV DNA; however, only brain CD4⁺ T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.

Objective

To describe the clinical and molecular genetic findings in a family segregating a novel mutation in the AIFM1 gene on the X chromosome.

Methods

We studied the clinical features and performed brain MRI scans, nerve conduction studies, audiometry, cognitive testing, and clinical exome sequencing (CES) in the proband, his mother, and maternal uncle. We used in silico tools, X chromosome inactivation assessment, and Western blot analysis to predict the consequences of an AIFM1 variant identified by CES and demonstrate its pathogenicity.

Results

The proband and his maternal uncle presented with childhood-onset nonprogressive cerebellar ataxia, hearing loss, intellectual disability (ID), peripheral neuropathy, and mood and behavioral disorder. The proband's mother had mild cerebellar ataxia, ID, and mood and behavior disorder, but no neuropathy or hearing loss. The 3 subjects shared a variant (c.1195G>A; p.Gly399Ser) in exon 12 of the AIFM1 gene, which is not reported in the exome/genome sequence databases, affecting a critical amino acid for protein function involved in NAD(H) binding and predicted to be pathogenic with very high probability by variant analysis programs. X chromosome inactivation was highly skewed in the proband's mother. The mutation did not cause quantitative changes in protein abundance.

Conclusions

Our report extends the molecular and phenotypic spectrum of AIFM1 mutations. Specific findings include limited progression of neurologic abnormalities after the first decade and the coexistence of mood and behavior disorder. This family also shows the confounding effect on the phenotype of nongenetic factors, such as alcohol and drug use and side effects of medication.

Alemtuzumab is approved for the treatment of relapsing-remitting MS and is used off-label for patients with chronic lymphocytic leukemia and as induction and antirejection therapy in kidney transplant recipients.¹ Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) complicating alemtuzumab treatment was reported in 9 patients with hematologic malignancy or MS.^1–3 The risk of GBS or CIDP in solid organ transplant recipients treated with alemtuzumab is unknown.

Objective

To assess whether neuropathy with anti-myelin-associated glycoprotein (MAG) antibody may improve after treatment with ibrutinib, an oral inhibitor of Bruton tyrosine kinase, we prospectively treated with ibrutinib a cohort of 3 patients with anti-MAG neuropathy and Waldenström macroglobulinemia (WM).

Methods

All 3 patients underwent bone marrow biopsy showing WM, with MYD88^L265P mutated and CXCR4^S338X wild type, and were started on ibrutinib 420 mg/die. Patients were assessed at baseline, at 3-6-9 months, and at 12 months in 2 patients with a longer follow-up, using Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Score, INCAT sensory sum score, and Medical Research Council sum score. The modified International Cooperative Ataxia Rating Scale was performed in 2 patients, whereas it was not used in the patient with Parkinson disease as a major comorbidity. Responders were considered the patients improving by at least one point in 2 clinical scales.

Results

All the patients reported an early and subjective benefit, consistent with the objective improvement, especially of the sensory symptoms as shown by clinical scales. Treatment was well tolerated.

Conclusion

These preliminary data point to a possible efficacy of ibrutinib in anti-MAG antibody neuropathy, which is the most common disabling paraproteinemic neuropathy, where active treatment is eagerly needed.

Classification of evidence

This study provides Class IV evidence that for patients with anti-MAG antibody neuropathy, ibrutinib improves neuropathy symptoms.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA_1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA_1c, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, β-blocker use, estimated glomerular filtration rate <60 mL/min/1.73 m², higher most recent pulse rate, and cigarette smoking. These findings identify risk factors and phenotypes of participants with diabetic neuropathy that can be used in the design of new interventional trials and for personalized approaches to neuropathy prevention.

The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population.We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro–B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, β-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A_1c [Hb A_1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016–2017; age 71–94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors.In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44–3.22]; no diabetes: OR, 2.31 [95%CI, 1.76–3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08–1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22–1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A_1c (OR, 1.76 [95% CI, 1.22–2.54]), fructosamine (OR, 1.71 [95% CI, 1.19–2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03–2.03]) with PN were significant only among participants with diabetes.Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Peripheral neuropathy (PN) is a condition affecting up to 20% of the general population. The symptoms range from mild to disabling, depending on the types of nerve fiber affected and the type and severity of damage.

The newly-remastered images show the icy surface of Europa, the sixth of Jupiter’s moons and the fourth largest, in enhanced color. All three high-resolution images were captured along the same longitude of Europa as NASA’s Galileo spacecraft flew by on September 26, 1998, in the eighth of the spacecraft’s 11 targeted flybys of the icy [...]

Proposed changes to the Champions League could 'end the Premier League top-four race' with qualification restricted, according to reports.

The Europas Awards — which have been recognising the hottest European tech startups in since 2009 — are now open for the public voting stage, prior to the formal judging process. The entries have been sorted and sifted by journalists to compile an editorially-driven ‘long list’ of some of Europe’s most exciting startups and investors. […]

The Europas Awards for European Tech Startups is doing what everyone in tech has done before: pivoting! Given the COVID-19 pandemic, we will be ‘going virtual’ on an amazing new platform, to be unveiled. (OK, but not VR – just yet!). A percentage of proceeds from the event will be donated to charities helping to […]

The Europas Awards — which have been recognising the hottest European tech startups in since 2009 — are now open for the public voting stage, prior to the formal judging process. The entries have been sorted and sifted by journalists to compile an editorially-driven ‘long list’ of some of Europe’s most exciting startups and investors. […]

Neil Lennon insisted Celtic had only themselves to blame for blowing a place in the last 16 of the Europa League.

Nothing sums up Sevilla’s transfer market brilliance quite like Carlos Bacca. Radamel Falcao may be the household striker in Colombia but Bacca is the future and he proved so in the Europa League final.

Atletico Madrid boss Diego Simeone has praised Diego Costa's performance against Sporting Lisbon as they won 2-0 in the first leg of their Europa League quarter-final.

Arsenal have been given a huge boost ahead of their Europa League semi-final first leg against Atletico Madrid as Diego Costa is 'unlikely' to play. The deadly striker has been in sensational form.

Diego Costa will be back to torment Arsene Wenger this week in Europe, three years after he last left his mark on the Arsenal manager in the Premier League.

One nil to the Arsenal. It was never going to be enough. Even before Atletico Madrid equalised, there was always the fear Arsenal might not be able to defend such a slender lead in seven days time.

Diego Costa appears at the doorway of the Atletico Madrid dressing-room, an hour before kick off. 'Lads,' he announces with a big grin. 'It's Arsenal.'

Sportsmail provide you with information for the Europa League final Marseille vs Atletico Madrid including time, date, location and how to watch plus how both teams made it to the final.

For the two enfant terribles in the recent history of the Premier League, this Europa League final threw up two sorely contrasting evenings.

Sportsmail provide you with all you need to know for Europa League draw for 2019/20 group stages including date, time and channel plus how the draw works, the pots and latest odds.

With football on a hiatus, Manchester United star Marcus Rashford has used his time off to reflect on the success of his trophy-laden career to date by trying to get a 'decent' picture with his silverware.

The Greek health ministry announced the two-week suspension in their latest attempt to combat the spread of coronavirus in the country.

A decision on the match is expected in the next 24 hours, with Wolves reluctant to travel to Athens after Olympiacos owner Evangelos Marinakis contracted coronavirus.

Pedro Neto let out an instinctive roar of delight as his deflected free-kick hit the Olympiacos net that echoed around the virtually empty Karaiskakis Stadium.

The latter stages of this season's Champions League and Europa League are set to be moved to July and August as the coronavirus pandemic continues to wreak havoc on the football calendar. 

The Champions League and Europa League could be suspended as UEFA consider action to combat the spread of coronavirus after domestic football in Italy and Spain was shut.

Rangers are looking to make Ianis Hagi's move to Ibrox permanent by signing the youngster from Genk for £4.3million. The record transfer will be in the clubs top ten biggest fees paid in history

Here, Sportsmail runs you through the 10 things to keep a close eye on in this historic fifth round of the FA Cup. The action, all in midweek, gets underway on Monday night as Portsmouth host Arsenal.

This season's Champions League final and Europa League final, due to be played in May, have been formally postponed because of the coronavirus pandemic, UEFA said on Tuesday. 

The latter stages of this season's Champions League and Europa League are set to be moved to July and August as the coronavirus pandemic continues to wreak havoc on the football calendar. 

Placing both the Champions League and Europa League on hold while domestic seasons are played out is one of the proposals being looked at by UEFA, Sportsmail understands.

UEFA president Aleksander Ceferin says playing behind closed doors is a better option than scrapping the season, but warned European competitions could be abandoned.

If domestic leagues are not back until July or August then UEFA is considering playing the remainder of the two competitions in a condensed timeframe.

The youngster returned to training in September following his brave battle against the disease and featured for the club's U23 side the following month in a 4-1 win over Swansea.