Classical ataxia telangiectasia patients have a congenitally aged immune system with high expression of CD95.

Ataxia-telangiectasia (A-T) is a rare neurodegenerative immunodeficiency disorder caused by mutations in the ataxia telangiectasia mutated gene. Patients commonly have lymphopenia and Ig-production abnormalities. We used multicolor flow cytometry and IL-7 ELISA to investigate the effect of A-T and age on the proportions of major lymphocyte subsets and their pattern of CD95 expression in relation to IL-7 levels in 15 classical A-T patients. We also analyzed the sensitivity of T cells from four classical A-T patients to CD95-mediated apoptosis using TUNEL and caspase-activation assays. Our results confirmed lymphopenia and a deficiency in naive T and B cells in A-T patients. In contrast to controls, the proportions of naive and memory T and B cell subsets in A-T patients did not vary in relation to age. There was no evidence of a deficiency in plasma IL-7 or IL-7R expression, and IL-7 concentration correlated positively with CD95 expression on CD4(+) T cells. CD95 expression on unstimulated A-T lymphocytes was high, and the apoptotic sensitivity of activated naive and central memory T cells was increased. These findings show that the immunodeficiency in A-T patients may be described as congenitally aged and is not progressive. The naive cell deficiency is not related to a deficiency in IL-7 or its receptor. However, IL-7 may upregulate CD95 on A-T lymphocytes. High CD95 expression and increased apoptotic sensitivity of activated naive and central memory T cells may result in an increased level of CD95-mediated apoptosis, which could contribute to the congenital lymphopenia in A-T.

A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics. PATIENTS AND METHODS: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28. FINDINGS: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection. INTERPRETATION: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS. TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.

Extending the reach of expert amyloidosis care: A feasibility study exploring the staged implementation of a UK amyloidosis network.

There has been an exponential increase in the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CA). In response, the Midlands Amyloidosis Service was launched with the aim of providing patients with a timely diagnosis, remote expertise from the National Amyloidosis Centre and access to emerging transthyretin (TTR)-directed therapies. This was a descriptive study of a pilot hub-and-spoke model of delivering specialist amyloidosis care. Patients with suspected amyloidosis were referred from the wider Midlands region, and seen in a consultant-led multidisciplinary clinic. The diagnosis of ATTR-CA was established according to either the validated non-biopsy criteria or histological confirmation of ATTR deposits with imaging evidence of amyloid. Study endpoints were the volume of service provision and the time to diagnosis from the receipt of referral. Patients (n=173, age 75±2 years; male 72 %) were referred between 2019 and 2021. Eighty patients (46 %) were found to have cardiac amyloidosis, of whom 68 (85 %) had ATTR-CA. The median time from referral to diagnosis was 43 days. By removing the need for patients to travel to London, an average of 187 patient-miles was saved. Fifteen (9 %) patients with wild-type ATTR-CA received tafamidis under the Early Access to Medicine scheme; 10 (6 %) were enrolled into phase 3 clinical trials of RNA interference or antisense oligonucleotide therapies. Our results suggest that implementing a UK amyloidosis network appears feasible and would enhance equity of access to specialised amyloidosis healthcare for the increasing numbers of older patients found to have ATTR-CA.

Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia.

BACKGROUND: The major clinical feature of ataxia telangiectasia (A-T) is severe progressive neurodegeneration with onset in infancy. This classical A-T phenotype is caused by biallelic null mutations in the ATM gene, leading to the absence of ATM protein and increased cellular radiosensitivity. We report an unusual case of A-T in a 41-year-old mother, A-T210, who had very mild neurological symptoms despite complete loss of ATM protein. METHODS: A neurological examination was performed, cellular radiosensitivity was assessed, and the ATM gene was sequenced. Skin fibroblasts and a lymphoblastoid cell line (LCL) were assayed for ATM protein expression and kinase activity. RESULTS: Patient A-T210 showed mild chorea, dystonia, and gait ataxia, walked independently, and drove a car. LCL and skin fibroblasts were radiosensitive and did not express ATM protein. Two ATM-null mutations were identified. CONCLUSIONS: The severe neurodegeneration resulting from loss of ATM can be mitigated in some circumstances.

Design and development of keratin/chitosan/glucosamine sulfate composite loaded MWCNT intended for osteoarthritis drug delivery.

Osteoarthritis (OA) is an inflammatory disease that affects the cartilage and tissues around the joints, which results in excessive pain and stiffness. One of the most critical challenges for improving the therapeutic effect in OA treatments is the current drug design utilizing functional polymers. Indeed, there is a need to design and develop novel therapeutic drugs for positive outcomes. In this view, glucosamine sulfate is a drug used to manage OA because of its potential therapeutic effects on cartilage and ability to inhibit disease progression. This research aims to develop a keratin/chitosan/glucosamine sulfate (KRT/CS/GLS) composite loaded functionalized multi-walled carbon nanotubes (MWCNTs) as a potential carrier for the treatment of OA. The nanocomposite was developed using various ratios of KRT/CS/GLS, and MWCNT. Molecular docking analysis has been performed with (D-glucosamine) and targeted proteins (Protein Data Bank ID: 1HJV, 1ALU) to determine the binding affinity and interactions. Field emission scanning electron microscopy study showed that the composite KRT/CS/GLS incorporated on the surface of functionalized MWCNTs effectively. Fourier transform infrared spectroscopy analysis confirmed the presence of KRT/CS/GLS in the nanocomposite and remained intact. X-ray diffraction analysis indicated that the nature of the composite in MWCNT transformed from a crystalline to an amorphous state. Thermo gravimetric analysis revealed that the nanocomposite has a high thermal decomposition temperature of 420 °C. The MTT assay results showed that 83% of cell viability has remained in RAW 264.7 cells at the maximum concentration (500 µg ml-1) of MWCNT-GLS/KRT/CS nanocomposite. Also, molecular docking results revealed the excellent binding affinity of D-glucosamine to each protein structure (PDB ID: 1HJV and 1ALU).

Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective.

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis.

Modeling ATM mutant proteins from missense changes confirms retained kinase activity.

Ataxia-telangiectasia mutated (ATM) is the gene mutated in the cancer-predisposing disorder ataxia-telangiectasia (A-T). We modeled ATM sequence variants identified in UK A-T patients to determine the stability and kinase activity of the resulting proteins as well as the distribution of these mutations across the coding region. Of 20 missense changes modeled, 10 proteins showed ATM kinase activity and 10 showed none. In the majority of cases the mutant ATM protein was unstable, although this was variable. Reduction in ATM kinase activity can result either from the presence of low levels of unstable mutant protein with relatively normal specific kinase activity or from stable mutant protein with deficient ATM kinase activation. Indeed, ATM mutant proteins without kinase activity toward downstream targets were still able to autophosphorylate on serine 1981, although in a much less efficient manner, suggesting that this was not sufficient for ATM activation. In terms of function, green fluorescent protein (GFP)-tagged kinase inactive ATM proteins could form ionizing radiation (IR)-induced foci (IRIF), at least temporarily, which colocalized with the DNA double-strand break (DSB) marker gammaH2AX. Consistent with this, both kinase active and inactive mutant ATM proteins were able to interfere with phosphorylation of targets by endogenous ATM. Since the majority of missense mutations occurred C-terminal to aa1966, including all 10 mutations with absence of kinase activity, the implication was that mutations N-terminal to this, with exceptions, are less likely to result in loss of kinase activity and therefore, are less likely to be identified in A-T patients.

Prominent oromandibular dystonia and pharyngeal telangiectasia in atypical ataxia telangiectasia.

Ataxia telangiectasia (A-T) typically presents with early-onset progressive cerebellar ataxia, oculomotor apraxia and later, oculo-cutaneous telangiectasia. Extrapyramidal symptoms, apart from chorea, are rare. In this paper, we report a case of A-T with an atypically mild and slowly progressive disease course. Although by history there was mild gait clumsiness in early childhood, the leading problem was that of dystonia with onset at age 15, in the absence of gross gait imbalance or ocular motor apraxia. Dystonia was generalized and with prominent oromandibular involvement. Unusually, a leash of telangiectasia was present on the posterior pharyngeal wall, while other features frequently associated with A-T were absent.

Adult tethered cord syndrome resembling plantar fasciitis and peripheral neuropathy.

Adult tethered cord syndrome without spinal dysraphism is rare, and can present with subtle symptoms that could mimic other pathologies. As a result, timely diagnosis of this condition has proved to be a significant challenge. It is crucial for clinicians to be aware of adult tethered cord syndrome and its presenting symptoms in order to achieve early diagnosis and subsequent management. We present such a case with particular attention to the presenting history and examination. Following diagnosis, the patient underwent a laminectomy and cord untethering, resulting in significant improvement to his symptoms.