A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia.

The exciting news about the US FDA approval of omaveloxolone as the first-ever drug to be approved for an inherited ataxia is welcome news for patients and families that deal with this devastating disease as well as for health care providers and investigators with an interest in this and other rare diseases. This event is the culmination of long and fruitful collaboration between patients, their families, clinicians, laboratory researchers, patient advocacy organizations, industry, and regulatory agencies. The process has generated intense discussion about outcome measures, biomarkers, trial design, and the nature of approval process for such diseases. It also has brought hope and enthusiasm for increasingly better therapies for genetic diseases in general.

Impact and Mechanism of Covid-19 on Mental Health and Wellbeing.

The Covid-19 pandemic has brought unprecedented pressure to healthcare systems worldwide, resulting in significant and precipitous changes in demand, burden and method of delivery. The psychosocial impact of this crisis is likely to increase over the course of the pandemic, peak later than medical cases and endure for longer thereby significantly exceeding medical morbidity. It will have far reaching impact on the individual, their family and their care providers. Frontline healthcare workers and those with pre-existing mental health difficulties are recognised at increased risk. Now that the initial surge has been expertly curtailed, it is essential that urgent consideration is now directed towards the mental health implications of the current outbreak and ensure that we are as ready for the increased MH needs of the community as we were for the intensive medical care.

Coeliac disease in Caucasian and South Asian patients in the North West of England.

BACKGROUND: Coeliac disease is an autoimmune enteropathy characterised by mucosal inflammation subsequent to gluten exposure, leading to malabsorption. Treatment is strict dietary control, relying on the patient's ability to maintain lifestyle modifications. The present study aimed to compare clinical presentation and adherence to a gluten-free diet between South Asian and Caucasian patients with coeliac disease in East Lancashire METHODS: In total, 33 South Asian and 113 Caucasian adult patients diagnosed with coeliac disease under the care of the Dietetics Department at East Lancashire Hospitals NHS Trust were selected using a convenience sampling method and then allocated to the South Asian or Caucasian group. A subjective assessment of dietetic notes from follow-up visits within 1 year of the first appointment was undertaken by two investigators who subsequently allocated the patients to one of the three categories: (i) fully-adherent; (ii) partly-adherent; and (iii) non-adherent. Presenting complaint, vitamin D, vitamin B12 , folate and ferritin levels were also compared. RESULTS: There was a significant difference in adherence to gluten-free diet between the groups, with a larger proportion of Caucasian patients being fully adherent to gluten-free diet compared to South Asian patients (64.6% versus 12.1%, P < 0.001). In addition, a significantly higher proportion of South Asian patients were vitamin D deficient compared with Caucasian patients (70.8% versus 32.8%, P = 0.002). CONCLUSIONS: The rates of strict adherence to gluten-free diet and vitamin D levels were significantly lower in South Asian patients with coeliac disease compared to the Caucasian coeliac population. Further studies are required to investigate the causes and improve adherence in the South Asian population.

Open-label pilot study of interferon gamma-1b in Friedreich ataxia.

OBJECTIVES/AIMS: This is an open-label trial of the safety of interferon gamma-1b (IFN-γ) and its effect on frataxin levels and neurologic measures in 12 children with Friedreich ataxia. MATERIALS AND METHODS: Interferon gamma-1b was administered via subcutaneous injection three times weekly. The dose increased from 10 to 50 mcg/m(2) during the first four weeks and then remained at 50 mcg/m(2) for final eight weeks. Safety assessments included laboratory testing, electrocardiogram, and monitoring of adverse events. The primary efficacy outcome measure was frataxin level in whole blood. Secondary measures included frataxin levels in multiple tissues, frataxin mRNA levels, Friedreich Ataxia Rating Scale (FARS) scores and other neurologic evaluations. Statistical analyses were performed via SAS and STATA. RESULTS: Interferon gamma-1b was well tolerated with no serious adverse events, and only two subjects reporting severe adverse events and subsequent dose reductions. Small but significant changes in frataxin levels were observed in red blood cells, PBMC, and platelets after 12 weeks of treatment. However, the magnitude of change was small and varied between tissues. Mean improvement in FARS score was equivalent to roughly 18 months of disease progression after 12 weeks of treatment (P = 0.008). No other statistically significant changes were observed. No statistically significant relationships were observed between frataxin protein levels, FARS scores, and in vivo IFN-γ levels. CONCLUSIONS: Interferon gamma-1b improved FARS scores without a clear relationship to changes in frataxin levels. Larger, longer placebo-controlled trials including biochemical assessments in affected tissues are necessary to evaluate fully the efficacy and utility of IFN-γ in FRDA.

High efficiency of photon-to-heat conversion with a 6-layered metal/dielectric film structure in the 250-1200 nm wavelength region.

The optical properties and thermal stability of a 6-layered metal/dielectric film structure are investigated in this work. A high optical absorption average of > 98% is achieved in the broad spectral range of 250-1200 nm with experiment results, in good agreement with our simulated results. The samples have a typical layered structure of: SiO(2)(57.3 nm)/Ti(5.7 nm)/SiO(2) (67.1 nm)/Ti(11.6 nm)/SiO(2)(51.4 nm)/Cu(>100 nm), deposited on optically polished Si or K9-glass substrates by magnetron sputtering. The sample of the 6-layered metal/dielectric film structure has an AM1.5G solar absorptance of 95.5% with the features of low thermal emittance of 0.136 at 700K and good thermal stability, and will be potentially suitable for practical application in high-efficiency solar absorber devices in many fields.

Reference standard and statistical model for intersite and temporal comparisons of CT attenuation in a multicenter quantitative lung study.

PURPOSE: The purpose of this study was to detect and analyze anomalies between a large number of computed tomography (CT) scanners, tracked over time, utilized to collect human pulmonary CT data for a national multicenter study: chronic obstructive pulmonary disease genetic epidemiology study (COPDGene). METHODS: A custom designed CT reference standard "Test Object" has been developed to evaluate the relevant differences in CT attenuation between CT scanners in COPDGene. The materials used in the Test Object to assess CT scanner accuracy and precision included lung equivalent foam (-856 HU), internal air (-1000 HU), water (0 HU), and acrylic (120 HU). Nineteen examples of the Test Object were manufactured. Initially, all Test Objects were scanned on the same CT scanner before the Test Objects were sent to the 20 specific sites and 42 individual CT scanners that were used in the study. The Test Objects were scanned over 17 months while the COPDGene study continued to recruit subjects. A mixed linear effect statistical analysis of the CT scans on the 19 Test Objects was performed. The statistical model reflected influence of reconstruction kernels, tube current, individual Test Objects, CT scanner models, and temporal consistency on CT attenuation. RESULTS: Depending on the Test Object material, there were significant differences between reconstruction kernels, tube current, individual Test Objects, CT scanner models, and temporal consistency. The two Test Object materials of most interest were lung equivalent foam and internal air. With lung equivalent foam, there were significant (p < 0.05) differences between the Siemens B31 (-856.6, ±0.82; mean ± SE) and the GE Standard (-856.6 ± 0.83) reconstruction kernel relative to the Siemens B35 reference standard (-852.5 ± 1.4). Comparing lung equivalent foam attenuation there were also significant differences between CT scanner models (p < 0.01), tube current (p < 0.005), and in temporal consistency (p < 0.005) at individual sites. However, there were no significant effects measurable using different examples of the Test Objects at the various sites compared to the reference scans of the 19 Test Objects. For internal air, significant (p < 0.005) differences were found between all reconstruction kernels (Siemens B31, GE Standard, and Phillips B) compared to the reference standard. There were significant differences between CT models (p < 0.005), and tube current (p < 0.005). There were no significant effects measurable using different examples of the Test Objects at the various sites compared to the reference scans of the 19 Test Objects. Differences, across scanners, between external air and internal air measures in this simple (relative to the in vivo lung) test object varied by as much as 15 HU. CONCLUSIONS: The authors conclude that the Test Object designed for this study was able to detect significant effects regarding individual CT scanners that altered the CT attenuation measurements relevant to the study that are used to determine lung density. Through an understanding of individual scanners, the Test Object analysis can be used to detect anomalies in an individual CT scanner and to statistically model out scanner differences and individual scanner changes over time in a large multicenter trial.

Changes in Body Composition in Older Adults after a Technology-Based Weight Loss Intervention.

We conducted a post-hoc analysis of a pre/post, single-arm, non-randomized, multicomponent weight loss intervention in older adults. Fifty-three older adults aged ≥65 with a body mass index ≥ 30 kg/m2 were recruited to participate in a six-month, remote monitoring and video-conferencing delivered, prescriptive intervention consisting of individual and group-led registered dietitian nutrition and physical therapy sessions. We assessed weight, height, and body composition using a SECA 514 bioelectrical impedance analyzer. Mean age was 72.9±3.9 years (70% female) and all had ≥2 chronic conditions. Of those with complete data (n=30), we observed a 4.6±3.5kg loss in weight, 6.1±14.3kg (1.9%) loss in fat mass, and 0.78±1.69L loss in visceral fat (all p<0.05). Fat-free mass (-3.4kg±6.8, p=0.19), appendicular lean mass (-0.25±1.83, p=0.22), and grip strength (+3.46±7.89, p=0.56) did not significantly change. These variables were preserved after stratifying by 5% weight loss. Our intervention led to significant body and visceral fat loss while maintaining fat-free and appendicular lean muscle mass.

Flt3 ligand induces tumor regression and antitumor immune responses in vivo.

Daily treatment of mice with recombinant human Flt3 ligand (huFlt3L) results in a dramatic numerical increase in the number of dendritic cells (DCs) in vivo. Since DCs are pivotal in the induction of immune responses, we tested whether Flt3L treatment of mice challenged with a syngeneic methylcholanthrene (MCA)-induced fibrosarcoma would augment the generation of effective antitumor immune responses in vivo. Flt3L treatment not only induced complete tumor regression in a significant proportion of mice, but also decreased tumor growth rate in the remaining mice. A preliminary characterization of the cellular mechanisms involved suggests that Flt3L may be important in the treatment of cancer in situ through the generation of specific antitumor immune responses.

Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo.

To evaluate the utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic, we created leucine zipper (LZ) forms of human (hu) and murine (mu) TRAIL to promote and stabilize the formation of trimers. Both were biologically active, inducing apoptosis of both human and murine target cells in vitro with similar specific activities. In contrast to the fulminant hepatotoxicity of LZ-huCD95L in vivo, administration of either LZ-huTRAIL or LZ-muTRAIL did not seem toxic to normal tissues of mice. Finally, repeated treatments with LZ-huTRAIL actively suppressed growth of the TRAIL-sensitive human mammary adenocarcinoma cell line MDA-231 in CB.17 (SCID) mice, and histologic examination of tumors from SCID mice treated with LZ-huTRAIL demonstrated clear areas of apoptotic necrosis within 9-12 hours of injection.

Oral complications in the treatment of cancer patients.

While treatment for cancer in terms of chemotherapy and radiation therapy have evolved significantly since their inception, both of these cancer treatment modalities, especially if used in combination (e.g., as with head and neck cancers), have a very real potential to result in painful and debilitating adverse effects that clearly decrease quality of life and, potentially, increase mortality due to cancer. Herein, we discuss the prevalence and etiology of three broad categories of oral complications found during the treatment of cancer patients: mucositis, dysgeusia, and infectious disease. Lastly, we present therapeutic options that may be helpful in ameliorating these uncomfortable and, sometimes, life-threatening oral complications.

Interleukin 7 promotes long-term in vitro growth of antitumor cytotoxic T lymphocytes with immunotherapeutic efficacy in vivo.

A major obstacle to the effective use of adoptive immunotherapeutic treatment of cancer is the difficulty of obtaining tumor-reactive lymphocytes in either sufficient numbers or with appropriate in vivo function to make such an approach feasible. Previous studies have shown that antitumor cytotoxic T lymphocytes (CTL) with in vivo efficacy can be generated in vitro from lymphoid cells obtained from lymph nodes that drain the anatomical site of a tumor. Results presented here demonstrate that inclusion of interleukin 7 (IL-7) into the medium in which such CTL are cultured can support their growth in vitro for prolonged periods of time in the absence of repeated stimulation with either tumor stimulator cells or tumor antigen. More importantly, antitumor CTL propagated in medium containing IL-7 have retained both their antigenic specificity and their ability to reject tumors in vivo subsequent to intravenous injection. Parallel cultures of antitumor CTL similarly cultured in medium containing only IL-2 could only be maintained for 5-6 wk, after which the number and proportion of viable cells that were recoverable from such cultures progressively decreased. Phenotypic analysis of CTL maintained after extended culture (i.e., 22 mo) in medium containing IL-7 demonstrated them to be CD3+4-8+ T cells. These cells were also found to express lymphocyte function associated 1, intercellular adhesion molecule 1, and Mel-14 cell interaction molecules. The data also demonstrate that these CTL do not require the presence of antigen-presenting cell populations to mount a proliferative response to tumor stimulator cells. Cells in these cultures were also demonstrated to produce IL-2 after stimulation with irradiated tumor cells, thereby indicating that these CTL have become independent of the requirement for CD4+ helper cells to survive and function either in vitro or in vivo. Collectively, the findings that IL-7 can beneficially augment the generation, and propagate the long-term growth, of antitumor CTL from lymph nodes draining a tumor site may have profound implications for promoting the immunotherapeutic treatment of cancer in humans.

CD4 regulates susceptibility to Fas ligand- and tumor necrosis factor-mediated apoptosis.

The current knowledge of CD4 function is limited to its role as a necessary coreceptor in TCR-initiated signaling. We have investigated whether CD4 regulates additional T cell functions. Using human primary resting CD4+ T cells, we demonstrate that CD4 activation is sufficient to induce lymphocyte death. Immediately after CD4 cross-linking, CD4+ T cells are rendered susceptible to apoptosis mediated by TNF or FasL. This, together with the concomitant induction of FasL within the same population, results in significant CD4+ T cell death in vitro. The CD4-dependent induction of susceptibility to apoptosis that is mediated by TNF or FasL is protein synthesis independent but phosphorylation dependent. After CD4 activation, PKC regulates susceptibility to apoptosis mediated by FasL but not the induction of susceptibility to TNF-dependent apoptosis. Moreover, significant differences between CD3 and CD4 activation were observed with regards to the kinetics of induction of CD4+ T cell susceptibility to FasL- and TNF-mediated apoptosis. Altogether, these results provide a model with which to study the molecular mechanisms regulating lymphocyte survival after CD4 activation, and highlight the potential role of CD4 in controlling lymphocyte apoptosis under physiological conditions or in disease states such as HIV infection.

Fas transduces activation signals in normal human T lymphocytes.

The Fas gene encodes a cell surface molecule that is a member of the the nerve growth factor/tumor necrosis factor receptor family of proteins and can mediate programmed cell death (apoptosis) in certain transformed cell lines. To characterize further the biological function of Fas, particularly with regard to its function in normal cells, a panel of monoclonal antibodies (mAbs) was generated against the extracellular portion of human Fas. Some of these mAbs induced apoptosis in transformed cell lines expressing Fas, but only when immobilized on the culture vessel. One of the new Fas mAbs (M38) was used for studies on normal lymphoid cells and found to stimulate the proliferation of purified human T cells and thymocytes when immobilized on culture wells along with CD3 antibody. T cell proliferation induced by Fas mAb was largely interleukin 2 independent and was demonstrated to be due to a direct effect on the precursor T cell. Thus, the data demonstrate that in addition to a role in the induction of apoptosis in certain transformed cell lines, the Fas protein may also play an important role in the activation and proliferation of normal T cells.

Apoptosis of Fashigh CD4+ synovial T cells by borrelia-reactive Fas-ligand(high) gamma delta T cells in Lyme arthritis.

The function of the minor subset of T lymphocytes bearing the gamma delta T cell antigen receptor is uncertain. Although some gamma delta T cells react to microbial products, responsiveness has only rarely been demonstrated toward a bacterial antigen from a naturally occurring human infection. Synovial fluid lymphocytes from patients with Lyme arthritis contain a large proportion of gamma delta cells that proliferate in response to the causative spirochete, Borrelia burgdorferi. Furthermore, synovial gamma delta T cell clones express elevated and sustained levels of the ligand for Fas (APO-1, CD95) compared to alpha beta T cells, and induce apoptosis of Fashigh CD4+ synovial lymphocytes. The findings suggest that gamma delta T cells contribute to defense in human infections, as well as manifest an immunoregulatory function at inflammatory sites by a Fas-dependent process.

Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor.

Apoptosis of bystander uninfected CD4+ T lymphocytes by neighboring HIV-infected cells is observed in cell culture and in lymphoid tissue of HIV-infected individuals. This study addresses whether antigen-presenting cells such as human macrophages mediate apoptosis of CD4+ T cells from HIV-infected individuals. Uninfected human macrophages, and to a larger degree, HIV-infected macrophages mediate apoptosis of T cells from HIV-infected, but not from uninfected control individuals. This macrophage-dependent killing targets CD4+, but not CD8+ T lymphocytes from HIV-infected individuals, and direct contact between macrophages and lymphocytes is required. Additional analyses indicated that the apoptosis-inducing ligands, FasL and tumor necrosis factor (TNF), mediate this macrophage-induced apoptosis of CD4+ T cells. These results support a role for macrophage-associated FasL and TNF in the selective depletion of CD4+ T cells in HIV-infected individuals.

Fas ligand mediates activation-induced cell death in human T lymphocytes.

A significant proportion of previously activated human T cells undergo apoptosis when triggered through the CD3/T cell receptor complex, a process termed activation-induced cell death (AICD). Ligation of Fas on activated T cells by either Fas antibodies or recombinant human Fas-ligand (Fas-L) also results in cytolysis. We demonstrate that these two pathways of apoptosis are causally related. Stimulation of previously activated T cells resulted in the expression of Fas-L mRNA and lysis of Fas-positive target cells. Fas-L antagonists inhibited AICD of T cell clones and staphylococcus enterotoxin B (SEB)-specific T cell lines. The data indicate AICD in previously stimulated T cells is mediated by Fas/Fas-L interactions.

Cognitive behavioural therapy for major psychiatric disorder: does it really work? A meta-analytical review of well-controlled trials.

BACKGROUND: Although cognitive behavioural therapy (CBT) is claimed to be effective in schizophrenia, major depression and bipolar disorder, there have been negative findings in well-conducted studies and meta-analyses have not fully considered the potential influence of blindness or the use of control interventions. METHOD: We pooled data from published trials of CBT in schizophrenia, major depression and bipolar disorder that used controls for non-specific effects of intervention. Trials of effectiveness against relapse were also pooled, including those that compared CBT to treatment as usual (TAU). Blinding was examined as a moderating factor. RESULTS: CBT was not effective in reducing symptoms in schizophrenia or in preventing relapse. CBT was effective in reducing symptoms in major depression, although the effect size was small, and in reducing relapse. CBT was ineffective in reducing relapse in bipolar disorder. CONCLUSIONS: CBT is no better than non-specific control interventions in the treatment of schizophrenia and does not reduce relapse rates. It is effective in major depression but the size of the effect is small in treatment studies. On present evidence CBT is not an effective treatment strategy for prevention of relapse in bipolar disorder.

A computer-aided diagnosis system for quantitative scoring of extent of lung fibrosis in scleroderma patients.

OBJECTIVES: To evaluate an improved quantitative lung fibrosis score based on a computer-aided diagnosis (CAD) system that classifies CT pixels with the visual semi-quantitative pulmonary fibrosis score in patients with scleroderma-related interstitial lung disease (SSc-ILD). METHODS: High-resolution, thin-section CT images were obtained and analysed on 129 subjects with SSc-ILD (36 men, 93 women; mean age 48.8±12.1 years) who underwent baseline CT in the prone position at full inspiration. The CAD system segmented each lung of each patient into 3 zones. A quantitative lung fibrosis (QLF) score was established via 5 steps: 1) images were denoised; 2) images were grid sampled; 3) the characteristics of grid intensities were converted into texture features; 4) texture features classified pixels as fibrotic or non-fibrotic, with fibrosis defined by a reticular pattern with architectural distortion; and 5) fibrotic pixels were reported as percentages. Quantitative scores were obtained from 709 zones with complete data and then compared with ordinal scores from two independent expert radiologists. ROC curve analyses were used to measure performance. RESULTS: When the two radiologists agreed that fibrosis affected more than 1% or 25% of a zone or zones, the areas under the ROC curves for QLF score were 0.86 and 0.96, respectively. CONCLUSIONS: Our technique exhibited good accuracy for detecting fibrosis at a threshold of both 1% (i.e. presence or absence of pulmonary fibrosis) and a clinically meaningful threshold of 25% extent of fibrosis in patients with SSc-ILD.