Cerebral amyloid angiopathy-related inflammation presenting with steroid-responsive higher brain dysfunction: case report and review of the literature

A 56-year-old man noticed discomfort in his left lower limb, followed by convulsion and numbness in the same area. Magnetic resonance imaging (MRI) showed white matter lesions in the right parietal lobe accompanied by leptomeningeal or leptomeningeal and cortical post-contrast enhancement along the parietal sulci. The patient also exhibited higher brain dysfunction corresponding with the lesions on MRI. Histological pathology disclosed β-amyloid in the blood vessels and perivascular inflammation, which highlights the diagnosis of cerebral amyloid angiopathy (CAA)-related inflammation. Pulse steroid therapy was so effective that clinical and radiological findings immediately improved

Identification of the Occipito-Pontine Tract Using Diffusion-Tensor Fiber Tracking in Adult-Onset Adrenoleukodystrophy with Topographic Disorientation

X-linked adrenoleukodystrophy is a severe and progressive neurodegenerative disease caused by the peroxisomal transporter ATP-binding cassette, subfamily D, member 1 gene mutations. The defect of this gene product results in accumulation of very-long-chain fatty acids in organs and serum, central demyelination, and peripheral axonopathy. Although there are different magnetic resonance (MR) findings which reflect various phenotypes in adrenoleukodystrophy, some cases present with specific symmetrical occipital white-matter lesions. We describe a patient with adult-onset X-linked adrenoleukodystrophy with topographic disorientation, whose brain MR images revealed T2-signal hyperintensity along the occipito-pontine tract and lateral lemnisci, but not in the cortico-spinal tract in the brainstem. The occipito-pontine tract and lateral lemnisci were clearly detected using diffusion-tensor fiber tracking, suggesting that the topographic disorientation of this patient might be related to the occipito-pontine tract. MR tractography can effectively identify the occipito-pontine tract and may help to localize the fibers associated with clinical symptoms

Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma

Radiofrequency ablation (RFA) is one of the treatments for hepatocellular carcinoma (HCC) and is known to enhance host immune response. However, the epitopes to which enhanced immune responses occur, the impact on patient prognosis, and the functions and phenotype of T cells induced are still unclear. To address these issues, we analyzed immune responses before and after RFA in 69 HCC patients using 11 tumor-associated antigen (TAA)-derived peptides that we identified to be appropriate to analyze HCC-specific immune responses. The immune responses were analyzed using enzyme-linked immunospot (ELISPOT) assay and tetramer assays using peripheral blood mononuclear cells. An increase in the number of TAA-specific T cells detected by interferon-γ ELISPOT assays occurred in 62.3% of patients after RFA. The antigens and their epitope to which enhanced T cell responses occur were diverse, and some of them were newly induced. The number of TAA-specific T cells after RFA was associated with the prevention of HCC recurrence, and it was clarified to be predictive of HCC recurrence after RFA by univariate and multivariate analyses. The number of TAA-specific T cells after RFA was inversely correlated with the frequency of CD14+HLA-DR-/low myeloid-derived suppressor cells (MDSCs). The modification of T cell phenotype was observed after RFA. The number of TAA-specific T cells at 24 weeks after RFA was decreased. Conclusion: Although RFA can enhance various TAA-specific T cell responses and the T cells induced contribute to the HCC recurrence-free survival of patients, besides immunosuppression by MDSCs, the memory phenotype and lifetime of TAA-specific T cells are not sufficient to prevent HCC recurrence completely. Additional treatments by vaccine or immunomodulatory drugs might be useful to improve the immunological effect of RFA. © 2012 American Association for the Study of Liver Diseases

Randomized, Phase II Study Comparing Interferon Combined with Hepatic Arterial Infusion of Fluorouracil plus Cisplatin and Fluorouracil Alone in Patients with Advanced Hepatocellular Carcinoma

Objective: This randomized phase II trial compared the response rates to treatment with interferon (IFN) combined with hepatic arterial infusion of fluorouracil (FU) plus cisplatin (CDDP) or FU alone in patients with advanced hepatocellular carcinoma (HCC). Methods: A total of 114 patients with measurable advanced HCC were enrolled and randomized into 2 groups. FU (300 mg/m2, days 1–5, days 8–12) with or without CDDP (20 mg/m2, days 1 and 8) was administered via the hepatic artery. IFNα-2b was administered 3 times per week for 4 weeks. Results: The response rates were 45.6% for the IFN/FU + CDDP group and 24.6% for the IFN/FU group. The response rate was significantly higher in the IFN/FU + CDDP group (p = 0.030). The median overall survival period was 17.6 months in the IFN/FU + CDDP group versus 10.5 months in the IFN/FU group (p = 0.522). The median progression-free survival period was 6.5 months in the IFN/FU + CDDP group versus 3.3 months in the IFN/FU group (p = 0.0048). Hematological toxicity was common, but no toxicity-related deaths were observed. Conclusion: These results show the clinical efficacy of adding CDDP to the hepatic arterial infusion of FU in combined chemotherapy regimens with IFN

Beneficial effect of branched-chain amino acid supplementation on glycemic control in chronic hepatitis C patients with insulin resistance: Implications for type 2 diabetes

Branched-chain amino acids (BCAAs) improve disorders of albumin metabolism, quality of life, subjective symptoms, and prognosis in patients with chronic hepatitis. However, it remains unclear whether they improve insulin resistance. We examined the effects of BCAAs on glucose tolerance and insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Individuals with a definitive diagnosis of chronic hepatitis C and insulin resistance were eligible for participation. Eligible participants were randomly assigned to the BCAA group or a control group. Participants were then crossed over to the other treatment for a further 12 weeks. Baseline clinical features, laboratory markers, fatty acid levels, and insulin sensitivity, assessed with oral glucose tolerance tests and a hyperinsulinemic euglycemic clamp, were also examined before and 12 and 24 weeks after the beginning of the study. Of the 27 patients who completed the study, 14 began in the BCAA group and 13 began as controls. There were no significant differences in glucose metabolism parameters or lipid profiles between the groups. HbA1c values were improved in 10 patients and worsened or remained unchanged in 17 patients. The only predictive variable for change in HbA1c was the baseline Matsuda index: the lower the index, the greater the improvement in HbA1c values. BCAA therapy did not have adverse effects on glucose tolerance or insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Moreover, it had a therapeutic effect on HbA1c values in patients with marked peripheral (primarily muscle) insulin resistance. © 2012 Elsevier Inc

RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS

Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone–collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.Shimizu Mikito, Shiraishi Naoyuki, Tada Satoru, et al. RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS. Science Advances 9, 686 (2023); https://doi.org/10.1126/sciadv.adg3193