Increased 18 F-FDG uptake in denervated muscles in a case of Parsonage-Turner syndrome.

BACKGROUND: Parsonage-Turner Syndrome (PTS) is a rare brachial plexopathy characterized by the sudden onset of pain in the shoulder girdle followed by upper limb weakness. PTS is frequently under-recognized or misdiagnosed as other more common neurological disorders presenting in a similar fashion, such as cervical radiculopathy which may require surgical intervention. Accurate diagnosis and prompt management implicate a good prognosis. Although electrophysiological studies are considered the most important for evaluating peripheral nerve injuries, it usually takes time, up to 3 weeks after the initial insult of the nerve for electromyogram (EMG) and nerve conduction studies (NCS) to display abnormalities. In the cases of PTS, especially when initial EMG/NCS and magnetic resonance neurography (MRN) results are inconclusive, 18 F-FDG positron emission tomography and computed tomography (18 F-FDG PET-CT) may be useful in helping the early detection of muscle denervation. CASE PRESENTATION: A 60-year-old right-handed Taiwanese woman presented with sudden onset of intense and sharp left shoulder girdle pain without radiating to the arm, followed by muscle weakness of her left arm in abduction and elevation 3 days after the onset of pain. A detailed neurological examination and EMG and NCS suggested the clinical diagnosis of left brachial plexopathy. MRN imaging revealed no significant abnormality. 18 F-FDG PET-CT showed increased uptake in denervated muscles (supraspinatus, deltoid, and biceps muscles). Treatment with oral prednisolone and physiotherapy significantly improved pain and muscle weakness. CONCLUSIONS: We present increased 18 F-FDG uptake in denervated muscles detected by 18 F-FDG PET-CT. 18 F-FDG PET-CT may serve as an adjunct examination to evaluate PTS, which has been suggested previously but rarely reported.

A Novel SETX Mutation in a Taiwanese Patient with Autosomal Recessive Cerebellar Ataxia Detected by Targeted Next-Generation Sequencing, and a Literature Review.

Ataxia with oculomotor apraxia type 2 (AOA2), also known as autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2) (OMIM #606002), is a neurodegenerative disorder characterized by early-onset progressive cerebellar ataxia, polyneuropathy, and elevated levels of alpha-fetoprotein. It is caused by mutations in the SETX (OMIM #608465) gene. The prevalence of this disease is widely varied, from non-existent up to 1/150,000, depending on the region. Until now, no cases of AOA2/SCAN2 have been reported in Taiwan. METHODS: Next-generation sequencing was used to detect disease-causing mutations of SETX in a Taiwanese patient presenting with autosomal recessive cerebellar ataxia, polyneuropathy, and elevated alpha-fetoprotein. The candidate mutations were further confirmed by polymerase chain reaction (PCR) and Sanger sequencing. RESULTS: A compound heterozygous mutation of SETX c.6859C > T (p.R2287X) and c.7034-7036del was identified. The c.6859C > T (p.R2287X) has been previously found in a Saudi Arabia family, whereas c.7034-7036del is a novel mutation. Both mutations were predicted by bioinformatics programs to be likely pathogenic (having a damaging effect). We also reviewed the literature to address the reported clinical features of AOA2 from different populations. CONCLUSIONS: To our knowledge, we are the first to report a Taiwanese patient with AOA2/SCAN2, a result obtained by utilizing next-generation sequencing. The literature review shows that ataxia, polyneuropathy, and elevated AFP are common features and ocular motor apraxia (OMA) is a variable sign of AOA2 from different populations. OMA is rare and saccadic ocular pursuit and nystagmus are common in East Asian AOA2.

TLR9 Deficiency Leads to Accelerated Renal Disease and Myeloid Lineage Abnormalities in Pristane-Induced Murine Lupus.

Systemic lupus erythematosus (SLE) is a chronic, life-threatening autoimmune disorder, leading to multiple organ pathologies and kidney destruction. Analyses of numerous murine models of spontaneous SLE have revealed a critical role for endosomal TLRs in the production of autoantibodies and development of other clinical disease manifestations. Nevertheless, the corresponding TLR9-deficient autoimmune-prone strains consistently develop more severe disease pathology. Injection of BALB/c mice with 2,6,10,14-tetramethylpentadecane (TMPD), commonly known as pristane, also results in the development of SLE-like disease. We now show that Tlr9(-/-) BALB/c mice injected i.p. with TMPD develop more severe autoimmunity than do their TLR-sufficient cohorts. Early indications include an increased accumulation of TLR7-expressing Ly6C(hi) inflammatory monocytes at the site of injection, upregulation of IFN-regulated gene expression in the peritoneal cavity, and an increased production of myeloid lineage precursors (common myeloid progenitors and granulocyte myeloid precursors) in the bone marrow. TMPD-injected Tlr9(-/-) BALB/c mice develop higher autoantibody titers against RNA, neutrophil cytoplasmic Ags, and myeloperoxidase than do TMPD-injected wild-type BALB/c mice. The TMP-injected Tlr9(-/-) mice, and not the wild-type mice, also develop a marked increase in glomerular IgG deposition and infiltrating granulocytes, much more severe glomerulonephritis, and a reduced lifespan. Collectively, the data point to a major role for TLR7 in the response to self-antigens in this model of experimental autoimmunity. Therefore, the BALB/c pristane model recapitulates other TLR7-driven spontaneous models of SLE and is negatively regulated by TLR9.

Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus.

Loss-of-function mutations in the Fas death receptor or its ligand result in a lymphoproliferative syndrome and exacerbate clinical disease in most lupus-prone strains of mice. One exception is mice injected with 2,6,10,14-tetramethylpentadecane (TMPD), a hydrocarbon oil commonly known as pristane, which induces systemic lupus erythematosus-like disease. Although Fas/Fas ligand (FasL) interactions have been strongly implicated in the activation-induced cell death of both lymphocytes and other APCs, FasL can also trigger the production of proinflammatory cytokines. FasL is a transmembrane protein with a matrix metalloproteinase cleavage site in the ectodomain. Matrix metalloproteinase cleavage inactivates membrane-bound FasL and releases a soluble form reported to have both antagonist and agonist activity. To better understand the impact of FasL cleavage on both the proapoptotic and proinflammatory activity of FasL, its cleavage site was deleted through targeted mutation to produce the deleted cleavage site (ΔCS) mouse line. ΔCS mice express higher levels of membrane-bound FasL than do wild-type mice and fail to release soluble FasL. To determine to what extent FasL promotes inflammation in lupus mice, TMPD-injected FasL-deficient and ΔCS BALB/c mice were compared with control TMPD-injected BALB/c mice. We found that FasL deficiency significantly reduced the early inflammatory exudate induced by TMPD injection. In contrast, ΔCS mice developed a markedly exacerbated disease profile associated with a higher frequency of splenic neutrophils and macrophages, a profound change in anti-nuclear Ab specificity, and markedly increased proteinuria and kidney pathology compared with controls. These results demonstrate that FasL promotes inflammation in TMPD-induced autoimmunity, and its cleavage limits FasL proinflammatory activity.

Cutting edge: FAS (CD95) mediates noncanonical IL-1ß and IL-18 maturation via caspase-8 in an RIP3-independent manner.

Fas, a TNF family receptor, is activated by the membrane protein Fas ligand expressed on various immune cells. Fas signaling triggers apoptosis and induces inflammatory cytokine production. Among the Fas-induced cytokines, the IL-1ß family cytokines require proteolysis to gain biological activity. Inflammasomes, which respond to pathogens and danger signals, cleave IL-1ß cytokines via caspase-1. However, the mechanisms by which Fas regulates IL-1ß activation remain unresolved. In this article, we demonstrate that macrophages exposed to TLR ligands upregulate Fas, which renders them responsive to receptor engagement by Fas ligand. Fas signaling activates caspase-8 in macrophages and dendritic cells, leading to the maturation of IL-1ß and IL-18 independently of inflammasomes or RIP3. Hence, Fas controls a novel noncanonical IL-1ß activation pathway in myeloid cells, which could play an essential role in inflammatory processes, tumor surveillance, and control of infectious diseases.