Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

BACKGROUND: The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. METHOD: Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aß production in COS cells transfected with wild-type or mutant PSEN1. RESULTS: The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aß42 in PSEN1 G266S-transfected cells significantly increased. CONCLUSION: Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Renal Insufficiency in Concert with Renin-angiotensin-aldosterone Inhibition Is a Major Risk Factor for Hyperkalemia Associated with Low-dose Trimethoprim-sulfamethoxazole in Adults.

OBJECTIVE: Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used to prevent pneumocystis pneumonia in daily practice. Previous reports have shown a relationship between high- or standard-dose of TMP-SMX and hyperkalemia, however it remains unclear whether this is true for low-dose TMP-SMX. In this study we sought to determine the risk factors for hyperkalemia associated with low-dose TMP-SMX. METHODS: In this retrospective cohort study, 186 consecutive adult patients who received TMP-SMX as prophylaxis for pneumocystis pneumonia from January 2014 to January 2015 were evaluated. Data on the patients' age, gender, baseline estimated glomerular filtration rate (eGFR), baseline serum potassium, maximum serum potassium, duration reaching the maximal serum potassium level, dosage, and concomitant use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), ß-blockers, non-steroidal anti-inflammatory drugs and potassium-sparing diuretics were retrospectively collected. Hyperkalemia was defined as a serum potassium level ≥5 mEq/L. Univariate and multivariate analyses were performed. RESULTS: The median age of the patients was 66 years and 51.1% were men. Hyperkalemia associated with low-dose TMP-SMX was observed in 32 patients (17.2%). The median duration to reach the maximal serum potassium level was 12 days. The multivariate logistic regression analysis identified renal insufficiency to be a major risk factor for hyperkalemia associated with low-dose TMP-SMX (eGFR <60 mL/min/1.73 m(2), adjusted OR 4.62). Moreover, in the subpopulation of patients with renal insufficiency, ACEi/ARB use was considered to be a major risk factor for hyperkalemia (adjusted OR 3.96). CONCLUSION: Renal insufficiency in concert with ACEi/ARB use is a major risk factor for hyperkalemia induced by low-dose TMP-SMX.

Successful Treatment of Lupus Cerebrovascular Disease with Mycophenolate Mofetil.

We report a case of neuropsychiatric systemic lupus erythematosus successfully treated with mycophenolate mofetil (MMF). The patient was a 40-year-old female who maintained with 7 mg of prednisolone plus 100 mg of azathioprine (AZ) per day. According to transient ischemic attack that occurred repeatedly and an elevated level of interleukin-6 (IL-6) in spinal fluid, she was diagnosed as having neuropsychiatric systemic lupus erythematosus (NPSLE). Initial increase in doses of prednisolone and AZ to 20 mg and 150 mg per day, respectively, was ineffective. After switching from AZ to MMF, her symptoms of NPSLE completely resolved with marked improvement of the IL-6 level in her spinal fluid, suggesting that MMF was effective.

A Case of Immunoglobulin G4-Related Disease with Extensive Multiorgan Involvements.

We report a case of IgG4-related disease (IgG4-RD) with multiple ten-organ involvement. This case showed many clinical findings, such as bilateral swelling of salivary and lacrimal glands, autoimmune pancreatitis, interstitial nephritis, retroperitoneal fibrosis, periaortitis, systemic swelling of lymph nodes, pulmonary lesions, splenomegaly, and jejunal lesions. He was suspected as having SLE or malignant lymphoma but diagnosed as having IgG4-RD by the elevated serum IgG4 level and histological findings from kidney and lymph node. We report a case of IgG4-RD with multiple ten-organ involvement that was successfully treated with prednisolone therapy.

Synovial hemangioma of the knee joint in a 3-year-old girl.

Synovial hemangioma has been reported to be relatively rare, and usually occurs in childhood and adolescence. However, there are a few reports of the disease in infants. In this report, we diagnosed synovial hemangioma in a 3-year-old girl who had swelling and pain in her left knee. Gadolinium-enhanced magnetic resonance imaging revealed abnormal intensity in an intra-articular lesion. We performed arthroscopy, and arrived at a final diagnosis based on a scopic biopsy. Synovial hemangioma should be considered as a possible diagnosis in infants with swelling and pain in the knee.

An Asian case of fibroblastic rheumatism: clinical, radiological, and histological features.

We report a case of fibroblastic rheumatism (FR) in a 61-year-old woman. The patient showed sclerodactyly and polyarthritis that involved both her hands and feet joints. Levels of C-reactive protein and matrix metallopeptidase-3 were within normal range. We diagnosed her condition as FR according to both the clinical features characterized with the destructive change of multiple joints and the histological sample. This is the first FR published case of FR in an Asian individual, and 23 published cases were reviewed.

3-D MRI/CT fusion imaging of the lumbar spine.

OBJECTIVE: The objective was to demonstrate the feasibility of MRI/CT fusion in demonstrating lumbar nerve root compromise. MATERIALS AND METHODS: We combined 3-dimensional (3-D) computed tomography (CT) imaging of bone with 3-D magnetic resonance imaging (MRI) of neural architecture (cauda equina and nerve roots) for two patients using VirtualPlace software. RESULTS: Although the pathological condition of nerve roots could not be assessed using MRI, myelography or CT myelography, 3-D MRI/CT fusion imaging enabled unambiguous, 3-D confirmation of the pathological state and courses of nerve roots, both inside and outside the foraminal arch, as well as thickening of the ligamentum flavum and the locations, forms and numbers of dorsal root ganglia. Positional relationships between intervertebral discs or bony spurs and nerve roots could also be depicted. CONCLUSION: Use of 3-D MRI/CT fusion imaging for the lumbar vertebral region successfully revealed the relationship between bone construction (bones, intervertebral joints, and intervertebral disks) and neural architecture (cauda equina and nerve roots) on a single film, three-dimensionally and in color. Such images may be useful in elucidating complex neurological conditions such as degenerative lumbar scoliosis(DLS), as well as in diagnosis and the planning of minimally invasive surgery.

Expression of sphingosine kinase 2 in synovial fibroblasts of rheumatoid arthritis contributing to apoptosis by a sphingosine analogue, FTY720.

Gene expression profiles in synovial tissues from rheumatoid arthritis (RA) patients have yielded useful information on the pathogenetic process of the synovitis. In one group of them, sphingosine kinase 2 (SPHK2), a nuclear protein regulating cell proliferation, seemed to be highly expressed, undergoing a different pathogenetic process of synovitis. In the present study it was clarified that SPHK2 was expressed in the synovial fibroblasts of the synovial tissues obtained from the knee joints of the RA patients. In the cultured synovial fibroblasts from these patients, SPHK2 was more highly expressed than that in the human macrophage cell line, THP-1 and human dermal fibroblasts. SPHK2 was expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine-1-phosphate. A sphingosine analogue, FTY720, which is activated by phosphorylation specifically by SPHK2, mediated apoptotic signaling of the cultured synovial fibroblasts. These findings suggest that SPHK2 may regulate the autonomous proliferation of synovial fibroblasts as one of the predisposing genes to RA and could be a target for a novel therapeutic strategy for RA.

Toll-like receptor 3 signaling induces chronic pancreatitis through the Fas/Fas ligand-mediated cytotoxicity.

Innate immunity plays important roles in host defense against pathogens, but may also contribute to the development of autoimmune diseases under certain conditions. Toll-like receptors (TLRs) recognize various pathogens and induce innate immunity. We herein present a mouse model for chronic pancreatitis, which was induced by TLR3 signaling that generated the Fas/Fas ligand (FasL)-mediated cytotoxicity. An analogue of viral double-stranded RNA, polyinosinic:polycytidylic acid (poly I:C), which is recognized by TLR3, was injected into autoimmune-prone strains: MRL/Mp mice (MRL/+), MRL/Mp mice with a deficit of Fas (MRL/lpr) and MRL/Mp mice with a deficit of functional FasL (MRL/gld). The pancreatitis in MRL/+ mice was initiated by the destruction of pancreatic ductules, and its severity was significantly higher than that in MRL/lpr mice or MRL/gld mice. Using a pancreatic duct epithelial cell line MRL/S-1 newly established from the MRL/gld mouse that lacks FasL, we showed that treatment with poly I:C significantly induced the expression of Fas on the cultured cells. MRL/S-1 cells were destructed when co-cultured with splenocytes bearing intact FasL prepared from MRL/+ or MRL/lpr mice, but the magnitude of cytotoxicity was smaller with splenocytes of MRL/gld mice. Likewise, synthetic FasL protein showed cytotoxicity on MRL/S-1 cells. Furthermore, MRL/S-1 cells expressed higher levels of chemokines after the treatment with poly I:C, suggesting that the poly I:C-mediated induction of chemokines may be responsible for recruitment of lymphoid cells to the pancreatic periductular regions. These findings indicate that TLR3 signaling generates the Fas/FasL-mediated cytotoxicity, thereby leading to the development of chronic pancreatitis.

Evaluation of clinical prognosis and activities of daily living using functional independence measure in patients with hip fractures.

BACKGROUND: The functional independence measure (FIM) is an evaluation method of activities of daily living (ADL) that assesses motor functions and cognitive functions in the Uniform Data System. The FIM has recently been used to assess disability. The purpose of this study was to standardize criteria using the FIM for determining when and to where patients can be discharged following surgery for hip fracture. METHODS: Patients with hip fracture (n=68) aged>or=65 years who underwent surgery at our hospital were classified by their residence at the time of injury (their own home, a hospital, or an elderly care facility) and by postoperative residence after discharge from hospital. We investigated the FIM of these patients before injury and at the time of discharge and retrospectively compared the results with the Japan Orthopaedic Association (JOA) hip score at the time of discharge. RESULTS: Patients who entered a facility after discharge following surgery demonstrated a reduction in motor function score on the FIM. Cognitive function scores in each group were not reduced postoperatively in the short term. The average reduction in scores on the FIM for patients who were discharged from hospital to their own home was 15.9 points, and it was 25.9 points for those who were injured in their own home and transferred to a facility after discharge. There was a significant correlation between the FIM and the JOA hip score at the time of discharge. CONCLUSIONS: The FIM cannot determine whether such patients should be discharged to their home or transferred to a care facility. However, the motor function scores on the FIM are valid for assessing hip fracture patients and may be suitable as a standardized procedure for determining their postdischarge residence.

Chronic subtalar instability due to insufficiency of the calcaneofibular ligament: a case report.

Calcaneofibular ligament insufficiency in isolation is an uncommon cause of chronic instability of the subtalar joint. We report one case of chronic subtalar instability due to calcaneofibular ligament insufficiency after an ankle sprain. It was diagnosed with clinical findings and stress radiograph, and successfully treated with proximal advancement of the elongated calcaneofibular ligament.