The morphology of amyloid fibrils and their impact on tissue damage in hereditary transthyretin amyloidosis: An ultrastructural study.

INTRODUCTION: We evaluated the morphology of amyloid fibrils in the peripheral nervous system using biopsy or autopsy specimens from hereditary transthyretin amyloidosis patients. The impact of amyloid fibril formation on neighboring tissues was also investigated. METHODS: Sural nerve biopsy specimens from 34 patients were examined using electron microscopy. Twenty-eight patients had Val30Met mutations, and the remaining 6 patients had non-Val30Met mutations (i.e., Glu54Lys, Pro24Ser, Thr49Ala, Val71Ala, Val94Gly, and Ala97Gly). The patients with the Val30Met mutation included a case from Brazil (supposedly of Portuguese origin), 6 early-onset cases from endemic foci in Japan, and 21 late-onset cases from non-endemic areas in Japan. RESULTS: Long amyloid fibers were abundant in the early-onset Val30Met cases from the Japanese endemic foci and Brazil, whereas the amyloid fibrils were generally short in the late-onset Val30Met and non-Val30Met cases. The amyloid fibrils seemed to mature from dotty structures among amorphous electron-dense extracellular materials and pull surrounding tissues during the maturation process. The distortion of Schwann cells close to amyloid fibril masses was conspicuous, particularly in cases with long amyloid fibrils. Atrophy was conspicuous in non-myelinating Schwann cells and bands of Büngner (i.e., Schwann cell subunits that previously contained myelinated axons), particularly those completely surrounded by amyloid fibrils. In contrast, the myelinated fibers tended to be only partially surrounded by amyloid fibrils and morphologically preserved due to their large size. Only a few demyelinated axons were found. CONCLUSION: Pre-fibrillar amyloid precursors appear to play a pivotal role during the initial phase of amyloid fibril formation. The mechanical distortion and subsequent atrophy of Schwann cells resulting from the elongation of amyloid fibrils may be related to small-fiber predominant loss, which is a classical characteristic of amyloid neuropathy. Although rather rare, the destruction of myelin (i.e., demyelination) resulting from amyloid deposition may relate to nerve conduction abnormalities mimicking chronic inflammatory demyelinating polyneuropathy.

Intervention of Isomaltodextrin Mitigates Intestinal Inflammation in a Dextran Sodium Sulfate-Induced Mouse Model of Colitis via Inhibition of Toll-like Receptor-4.

Isomaltodextrin (IMD), a highly branched α-glucan, is a type of resistant starch. Earlier studies have indicated that polysaccharides could prevent inflammation and can be effective in reducing the complications of chronic gastrointestinal diseases such as inflammatory bowel disease (IBD). Therefore, the aim of the present study was to evaluate the anti-inflammatory effect of IMD in dextran sodium sulfate (DSS)-induced colitis in a mouse model. IMD (0.5, 1.0, 2.5, and 5.0% (w/v)) was given orally for 23 days to female Balb/c mice, and then 5% DSS was administered to induce colitis (from day 15 onward to the end of the trial). IMD could not prevent DSS-induced weight loss or colon shortening. However, IMD could reduce inflammatory cytokines, TNF-α and IL-6, in the colon. Gene expression indicated the tendency of IMD to suppress pro-inflammatory cytokines IL-1ß, MCP-1, and IL-17 and to increase an anti-inflammatory cytokine, IL-10. Further study revealed that the anti-inflammatory action of IMD mediates through inhibition of the expression of Toll-like receptor-4.

Sporadic adult-onset neuronal intranuclear inclusion disease with the main presentation of repeated cerebellar ataxia: a case study.

A 66-year-old woman suddenly experienced unsteadiness while walking; she had experienced the same symptom before, but it had resolved immediately. Her neurological findings showed cerebellar ataxia, absence of tendon reflex in the extremities, and orthostatic hypotension. MRI with DWI of the brain showed linear high-intensity areas at the white matter just below the cerebral cortex. Therefore, we suspected neuronal intranuclear inclusion disease (NIID). In her cutaneous skin biopsy, intranuclear inclusion bodies, which tested positive for an anti-ubiquitin antibody and anti-p62 antibody, were observed in sweat gland cells and fibroblasts; therefore, we diagnosed her with NIID. As no one in her family had similar symptoms, this was a case of sporadic NIID. Adult-onset NIID with the main presentation of cerebellar ataxia is rare; in our case, this repeated acute-onset symptom was a unique manifestation of the condition.

Cervical Posterior Spinal Artery Syndrome: A Case Report and Literature Review.

We report a case of left upper cervical posterior spinal artery (PSA) syndrome caused by atherosclerosis of the left vertebral artery. A 70-year-old female experienced sudden dizziness and paralysis of the left upper and lower limbs. Diffusion-weighted magnetic resonance imaging (DWI) of the brain showed high signal intensity at the vermis and lower left hemisphere of the cerebellum, and magnetic resonance angiography showed that the entire left vertebral artery was thin. The patient was treated with an intravenous infusion of tissue plasminogen activator 2 hours after symptom onset and made a full recovery. Repeat DWI, fluid-attenuated inversion recovery images, and T2-weighted images showed high signal intensity in the left upper cervical PSA area from the lower medulla oblongata to the C2 level in addition to the cerebellum. Previously reported cases of cervical posterior artery syndrome are reviewed.

A longitudinal genome-wide association study of anti-tumor necrosis factor response among Japanese patients with rheumatoid arthritis.

BACKGROUND: Studies of Caucasian patients with rheumatoid arthritis (RA) to identify genetic biomarkers of anti-tumor necrosis factor (TNF) response have used response at a single time point as the phenotype with which single nucleotide polymorphism (SNP) associations have been tested. The findings have been inconsistent across studies. Among Japanese patients, only a few SNPs have been investigated. We report here the first genome-wide association study (GWAS) to identify genetic biomarkers of anti-TNF response among Japanese RA patients, using response at 2 time-points for a more reliable clinical phenotype over time. METHODS: Disease Activity Scores based on 28 joint counts (DAS28) were assessed at baseline (before initial therapy), and after 3 and 6 months in 487 Japanese RA patients starting anti-TNF therapy for the first time or switching to a new anti-TNF agent. A genome-wide panel of SNPs was genotyped and additional SNPs were imputed. Using change in DAS28 scores from baseline at both 3 (ΔDAS-3) and 6 months (ΔDAS-6) as the response phenotype, a longitudinal genome-wide association analysis was conducted using generalized estimating equations (GEE) models, adjusting for baseline DAS28, treatment duration, type of anti-TNF agent and concomitant methotrexate. Cross-sectional analyses were performed using multivariate linear regression models, with response from a single time point (ΔDAS-3 or ΔDAS-6) as phenotype; all other variables were the same as in the GEE models. RESULTS: In the GEE models, borderline significant association was observed at 3 chromosomal regions (6q15: rs284515, p = 6.6x10(-7); 6q27: rs75908454, p = 6.3x10(-7) and 10q25.3: rs1679568, p = 8.1x10(-7)), extending to numerous SNPs in linkage disequilibrium (LD) across each region. Potential candidate genes in these regions include MAP3K7, BACH2 (6q15), GFRA1 (10q25.3), and WDR27 (6q27). The association at GFRA1 replicates a previous finding from a Caucasian dataset. In the cross-sectional analyses, ΔDAS-6 was significantly associated with the 6q15 locus (rs284511, p = 2.5x10(-8)). No other significant or borderline significant associations were identified. CONCLUSION: Three genomic regions demonstrated significant or borderline significant associations with anti-TNF response in our dataset of Japanese RA patients, including a locus previously associated among Caucasians. Using repeated measures of response as phenotype enhanced the power to detect these associations.

[Anti-Hu antibody-positive paraneoplastic limbic encephalitis with acute motor sensory neuropathy resembling Guillain-Barré syndrome: a case study].

A 69-year-old man experienced general malaise, weight loss, amnesia, gait disturbance, and restlessness a month prior to admission. Brain MRI showed high intensity areas in the bilateral medial temporal lobes and insular cortices on FLAIR images, and therefore, he was diagnosed with limbic encephalitis. After admission, quadriplegia and respiratory failure progressed rapidly, and he needed ventilatory management. A nerve conduction study revealed low compound muscle action potential amplitude with loss of sensory nerve action potential, which indicated axonal sensorimotor neuropathy. We administered intravenous immunoglobulin and methylprednisolone pulse therapy, but he did not recover. Although no tumor was found on CT, his serum was positive for anti-Hu antibody; therefore, we diagnosed him with paraneoplastic neurological syndrome. An FDG-PET study showed accumulation at lesions on two hilar lymph nodes. Small cell lung carcinoma was detected by endobronchial ultrasound-guided transbronchial needle aspiration. Although paraneoplastic acute sensorimotor neuropathy with respiratory failure resembling Guillain-Barré syndrome is rare, identification of antibodies and servey of tumors aids accurate diagnosis.

Loss of cellular cohesion in cytology composes a special subgroup of breast tumors - analysis of 37 cases.

OBJECTIVE: We analyzed smears by fine needle aspiration (FNA) from 37 cases that displayed numerous dissociated cells and correlated the results with histological findings. STUDY DESIGN: Between 1996 and 2005, 1,583 patients underwent breast FNA and resection. Loss of cellular cohesion was observed in 37 of these cases. RESULTS: From the cytological findings, we classified cases into 3 groups according to cell size and shape. Type A: numerous isolated spindle cells with a necrotic background. Four cases were classified into this group (3 cases of intraductal papilloma and 1 case of adenomyoepithelioma). Type B: lymphocytes and large isolated cells such as medullary carcinoma. Five cases were classified into this group [1 case of classic medullary carcinoma, 1 case of ductal carcinoma in situ (DCIS) and 3 cases of invasive carcinoma of no special type (NST)]. Type C: numerous uniform small round cells. Twenty-eight cases were classified into this group (2 cases of lobular carcinoma, 1 case of DCIS, 22 cases of invasive carcinoma NST, and 3 cases of solid papillary carcinoma). CONCLUSION: Numerous isolated cells are sometimes seen in both benign and malignant cytology.

Corticosteroid therapy in a patient with cerebral amyloid angiopathy-related inflammation.

We studied longitudinal changes of the levels of anti-amyloid ß (anti-Aß) antibody, amyloid ß (Aß) protein, and interleukin 8 (IL-8) in cerebrospinal fluid (CSF) of a patient with cerebral amyloid angiopathy-related inflammation (CAA-ri) in whom steroid treatment resulted in clinical improvement. The diagnosis of CAA-ri was established with brain biopsy. Levels of anti-Aß 42 antibody, Aß 40, Aß 42 and IL-8 in CSF were measured in the CAA-ri patient at 23 time points in the 8-month clinical course. These CSF samples were divided into 2 groups: those obtained before (n = 12) and those after (n = 11) oral corticosteroid therapy was started. We compared these levels between CSF samples obtained before and after therapy. The mean levels of anti-Aß 42 antibody and IL-8 were significantly higher in CSF samples of the CAA-ri patient before oral corticosteroid therapy than those after therapy. A positive correlation was noted between levels of anti-Aß 42 antibodies and IL-8 in CSF of this patient. There were no significant differences of mean levels of Aß 40 and Aß 42 between CSF samples obtained before and after oral corticosteroid therapy. It was possible that the autoinflammatory process with anti-Aß 42 antibodies and IL-8 may have been involved in the pathogenesis of CAA-ri, and that corticosteroid therapy directly affected levels of anti-Aß 42 antibody and IL-8. In summary, CAA-ri encephalopathy is a relapsing or progressive disorder and may be treatable by adequate immunosuppressive therapy. The anti-Aß 42 antibody in CSF is a useful biological marker for therapeutic monitoring of CAA-ri.

Long-term follow-up of nipple-sparing mastectomy without radiotherapy: a single center study at a Japanese institution.

Recent reports have suggested that nipple-sparing mastectomy (NSM) is a potential alternative to mastectomy (MT). The aim of our study was to investigate the oncological and technical outcomes of NSM compared with MT using long-term follow-up data. A total of 932 patients between April 1985 and March 2004 were enrolled in our study. Among them, 788 patients received NSM, whereas 144 patients received the routine mastectomy. The median follow-up time was 78 months. No significant difference in the probability of local recurrence between the NSM cohort and the MT cohort was found (8.2 vs. 7.6 %, p = 0.81). The rate of nipple-areola complex (NAC) relapse was low (3.7 %), and all of the nipple and/or areola recurrence cases were treated with NAC removal. Furthermore, nipple and/or areola recurrence was associated with a significantly better prognosis than that of skin flap recurrences and local lymph node recurrences. For the 21-year disease-free survival and the 21-year overall survival, no significant difference between the NSM and MT cohorts was observed. There was no occurrence of nipple necrosis in our trial. This was the first study to investigate the long-term follow-up of NSM in a large Japanese population. We reported the NSM could be performed without nipple necrosis and is oncologically as safe as mastectomy without radiotherapy. Therefore, we suggest that NSM without radiotherapy is a potential alternative to mastectomy for breast cancer patients for both outcome and aesthetic benefits.

[Bi-weekly nab-paclitaxel and trastuzumab therapy effective against recurrent breast cancer with multiple lung metastases in elderly patient who had previously undergone two chemotherapeutic regimens for treatment of metastatic disease-a case Report].

We herein report a 75-year-old patient with recurrent hormone-nonresponsive, HER2-positive breast cancer who presented with multiple lung metastases. She had undergone a mastectomy followed by adjuvant chemotherapy with FEC, CMF, and UFT. Forty-six months after the surgery, multiple lung, liver, and bone metastases were observed. Docetaxel and trastuzumab were administered as first-line chemotherapy for 13 months. A partial response and stable disease were observed, but progressive disease in the lung and brain was subsequently revealed. The patient then underwent g-knife treatment for brain metastasis. Lapatinib and capecitabine treatment was administered as second-line chemotherapy for 9 months. Stable disease was observed, but progressive disease in the lung metastases with clinical symptoms including cough, exertional dyspnea, and general malaise was revealed. As third-line chemotherapy, the patient was administered low-dose, bi-weekly nab-paclitaxel(150mg/m2)and trastuzumab therapy. Four weeks after beginning the nab-paclitaxel and trastuzumab treatment, the cough disappeared; 2 months after beginning the therapy, a partialresponse in the lung metastases was seen. The patient is well and the treatment has been continued for 50 weeks. No progression has been seen. Bi-weekly nab-paclitaxel treatment appears to have few side effects and might be an effective treatment option for patients with recurrent breast cancer.

Diffuse skeletal muscles uptake of [18F] fluorodeoxyglucose on positron emission tomography in primary muscle peripheral T-cell lymphoma.

A 40-year-old man presented with weakness of neck extensor muscles. Cervical magnetic resonance imaging showed high-intensity areas in muscles of the left lateral cervical region on T2-weighted images. Fluorodeoxyglucose-positron emission tomography scan demonstrated striking fluorodeoxyglucose uptake by multiple skeletal muscles of the neck, chest, and abdominal region. Muscle biopsy demonstrated peripheral T-cell lymphoma, unspecified. The diagnosis was primary skeletal muscle peripheral T-cell lymphoma. Primary skeletal muscle non-Hodgkin's lymphoma of T-cell immunophenotype is extremely rare and fluorodeoxyglucose-positron emission tomography demonstrated striking fluorodeoxyglucose uptake in multiple skeletal muscles and served as a quite useful modality for the diagnosis of this patient.

High Levels of Copper, Zinc, Iron and Magnesium, but not Calcium, in the Cerebrospinal Fluid of Patients with Fahr's Disease.

Patients with marked calcification of the basal ganglia and cerebellum have traditionally been referred to as having Fahr's disease, but the nomenclature has been criticized for including heterogeneous etiology. We describe 3 patients with idiopathic bilateral striatopallidodentate calcinosis (IBSPDC). The patients were a 24-year-old man with mental deterioration, a 57-year-old man with parkinsonism and dementia, and a 76-year-old woman with dementia and mild parkinsonism. The former 2 patients showed severe calcification of the basal ganglia and cerebellum, and the latter patient showed severe calcification of the cerebellum. We found significantly increased levels of copper (Cu), zinc (Zn), iron (Fe) and magnesium (Mg), using inductively coupled plasma mass spectrometry in the CSF of all these 3 patients. The increased levels of Cu, Zn, Fe and Mg reflect the involvement of metabolism of several metals and/or metal-binding proteins during the progression of IBSPDC. More numerous patients with IBSPDC should be examined in other races to clarify the common mechanism of the disease and to investigate the specific treatment.

[Rapidly progressive parkinsonism that developed one year after ventriculoperitoneal shunting for idiopathic aqueductal stenosis: a case report].

A 46-year-old woman was diagnosed with having idiopathic aqueductal stenosis for which she underwent ventriculoperitoneal (V-P) shunting. One year after the surgery, she developed acute parkinsonism and sylvian aqueduct syndrome. Brain magnetic resonance imaging (MRI) did not reveal any signs of hydrocephalus and fluorodopa positron emission tomography (PET) did not reveal any decrease in accumulation of fluorodopa at the striatum. On admission, the Unified Parkinson Disease Rating Scale (UPDRS) (Part III) score was 30 points. The preliminary diagnosis was parkinsonism associated with V-P shunting: therefore, the levodopa dosage was increased from 200 mg/day to 600 mg/day. Thereafter, the symptoms of parkinsonism and the sylvian aqueduct syndrome markedly improved, and the UPDRS (Part III) score decreased. If such a patient presents without signs of hydrocephalus or shunt malfunction, dopaminergic medication should be used as the initial treatment.

[Nineteen years postoperatively, anastrozole, UFT and cyclophosphamide combination therapy remained effective against recurrent hormone responsive breast cancer with intraabdominal lymphnode, pleural, skin and bone metastases in old age following sixteen-year tamoxifen treatment - a case report].

We report an 89-year-old patient with recurrent hormone-responsive breast cancer who presented with pleural, skin and bone metastases. Nineteen years previously, she had undergone a mastectomy and then for 16 years received adjuvant hormone therapy. The patient was orally administered a combination therapy of anastrozole, UFT and cyclophosphamide. A remarkable response was seen after 5 months, and no side effects were observed. The patient became well and the treatment was continued without relapse at 8 months. Oral anti-cancer treatments in combination with hormone therapy appear to have few side effects and might be an effective treatment option for recurrent breast cancer patients.

[Doxifluridine, medroxyprogesterone acetate and cyclophosphamide (DMpC) combination therapy is effective against recurrent triple negative breast cancer--a case report].

We report a postmenopausal recurrent breast cancer patient with triple negative disease who presented with right recurrent nerve palsy. Nine years previously, she had undergone a mastectomy. FDG-PET scan revealed neck lymph node metastases from the breast cancer. The recurrent nerve palsy was thus considered to have been caused by the lymph node metastases. The patient was orally administered DMpC (doxifluridine, medroxyprogesterone acetate and cyclophosphamide) combination therapy. This resulted in a remarkable response after five months, with the recurrent nerve palsy completely disappearing at six months. No side effects from the treatment were observed. The patient was well and the treatment was being continued without relapse at nine months. Oral anti-cancer treatments such as DMpC appear to have few side effects and might be an effective treatment option for recurrent breast cancer patients with triple negative disease.

[Case report of a patient with Hashimoto's encephalopathy associated with Basedow's disease mimicking Creutzfeldt-Jakob disease].

A 79-year-old female was admitted to our hospital because of unconsciousness and convulsion following mental deterioration. On admission, she exhibited myoclonic movement of the right side of the face and right fingers in addition to rigospasticity and tremors in the right arm and leg. Laboratory tests revealed hyperthyroidism with an increased anti-TSH-R antibody titer. In addition, an echogram indicated excessive blood flow at the thyroid; hence, the patient was diagnosed with Basedow's disease. Interestingly, the tests also revealed increased titer of anti-TPO antibody, anti-Tg antibody, and anti-NH2 terminal of alpha-enolase (NAE) antibody; in addition, an EEG showed abnormal findings potentially indicating periodic synchronous discharge. Brain MRI showed cerebral atrophy, and brain 99mTc-ECD-SPECT images demonstrated an overall decrease in the accumulation of 99mTc in the cerebrum. The abovementioned findings are common to patients with Creutzfeldt-Jakob disease (CJD). We initiated treatment for hyperthyroidism with thiamazole and lugol, but this did not regain consciousness. Because she had anti-thyroid antibody was observed, we considered a differential diagnosis of Hashimoto's encephalopathy and, in fact, methylprednisolone pulse therapy alleviated her symptoms and normalized the EEG findings. The condition in this case clinically mimicked CJD; therefore, the differentiated diagnosis is important because Hashimoto's encephalopathy is treatable disease.