Spread of vimentin-immunoreactive cells within the plaque-like lesion in the spinal anterior horn of a patient with post-poliomyelitis syndrome.

A Japanese man in the present study experienced acute weakness in his right leg as a two year old. The strength in his leg gradually recovered and developed, and he could play golf and climb mountains up to around the age of 50. From approximately 55 years of age, he became unable to stand up from a stooped position. Muscle weakness and atrophy spread to his right arm, and an electromyography revealed a neurogenic pattern in his lower and upper extremities. The patient was diagnosed as having post-poliomyelitis syndrome (PPS). Numbness in both the legs and pain in the buttocks occurred after 60 years of age. Computed tomography and magnetic resonance imaging at that time revealed spondylosis and protrusion of an osteophye in lower thoracic vertebrae compressing the second lumbar segment of the spinal cord. He died of malignant lymphoma and acute interstitial pneumonia at 80 years of age. Pathological examination revealed transverse myelopathy at the second lumbar segment of the spinal cord and total necrosis. The anterior horn and the intermediate zone of the third and fourth lumbar segments of the spinal cord on the right side were atrophic and diffusely gliotic. An oval-shaped plaque-like lesion was observed in the right anterior horn at the third and fourth lumbar segments of the spinal cord. Neurons and synaptophysin immunoreactivity had completely disappeared in the plaque-like lesion. A striking spread of vimentin-immunoreactive cells was found corresponding to the lesion, while glial fibrillary acidic protein-immunoreactive astrocytes existed evenly in the anterior horn and intermediate zone on both sides of the third and fourth lumber segments of the spinal cord. Virological examination using the autopsied materials was negative for poliovirus. Neither transactivation response DNA-binding protein of 43 kDa-immunoreactive inclusion nor Bunina body was seen in the spinal cord. The present paper demonstrates new findings of a noteworthy response of the vimentin-immunoreactive cells within the peculiar "plaque-like lesion" in the PPS.

Bortezomib-dexamethasone versus high-dose melphalan for Japanese patients with systemic light-chain (AL) amyloidosis: a retrospective single-center study.

Bortezomib-dexamethasone (BD) and high-dose melphalan (HDM) are effective for systemic light-chain (AL) amyloidosis, but have not been compared in detail. We retrospectively investigated patients treated with BD or HDM at our center between September 2001 and June 2016. Among 234 patients, 20 were treated with BD and 30 received HDM. With the exception of age, transplant eligibility, and previous history of other chemotherapy, there were no significant differences in most background parameters between the two groups. Median age was higher (63.2 vs. 55.8, P = 0.001), number of transplant-eligible patients was lower (60.0 vs. 96.7%, P = 0.002), and number of previously treated patients was higher (35.0 vs. 0.0%, P < 0.001) in the BD group. The BD group showed trends toward lower treatment-related mortality (5.0 vs. 10.0%, P = 0.641), greater hematological response (partial response or better) (90.0 vs. 73.3%, P = 0.279), higher complete response (60 vs. 50%, P = 0.487), and similar survival with the HDM group (neither reached, P = 0.705). In conclusion, BD was as effective and safe as HDM. Notably, BD achieved this outcome among patients with poorer clinical backgrounds compared with HDM.

Motor branch biopsy of the pronator teres muscle in a patient with painful forearm neuropathy.

Histological evaluation of a peripheral nerve is often the final diagnostic work-up for a neuropathy of unknown origin, and a distal sensory nerve is usually biopsied. Here, we report the case of a female patient with painful unilateral neuropathy in the upper arm. According to the histological evaluation of the pronator teres motor branch, vasculitis seemed to be the most probable cause of the condition, and steroid therapy improved the patients' symptoms. A biopsy of the motor branch of the pronator teres muscle nerve may be considered a valuable diagnostic option in selected cases with neuropathy affecting the upper limb, when performed in cooperation with neurologists and orthopedic surgeons.

Spinal intradural extramedullary cavernous angioma presenting with superficial siderosis and hydrocephalus: a case report and review of the literature.

A 36-year-old man with progressive hearing impairment visited our hospital complaining of a severe headache. A neurological examination revealed bilateral sensorineural hearing impairment, mild ataxia, hyperreflexia and mild cognitive dysfunction. Brain MRI demonstrated hydrocephalus and typical hypointensity rimming the brain surface on T2(*)-weighted images. The patient was diagnosed as having superficial siderosis. Spinal MRI disclosed the presence of a lumbar intradural extramedullary mass. The surgically resected tumor was histologically found to be a cavernous angioma. Superficial siderosis is an important cause of hearing loss. With respect to the detection of disorders underlying this pathological condition, MRI examinations, including those of the brain and whole spinal cord, are recommended.

Coupling deep transcriptome analysis with untargeted metabolic profiling in Ophiorrhiza pumila to further the understanding of the biosynthesis of the anti-cancer alkaloid camptothecin and anthraquinones.

The Rubiaceae species, Ophiorrhiza pumila, accumulates camptothecin, an anti-cancer alkaloid with a potent DNA topoisomerase I inhibitory activity, as well as anthraquinones that are derived from the combination of the isochorismate and hemiterpenoid pathways. The biosynthesis of these secondary products is active in O. pumila hairy roots yet very low in cell suspension culture. Deep transcriptome analysis was conducted in O. pumila hairy roots and cell suspension cultures using the Illumina platform, yielding a total of 2 Gb of sequence for each sample. We generated a hybrid transcriptome assembly of O. pumila using the Illumina-derived short read sequences and conventional Sanger-derived expressed sequence tag clones derived from a full-length cDNA library constructed using RNA from hairy roots. Among 35,608 non-redundant unigenes, 3,649 were preferentially expressed in hairy roots compared with cell suspension culture. Candidate genes involved in the biosynthetic pathway for the monoterpenoid indole alkaloid camptothecin were identified; specifically, genes involved in post-strictosamide biosynthetic events and genes involved in the biosynthesis of anthraquinones and chlorogenic acid. Untargeted metabolomic analysis by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) indicated that most of the proposed intermediates in the camptothecin biosynthetic pathway accumulated in hairy roots in a preferential manner compared with cell suspension culture. In addition, a number of anthraquinones and chlorogenic acid preferentially accumulated in hairy roots compared with cell suspension culture. These results suggest that deep transcriptome and metabolome data sets can facilitate the identification of genes and intermediates involved in the biosynthesis of secondary products including camptothecin in O. pumila.

Expression of various glutamate receptors including N-methyl-D-aspartate receptor (NMDAR) in an ovarian teratoma removed from a young woman with anti-NMDAR encephalitis.

A 21-year-old woman developed psychiatric symptoms, progressive unresponsiveness, generalized seizures, severe dyskinesia, marked fluctuation of blood pressure, and hypersalivation after a flu-like episode. Anti-glutamate receptor (GluR)ε2 and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies were positive in both her serum and CSF. After she recovered five months later she underwent surgery to remove a right ovarian teratoma. Immunohistochemical examinations of her teratoma disclosed abundant expression of various GluRs including NR2B subunit of NMDAR, GluR1, and GluR2/3. These immunoreactivities of GluRs were seen not only in small areas of neural tissue identified as anti-glial fibrillary acidic protein (GFAP)-immunoreactive areas but also in other large areas of undifferentiated neuroepithelial tissue without GFAP immunoreactivity. Our findings strongly support the recent idea that neural elements in ovarian teratoma play an important role in the production of antibodies to NMDARs in anti-NMDAR encephalitis. Additionally, the study of control ovaries clearly showed NR2B-related immunoreactivity in the cytoplasm of oocytes, indicating that the normal ovary itself has expression of NMDARs. This finding might provide a clue to understand the pathogenesis of this disease in female patients without ovarian teratoma.

CPPD crystal deposition disease of the cervical spine: a common cause of acute neck pain encountered in the neurology department.

BACKGROUND: Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is one of the most common forms of crystal-associated arthropathy in the elderly. However, CPPD deposition on the cervical spine is less well known, and only a limited number of cases have been reported to date. Here, we report our recent clinical experience with CPPD crystal deposition disease of the cervical spine and describe the clinical features of this disease. METHODS: Fourteen patients with clinically diagnosed CPPD crystal deposition disease of the cervical spine at our department during the period from January 2005 to December 2008 were analyzed retrospectively. RESULTS: Patients ranged in age from 54 to 92 (mean+/-SD, 77.5+/-8.5). Chief symptoms of patients were acute posterior neck pain and fever. All patients had markedly restricted neck rotation. Serum CRP level was highly elevated in all patients (10.16+/-5.35 mg/dL). Computed tomography of the cervical spine demonstrated linear calcific deposits in the transverse ligament of atlas (crowned dens syndrome) in all patients. Calcific deposits were also found in other periodontoid structures and the ligamenta flava in some patients. Posterior neck pain, fever, and increased serum inflammatory indicators were relieved within 1 to 3 weeks by nonsteroidal antiinflammatory drugs (NSAIDs) or a combination of NSAIDs and prednisolone. Most of the patients were misdiagnosed as having other diseases before consultation. CONCLUSIONS: CPPD crystal deposition disease of the cervical spine is one of the most common underrecognized causes of acute neck pain in the neurology department, especially in elderly patients.

Primary AL amyloid polyneuropathy successfully treated with high-dose melphalan followed by autologous stem cell transplantation.

We report 2 patients with polyneuropathy associated with amyloid derived from light chains (AL) who were treated successfully with high-dose melphalan followed by autologous peripheral blood stem cell transplantation (HDM/SCT). Neuropathic symptoms improved in conjunction with normalization of serum-free light chains. In addition to amyloid deposits in tissues, an amyloidogenic light chain itself produced by abnormal plasma cells might be harmful to peripheral nerve function, and thus HDM/SCT seems to be a promising therapy for primary AL amyloid polyneuropathy.

Slaughtered aged cattle might be one dietary source exhibiting amyloid enhancing factor activity.

It has been shown that experimental murine AA amyloidosis can be enhanced by dietary ingestion of amyloid fibrils, and it is known that systemic AA amyloidosis occasionally develops in aged cattle. In this study, we examined amyloid deposits in renal and muscular tissues simultaneously obtained from slaughtered aged cattle; from both tissues when affected, amyloid-enhancing activity was also investigated. On histopathology, renal amyloid deposition was seen in nine of the 293 cattle with no history of disease, and minute amyloid deposition in muscular tissue was detectable in one of these nine. All these amyloid deposits were immunohistochemically demonstrated to be AA. Extracts, which might contain amyloid fibril fractions, were isolated from renal and muscular tissues in five of these nine cattle. On SDS-PAGE and Western blot analysis, protein bands immunoreactive to anti-AA serum were detected in the kidney fractions obtained from four of the five latter cattle, but no bands were seen in the muscle fractions of any of the five cattle. Amyloid fibril fractions from two cattle were intravenously injected into group of seven experimentally designed mice for induction of AA amyloidosis. All seven mice injected with kidney fraction developed severe AA amyloidosis, whereas only one of the seven mice given muscle fraction showed slight amyloid deposition in the spleen. These data suggest that food products made from aged cattle possess amyloid-enhancing potential.

Long-term follow-up of plasma cells in bone marrow and serum free light chains in primary systemic AL amyloidosis.

OBJECTIVE: Primary systemic AL amyloidosis arises from immunoglobulin light chains produced by plasma cell dyscrasia. To prospectively investigate the production of M-protein and plasma cells in bone marrow before and after chemotherapy, we performed flow cytometry and analysis of serum free light chains (FLCs). PATIENTS AND METHODS: Fifty-nine patients with primary systemic AL amyloidosis (mean age, 59.9+/-8.8 years) were enrolled in this study, and of these 31 were serially studied before and after chemotherapy. Complete hematological remission was defined as normalization of the FLC kappa/lambda ratio. RESULTS: MPC-1(-)CD45(-) (p<0.05) and MPC-1(+)CD45(-)CD49e(-) (p<0.005) were significantly higher, and MPC-1(-)-CD45(+) (p<0.05), MPC-1(+)CD45(+)CD49e(-) (p<0.0001) and MPC-1(+)CD45(+)CD49e(+) (p<0.0005) were significantly lower in the patients with AL amyloidosis than in controls. There was a significantly positive correlation between the serum predominant FLC/serum creatinine ratio and MPC-1(+)CD45(-)CD49e(-) (p<0.05). After chemotherapies, such as high-dose melphalan with autologous stem cell support, 20 of 31 patients with AL amyloidosis achieved complete hematological remission. There were no significant differences in any subtype of plasma cells before treatment between the remission and non-remission groups, but in the former group MPC-1(+)CD45(-)CD49e(-) and MPC-1(-)CD45(+) were significantly decreased and increased after chemotherapy compared with before, respectively. CONCLUSION: Abnormal plasma cells in the bone marrow, particularly the MPC-1(+)CD45(-)CD49e(-) subset, may be important as a follow-up marker before and after chemotherapy in primary systemic AL amyloidosis. These cells maintain low levels as long as no relapse occurs.

Therapeutic outcome of cyclic VAD (vincristine, doxorubicin and dexamethasone) therapy in primary systemic AL amyloidosis patients.

OBJECTIVE: Intensive chemotherapy targeting plasma cell dyscrasia has been recently employed for the treatment of primary systemic AL amyloidosis. We prospectively studied the clinical usefulness of cyclic VAD (vincristine, doxorubicin and dexamethasone) in patients with primary systemic AL amyloidosis who were ineligible for high-dose melphalan with autologous stem cell support. PATIENTS AND METHODS: Eight patients (mean age, 60.4+/-8.8 years) were treated with cyclic VAD until the disappearance of M-protein from both serum and urine. Of these, seven showed nephrotic syndrome before the start of VAD irrespective of a decrease in creatinine clearance. Serial follow-up studies after VAD evaluated hematological status and organ function. RESULTS: Four patients (50%) showed a marked decrease in abnormal plasma cells in the bone marrow and normalized kappa/lambda ratios of serum free light chain in conjunction with disappearance of M-protein after 1 to 3 courses of VAD. There were no serious adverse events, and nephrotic syndrome gradually improved with no hematological relapse in the follow-up period of 3 to 5 years. The remaining 4 patients showed worsening of congestive heart failure and/or systemic edema ascribable to dexamethasone, resulting in cessation of cyclic VAD before disappearance of M-protein. All of these patients died of multiple organ failure or required permanent hemodialysis within 1 year after the start of cyclic VAD. CONCLUSION: Cyclic VAD is a potent therapeutic option in primary systemic AL amyloidosis, but in patients with renal or cardiac dysfunction careful management for adverse events, especially body fluid retention, is necessary.

AL amyloidosis manifesting as systemic lymphadenopathy.

We report three patients with AL amyloidosis manifesting as systemic lymphadenopathy, mainly in the cervical and supraclavicular regions. Histopathology of lymph nodes showed massive deposition of AL amyloid with no abnormal findings suggestive of lymphoproliferative disorders. Two of the patients were considered to be classifiable as primary systemic AL amyloidosis based on the presence of M-protein in serum and abnormal plasma cells or lymphoplasmacytoid cells in the bone marrow probably producing the precursor immunoglobulin, although no visceral organs were affected. The size of the involved lymph nodes in these two patients increased gradually, and one was treated with rituximab and VAD (vincristine, doxorubicin and dexamethasone) followed by high-dose melphalan with autologous peripheral blood stem cell transplantation (auto-PBSCT). The remaining patient showed no obvious change in the size of lymph nodes or detectable M-protein in serum. The prognosis of AL amyloidosis manifesting as lymphadenopathy is usually good as long as there are no hematological malignancies or rapid increases in the size of lymph nodes, but in cases of the systemic type, intensive chemotherapy, such as high-dose melphalan with auto-PBSCT, should be actively considered in order to avoid possible involvement of visceral organs.

Nephrotic syndrome due to primary systemic AL amyloidosis, successfully treated with VAD (vincristine, doxorubicin and dexamethasone) alone.

We report 3 patients with nephrotic syndrome ascribed to primary systemic AL amyloidosis that were successfully treated with VAD (vincristine, doxorubicin and dexamethasone) alone. M-protein in serum disappeared soon after VAD, and nephrotic syndrome gradually improved in parallel with a decrease in daily protein excretion in urine. Long-term follow-up of these patients showed neither relapse of nephrotic syndrome nor reappearance of M-protein. High-dose melphalan followed by autologous stem cell support is a standard therapy for primary systemic AL amyloidosis, but in high-risk cases for this treatment, such as elderly patients and those with multiple organ involvement, VAD might be a therapeutic option.

Severe cranial nerve involvement in a patient with monoclonal anti-MAG/SGPG IgM antibody and localized hard palate amyloidosis.

We report a patient with severe cranial polyneuropathy as well as sensory limb neuropathy. Biclonal serum IgM-kappa/IgM-lambda gammopathy was found and serum anti-myelin-associated glycoprotein (MAG)/sulfoglucuronyl paragloboside (SGPG) IgM antibody was also detected. Immunofluorescence analysis of a sural nerve biopsy specimen revealed binding of IgM and lambda-light chain on myelin sheaths. No amyloid deposition was detected in biopsied tissues except for the hard palate, suggesting that the amyloidosis was of the localized type and had no relation to the pathogenesis of cranial neuropathy. Our observations indicate that the anti-MAG/SGPG IgM antibody may be responsible for this patient's cranial polyneuropathy, which is a rare manifestation in anti-MAG/SGPG-associated neuropathy.

[Two patients with pseudogout manifested by severe neck pain].

We reported 2 patients with pseudogout manifested by severe posterior neck pain. Patient 1 was a 78-year-old woman. She had experienced attacks of posterior neck pain several times for 4 years. On July 3, 2001, she developed severe pain in the posterior neck and left acromioclavicular joint, and was admitted to our hospital. On examination, her body temperature was 38.1 degrees C, ESR 140 mm/hr and CRP 14.7 mg/dl. Linear calcifications in meniscus of the right knee and left acromioclavicular joint were observed in roentgenograms. The CT of the cervical spines revealed multiple nodular calcifications in the ligamenta flava at the level of C3-C7. She was treated with NSAIDs, and her symptoms and inflammatory reactions rapidly subsided. Patient 2 was was a 76-year-old man. His clinical courses and laboratory findings were very similar to those of patient 1. Both patients presented here were older than 70, and shared such common clinical findings as back neck pain, fever, elevations of serum ESR and CRP level, and effiveness of NSAIDs. We could not detect any findings that could explain the neck pain and fever in cervical spinal roentgenograms and MRIs. Cerebrospinal fluid examinations showed no abnormalities. We diagnosed them as having cervical arthritis caused by calcium pyrophosphate dihydrate deposition (pseudogout) based on the cervical CT examinations, which showed multiple nodular calcifications in the ligamenta flava. Calcium pyrophosphate dihydrate deposition on cervical spine is very rare, and only 50 patients with this condition have been reported to date. In the literatures, the mean age of patients with cervical spine pseudogout is old (72.3 years old) and 84% of them are females. The ligamenta flava at the level of C3-C6 and transverse ligament of the atlas are most commonly involved. Pseudogout of the cervical spine should be considered as a differential diagnosis when we examine the elderly patients with back neck pain. Cervical spinal CT is the most sensitive and useful examination to diagnose this disease.