Correction to: Bilateral atypical ulnar fractures occurring after long-term treatment with bisphosphonate for 7 years and with teriparatide for 2 years: a case report.

The original version of this article, published on 10 September 2020 contained a mistake.

Bilateral atypical ulnar fractures occurring after long-term treatment with bisphosphonate for 7 years and with teriparatide for 2 years: a case report.

Most atypical fractures associated with the long-term treatment with bisphosphonates (BP) commonly develop in the femoral shaft or subtrochanteric region. We report a rare case of bilateral atypical ulnar fractures in an 86-year-old woman with osteoporosis who finished the treatment with teriparatide for 2 years after long-term treatment with BP. She slid down from an approximately 30-cm-tall seat and slightly contused her left elbow. Plain radiography revealed that both ulnae had a noncomminuted short oblique fracture with cortical thickening and sclerosis at the fracture site. Based on the clinical and radiological findings, she was diagnosed with bilateral atypical ulnar fractures. The fracture of the left ulna was completely displaced and treated surgically. On the other hand, since the right ulna was an incomplete fracture, it was treated conservatively. During surgery, drilling with Kirschner wire and curettage were performed in the osteosclerotic lesion, and an autologous cancellous bone graft was inserted from the ipsilateral olecranon. Bone union was achieved in both fractures at 1 year after surgery. There have been no reports regarding the development of atypical ulnar fractures occurring after the long-term treatment with BP and 2-year use of teriparatide, and the treatment strategies of such fractures have not been established. If teriparatide cannot be used after occurring atypical fractures, the use of low-intensity pulsed ultrasound (LIPUS) and subsequent treatment for osteoporosis are recommended for the bone union. In addition, the treatment of the osteosclerotic lesion and rigid internal fixation are required in surgery.

Prostaglandin F2α FP receptor inhibitor reduces demyelination and motor dysfunction in a cuprizone-induced multiple sclerosis mouse model.

Previously, we have demonstrated that prostamide/PGF synthase, which catalyzes the reduction of prostaglandin (PG) H2 to PGF2α, is constitutively expressed in myelin sheaths and cultured oligodendrocytes, suggesting that PGF2α has functional significance in myelin-forming oligodendrocytes. To investigate the effects of PGF2α/FP receptor signaling on demyelination, we administrated FP receptor agonist and antagonist to cuprizone-exposed mice, a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, glial activation, proinflammatory cytokine expression, and motor dysfunction. Administration of the FP receptor antagonist AL-8810 attenuated cuprizone-induced demyelination, glial activation, and TNFα expression in the corpus callosum, and also improved the motor function. These data suggest that during cuprizone-induced demyelination, PGF2α/FP receptor signaling contributes to glial activation, neuroinflammation, and demyelination, resulting in motor dysfunction. Thus, FP receptor inhibition may be a useful symptomatic treatment in multiple sclerosis.

Changes of human menisci in osteoarthritic knee joints.

OBJECTIVE: To investigate the changes of knee menisci in osteoarthritis (OA) in human. METHODS: OA and control menisci were obtained from 42 end-stage OA knees with medial involvement and 28 non-arthritic knees of age-matched donors, respectively. The change of menisci in OA was evaluated by histology, and gene expression of major matrix components and anabolic factors was analyzed in the anterior horn segments by quantitative PCR (qPCR). In those regions of menisci, the rate of collagen neo-synthesis was evaluated by [(3)H]proline incorporation, and the change of matrix was investigated by ultrastructural observation and biomechanical measurement. RESULTS: In OA menisci, the change in histology was rather moderate in the anterior horn segments. However, despite the modest change in histology, the expression of type I, II, III procollagens was dramatically increased in those regions. The expression of insulin-like growth factor 1 (IGF-1) was markedly enhanced in OA menisci, which was considered to be responsible, at least partly, for the increase in procollagen gene expression. Interestingly, in spite of marked increase in procollagen gene expression, incorporation of [(3)H]proline increased only modestly in OA menisci, and impaired collagen synthesis was suggested. This finding was consistent with the results of ultrastructural observation and biomechanical measurement, which indicated that the change of meniscal matrix was modest in the macroscopically preserved areas of OA menisci. CONCLUSION: Although the expression of major matrix components was markedly enhanced, matrix synthesis was enhanced only modestly, and the changes of matrix in human OA menisci were rather modest in the non-degenerated areas.

Onset of steroid-induced osteonecrosis in rabbits and its relationship to hyperlipaemia and increased free fatty acids.

OBJECTIVES: To clarify the initial onset time of osteonecrosis after the start of steroid treatment and its relation to the onset of abnormal lipid metabolism. METHODS: Animal models were prepared by administering methylprednisolone to rabbits using five different steroid regimens. RESULTS: A single, acute ischaemic event suggested by the frequency, size or number of necrotic foci within the proximal femur was not different among the groups. Histological evidence of osteonecrosis first occurred 1-2 weeks after initial steroid administration. At the same time there were significantly abnormal elevations in serum lipids, which persisted for between 1 and 2 weeks after the initial corticoid treatment. Triglycerides, total cholesterol and free fatty acids were markedly elevated in all groups; these lipid abnormalities were significantly present in the rabbits with osteonecrosis but not in the rabbits without osteonecrosis. CONCLUSIONS: This study shows that (i) osteonecrosis appears in rabbits shortly after corticoids are first administered, and (ii) osteonecrosis in rabbits is chronologically associated with the onset of hyperlipaemia and increased free fatty acids. This supports the occurrence of intraosseous fat embolism as a cause of osteonecrosis.

Attenuated nuclear shrinkage in neurones with nuclear inclusions of SCA1 brains.

BACKGROUND: Spinocerebellar ataxia type 1 (SCA1) is one of the autosomal dominant neurodegenerative disorders commonly linked to pathological expansion of the CAG repeat of the relevant gene. Nuclear inclusions and neurodegeneration are both triggered by this pathological expansion of the CAG/polyglutamine repeat on ataxin-1, but it remains to be determined whether or not nuclear inclusion formation is associated with accelerated neurodegeneration. OBJECTIVE: To examine the influence of nuclear inclusions on nuclear size and deformity in human brains from patients suffering from SCA1. MATERIAL: Pontine sections of brains obtained at necropsy from seven patients with SCA1 and five controls. METHODS: The size and deformity of each neuronal nucleus was quantified. Nuclei with and without inclusions were examined separately to assess the possible influence of nuclear inclusions on neurodegeneration. RESULTS: Nuclear shrinkage and deformity were more marked in SCA1 brains than in controls. This shrinkage was attenuated in neurones containing nuclear inclusions. CONCLUSIONS: The existence of nuclear inclusions in SCA1 is presumably linked to a mechanism that attenuates rather than accelerates nuclear shrinkage. This in vivo finding may provide a clue to constructing a rational therapeutic strategy for combating neurodegeneration associated with nuclear inclusions.

Germinoma with a granulomatous reaction. Problems of differential diagnosis.

The patient was a 6 year-old girl with a progressive loss of visual acuity. Magnetic resonance imaging showed a suprasellar mass lesion with enhanced gadolinium which was resected. Histopathological study showed a remarkable granulomatous reaction, but a diagnosis was difficult. However, immunohistochemical study showed a few cells that were positive for placental alkaline phosphatase and it was diagnosed as germinoma. Intracranial germinoma with a remarkable granulomatous reaction is rare. However, when germinoma is suspected clinically, an immunohistochemical study is able to identify germinoma even if granulomatous disease is diagnosed histopathologically.

Paradoxical absence of nuclear inclusion in cerebellar Purkinje cells of hereditary ataxias linked to CAG expansion.

Degeneration of cerebellar cortex is one of the principal features of hereditary ataxias linked to expansion of CAG repeat. In an attempt to clarify possible correlation between neuronal depletion and neuronal intranuclear inclusions, both triggered by the pathological expansion of CAG repeat, cerebellar sections from SCA1, SCA2, SCA3, and DRPLA cases were immunostained with anti-ubiquitin or anti-expanded polyglutamine antibody (1C2) and were screened for the presence of neuronal intranuclear inclusions. Although the degree of cerebellar degeneration varied greatly, cerebellar Purkinje cells were uniformly characterised by the absence of neuronal intranuclear inclusion. Complete absence of neuronal intranuclear inclusion in Purkinje cells is apparently paradoxical and hardly explained if neuronal intranuclear inclusion formation is positively correlated to a mechanism accelerating neuronal death. It may, otherwise, suggest an intrinsic link between neuronal intranuclear inclusion formation and neurodegeneration in opposite directions in human Purkinje cells, more or less affected in these CAG repeat disorders.

Distribution and dynamic process of neuronal cytoplasmic inclusion (NCI) in MSA: correlation of the density of NCI and the degree of involvement of the pontine nuclei.

MSA is a sporadic degenerative disease that occurs in striatonigral degeneration (SND), SDS and most cases of sporadic OPCA. Oligodendroglial inclusion is a hallmark of MSA. Recently there have been a small number of reports of neuronal argyrophilic inclusions. To clarify the distribution and dynamic process of neuronal cytoplasmic inclusions (NCI), 31 cases of MSA were studied using histology, immunohistochemistry, and electron microscopy. The inclusions were exclusively found in the pontine nucleus and there was a correlation between the incidence of NCI and the severity of OPCA, but not of SND. NCI were increased to some extent in the cases with moderate OPCA and decreased in number in proportion to devastation of the pontine nuclei. Immunohistochemical and ultrastructural features of NCI were virtually identical to those of glial cytoplasmic inclusions (GCI), which gives some clues to the pathogenesis of MSA. It is tempting to interpret this as NCI playing a significant role in the degenerative changes of the neurons at least in the pons. Further systematic studies on NCI in the other brain regions are necessary to elucidate the pathogenesis of neuronal degeneration in MSA.

Non-expanded polyglutamine proteins in intranuclear inclusions of hereditary ataxias--triple-labeling immunofluorescence study.

Neuronal intranuclear inclusions (NIIs) found in CAG/polyglutamine-expansion disorders contain both expanded polyglutamine and the gene product without the CAG repeat. The gene product containing expanded polyglutamine has, therefore, been considered to be a major component of NIIs. In this immunohistochemical study, we showed recruitment of ataxin-2, ataxin-3 and TATA box binding protein (TBP) into NIIs of the pontine neurons of spinocerebellar ataxia type (SCA) 1, SCA2, SCA3 and dentatorubral-pallidoluysian atrophy brains. Triple-labeling immunofluorescence demonstrated colocalization of ataxin-2 and ataxin-3 in NIIs containing expanded polyglutamine, irrespective of the disease examined. These in vivo findings indicate that polyglutamine proteins recruited into NIIs are not restricted to their expanded form. Among these proteins, recruitment of ataxin-2 was least frequent in every case examined, suggesting that the rate of recruitment partly depends on the protein transported into NIIs. Because other proteins lacking polyglutamine motif were not detected in NIIs, it is suggested that the presence of polyglutamine is a prerequisite for these proteins to be recruited into nucleus and to form NIIs. Interaction between expanded and non-expanded polyglutamine may play roles during these processes.

Intracellular processing of aggregated tau differs between corticobasal degeneration and progressive supranuclear palsy.

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are sporadic neurodegenerative diseases with intracytoplasmic aggregates of the microtubule-associated protein, tau, in neurons and glial cells. Immunoblot analysis of detergent-insoluble brain extracts of patients with CBD and PSP shows distinctive patterns of tau fragments. These results suggest differing intracellular processing of aggregated tau in these two diseases despite an identical composition of tau isoforms. Such biochemical differences may be related to the neuropathological features of these diseases.

Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick's disease, corticobasal degeneration and progressive supranuclear palsy.

We investigated isoform composition of aggregated tau protein in brains with Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) by immunoblot analysis of sarkosyl-insoluble fractions of brain homogenates. We also examined the adjacent brain tissues immunohistochemically with a rabbit antibody, Ex10, which specifically recognizes exon 10 of tau. The Ex10 recognizes tau isoforms with four microtubule-binding repeats (4Rtau) but not those with three microtubule-binding repeats (3Rtau). Sarkosyl-insoluble tau from the brains of patients with CBD and PSP consisted of 4Rtau. Insoluble tau from the PiD brains contained both 3Rtau and 4Rtau, where 3Rtau predominated over 4Rtau. In brain tissues of CBD and PSP, Ex10 immunostained all neuronal and glial tau-positive structures. They included pre-tangles, astrocytic plaques, tuft-shaped astrocytes, and oligodendroglial coiled bodies. In PiD brains, astrocytic inclusions were also positive for 4Rtau. However, the majority of, if not all, Pick bodies and oligodendroglial tau inclusions were negative for 4Rtau. Such results suggest that, in neurons and oligodendroglia, tau isoforms involved in the pathological processes differ between CBD/PSP and PiD, and are thus disease specific. This contrasts with the astrocytic tau isoforms that accumulate similarly in all three disorders.

Spinal tanycytic ependymomas.

Three cases of spinal tanycytic ependymoma are reported, a man aged 45 years and two women aged 36 and 55 years. Each patient developed gradual paraparesis over a few months prior to admission. Magnetic resonance imaging showed an enhancing, well-circumscribed tumor in the spinal cord in each case. Histologically, the tumors consisted of monotonous proliferation of long spindle cells with markedly eosinophilic cell processes; focally forming perivascular pseudorosettes. The tumor cells were strongly immunopositive for glial fibrillary acidic protein, S-100 protein and vimentin. Ultrastructurally, in addition to massive intermediate filaments, many tumor cells showed abundant microtubules. Well-developed desmosomes and microvilli/cilia-lined microlumina were occasionally observed. The tumors were grossly totally removed and the patients remain recurrence free at 9, 9, and 2 years postoperatively. Reviewing reported cases including our three cases, tanycytic ependymoma may occur frequently in spinal cord, especially in the cervical region of the spinal cord. Since histologically it resembles pilocytic astrocytoma and schwannoma, tanycytic ependymoma should be included in the differential diagnosis of benign spindle cell tumors of the central nervous system.

Distribution of cerebral cortical lesions in Pick's disease with Pick bodies: a clinicopathological study of six autopsy cases showing unusual clinical presentations.

We investigated six Japanese autopsy cases of Pick's disease with Pick bodies (PDPB) both clinically and pathologically, and examined the distribution of their cerebral cortical lesions using hemisphere and/or bisphere specimens. The lesions were classified into three categories (slight, moderate, and severe). Two patients with a clinical diagnosis of primary progressive apraxia and of slowly progressive aphasia had speech apraxia as their initial signs, and the other two patients were suspected as having Alzheimer's disease, with the clinical diagnosis of the remainder two patients being presenile dementia and depression, respectively. Extrapyramidal signs, believed to be rare in PDPB, were present in four patients. Severe lesions were multicentrically present in the cerebral cortices of all six cases. In two patients with speech apraxia, severe lesions were seen in the primary motor area, which generally has not been regarded as an "atrophic center" in Pick's disease. Furthermore, in a patient with depression, severe lesions were more widespread in the convexity than in the orbital region of the frontal lobe. The parietal lobes, including the postcentral gyrus usually believed to be spared in Pick's disease, were severely involved in three patients. We postulate that the clinical features of PDPB have a much wider spectrum than previously believed. In addition, we believe that the distribution of the cerebral cortical lesions in PDPB is more widespread than previously assumed, and that clinical manifestations of PDPB depend to some extent on the topographic distribution of the cerebral cortical lesions.

Asymmetrical temporal lobe atrophy with massive neuronal inclusions in multiple system atrophy.

This report concerns a rare association of asymmetrical temporal lobe atrophy with multiple system atrophy (MSA). A 53-year-old Japanese woman developed cerebellar ataxia and parkinsonism and was diagnosed as olivopontocerebellar atrophy (OPCA). This patient showed forgetfulness and subsequent disorientation even in the early stage of the disease. She fell into a decorticate state at the age of 64, and died a year later. The autopsy showed MSA with asymmetrical atrophy of temporal lobes, intraneuronal globular inclusions mostly confined to the hippocampus, amygdaloid nucleus, and most abundant in the granule cells in the dentate fascia. These inclusions were intensely argyrophilic and expressed marked immunoreactivity to ubiquitin, but not to neurofilament (NF), tau and paired helical filaments (PHF). Ultrastructurally, they were composed of scattered short filamentous structures of 15 to 30 nm in diameter, ribosome-like granules, mitochondria and lipofuscin. The lack of immunoreactivity against tau, NF and PHF suggests that the inclusions are distinct from Pick bodies. To our knowledge, MSA in association with asymmetrical temporal lobe atrophy with the present neuronal inclusions has not been reported. This case is distinct from MSA combined with atypical Pick's disease in the distribution and immunohistochemical properties of neuronal inclusions, and may present a new variant of MSA since the neuronal inclusions are similar, in many respects, to those of neuronal inclusions reported in MSA. Globular inclusions are also discussed in variants of Pick's disease, amyotrophic lateral sclerosis and Alzheimer's disease.

An autopsy case of atypical adrenoleukomyeloneuropathy in childhood.

Adrenoleukomyeloneuropathy (ALMN) usually occurs in adulthood, it being extremely rare in childhood. We reported a quite atypical clinical case of ALMN as a variant of adrenoleukodystrophy (ALD). The onset was at 5 years 7 months and ataxia was the major symptom. His condition progressed rapidly to a vegetative state within 1 year. At the age of 11 years and 11 months he died of pneumonia and an autopsy was performed. We herein reported the neuropathological findings in this rare case. The autopsy revealed marked atrophy with diffuse demyelination and astrogliosis throughout the cerebrum, cerebellum and brainstem. Massive degeneration of the pyramidal tracts and loss of neurons were also seen in the spinal cord. The adrenal cortex showed marked atrophy with a striated cytoplasm in ballooned cells. These findings include pathological characteristics of both ALD and adrenomyeloneuropathy (AMN), suggesting ALMN. However, diffuse demyelination with gliosis in the cerebrum and cerebellum is quite atypical for ALMN. They might explain his atypical clinical course, especially the early onset of the disease with ataxia and rapid deterioration.

Ataxin-3 is translocated into the nucleus for the formation of intranuclear inclusions in normal and Machado-Joseph disease brains.

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is one of the dominantly inherited cerebellar ataxias. The gene responsible for the disease, a novel gene of unknown function, encodes ataxin-3 containing a polyglutamine stretch. Although it has been known that ataxin-3 is incorporated into neuronal intranuclear inclusions (NIIs) in neurons of affected regions, the relationship between NII formation and neuronal degeneration still remains uncertain. In the present study we show two different conditions in which ataxin-3 is recruited into the nucleus and suggest a process to form nuclear inclusions. In normal brains, wild-type ataxin-3 localizes within the ubiquitin-positive nuclear inclusion, the Marinesco body, indicating that ataxin-3 is recruited into the nuclear inclusion even in the absence of pathologically expanded polyglutamine. In MJD/SCA3 brains, immunohistochemical analyses with anti-ataxin-3 antibody, anti-ubiquitin antibody, and monoclonal antibody 1C2 known to recognize expanded polyglutamine revealed differences in frequency and in diameter among NIIs recognized by each antibody. These results were confirmed in the same inclusions by double immunofluorescent staining, suggesting that expanded ataxin-3 forms a core, thereby recruiting wild-type ataxin-3 into the nucleus around the core portion, and then followed by activation of the ubiquitin/ATP-dependent pathway. Recruitment of ataxin-3 into the nucleus and formation of nuclear inclusion under two different conditions suggest that ataxin-3 may be translocated into the nucleus under certain conditions stressful on neuronal cells such as aging and polyglutamine neurotoxicity.

Neurotoxicity of intrathecally administered tetracaine commences at the posterior roots near entry into the spinal cord.

BACKGROUND AND OBJECTIVES: Neurotoxicity of intrathecally administered local anesthetics is generating increased interest. This study was designed to examine the histopathologic effects of intrathecally administered tetracaine. METHODS: Sixty Wistar rats randomly received either 20%, 10%, 5%, 3%, 1%, 0.5%, or 0% tetracaine dissolved in 10% glucose solution or no solution via a chronically implanted intrathecal catheter. The spinal cord at L1, posterior and anterior roots and cauda equina were excised 5 days later, sectioned, processed, and prepared for light and electron microscopic examinations. RESULTS: Rats treated with tetracaine at 10% or 20% developed lesions in the posterior white matter and posterior roots. Rats injected with 3% or 5% tetracaine developed lesions, which began in the posterior roots close to the spinal cord and extended to the posterior white matter. The lesions were characterized by axonal degeneration. Injections of < or =1% of tetracaine did not cause any pathological changes. CONCLUSIONS: Our results suggest that the initial target of intrathecal tetracaine neurotoxicity may be the posterior roots at their entry into the spinal cord, where the axons are devoid of myelin sheath and thus representing a sensitive area for neurotoxic change.

Vascular structure of arteriovenous malformations.

Cerebral arteriovenous malformations (AVMs) are classified angiographically into two types: the arteriovenous fistula (AVF) type and the plexiform type. However, the differences in vascular structure of these two types have not been clarified. The purpose of the present study is to elucidate the vascular structure of plexiform AVMs and to discuss the clinical significance of this classification of AVMs. Specimens of AVMs resected in 8 cases and identified by cerebral angiography as plexiform AVMs were examined. Immediately after their removal, microdissection of the terminal arterial feeder, the nidus, and the venous drainer was performed under a microscope. A histological examination of each element was then conducted. Microdissection of a portion of the vascular mass that formed the nidus made it possible to separate individual vessels of the mass from each other. Many of these individual vessels connected with the feeder on one side, while the other side anastomosed with the drainer, thus exhibiting the morphology of an AVF. From our examination of the AVMs in the present study, we inferred that the plexiform type is fundamentally a conglomeration of AVFs. It is therefore suggested that the vascular structure of this type of AVM is not fundamentally different from that of the AVF type.