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Purpose: Intermittent claudication (IC) refers to leg pain that is induced by walking and relieved by rest. Neurogenic IC is usually associated with lumbar canal stenosis (LCS). We present rare findings from an autopsied patient who had neurogenic IC caused by vasculitis in the cauda equina. Methods: We performed antemortem neurological and electrophysiological assessments, sural nerve biopsy, and post-mortem examination of the spinal cord and brain. Results: A 61-year-old man noted sudden-onset leg pain that was not associated with any traumatic trigger. His leg pain consistently appeared when the patient walked and quickly faded on stopping. Spine surgery and cardiovascular departments both made a diagnosis of IC. However, magnetic resonance imaging (MRI) did not show LCS, and all ankle-brachial pressure indices were normal. He subsequently developed diffuse muscle weakness of the legs a month after disease onset. Myeloperoxidase antineutrophil cytoplasmic autoantibody was seropositive (140 IU/mL), and a sural nerve biopsy revealed axonal injury and angiitis. MRI showed multiple cerebral infarctions. He was diagnosed with microscopic polyangiitis (MPA) and underwent corticosteroid therapy. He died from complications two months after the onset. A post-mortem study revealed vasculitis in the subarachnoid space of the cauda equina, spinal cord, and brain parenchyma. The cauda equina showed a combined loss of small and large axonal fibres. The lumbar cord displayed central chromatolysis of the lower motor neurons. Conclusion: MPA is a rare cause of neurogenic IC when the symptom is acute and multimodal. Small-vessel vasculitis affecting the cauda equina may underlie MPA-associated IC. [ABSTRACT FROM AUTHOR]

A missense variant from methionine to arginine at codon 232 (M232R) of the prion protein gene accounts for ~ 15% of Japanese patients with genetic prion diseases. However, pathogenic roles of the M232R substitution for the induction of prion disease have remained elusive because family history is usually absent in patients with M232R. In addition, the clinicopathologic phenotypes of patients with M232R are indistinguishable from those of sporadic Creutzfeldt-Jakob disease patients. Furthermore, the M232R substitution is located in the glycosylphosphatidylinositol (GPI)-attachment signal peptide that is cleaved off during the maturation of prion proteins. Therefore, there has been an argument that the M232R substitution might be an uncommon polymorphism rather than a pathogenic mutation. To unveil the role of the M232R substitution in the GPI-attachment signal peptide of prion protein in the pathogenesis of prion disease, here we generated a mouse model expressing human prion proteins with M232R and investigated the susceptibility to prion disease. The M232R substitution accelerates the development of prion disease in a prion strain-dependent manner, without affecting prion strain-specific histopathologic and biochemical features. The M232R substitution did not alter the attachment of GPI nor GPI-attachment site. Instead, the substitution altered endoplasmic reticulum translocation pathway of prion proteins by reducing the hydrophobicity of the GPI-attachment signal peptide, resulting in the reduction of N-linked glycosylation and GPI glycosylation of prion proteins. To the best of our knowledge, this is the first time to show a direct relationship between a point mutation in the GPI-attachment signal peptide and the development of disease. [ABSTRACT FROM AUTHOR]

From the 202 patients with MSA, we excluded 33 patients due to insufficient clinical or pathological data; finally, we included the remaining 169 patients. Eleven (6.5%) of the 169 patients showed disease onset at the age of 75 or older; we defined those as patients with LO-MSA. Patients with LO-MSA showed a shorter disease duration (3.8 ± 1.5 years) than patients with UO-MSA (7.5 ± 4.1 years) (Mann-Whitney I U i test, I P i = 0.000527). [Extracted from the article]

The role of oligodendrocyte lineage cells, the largest glial population in the adult central nervous system (CNS), in the pathogenesis of Alzheimer's disease (AD) remains elusive. Here, we developed a culture method for adult oligodendrocyte progenitor cells (aOPCs). Fibroblast growth factor 2 (FGF2) promotes survival and proliferation of NG2+ aOPCs in a serum-free defined medium; a subpopulation (~5%) of plexin-B3+ aOPCs was also found. FGF2 withdrawal decreased NG2+, but increased plexin-B3+ aOPCs and Aβ1-42 secretion. Plexin-B3+ aOPCs were distributed throughout the adult rat brain, although less densely than NG2+ aOPCs. Spreading depolarization induced delayed cortical plexin-B3+ aOPC gliosis in the ipsilateral remote cortex. Furthermore, extracellular Aβ1-42 accumulation was occasionally found around plexin-B3+ aOPCs near the lesions. In AD brains, virtually all cortical SPs were immunostained for plexin-B3, and plexin-B3 levels increased significantly in the Sarkosyl-soluble fractions. These findings suggest that plexin-B3+ aOPCs may play essential roles in AD pathogenesis, as natural Aβ-secreting cells. In order to investigate the role of oligodendrocyte lineage cells in Alzheimer's Disease (AD) pathology, Nihonmatsu-Kikuchi et al developed a culture method for adult oligodendrocyte progenitor cells in the rat. Using this method as well as imaging AD patient brain tissue, they found that plexin-B3-expressing cells could be a potential source of amyloid β peptide. [ABSTRACT FROM AUTHOR]

The prion-like seeding of misfolded α-synuclein (αSyn) involved in the pathogenesis of Lewy body diseases (LBD) remains poorly understood at the molecular level. Using the real-time quaking-induced conversion (RT-QUIC) seeding assay, we investigated whether brain tissues from cases of dementia with Lewy bodies (DLB), which contain serine 129 (Ser129)-phosphorylated insoluble aggregates of αSyn, can convert Escherichia coli-derived recombinant αSyn (r-αSyn) to fibrils. Diffuse neocortical DLB yielded 50% seeding dose (SD50) values of 107~1010/g brain. Limbic DLB was estimated to have an SD50 value of ~105/g brain. Furthermore, RT-QUIC assay discriminated DLB from other neurological and neurodegenerative disorders. Unexpectedly, the prion-like seeding was reconstructed in reactions seeded with oligomer-like species, but not with insoluble aggregates of r-αSyn, regardless of Ser129 phosphorylation status. Our findings suggest that RT-QUIC using r-αSyn can be applied to detect seeding activity in LBD, and the culprit that causes prion-like seeding may be oligomeric forms of αSyn. [ABSTRACT FROM AUTHOR]

Multiple system atrophy (MSA) manifests as a combination of dysautonomia and motor symptoms/signs. However, rare cases presenting with autonomic failures in absence of motor symptoms/signs until their deaths have been reported and are referred to as non-motor MSA. To clarify pathological findings underlying non-motor MSA patients, we analyzed consecutively autopsied 161 patients with MSA. In results, four patients were identified as having non-motor MSA, who showed isolated autonomic disorders throughout their lives and had minimal pathological changes in the motor systems. We also identified two patients with pathologically minimal MSA, who had minimal pathological involvement in the motor systems and presented with definite parkinsonism and dysautonomia. Survival durations of the non-motor MSA patients were much shorter (1.3-2.0 years) than those of the classical MSA patients (3.0-7.0 years), and the causes of death were all sudden death. The medullary serotonergic neurons were severely involved in the non-motor MSA patients in comparison with the classical MSA patients. Also, one of the pathologically minimal MSA patients had died suddenly and exhibited marked involvement of the medullary serotonergic neurons. The involvement of the medullary catecholaminergic or cholinergic neurons did not differ in severities among the groups. We conclude that non-motor MSA may be a pathological variant of MSA that preferentially involves the medullary serotonergic neurons and autonomic systems in association with poor prognosis. [ABSTRACT FROM AUTHOR]

Purpose: This retrospective and observational study attempted to determine whether the rapid improvement in hemodynamic parameters and the subsequent discontinuation or decrease of catecholamine infusion shortly after direct hemoperfusion with polymyxin B-immobilized fibers (PMX) may be strong predictors of mortality in patients with septic shock. Methods: Retrospectively, 46 patients were divided into two groups; those who survived more than 30 days after PMX (survival group, S group) and those who died within 30 days (nonsurvival group, NS group). Sequential Organ Failure Assessment (SOFA) scores, mean arterial pressure, catecholamine index (CAI), and vasopressor dependency index (VDI) were examined before and after PMX. The same parameters were examined on days 3, 4, 5, 6, 8, and 16 after PMX. Results: CAI in the S group significantly decreased from 14.7 (95% CI, 10.3-19.1) at baseline to 6.4 (95% CI, 3.7-9.2; P < 0.001) at post-PMX, whereas a significant decrease in CAI was not observed in the NS group (23.1; 95% CI, 15.4-30.7 to 18.1; 95% CI, 11.6-24.7; P = 0.114). The significant decrease in VDI at post-PMX was observed both in the S group and in the NS group. If the cutoff point of VDI at post-PMX is 0.2, there is a significant difference in numbers of the S group (VDI ≥ 0.2, n = 24; VDI < 0.2, n = 2) and NS group (VDI ≥ 0.2, n = 8; VDI < 0.2, n = 20) using Fisher's exact test. Conclusions: We concluded that the early improvement in CAI and VDI shortly after PMX might be prognostic indicators for survival. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article about the significant association of cadaveric dura mater grafting with subpial Aß deposition and meningeal amyloid angiopathy.

We analyzed neuropathologic features of 23 Japanese patients with sporadic Creutzfeldt–Jakob disease (sCJD) by means of prion protein (PrP) immunolabeling associated with codon 129 polymorphism of the PrP gene and western blot analysis of protease-resistant PrP (PrP type). Clinical features, particularly age at onset, disease duration, periodic synchronous discharge and presence of myoclonus, were also analyzed. This study included 11 cases of subacute spongiform encephalopathy (SSE), 10 cases of panencephalopathic (PE)-type sCJD and two cases of thalamic-type sCJD, classified according to cerebral pathology findings. According to PrP gene polymorphism and PrP type, 18 cases were classified as MM1-type, two as MV1-type, two as MM2-type and one as MM1 + 2-type sCJD. SSE and PE-type sCJD showed similar clinical features, with the exception of disease duration, codon 129 polymorphism and PrP type. Thalamic-type sCJD showed different clinical features and PrP type. We suggest that SSE and PE-type sCJD comprise the sCJD subtype and that PE-type sCJD is a prolonged pathologic phenotype of SSE. When we compare our results with those from a series of Caucasian sCJD patients, the percentages of codon 129 polymorphisms differed, as did classification based on PrP gene polymorphism and PrP type; our series included many PE-type sCJD cases and disease duration was relatively long and MM2-type cases showed clinicopathologic variability. [ABSTRACT FROM AUTHOR]

We report an autopsy case of MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) with widespread cerebral neocortical pathology. Initial symptoms were progressive insomnia and mental disturbance. Magnetic resonance imaging revealed no high-signal intensity lesions on diffusion-weighted images and later showed gradually progressive cerebral atrophy. Periodic synchronous discharges and myoclonus were not observed. Upon neuropathologic examination, widespread cerebral neocortical involvement with fine vacuole-type spongiform change was observed. Severe degeneration with almost complete neuronal loss, tissue rarefaction, numerous fat-laden macrophages and hypertrophic astrocytosis of the medial thalamic nucleus was evident. The inferior olivary nucleus showed severe involvement with neuronal loss and hypertrophic astrocytosis. In the cerebellar cortex, moderate depletion of Purkinje neurons was evident, with no spongiform change in the molecular layer and no neuronal loss in the granule cell layer. Immunohistochemistry for prion protein (PrP) revealed widespread synaptic-type deposits with some primitive plaque-type deposits in the cerebral neocortex, basal ganglia and cerebellar cortex. PrP deposition was also observed in the brainstem, particularly the tegmentum, substantia nigra and pontine nucleus, and spinal cord, particularly the posterior horn. In the medial thalamus and inferior olivary nucleus, PrP deposition was sparse. Analysis of the PrP gene showed no mutation but did show methionine homozygosity at polymorphic codon 129. Western blot analysis of protease-resistant PrP indicated the presence of type 2 PrP. We believe that this patient suffered from MM2-thalamic-type sCJD (sporadic fatal insomnia) with widespread cerebral neocortical pathology due to prolonged disease duration. The present case showed different patterns of spongiform degeneration and PrP deposition in the cerebral neocortex than those in previously reported MM2-thalamic-type sCJD cases. [ABSTRACT FROM AUTHOR]

We investigated the neuropathologic features of spinal cord lesions in 23 patients with sporadic Creutzfeldt-Jakob disease (sCJD), paying particular attention to neuronal loss and gliosis, pyramidal tract degeneration and prion protein (PrP) deposition. The study included 9 cases of subacute spongiform encephalopathy, 13 cases of panencephalopathic-type sCJD and 1 case of sporadic fatal insomnia (sFI). In the spinal gray matter, although gliosis was present in some patients with disease of relatively long duration, the number of neurons, including large motor neurons, was well preserved regardless of disease duration. Pyramidal tract degeneration was observed in some patients with disease lasting more than 14 months but not in the patient with sFI. PrP deposition was present in the spinal cord of all sCJD patients, and was identified predominantly in the posterior horn, particularly in the substantia gelatinosa, regardless of disease duration or disease classification based on cerebral pathology. Relatively prominent PrP deposition was also observed in Clarke’s column. The density of PrP deposition in the sCJD spinal cord was not associated with disease duration or neuronal degeneration. Our results indicate that PrP deposition in the spinal cord is an early pathologic event in sCJD and may remain to the end stage. Although no VV1, VV2 or MV2 cases were included in our study, we suggest that stereotypic accumulation of PrP is a consistent pathologic feature of sCJD and that the spinal cord remains relatively resistant to the pathologic process of sCJD, at least in patients with MM1 sCJD. [ABSTRACT FROM AUTHOR]

We investigated whether the brainstem is affected by the pathologic process of sporadic Creutzfeldt-Jakob disease (sCJD), with particular attention to brainstem atrophy, neuronal loss, pyramidal tract degeneration, and prion protein (PrP) deposition, in 33 patients with sCJD. Brainstem atrophy, particularly in the pontine base, was relatively prominent in patients with disease of unusually prolonged duration. Neuronal loss and pyramidal tract degeneration were also identified in some but not all patients with prolonged disease. Neuronal loss was relatively prominent in the pontine nucleus and less so in the substantia nigra and inferior olivary nucleus; motor nuclei of the brainstem tegmentum were well preserved. PrP deposition was present in the brainstem in all patients, and was identified predominantly in the substantia nigra, quadrigeminal body, pontine nucleus, and inferior olivary nucleus. PrP deposition was less prominent in the red nucleus and tegmentum of the pons and medulla oblongata. PrP deposition occurred least or not at all in the pyramidal tract. The density of PrP deposition in the sCJD brainstem was not associated with disease duration or neuronal degeneration until the late stage. Our results show that atrophy, neuronal loss, and pyramidal tract degeneration occur in the sCJD brainstem, particularly in patients with an unusually prolonged disease course. These findings are not associated directly with PrP deposition and may reflect end-stage sCJD. No VV1, VV2, or MV2 cases were included in our study; however, we suggest that widespread and relatively stereotypic PrP deposition is a consistent pathologic feature of sCJD, at least in MM1 sCJD patients. Although accumulation of PrP in the brainstem appears to be an early pathologic event in sCJD, and may remain into the late disease stage, the brainstem remains relatively resistant to the pathologic process of sCJD. [ABSTRACT FROM AUTHOR]

We examined spinal cord lesions in eight patients with a pathological diagnosis of corticobasal degeneration (CBD). Using Gallyas-Braak (G-B) staining or AT-8 tau immunostaining, a few neuropil threads were identified in the white matter of the CBD spinal cords, mainly in the anterior funiculus, whereas the posterior funiculus was well preserved without threads. In the gray matter of the CBD spinal cords, particularly in the intermediate gray matter, there were widespread neuropil threads and neuronal inclusions. Large motor neurons in the anterior horn, neurons in the intermediolateral column, and Clarke’s column were relatively well preserved from neuronal loss and gliosis. Neuronal inclusions were of the globose type, suggestive of neurofibrillary tangles (NFTs), or showed diffuse granular accumulations of cytoplasmic tau, suggestive of pretangles. No typical NFTs, recognized by Bodian silver staining, were identified. The distribution of neuropil threads and G-B- or AT-8 tau-positive small neurons resembled that of interneurons. No astrocytic plaques were present in any of the CBD spinal cords, and only a few coiled bodies were seen. Neuropil threads in the white and gray matter and neuronal inclusions in the gray matter were prominent in cervical segments, and their density decreased caudally. We suggest that the presence of neuropil threads, particularly in the cervical intermediate gray matter, and the presence of neuronal inclusions, particularly in cervical interneurons, is an essential pathological feature of CBD. [ABSTRACT FROM AUTHOR]

An autopsy case of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) of 29 years' duration is reported. The patient had no history of surgery or blood transfusion and likely contracted HTLV-I sexually while traveling in an endemic area. At age 45, the patient began to experience gait disturbance; he later developed spastic tetraparesis. Autopsy revealed marked gross spinal cord atrophy, particularly in the middle to lower thoracic levels. Myelin and axonal degeneration were identified predominantly in the middle to lower thoracic spinal cord, extending into the medulla oblongata and lumbar cord. Inflammatory infiltrates of mononuclear cells were diffuse in the white and gray matter of the spinal cord and medulla oblongata, particularly in perivascular areas. These infiltrates were also observed in perivascular areas of the pons, midbrain, cerebellum, and cerebrum. More than half of the infiltrating cells were positive for the pan-T cell marker UCH LI, but some were positive for the B cell marker SL-26. There were far more CD8-positive cells than CD4-positive cells in the spinal parenchyma and perivascular areas. Neurons in the anterior horn, Clarke's column, and intermediolateral column were relatively well preserved. Active chronic inflammation was indicated. Despite the 29-year history of HAM, the presence of an active inflammatory reaction is surprising. We discuss possible modulation of the histopathological manifestations of HAM by corticosteroid therapy. [ABSTRACT FROM AUTHOR]

The deposition of abnormal levels of tau protein is a major neuropathological feature of progressive supranuclear palsy (PSP), and the presence of tuft-shaped astrocytes is a neuropathological hallmark of PSP. We examined the topographic distribution of tuft-shaped astrocytes in the cerebral hemisphere by Gallyas-Braak silver staining in three Japanese autopsy cases of typical PSP. The distribution of tuft-shaped astrocytes was relatively uniform between cases. Tuft-shaped astrocytes were identified predominantly in posterior frontal areas such as the precentral gyrus and premotor and supplementary motor areas (Brodmann areas 4, 6 and 8). Tuft-shaped astrocytes were most dense in areas of cortical convexity, and they were more abundant in the crests of the cerebral gyri than in the valleys of the cerebral sulci. The temporal, parietal and occipital cortices, including the hippocampal formation and cingulate gyrus, were relatively free of tuft-shaped astrocytes. We confirmed involvement of the cerebral cortex in the pathology of PSP, and showed the widespread presence of tuft-shaped astrocytes, particularly in the precentral gyrus and premotor and supplementary motor areas, to be an essential neuropathological feature of PSP. The extra-pyramidal and pyramidal signs, supranuclear oculomotor abnormalities and other cortical signs associated with PSP may be related to the high density of tuft-shaped astrocytes in the precentral gyrus and premotor and supplementary motor areas. Dementia, apraxia, aphasia and frontal lobe signs may also result, at least in part, from this cortical involvement. [ABSTRACT FROM AUTHOR]

Hepatitis B virus envelope L particles form hollow nanoparticles displaying a peptide that is indispensable for liver-specific infection by hepatitis B virus in humans. Here we demonstrate the use of L particles for the efficient and specific transfer of a gene or drug into human hepatocytes both in culture and in a mouse xenograft model. In this model, intravenous injection of L particles carrying the gene for green fluorescent protein (GFP) or a fluorescent dye resulted in observable fluorescence only in human hepatocellular carcinomas but not in other human carcinomas or in mouse tissues. When the gene encoding human clotting factor IX was transferred into the xenograft model using L particles, factor IX was produced at levels relevant to the treatment of hemophilia B. The yeast-derived L particle is free of viral genomes, highly specific to human liver cells and able to accommodate drugs as well as genes. These advantages should facilitate targeted delivery of genes and drugs to the human liver. [ABSTRACT FROM AUTHOR]

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) have some clinical and pathological features in common. Each, however, has been shown to have specific astrocytic inclusions. CBD is characterized by astrocytic plaques, and PSP is characterized by tuft-shaped astrocytes. To clarify differences between these inclusions, we investigated intracerebral distribution of astrocytic plaques and tuft-shaped astrocytes in autopsied brains of patients with either CBD or PSP. Specimens from ten patients with CBD and five patients with PSP were stained by the Gallyas-Braak method. Densities of the astrocytic plaques and tuft-shaped astrocytes were determined for 11 cerebral cortical regions, 6 subcortical nuclei, 5 brain stem regions, the cerebellar cortex and the dentate nucleus. Astrocytic plaques were most abundant in the prefrontal and premotor areas in the cerebral cortex of CBD brains, whereas tuft-shaped astrocytes were most prominent in the precentral gyrus and premotor area of PSP brains. Many astrocytic plaques were observed in the caudate nucleus of CBD brains, whereas tuft-shaped astrocytes were abundant in both the caudate and putamen and moderate in number in the globus pallidus, subthalamic nucleus and thalamus in PSP brains. Very slight accumulation of astrocytic plaques was seen in the brain stem of CBD brains, whereas numerous tuft-shaped astrocytes were found in the red nucleus and superior colliculus of PSP brains. Distribution of the astrocytic plaques and tuft-shaped astrocytes differed greatly. Thus, CBD and PSP can be considered different entities. [ABSTRACT FROM AUTHOR]

Dopamine D receptor imaging was performed withI labeled 2′-iodospiperone (2′-ISP) and single-photon emission computed tomography (SPECT) in 9 patients: 4 with idiopathic Parkinson's disease, 2 with parkinsonism, 1 with Wilson's disease and 2 with pituitary tumor, and the results were compared with the data for 9 normal subjects. Following an intravenous injection ofI-2′-ISP, early (within 30 min) and late (between 2 and 4 hr) SPECT images were obtained by means of a multi-detector SPECT scanner or a rotating gamma camera. In normal subjects, early SPECT images demonstrated uniform distribution of radioactivity in the cerebral gray matter and cerebellum reflecting regional cerebral blood flow, whereas late SPECT images showed high radioactivity only in the basal ganglia. All the patients with Parkinson's disease also demonstrated symmetrical basal ganglia uptake in the late SPECT images, but it was diminished in parkinsonism and Wilson's disease. One patient with a growth hormone-producing pituitary tumor had a positive uptake in the tumor. These preliminary clinical data demonstrated that 2′-ISP can be used for SPECT imaging of D dopamine receptors and may be of clinical value for the diagnosis and planning of the treatment of neurological diseases. [ABSTRACT FROM AUTHOR]

I-2′-iodospiperone (2′-ISP), which has a high and selective affinity for dopamine D receptors, produced a high myocardial accumulation of radioactivity in the early phase after intravenous injection into mice. A human scintigraphic study also showed that the myocardium was clearly visualized soon after intravenous injection of the tracer. Analysis of the myocardial homogenate obtained from mice showed thatI-2′-ISP was metabolically stable and was taken up the myocardium in its intact form. Administration of spiperone significantly reduced the myocardial uptake ofI-2′-ISP in mice. Treatment with haloperidol and (+) butaclamol, which have a high affinity for dopamine D receptors, also tended to reduce the myocardial uptake of radioactivity, while (−)-butaclamol, which has no affinity for dopamine D receptors, caused no change in uptake. These findings suggest that the myocardial accumulation of 2′-ISP occurred in association with dopamine D (DA) receptors. [ABSTRACT FROM AUTHOR]

Dynamic positron emission tomography (PET) was performed following an intravenous bolus injection ofO-water for the assessment of regional pancreatic blood flow in 4 normal volunteers and 11 patients with pancreatic cancer. The regional pancreatic blood flow index (PFI) was calculated by the autoradiographic method assuming the time-activity curves of the aorta as an input function. The mean PFI value was 0.514±0,098 in the normal pancreas but it was decreased in pancreatic cancer (0,249±0,076) (p< 0,0l), with a concomitant decrease in the pancreatic region distal to the tumor. On the other hand, in cases with body or tail cancer, the part proximal to the tumor (nontumorous head region) had a similar PFI value (0.554±0.211) to that of normal cases. Thus, a PET study withO-water permits quantitative assessment of pancreatic blood flow which decreased in both pancreatic cancer and concomitant obstructive pancreatitis distal to the tumor. [ABSTRACT FROM AUTHOR]

We removed from 4 patients pacemaker leads that had migrated or become infected. Case 1: A 62-year-old man developed uncontrollable infection of the pacing leads. Case 2: A 78-year-old man, whose infected pacemaker was removed, had a second one implanted in the contralateral side; the pacing lead infection from the first procedure, however, was uncontrollable. Case 3: A 56-year-old woman presented with dyspnea and hepatomegaly subsequent to the second implantation of a pacemaker; the pacing leads from the first procedure caused severe stenosis in both the superior and inferior vena cavae. Case 4: A 60-year-old woman had a ruptured and migrated pacing lead in the right ventricle. We operated using a cardiopulmonary bypass and a specially designed plastic tube for removal of the leads. Although Case 2 required reconstruction of the vena cavae, all patients recovered. When removal of pacing leads is necessary, it should be done as soon as possible with cardiopulmonary bypass. [ABSTRACT FROM AUTHOR]