Cystatin C as an index of cerebral small vessel disease: results of a cross-sectional study in community-based Japanese elderly.

BACKGROUND AND PURPOSE: Recent studies have shown that kidney dysfunction is associated with cerebral small vessel disease (SVD). Although creatinine-based estimating equations have been used as the standard measure for the evaluation of kidney function, the accuracy of these is limited in the elderly because of muscle mass decrease with aging. Cystatin C is a more useful measurement than creatinine-based estimating equations for evaluating kidney function, however, the relationship amongst cystatin C, cognitive dysfunction, and cerebral SVD has not been fully examined in community-based elderly. METHODS: We performed a cross-sectional study using MRI to determine the relationship amongst cystatin C, cognitive function, and cerebral SVD in a total of 604 community-based Japanese elderly. RESULTS: In this study, subjects with higher cystatin C levels tended to have more lacunas and higher grades of white matter lesions. Although a decline of the Mini-Mental State Examination (MMSE) scores was associated with SVD-related lesions, the relationship between the tertiles of cystatin C and mean MMSE scores was not statistically significant. In the logistic regression analysis, the association between cystatin C and SVD-related lesions was statistically significant, even after adjustment for conventional risk factors and high-sensitivity C-reactive protein. Furthermore, subjects with higher cystatin C levels accompanied with albuminuria had a greater risk for the presence of subclinical cerebral SVD than those with lower cystatin C levels without albuminuria. CONCLUSIONS: The present study suggests that there is a close relationship between cystatin C and subclinical cerebral SVD, independently of conventional risk factors, in community-based elderly.

Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders.

BACKGROUND: Mikulicz's disease (MD) has been considered as one manifestation of Sjögren's syndrome (SS). Recently, it has also been considered as an IgG(4)-related disorder. OBJECTIVE: To determine the differences between IgG(4)-related disorders including MD and SS. METHODS: A study was undertaken to investigate patients with MD and IgG(4)-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG(4)-positive multiorgan lymphoproliferative syndrome (IgG(4)+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG(4) (>135 mg/dl) and infiltration of IgG(4)(+) plasma cells in the tissue (IgG(4)+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG(4)+MOLPS and 31 patients with typical SS were compared. RESULTS: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG(4)+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG(2), IgG(4) and IgE levels were significantly increased in IgG(4)+MOLPS. Histological specimens from patients with IgG(4)+MOLPS revealed marked IgG(4)+ plasma cell infiltration. Many patients with IgG(4)+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG(4)+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG(4)+MOLPS treated with glucocorticoids showed marked clinical improvement. CONCLUSION: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG(4)+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG(4)+MOLPS.

Clonality analysis of lymphoproliferative disorders in patients with Sjögren's syndrome.

The aim of this study was to clarify the nature of the clonal lymphocyte infiltration in Sjögren's syndrome (SS) patients associated with lymphoproliferative disorders. We examined B cell clonality in lymphoproliferative tissues from six primary SS patients associated with lymphoproliferative disorders or lymphoma by cloning and sequencing of the gene rearrangement of the immunoglobulin heavy chain complementarity determining region 3 (IgVH-CDR3). Three patients with sequential observation showed progressional clonal expansion with the presence of the same subclone in different tissues during the course of disease. Among them, one patient developed mucosa-associated lymphoid tissue (MALT) lymphoma in glandular parotid. The other three SS patients concomitant with malignant B cells lymphomas showed different clonal expansion of B cells between nodal sites and salivary glands. The cloanality analysis indicated that monoclonal B cell population could spread from one glandular site to another site during the course of SS, suggesting that the malignant clone may arise from the general abnormal microenvironment, not restricted to the glandular tissue, in some SS patients.

A polymorphism of the aldehyde dehydrogenase 2 gene is a risk factor for multiple lacunar infarcts in Japanese men: the Takahata Study.

The objective of the present study was to examine the association between a polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene and lacunar infarcts of the brain. We conducted a population-based, cross-sectional study on residents from two age groups (61- and 72-year olds). A total of 376 subjects participated in the study, which included brain magnetic resonance image and genetic analysis of the ALDH2 gene. Of the 61- and 72-year-old subjects, 46.4% and 64.3%, respectively, had one or more lacunar infarcts. The average number of infarcts also increased from 2.0 to 2.8 in men and from 2.3 to 3.5 in women. No significant association between the ALDH2 genotype and the presence of lacunar infarction (> or =1) was found. However, in subjects with lacunar infarction, the genotype of ALDH2 *1/*1 was associated with a larger number of the lesion ['single' versus 'multiple' odds ratio (OR) 3.73, 95%CI: 1.43-9.74] in men. The OR was comparable even after adjusting for alcohol consumption, tobacco habits, age, hypertension, hypercholesterolemia, and diabetes mellitus (DM) (OR 3.88; 95% CI: 1.10-13.66). In women, there was no significant association between the ALDH2 genotypes and lacunar infarcts. The present study revealed that the ALDH2 *1/*1 genotype was significantly associated with the prevalence of multiple lacunar infarcts in Japanese men.

Characteristic signal changes in the pontine base on T2- and multishot diffusion-weighted images in spinocerebellar ataxia type 1.

The aim of the present study was to demonstrate characteristic signal changes of the pontine base on T2-weighted images of patients with SCA 1, and to elucidate the relationship between abnormal high-intensities of the pontine base on T2-weighted images and the findings on multishot diffusion-weighted images. We assessed abnormal signals of the pontine base on T2-weighted images from 50 controls and six patients with SCA 1 diagnosed by genetic analysis. At the same time, we evaluated the degeneration of the transverse pontine fibers in the pontine base by multishot diffusion-weighted imaging. A midline high-intensity was seen in the pontine base on T2-weighted images in two of the 50 controls and five of the six patients with SCA 1. The midline high-intensity had a sensitivity of 83.3% for patients and a specificity of 96.0% for controls. Multishot diffusion-weighted imaging demonstrated the degeneration--the amorphous-pattern signal--of the transverse pontine fibers in four (66.7%) of the six patients. In the other two patients, the zebra-pattern signal was seen in the pontine base. The midline high-intensity on T2-weighted images appears to be one of characteristic MRI findings of SCA 1. Multishot diffusion-weighted imaging suggested that the midline high-intensity should reflect the degeneration of the transverse pontine fibers.

Galectin-1 as a potential therapeutic agent for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects almost selectively motor neurons in the central nervous system. Most ALS patients die within five years of onset. One of the neuropathological features of ALS is an "axonal spheroid," a large swelling of a motor axon within the anterior horn of the spinal cord; this abnormal structure seems to be related to the pathogenesis of motor neuron degeneration in ALS. In 2001, using biochemical and immunohistochemical methods, we found an accumulation of galectin-1 in ALS spheroids. By immuno-electron microscopy, the galectin-1 accumulated in the spheroids was observed to be closely associated with neurofilaments. Furthermore, we observed a marked depletion of galectin-1 in the skin of ALS patients; another abnormality frequently observed in ALS. These findings, therefore, suggest that galectin-1 may be involved in the pathogenesis of ALS. It is known that an oxidized form of galectin-1 promotes axonal regeneration; however, it is not known whether oxidized galectin-1 has a beneficial or an adverse effect on the pathophysiology of ALS. To examine this issue, we administered oxidized galectin-1 to transgenic mice with H46R mutant SOD1, an ALS model mouse. The results showed that the administration of oxidized galectin-1 improved the motor activity, delayed the onset of symptoms, and prolonged the survival of the galectin-1-treated mice. Furthermore, the number of remaining motor neurons in the spinal cord was more preserved in the galectin-1-treated mice than in the non-treated mice. We conclude that galectin-1 could be a candidate agent for the treatment of ALS.

Lateral and medial medullary infarction: a comparative analysis of 214 patients.

BACKGROUND AND PURPOSE: No large-scale study has ever compared the clinical and radiological features of lateral medullary infarction (LMI) and medial medullary infarction (MMI). The aim of this study was to investigate them through the use of cooperatively collected cases. METHODS: Medical information on all patients from 1996 to 2000 with medullary infarction (MI) proven by brain MR images at 35 stroke centers in the Tohoku district, Japan, was collected, and their clinical and radiological features were analyzed. RESULTS: A total of 214 cases of MI were registered. They included 167 cases (78%) of LMI, 41 (19%) of MMI, and 6 (3%) of LMI plus MMI. The mean age of onset and the male-to-female ratio were 60.7 years and 2.7:1 in LMI and 65.0 years and 3.6:1 in MMI, respectively. The middle medulla was most frequently affected in LMI, and the upper medulla was most frequently affected in MMI. Dissection of the vertebral artery was observed in 29% of LMI and 21% of MMI. Prognosis, assessed by the Barthel Index, was favorable in both LMI and MMI. Diabetes mellitus was more frequently associated with MMI than with LMI. CONCLUSIONS: The present study surveyed a large number of MI cases and revealed that (1) the mean age of onset of MMI is higher than that of LMI, (2) the dissection of the vertebral artery is an important cause not only of LMI but also of MMI, and (3) diabetes mellitus is frequently associated with MMI.

Characterization of pNI10 plasmid in Pseudomonas, and the construction of an improved Escherichia and Pseudomonas shuttle vector, pNUK73.

The complete nucleotide sequence of pNI10 (3.75 kb), from which pNI105 and pNI107 were constructed as medium-host-range vectors for Gram-negative bacteria, was determined. A fragment of about 2.1 kb of pNI10 was essential for replication in Escherichia coli and Pseudomonas fluorescens. This fragment encodes a putative origin of replication ( ori) and one putative replication-controlling protein (Rep). An improved version of the medium-host-range plasmid vector pNUK73 (5.13 kb) was constructed with the basic-replicon of pNI10 and pHSG298 (2.68 kb). We show that expression in pseudomonads of the bromoperoxidase gene ( bpo) of Pseudomonas putida, inserted downstream of the lac promoter in pNUK73, resulted in about 30% (13.6 U/l culture) of the enzyme level obtained in E. coli.

A case of inflammatory demyelinating polyradiculoneuropathy associated with T-cell lymphoma.

Malignant lymphoma may present prominent peripheral nervous system disorders with variable etiologies. We describe a patient who presented with chronic relapsing polyradiculoneuropathy accompanied by right facial nerve palsy. Gadolinium enhancement of the right facial nerve and cervical spinal roots was noted on magnetic resonance imaging (MRI). Sural nerve biopsy specimens showed mononuclear cell infiltration around the vessels in the epineurium. Histopathological and immunohistochemical investigations of sural nerve specimens revealed perivascular infiltration of lymphocytes with T-cell dominancy. No apparent direct invasion of lymphoma cells was seen. The results of nerve conduction studies, sural nerve biopsy and cerebrospinal fluid examination were suggestive of immune-mediated inflammatory demyelinating neuropathy. The chronic and relapsing fashion and unique radiological findings in our patient expand on the previously reported features of peripheral neuropathy associated with peripheral T-cell lymphoma.

Female preponderance of Parkinson's disease in Japan.

A male preponderance of Parkinson's disease (PD) has been reported in European countries and the USA. To verify this issue in Japanese patients with PD, we examined the age- and gender-specific prevalence of PD in Yamagata Prefecture (population 1,244,040), Japan. The prevalence of PD was 61.3/100,000 men and 91.0/100,000 women, showing that women were significantly more affected by PD than men (p < 0.001). Contrary to the findings in Europe and the USA, the results indicate a female preponderance of PD among the Japanese population.

Importance of CCK-A receptor for gallbladder contraction and pancreatic secretion: a study in CCK-A receptor knockout mice.

Bile and pancreatic secretions were determined in a CCK-A receptor deficient mouse mutant generated by gene targeting in embryonic stem cells. The targeting vector contained lacZ and neo insertions in exon 2. Under the urethane anesthesia, the common bile duct was cannulated, and the mixture of bile-pancreatic juice was collected every 30 min. After the 1 h basal secretion, CCK-8 (0.5 and 1.0 nmol/kg), acetylcholine (500 nmol/kg), and neuromedin C (1.0 micromol/kg) were injected subcutaneously, and the secretions were collected following 1 h. Amylase and bile acid outputs were determined as parameters of pancreatic secretion and gallbladder contraction, respectively. In some CCK-A receptor (+/-) animals, LacZ staining was performed. CCK-8 significantly increased amylase and bile acid outputs in CCK-A receptor (+/+) and (+/-) mice, whereas no response was observed in (-/-) mice. Neuromedin C and acetylcholine increased amylase secretion in CCK-A receptor (-/-) mice similar to (+/-) and (+/+) mice. The same doses of neuromedin C and acetylcholine could not increase bile acid secretion. The gallbladder smooth muscles, pancreatic acinar cells, duct cells, and islets were stained by LacZ. CCK and CCK-A receptor are important for pancreatic secretion and gallbladder contraction. Neuromedin C and acetylcholine may compensate pancreatic function, but not gallbladder contraction.

Cholecystokinin-8 (CCK-8) has no effect on heart rate in rats lacking CCK-A receptors.

Heart rate responses to i.v. administration of cholecystokinin-8 (CCK-8) were investigated in Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors and control Long-Evans Tokushima Otsuka (LETO) rats. The heart rate decreased after i.v. administration of 3 nmol.kg(-)(1) of CCK-8 in LETO rats, but not in OLETF rats. Bradycardia in the LETO rats disappeared after treatment with MK-329, but not after treatment with L-365,260. The expression of CCK-A receptor precursor mRNA was found exclusively in the atrium in LETO rats. These results suggest that CCK-8 decreases heart rate via CCK-A receptors located in the atrium of the rats.

Cytoplasmic and nuclear polyglutamine aggregates in SCA6 Purkinje cells.

Aggregations of the alpha1A-calcium channel protein have been previously demonstrated in spinocerebellar ataxia type 6 (SCA6). Here the authors show that small aggregates, labeled by a monoclonal antibody 1C2 that preferentially detects expanded polyglutamine larger than that in SCA6 mutation, are present mainly in the cytoplasm but also in the nucleus of Purkinje cells. Although the length of expansion is small in SCA6, the current finding might indicate that SCA6 conforms to the pathogenic mechanism(s) in other polyglutamine diseases.

Cloning and biochemical characterization of Co(2+)-activated bromoperoxidase-esterase (perhydrolase) from Pseudomonas putida IF-3 strain.

The gene encoding Co(2+)-activated bromoperoxidase (BPO)-esterase (EST), catalyzing the organic acid-assisted bromination of some organic compounds with H2O2 and Br(-) and quite specific hydrolysis of (R)-acetylthioisobutyric acid methyl ester, was cloned from the chromosomal DNA of the Pseudomonas putida IF-3 strain. The bpo-est gene comprises 831 bp and encoded a protein of 30181 Da. The enzyme was expressed at a high level in Escherichia coli and purified to homogeneity by ammonium sulfate fractionation and two-step column chromatographies. The recombinant enzyme required acetic acid, propionic acid, isobutyric acid or n-butyric acid in addition to H2O2 and Br(-) for the brominating reaction and was activated by Co(2+) ions. It catalyzed the bromination of styrene and indene to give the corresponding racemic bromohydrin. Although the enzyme did not release free peracetic acid in the reaction mixture, chemical reaction with peracetic acid could well explain such enzymatic reactions via a peracetic acid intermediate. The results indicated that the enzyme was a novel Co(2+)-activated organic acid-dependent BPO (perhydrolase)-EST, belonging to the non-metal haloperoxidase-hydrolase family.

Galectin-1 is a component of neurofilamentous lesions in sporadic and familial amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS), abnormal accumulation of neurofilaments induces pathological changes such as axonal spheroids, cord-like neurite swellings, and perikaryal conglomerate inclusions in degenerating motor neurons of the spinal cord, and the accumulation seems to cause motor neuron degeneration in this disease. Such ALS lesions were intensely labeled with HepSS-1, a monoclonal antibody to heparan sulfate. Since the identification of HepSS-1-immunoreactive substance seems to be an important step for understanding the molecular pathology of ALS, we purified the substance from human spinal cord tissue to homogeneity. Amino acid sequence of the protein was consistent with that of galectin-1. Immunohistochemistry using antibodies against recombinant human galectin-1 showed that galectin-1 was accumulated in these lesions in ALS. Although HepSS-1 was believed to be specific for heparan sulfate, it reacted with recombinant human galectin-1 which has no heparan sulfate moiety. The results show that galectin-1 is a component of the neurofilamentous lesions in ALS. Since galectin-1 has axonal regeneration-enhancing activity, the abnormal accumulation of galectin-1 to the lesions seems to be related to the pathological process of ALS.

Small bowel transplantation using grafts from living-related donors. Two case reports.

A living-related small bowel transplantation (SBT) was performed in two pediatric patients with short bowel syndrome. In both cases, the donor was the patient's mother. The distal ileum (100 cm, 120 cm) was harvested and the ileocolic vessels, ileocecal valve, and terminal ileum were left intact. The two donors were discharged from the hospital on postoperative days 15 and 6, respectively. Recipient 1 was a 2 year 6 month-old boy with short bowel syndrome who underwent SBT due to loss of venous access. The graft vein was anastomosed to the recipient's infrarenal inferior vena cava. Despite triple immunosuppression (tacrolimus, steroid, and azathioprine), there were four episodes of rejection. The patient had been on total parenteral nutrition for almost his entire posttransplant course. He died from Pneumocystis carinii pneumonia 16 months after the transplantation. Recipient 2 was a 4 year 5 month-old girl with short bowel syndrome who underwent an isolated small bowel transplantation because of recurrent line sepsis. Her pretransplant bilirubin was 8.0 mg/dl and a biopsy showed severe fibrosis. The graft vein was anastomosed to the recipient's inferior mesenteric vein. After transplantation, her bilirubin level became normal within 10 days. Triple immunosuppression (tacrolimus, steroid, and cyclophosphamide) together with a 3-day course of OKT-3 made her post-transplant course feasible. After overcoming a single episode of rejection she left the hospital 4 months after SBT. The patient is currently (10 months after transplantation) hospitalized due to rejection, which is being successfully controlled, and she is off total parenteral nutrition. From our experience, harvesting of the distal ileum for use as a bowel graft can be safely performed. The advantages of living-related grafts, optimal graft length, and choice of vascular reconstruction in SBT are yet to be explored.

A novel mutation of the ceruloplasmin gene in a patient with heteroallelic ceruloplasmin gene mutation (HypoCPGM).

We found a novel missense mutation in the ceruloplasmin (Cp) gene in a patient with the heteroallelic Cp gene mutation (HypoCPGM). The patient was a 72-year-old woman who came to our hospital with a 1-year history of postural tremor of the hands. The diagnosis was made based on serum Cp and copper readings which were about half the normal levels, as well as MRI tests of her brain which showed characteristics for hereditary ceruloplasmin deficiency (HCD), known to be caused by the homoallelic Cp gene mutation. Polymerase chain reaction (PCR)-direct sequencing analysis of the Cp gene of the patient revealed a novel point mutation, A to T, at nucleotide position 82 in Exon 1. This mutation changes the Ile28 codon (ATT) to a Phe codon (TTT) (missense mutation). PCR-restriction analysis with restriction enzyme Tsp EI for the mutation revealed that both the patient and her son were heterozygotes for the mutation.