Neuromelanin or DaT-SPECT: which is the better marker for discriminating advanced Parkinson's disease?

BACKGROUND AND PURPOSE: Whether the neuromelanin-positive substantia nigra pars compacta area (NM-SNc) on neuromelanin magnetic resonance imaging (NM-MRI) and the specific binding ratio (SBR) on 123 I-N-v-fluoropropyl-2b-carbomethoxy3b-(4-iodophenyl)nortropane single photon emission computed tomography (DaT-SPECT) can be correlated with motor fluctuations (MFs) in advanced Parkinson's disease (PD) was investigated. METHODS: Thirty-five PD patients (60 ± 13 years) and 23 healthy individuals as controls (59 ± 19 years) were enrolled. The relationships between NM-MRI and DaT-SPECT were prospectively examined in two subgroups divided according to the presence or absence of MFs. Multivariate analysis was performed using the Cox proportional hazard model to screen for association factors. RESULTS: The NM-SNc size was correlated with the SBR (Spearman's ρ = 0.43, P < 0.05). The NM-SNc size was significantly reduced in PD with MFs compared with the subgroup without (P < 0.001), whereas the SBR did not significantly differ between the groups. NM-SNc size was a significant association factor for MFs (hazard ratio 0.94, P = 0.04). In receiver operating characteristic analysis of the factors for MF occurrence, the area under the receiver operating characteristic curve of the NM-SNc size showed a significant difference of 0.89 (P < 0.05) but no significant difference was found in the SBR. CONCLUSIONS: NM-SNc size was significantly correlated with the SBR in PD, but several factors in advanced PD were more closely associated with NM-SNc size than the SBR. NM-MRI might reflect the status of advanced PD more accurately than DaT-SPECT. Therefore, NM-MRI appears to provide a better marker for discriminating advanced PD than DaT-SPECT.

Flagellar filament structural protein induces Sjögren's syndrome-like sialadenitis in mice.

OBJECTIVE: Sjögren's syndrome (SS) is a systemic autoimmune disease that primarily affects lacrimal and salivary glands. We previously reported that FliC derived from Escherichia coli could induce autoimmune pancreatitis-like lesions. From these results, we speculated that FliC could also induce SS-like exocrinopathy. In this study, we investigated the effects of chronic exposure to FliC on lacrimal and salivary glands and the possibility that it might lead to an autoimmune response. METHODS: C57BL/6 mice were repeatedly injected with FliC and histological changes, serum levels of cytokine/chemokines and autoantibodies were evaluated at different time points after the final injection. The presence of sialadenitis was diagnosed by histological methods. RESULTS: In FliC-treated groups, 57% of subjects developed inflammatory cell infiltrates around ducts in mandibular salivary glands, but not lacrimal glands. In addition, serum levels of total IgG, IgG1, and IgG2a were significantly higher in FliC-treated groups. Intriguingly, serum anti-SSA/Ro levels were also significantly higher in FliC-treated groups. Cytokine analysis revealed that serum levels of IL-1ß, IL-12p70, IL-13, IFN-γ, IL-15, and IL-23 seemed to be higher in FliC-treated mice. CONCLUSIONS: Our data suggest that FliC-treated mice develop an SS-like phenotype. Our model may elucidate the relationship between commensal bacteria and SS.

Effect of Lipopolysaccharide on the Progression of Non-Alcoholic Fatty Liver Disease in High Caloric Diet-Fed Mice.

The incidence of non-alcoholic steatohepatitis (NASH) is increasing. Because gut microbiota have been highlighted as one of the key factors in the pathogenesis of metabolic syndrome, we investigated the involvement of the bacterial component in the progression of non-alcoholic fatty liver (NAFL) to NASH. C57BL/6 mice were fed with maintenance food (MF, groups A and B) or a high caloric diet (HCD, groups C and D) for 1 month. Mice were then divided into four groups: Groups A and C were inoculated with PBS, while groups B and D were inoculated with lipopolysaccharide (LPS) plus complete Freund's adjuvant (CFA). The inoculations were performed a total of 3 times over 3 months. At 6 months, while hepatic steatosis was observed in groups C and D, cellular infiltration and fibrosis were less evident in group C than in group D. Inflammatory cytokines were upregulated in groups B and D. 16S rRNA pyrosequencing of whole colon homogenates containing faeces showed that certain bacterial groups, such as Bacteroidaceae, Peptostreptococcaceae and Erysipelotrichaceae, were increased in groups C and D. Although loading of bacterial components (LPS) resulted in hepatic inflammation in both MF- and HCD-fed mice, HCD feeding was more crucial in the progression of NAFL during the triggering phase.

A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans.

We identified a mutation in the ceruloplasmin (Cp) gene in a Japanese family with aceruloplasminemia, some of whose members showed extrapyramidal disorders, cerebellar ataxia, and diabetes mellitus. A post-mortem study of the proband revealed excessive iron deposition mainly in the brain, liver and pancreas. The G to A transition at the splice acceptor site introduces a premature termination codon at the amino acid position 991 by defective splicing, thereby truncating the carboxyl terminus of Cp in affected individuals. We conclude that the mutation in the Cp gene is associated with systemic hemosiderosis in humans.

Dental and Temporomandibular Joint Pathology of the Kit Fox (Vulpes macrotis).

Skull specimens from 836 kit foxes (Vulpes macrotis) were examined macroscopically according to predefined criteria; 559 specimens were included in this study. The study group consisted of 248 (44.4%) females, 267 (47.8%) males and 44 (7.9%) specimens of unknown sex; 128 (22.9%) skulls were from young adults and 431 (77.1%) were from adults. Of the 23,478 possible teeth, 21,883 teeth (93.2%) were present for examination, 45 (1.9%) were absent congenitally, 405 (1.7%) were acquired losses and 1,145 (4.9%) were missing artefactually. No persistent deciduous teeth were observed. Eight (0.04%) supernumerary teeth were found in seven (1.3%) specimens and 13 (0.06%) teeth from 12 (2.1%) specimens were malformed. Root number variation was present in 20.3% (403/1,984) of the present maxillary and mandibular first premolar teeth. Eleven (2.0%) foxes had lesions consistent with enamel hypoplasia and 77 (13.8%) had fenestrations in the maxillary alveolar bone. Periodontitis and attrition/abrasion affected the majority of foxes (71.6% and 90.5%, respectively). Nine-hundred and fifty-eight (4.4%) teeth were fractured, a large proportion (41.8%) of which were characterized as complicated crown fractures. Sixty-six periapical lesions from 52 (9.3%) skulls were found. A considerable portion of foxes (5.9%) showed evidence of low-grade temporomandibular joint osteoarthritis. Overall, kit foxes share dental pathology similar to that of the grey fox (Urocyon cinereoargenteus).

Bifidobacterium longum BB536 alleviated upper respiratory illnesses and modulated gut microbiota profiles in Malaysian pre-school children.

This 10-months randomised, double-blind, parallel and placebo-controlled study evaluated the effects of Bifidobacterium longum BB536 on diarrhoea and/or upper respiratory illnesses in 520 healthy Malaysian pre-school children aged 2-6 years old. The subjects randomly received a one-gram sachet containing either BB536 (5×109 cfu) or placebo daily. Data analysis was performed on 219 subjects who fully complied over 10-months (placebo n=110, BB536 n=109). While BB536 did not exert significant effects against diarrhoea in children, Poisson regression with generalised estimating equations model indicated significant intergroup difference in the mean number of times of respiratory illnesses over 10 months. The duration of sore throat was reduced by 46% (P=0.018), with marginal reduction for duration of fever (reduced by 27%, P=0.084), runny nose (reduced by 15%, P=0.087) and cough (reduced by 16%, P=0.087) as compared to the placebo. Principal coordinate analysis at genus level of the gut microbiota revealed significant differences between 0 and 10 months in the BB536 group (P<0.01) but not in placebo group (P>0.05). The abundance of the genus Faecalibacterium which is associated with anti-inflammatory and immuno-modulatory properties was significantly higher in the BB536 group (P<0.05) compared to the placebo group. Altogether, our present study illustrated the potential protective effects of BB536 against upper respiratory illnesses in pre-school Malaysian children, with gut microbiota modulating properties.

Molecular analysis of a variant type of familial amyloidotic polyneuropathy showing cerebellar ataxia and pyramidal tract signs.

A Japanese family with atypical type I familial amyloidotic polyneuropathy (FAP) in Iiyama, Japan was studied. Most of the family members have dysfunctions in the central nervous system, in addition to typical symptoms of type I FAP. The transthyretin (TTR, also called prealbumin) gene of the atypical FAP(FAP-IY) was analyzed with recombinant DNA techniques and a RIA method. FAP-IY was found to have the mutation responsible for the methionine-for-valine substitution at position 30 of TTR, as in the case of typical type I FAP. However, analysis of DNA polymorphisms in the TTR locus showed that FAP-IY has a genetic background differing from that of the typical type I FAP. These observations lead to the consideration that a genetic factor(s) involved in the dysfunction of the central nervous system may locate in a chromosome region in close proximity to the TTR gene.

Sarin experiences in Japan: acute toxicity and long-term effects.

Two terrorist attacks with the nerve agent Sarin affected citizens in Matsumoto and Tokyo, Japan in 1994 and 1995, killing 19 and injuring more the 6000. Sarin, a very potent organophosphate nerve agent, inhibits acetylcholinesterase (AchE) activity within the central, peripheral, and autonomic nervous systems. Acute and long-term Sarin effects upon humans were well documented in these two events. Sarin gas inhalation caused instantaneous death by respiratory arrest in 4 victims in Matsumoto. In Tokyo, two died in station yards and another ten victims died in hospitals within a few hours to 3 months after poisoning. Six victims with serum ChE below 20% of the lowest normal were resuscitated from cardiopulmonary arrest (CPA) or coma with generalized convulsion. Five recovered completely and one remained in vegetative state due to anoxic brain damage. EEG abnormalities persisted for up to 5 years. Miosis and copious secretions from the respiratory and GI tracts (muscarinic effects) were common in severely to slightly affected victims. Weakness and twitches of muscles (nicotinic effects) appeared in severely affected victims. Neuropathy and ataxia were observed in small number (less than 10%) of victims, which findings disappeared between 3 days and 3 months. Leukocytosis and high serum CK levels were common. Hyperglycemia, ketonuria, low serum triglyceride, hypopotassemia were observed in severely affected victims, which abnormalities were attributed to damage of the adrenal medulla. Oximes, atropine sulphate, diazepam and ample intravenous infusion were effective treatments. Pralidoxime iodide IV reversed cholinesterase and symptoms quickly even if administered 6 h after exposure. Post Traumatic Stress Disorder (PTSD) was less than 8% after 5 years. However, psychological symptoms continue in victims of both incidents. In summary, both potent toxicity and quick recovery from critical ill conditions were prominent features. Conventional therapies proved effective in Sarin incidents in Japan.

Effect of probiotic Bifidobacterium longum BB536 [corrected] in relieving clinical symptoms and modulating plasma cytokine levels of Japanese cedar pollinosis during the pollen season. A randomized double-blind, placebo-controlled trial.

Probiotic microorganisms have been shown to be effective in the treatment of allergic inflammation and food allergy, but their efficacy remains controversial. This study tested the effect of a yogurt supplemented with a probiotic strain Bifidobacterium longum BB536 in the treatment of Japanese cedar pollinosis (JCPsis). Forty subjects with a clinical history of JCPsis were given yoghurt either containing BB536 (BB536 yoghurt) or without BB536 (placebo yoghurt) at 2 X 100 g per day for 14 weeks, in a randomized, double-blind, placebo-controlled trial. Subjective symptoms and self-care measures were recorded daily and blood samples were taken before and during the intervention (at weeks 4, 9, and 14) to measure the blood parameter levels related to JCPsis. Yoghurt supplemented with BB536 significantly alleviated eye symptoms compared with placebo yoghurt (odds ratio 0.31; 95% confidence interval 0.10-0.97; p = 0.044). Although no statistically significant differences were detected, nasal symptoms such as itching, rhinorrhea, and blockage, as well as throat symptoms tended to be relieved with the BB536 yoghurt. BB536 tended to suppress the decreasing blood levels of interferon-gamma (IFN-y) and the increasing blood eosinophil rates; a significantly higher IFN-gamma level was observed for the difference from baseline at week 4. A decreased trend in the difference from baseline levels of JCP-specific IgE levels was also observed at week 4 in the BB536 group compared with the placebo group. In conclusion, these results suggest that intake of BB536-supplemented yoghurt may relieve JCPsis symptoms, probably through a modulating effect on Th balance.

More frequent beta-catenin exon 3 mutations in gallbladder adenomas than in carcinomas indicate different lineages.

To clarify the contribution of beta-catenin, which is related to cell adhesion and intranuclear transcription, to gallbladder carcinogenesis, we investigated its expression using immunohistochemistry, and beta-catenin exon 3 mutations by DNA direct sequencing, in 18 gallbladder adenomas and 82 adenocarcinomas. Membranous expression was significantly lower in moderately and poorly differentiated than in well-differentiated adenocarcinoma cases (P < 0.001). The gallbladder adenomas showed significantly stronger expression in the cytoplasm and the nucleus than carcinomas (P < 0.05 and P < 0.001, respectively), and exon 3 mutations were observed in 62.5% (10 of 16) of adenomas, but only 4.8% (1 of 21) of carcinomas. With beta-catenin as a molecular marker, the adenoma-carcinoma sequence can be considered to be a minor pathway in gallbladder carcinogenesis.

Methionyl-tRNA synthetase of Escherichia coli. A zinc metalloprotein.

The native dimeric form of methionyl-tRNA synthetase of Escherichia coli contains two zinc atoms per dimer, one per subunit. The bound zinc is retained upon trypsin modification which yields a monomer with one zinc atom. The enzymatic activity of both the dimeric forms is reversibly inhibited by 1,10-phenanthroline but not by its non-chelating analogues. In addition, the native enzyme binds two Mn2+ per dimer with a binding constant of approx. 70 micron but no binding is observed with the trypsin-modified monomer.

Molecular cloning of cDNA encoding the c-kit receptor of Shiba goats and a novel alanine insertion specific to goats and sheep in the kinase insert region.

The complete open reading frame (ORF) of the c-kit cDNA was cloned from a cerebellar cDNA library of the Shiba goat (Capra hircus var Shiba) with the dominant black-eyed white phenotype. The analysis of the deduced amino acid sequence revealed the presence of a single amino acid insertion (alanine) in the kinase insert (KI) region. While the newly found alanine insertion is not correlated with the coat color phenotype of goats, it appears to be characteristic of the c-kit genes in goats and sheep. Although the biological significance of the insert remains to be investigated, its phylogenetically limited distribution will provide us with a useful and interesting tool to analyze the problems of evolution of sheep and goats in bovidae.

Spinocerebellar degenerations in Japan: a nationwide epidemiological and clinical study.

A nationwide survey of patients in Japan with spinocerebellar degenerations (SCD), including SDS and SND, was conducted from 1988 to 1989. The survey consisted of two parts. The first revealed that the estimated total number of patients with SCD in Japan was 5,050 (range: 4,100-6,000) with an estimated prevalence of 4.53 per 100,000 in 1987. The second part investigated the neurological and functional status of patients with SCD. The percentages of those belonging to each subtype of SCD were: OPCA; 34.4%, LCCA; 15.2%, MHCA; 12.6%, HHCA; 7.5%, SDS; 7.0%, HSP; 3.9%, DRPLA; 2.5%, FA; 2.4%, MJD; 2.0% and SND; 1.5%. Compared with European epidemiological studies Japan had a higher proportion of non-hereditary types of SCD. Various clinical features of SCD subtypes were compared grouped by pathological lesion and heredity. HHCA and LCCA: cerebellar ataxia predominated in all stages, and neurological signs other than cerebellar ataxia were rare. MHCA, DRPLA and MJD: in the early phase ataxia was the most common symptom in MHCA, the AC form of DRPLA and MJD, but ataxia was less common and chorea or epilepsy were often observed in ME and PH forms of DRPLA. Other frequently observed clinical features were parkinsonian rigidity in MHCA, abnormal movements and posture in DRPLA and MJD, and disturbances of eye movements in MHCA, the AC form of DRPLA and MJD. OPCA, SDS and SND: dominant clinical features were cerebellar ataxia in OPCA, autonomic disturbance in SDS, and parkinsonian rigidity in SND. FA and HSP: both were rare in Japan. Clinical features related to supra-supinal lesions were frequently observed in FA. Functional status of SCD: the severity of illness was significantly associated with the level of independence in each item of ADL. Activities not requiring dynamic balance were performed independently for a longer period than those requiring dynamic balance. Among SCD subtypes, functional prognosis was poorest in non-hereditary, multi-systemic types (OPCA, SDS and SND) followed by hereditary multi-systemic types (MHCA, DRPLA and MJD), and better in spinal types (FA and HSP) and cerebellar types (HHCA and LCCA).

Gait disturbances in patients with pontine medial tegmental lesions: clinical characteristics and gait analysis.

OBJECTIVE: To determine the clinical characteristics of gait disorders in patients with pontine medial tegmental lesions. DESIGN: We compared features of gait disorders between patients with infarcts in the medial tegmentum and those with stroke in other areas of the pons (pathological control subjects) by measuring electromyographic results of lower limb muscles and several biomechanical parameters. PATIENTS: Two patients with infarcts in the rostral medial tegmentum and 4 control subjects. Two of the control patients had lesions in the pontine base, while the lesions in the other 2 were in the pontine tegmentum and base (combined lesions). RESULTS: Patients with rostral medial tegmental lesions and controls with pontine base lesions showed unstable walking characterized by irregular angular displacements and foot pressures. However, they differed by the following 3 features. (1) Rostral medial tegmental lesions elicited truncal ataxia without limb ataxia. In comparison, pontine base lesions elicited limb ataxia without truncal ataxia and caused hemiparesis. (2) Instability was more severe and persistent in patients with the former lesions than in those with the latter lesions. Slowness of walking speed and prolongation of the double-support period were clearly observed in the former group. (3) Electromyographic changes characteristic of cerebellar ataxia were clearly evident in patients with rostral medial tegmental lesions. The electromyographic amplitudes of the gastrocnemius and tibialis anterior muscles were almost constant throughout the gait cycle, resulting in the disappearance of the inherent periodic pattern of each muscle. CONCLUSION: Medial tegmental lesions in the rostral pons cause prolonged and severe unstable walking that resembles spinocerebellar ataxic pattern, and impairment of the spinocerebellar loop might be the pathomechanism underlying such a gait disturbance.

Increased levels of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor receptor in the cerebrospinal fluid of patients with multiple sclerosis.

We investigated the presence of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble tumor necrosis factor receptor (sTNF-R) antigens in the CSF of patients with multiple sclerosis (MS) using a double-determinant ELISA. Patients with acute relapsing MS during an exacerbation (p < 0.001) and those with chronic progressive MS (p < 0.001) had significantly increased CSF levels of sICAM-1 compared with subjects with other neurologic diseases. CSF levels of sTNF-R were also significantly increased in patients with acute relapsing MS during an exacerbation (p < 0.001) and chronic progressive MS (p < 0.001) compared with subjects with other neurologic diseases. CSF levels of sICAM-1 and sTNF-R were positively correlated in patients with acute relapsing MS during an exacerbation (r = 0.81, p < 0.01) and chronic progressive MS (r = 0.86, p < 0.001). These results suggest that active immune reactions involving ICAM-1 and TNF-R production are present within the CNS and that both sICAM-1 and sTNF-R are important immunologic markers of the clinical activity of MS.

Adult GM1 gangliosidosis: immunohistochemical and ultrastructural findings in an autopsy case.

We report neuropathologic findings for a 66-year-old Japanese man with adult/chronic GM1 gangliosidosis whose main clinical symptoms were speech and gait disturbance attributable to dystonia with rigidity. He was a homozygote for the 51isoleucine (ATC)-->threonine (ACC) mutation in the beta-galactosidase gene. Neuronal loss and intracytoplasmic storage were most prominent in the caudate nucleus and putamen and, to a lesser degree, in the amygdala, globus pallidus, and Purkinje cells in the cerebellum. Other areas of the CNS were relatively spared. We believe that this selective neuronal involvement in the CNS is characteristic of adult/chronic GM1 gangliosidosis and that it reflects a more active turnover of GM1 ganglioside in the affected areas than elsewhere in the CNS.

Soluble E-selectin in the serum and cerebrospinal fluid of patients with multiple sclerosis and human T-lymphotropic virus type 1-associated myelopathy.

To evaluate the activation of endothelial cells of the brain and the spinal cord, we investigated the presence of soluble endothelial leukocyte adhesion molecule-1 (sE-selectin) in the serum and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and those with human T-lymphotropic virus type 1-associated myelopathy (HAM). There were significantly higher levels of sE-selectin found in the serum of patients with relapsing-remitting MS during an exacerbation (p < 0.001) and those with chronic progressive MS (p < 0.01) compared with controls. Serum levels of sE-selectin in patients with HAM did not differ significantly from serum levels in controls or non-HAM carriers. We also found sE-selectin in the CSF of eight patients during an exacerbation of relapsing-remitting MS. These results suggest that an active immune reaction involving E-selectin production that is indicative of endothelial cell damage occurs in the CNS of patients during an exacerbation of relapsing-remitting MS. Thus, sE-selectin may be useful in monitoring disease activity in patients with relapsing-remitting MS.

Adult GM1-gangliosidosis: clinical patterns and rectal biopsy.

We studied a family with adult GM1-gangliosidosis. The proband, aged 38, had slowly progressive extrapyramidal signs with prominent dystonia, starting at about age 19. Two other patients, aged 45 and 43, had occasional slight dystonia, but led normal social lives because of mildness of their symptoms. Rectal biopsy of the proband showed histiocytic infiltration and membranous cytoplasmic bodies in the autonomic neurons. This family shows the clinical heterogeneity in adult GM1-gangliosidosis.

Chronic relapsing demyelinating polyneuropathy associated with hepatitis B infection.

We studied a patient with chronic relapsing polyneuropathy associated with immune complexes of hepatitis B virus. There were cycles of remission and exacerbation in parallel with liver dysfunction. Immunofluorescent deposits of hepatitis B antigen, immunoglobulin, and C3 component were detected in the vasa nervorum. Ultrastructural study revealed electron-dense deposits that might have been immune complexes composed of hepatitis B virus, both around the endoneural capillary and in the endoneurium. Immune complexes composed of hepatitis B virus may play a role in the pathogenesis of chronic relapsing polyneuropathy.

Histochemical study of rectal aminergic nerves in type I familial amyloid polyneuropathy.

We found degeneration of aminergic nerves in nine patients with type I familial amyloid polyneuropathy by histochemical study of rectal mucosa obtained by biopsy. There was prominent degeneration of aminergic nerves in four patients with uncontrollable alternating constipation and diarrhea, but aminergic nerves were relatively preserved in two patients with intermittent constipation or diarrhea. Sympathetic denervation of the gastrointestinal tract was probably important in causing bowel symptoms.