Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation.

BACKGROUND AND PURPOSE: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. METHODS: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide 'probable' and 'possible' designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. RESULTS: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as 'probable' and 32 (39%) were diagnosed as 'possible,' leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled 'probable' or 'possible' to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. CONCLUSIONS: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation.

BACKGROUND AND PURPOSE: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated. METHODS: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data. RESULTS: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18-78 years), the mean age at death was 53 years (range 23-84 years) and the mean disease duration was 6.8 years (range 1-29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158-11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype-genotype correlations. CONCLUSIONS: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

Metastasis of extra-ampullary duodenal adenocarcinoma to the uterine cervix.

Secondary metastatic tumours of the uterine cervix are rare. There have been no reports of duodenal cancer metastasizing to the uterine cervix. Here we present a rare case of an extra-ampullary duodenal adenocarcinoma that has metastasized to the uterine cervix. The patient was a 71-year-old woman who had surgery for an extra-ampullary duodenal adenocarcinoma five years previously. Follow-up examination revealed a suspicious right ovarian mass and nodules in the cervix and posterior fornix of the vagina. Biopsies suggested squamous cell carcinoma in the cervix and adenocarcinoma in the fornix. Intraoperatively, the right ovary was enlarged and peritoneal disseminations were found in the pouch of Douglas and the sigmoid colon mesentery. Histopathology of the subsequent hysterectomy and bilateral salpingo-oophorectomy specimen revealed a cervical squamous cell carcinoma categorized as pT1b1. Adenocarcinoma infiltration into the ovaries, uterine cervix and vagina, with vascular involvement was detected. Immunohistochemistry revealed the tumour in the cervix and ovaries to be positive for CK7, MUC5AC and MUC6, and immunonegative for CK20, CDX2, Pax8, ER, MUC2 and CD10, similar to the original duodenal adenocarcinoma. This case illustrates the difficulty in making a preoperative diagnosis of metastatic adenocarcinoma in the uterine cervix with a coexisting primary cervical squamous cell carcinoma. The absence of atypia in cervical glandular cells and immunohistochemical profiling of the adenocarcinoma clusters helped to reach a final diagnosis. This is the first report of an extra-ampullary duodenal adenocarcinoma metastasis to the uterine cervix.

p.E66Q mutation in the GLA gene is associated with a high risk of cerebral small-vessel occlusion in elderly Japanese males.

BACKGROUND AND PURPOSE: GLA is the causative gene of Fabry disease, an X-linked lysosomal storage disorder resulting from α-galactosidase A (α-GAL) deficiency. Stroke is an important manifestation of Fabry disease, and recent epidemiological studies have indicated that up to 4.9% of young male cryptogenic stroke patients have GLA mutations. To determine the importance of GLA mutations in the general stroke population, the frequency of GLA mutations in Japanese male ischaemic stroke (IS) patients with various risk factors and ages was measured. METHODS: A total of 475 male IS patients (mean age 69.7 ± 12.5 years), were enrolled in this study. A blood sample was obtained to produce blood spots for measurement of α-GAL activity. Blood samples with decreased enzymatic activity were reassayed and the entire GLA gene was analyzed by direct DNA sequencing if α-Gal A activity was consistently low. RESULTS: α-Gal A activity was decreased in 10 men, five of whom (1.1%) had the GLA gene mutation, p.E66Q. All IS patients with p.E66Q mutation had substantial residual α-Gal A activity, in contrast to patients with classic-type Fabry disease. Clinically, all patients with p.E66Q mutation were > 50 years old and had multiple small-vessel occlusions (lacunar infarctions). Statistical analysis using Fisher's exact test showed the allele frequency of GLA p.E66Q in patients with small-vessel occlusion to be significantly higher than that in the general Japanese population [odds ratio (OR) = 3.34, P = 0.025). CONCLUSIONS: GLA p.E66Q mutation is a genetic risk factor for cerebral small-vessel occlusion in elderly Japanese males.

Clinical features of non-hypertensive lobar intracerebral hemorrhage related to cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: The present study aims to clarify the clinical features of non-hypertensive cerebral amyloid angiopathy-related lobar intracerebral hemorrhage (CAA-L-ICH). METHODS: We investigated clinical, laboratory, and neuroimaging findings in 41 patients (30, women; 11, men) with pathologically supported CAA-L-ICH from 303 non-hypertensive Japanese patients aged >OR=55, identified via a nationwide survey as symptomatic CAA-L-ICH. RESULTS: The mean age of patients at onset of CAA-L-ICH was 73.2 +/- 7.4 years; the number of patients increased with age. The corrected female-to-male ratio for the population was 2.2, with significant female predominance. At onset, 7.3% of patients received anti-platelet therapy. In brain imaging studies, the actual frequency of CAA-L-ICHs was higher in the frontal and parietal lobes; however, after correcting for the estimated cortical volume, the parietal lobe was found to be the most frequently affected. CAA-L-ICH recurred in 31.7% of patients during the average 35.3-month follow-up period. The mean interval between intracerebral hemorrhages (ICHs) was 11.3 months. The case fatality rate was 12.2% at 1 month and 19.5% at 12 months after initial ICH. In 97.1% of patients, neurosurgical procedures were performed without uncontrollable intraoperative or post-operative hemorrhage. CONCLUSIONS: Our study revealed the clinical features of non-hypertensive CAA-L-ICH, including its parietal predilection, which will require further study with a larger number of patients with different ethnic backgrounds.

Magnetic field-tuned quantum criticality in the metallic ruthenate Sr3Ru2O7.

The concept of quantum criticality is proving to be central to attempts to understand the physics of strongly correlated electrons. Here, we argue that observations on the itinerant metamagnet Sr3Ru2O7 represent good evidence for a new class of quantum critical point, arising when the critical end point terminating a line of first-order transitions is depressed toward zero temperature. This is of interest both in its own right and because of the convenience of having a quantum critical point for which the tuning parameter is the magnetic field. The relationship between the resultant critical fluctuations and novel behavior very near the critical field is discussed.

Local tunneling spectroscopy across a metamagnetic critical point in the bilayer ruthenate Sr3Ru2O7.

The local spectroscopic signatures of metamagnetic criticality in Sr(3)Ru(2)O(7) were explored using scanning tunneling microscopy (STM). Singular features in the tunneling spectrum were found close to the Fermi level, as would be expected in a Stoner picture of itinerant electron metamagnetism. These features showed a pronounced magnetic field dependence across the metamagnetic critical point, which cannot be understood in terms of a naive Stoner theory. In addition, a pseudogap structure was observed over several tens of meV, accompanied by a c(2 x 2) superstructure in STM images. This result represents a new electronic ordering at the surface in the absence of any measurable surface reconstruction.

Affinity chromatography of amine oxidase from Aspergillus niger.

Omega-Aminohexyl-Sepharose 4B served as an excellent biospecific adsorbent for affinity chromatography of amine oxidase (monoamine:O2 oxidoreductase (deaminating), EC 1.4.3.4) from Aspergillus niger. The enzyme was completely adsorbed on this affinity resin when applied to a column in 0.1 M potassium phosphate buffer (pH 7.2). Although a small part of the enzyme was retained on the column through ionic interaction and eluted with 1.0 M potassium phosphate buffer (pH 7.2), most of the enzyme adsorbed was eluted with 0.5 M potassium phosphate buffer (pH 7.2) containing 10 mM butylamine. Essentially no retention of the enzyme on a column of epsilon-aminopentyl-Sepharose or delta-aminobutyl-Sepharose occurred under the same conditions, indicating that an appropriate length (more than approx. 12 A) of a hydrocarbon extension between the agarose matrix and the terminal amino group would be necessary for efficient adsorption of amine oxidase. The modification of the enzyme with 3-methyl-2-benzothiazolinone hydrazone (carbonyl inhibitor) or dithionite (reducing agent) resulted in loss of the ability to bind to omega-aminohexyl-Sepharose. It was also demonstrated that the affinity chromatography on omega-aminohexyl-Sepharose can be used as a powerful means of purifying this enzyme from crude extracts of Aspergillus niger. All of the three adsorbents were effective as a substrate in the amine oxidase reaction, but their substrate activities were as low as the corresponding free diamines.

Gastrointestinal amyloid deposition in familial amyloid polyneuropathy.

We found degeneration of enteric nerve plexuses in two patients with type I familial amyloid polyneuropathy. Amyloid deposition was more severe in the wall of the stomach than in the rectum. Hypomotility of the upper gastrointestinal tract, resulting from both amyloid deposition in the stomach and upper bowel and degeneration of the intrinsic autonomic nerves, may be responsible for anorexia, nausea, and vomiting. Diarrhea and constipation may be caused by degeneration of the enteric nerve plexuses. Gastric biopsy is valuable and safe in the diagnosis to type I familial amyloid polyneuropathy.

Novel screening method for agents that overcome classical multidrug resistance in a human cell line.

P-glycoprotein (P-gp) is involved in the transport of a wide variety of organic compounds including a fluorescent dye, rhodamine 6G (RG), as well as anti-cancer drugs. Agents that overcome classical multidrug-resistance (MDR) increased the accumulation of RG in a MDR cell line, KB-C1. The effect of agents on RG-accumulation in KB-C1 cells was highly correlated with their effect on the reversion of vincristine-resistance in KB-C1 cells. RG was detected on a fluorescence microplate reader with a rhodamine channel. This assay may become a useful method for the screening of agents that overcome classical MBR, since it is quick and simple.

Postmortem findings in two familial amyloidosis patients with transthyretin variant Asp38Ala.

Postmortem findings in 2 familial amyloidosis patients with the transthyretin variant (ATTR), Asp38Ala, are described Both showed cardiac failure, and progressive peripheral and autonomic neuropathy and died at the ages 82 and 57, respectively. TTR immunoreactive amyloid deposition was observed to be extensive in the myocardium, peripheral nerves, sympathetic ganglia and gastrointestinal tract. The pulmonary parenchyma was also diffusely involved, but renal glomeruli, follicular tissues of the thyroid, and the leptomeninges and subarachnoidal vessels of the central nervous system showed little deposition. The latter findings are not usually seen in the patients with ATTR Val30Met, the most common form of familial amyloidosis. Additionally, the clinicopathological findings of familial amyloidosis with ATTR Asp38Ala seem to vary in the different individuals.

Three patients with isolated adrenocorticotropin deficiency presenting with neuroleptic malignant syndrome-like symptoms.

We report 3 patients with isolated adrenocorticotropin (ACTH) deficiency presenting with neuroleptic malignant syndrome (NMS)-like symptoms. All patients were in their 60's or 70's and showed consciousness disturbance, a high-grade fever, extrapyramydal signs, and muscle enzyme elevations, which met the criteria for NMS. Also, they all showed hyponatremia induced by isolated ACTH deficiency. In addition to the standard therapy for NMS, corticosteroid supplement therapy was effective in all patients. There thus appear to be subjects with isolated ACTH deficiency among patients presenting with NMS-like symptoms, and adrenal and pituitary function should be checked in NMS patients with hyponatremia.

Progressive wild-type transthyretin deposition after liver transplantation preferentially occurs onto myocardium in FAP patients.

To elucidate whether progressive wild-type transthyretin (TTR) deposition can actually occur after liver transplantation (LT), amyloid fibrils were investigated in two familial amyloid polyneuropathy patients with TTR Val30Leu variant, who died 1 year after LT. Amyloid fibrils were extracted from cardiac muscles, sciatic nerves and kidney, which were investigated by the immunoprecipitation-mass spectrometry method and liquid chromatography-ion trap mass spectrometry analysis. The ratio of wild-type to variant TTR in cardiac muscle was approximately 5:5 before LT, but greatly increased to about 9:1 after transplantation. The ratios in sciatic nerves and kidney obtained at autopsy were approximately 5:5. Wild-type TTR was undetectable in kidney amyloid obtained before LT. Our results indicate that paradoxical wild-type TTR deposition after LT can preferentially occur in myocardium, leading to fatal cardiac dysfunction, but it is quite likely that this phenomenon can also occur in other visceral organs.

Pseudogap dependence of the optical conductivity spectra of Ca3Ru2O7: a possible contribution of the orbital flip excitation.

Optical spectra of a double-layered perovskite ruthenate Ca3Ru2O7 show a pseudogap opening around 200 cm(-1) below 50 K, which is attributable to the partial k-space gap opening due to the density wave instability. Unlike most other density wave materials, Ca3Ru2O7 has spectral weight redistributions, not near the energy gap region, but at a much higher energy region around 800 cm(-1). As a possible origin of these intriguing features, we discuss the orbital flip excitation in the density wave ground state.

Missing xy-band Fermi surface in 4d transition-metal oxide Sr2RhO4: effect of the octahedra rotation on the electronic structure.

Electronic structures of the 4d transition-metal oxide compound Sr2RhO4 are investigated by angle-resolved photoemission spectroscopy and density-functional electronic structure calculations. In the measured Fermi surfaces (FS) of Sr2RhO4, the xy-band FS sheet expected from the well-established results of the FS of Sr2RuO4 is missing, the volume of which should be different only by one additional electron for Sr2RhO4. The apparent contradiction is resolved by a careful analysis of the band structure where the rotation of octahedra results in the hybridization of e(g) and t(2g) states and thus plays a key role in the determination of the electronic structure near EF. The modification of the FS structure due to the distorted lattice is related to the charge transfer among the orbital states and suggested to be relevant to the metal-insulator transition in Ca(2-x)Sr(x)RuO4.

Substrate-induced conformational changes in lactate dehydrogenase. Proteolysis of the immobilized enzyme in the presence of specific substrates.

We report here a new approach to the study of the conformation of enzymes in the presence of specific substrates. Rabbit muscle lactate dehydrogenase was attached to CL-Sepharose via a cleavable spacer arm (-NH-(CH2)6NHCO(CH2)2SS(CH2)2CO-). The bound lactate dehydrogenase was digested with subtilisin BPN' in the presence of substrates of lactate dehydrogenase. The use of a flow system permits the maintenance of saturating levels of substrates. Proteolysis was followed by loss of activity of the enzyme column. The time course of proteolysis in the presence of either NADH, NAD+, or pyruvate alone did not differ from the control. However, when NADH and pyruvate were present simultaneously, the enzyme became more susceptible to proteolysis. The initial rate of proteolysis was increased by 40%. The abortive ternary complex (lactate dehydrogenase - NAD+ - pyruvate) also showed an increase in susceptibility to proteolysis. These findings clearly show that the productive ternary complex (lactate dehydrogenase - NADH - pyruvate) is conformationally different from the apoenzyme and binary complexes under optimal catalytic conditions.