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.

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.

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.

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.

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.

Kink in the dispersion of layered strontium ruthenates.

We present detailed energy dispersions near the Fermi level along the high symmetry line GammaX on the monolayer and bilayer strontium ruthenates Sr2RuO4 and Sr3Ru2O7, determined by high-resolution angle-resolved photoemission spectroscopy. A kink in the dispersion is clearly shown for the both ruthenates. The energy position of the kink and the slope in the low-energy part near the Fermi level are almost identical between them, whereas the dispersion in the high-energy part varies, like the behavior of the kink for the cuprate superconductors.

Expression of carbamoylphosphate synthetase I and glutamine synthetase in hepatic organoids reconstructed by rat small hepatocytes and hepatic nonparenchymal cells.

The objective of this study was to investigate the expression of carbamoylphosphate synthetase I (CPS) and glutamine synthetase (GS) in small hepatocyte colonies and whether the heterogeneous expression of the enzymes could be induced during the maturation of small hepatocytes. Small hepatocytes isolated from an adult rat liver were cultured and proliferated to form colonies. The expression of CPS and GS was examined using immunocytochemistry and immunoblotting. In this culture more than 99% of morphologically hepatic cells were positive for CPS and all small hepatocytes were negative for GS at day 5. CPS-positive cells dramatically decreased with time in culture, whereas GS-positive ones appeared and their number increased in the colonies. Two to 3 weeks after plating, colonies with rising and piled-up cells appeared and the number of such colonies reached about 25% of all colonies at day 30. In most rising and piled-up cells in colonies both proteins were strongly expressed, whereas many small hepatocytes in monolayer colonies did not express either protein. When small hepatocytes in monolayer colonies were overlayed with Matrigel, the cells gradually piled up and both CPS and GS proteins were dramatically induced. The expression of CPS and GS in small hepatocytes may interact with the extracellular matrix because the rising and piled-up cells appear to be induced by the extracellular matrix produced by hepatic nonparenchymal cells.

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.

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.

Metamagnetism and critical fluctuations in high quality single crystals of the bilayer ruthenate Sr3Ru2O7.

We report the results of low temperature transport, specific heat, and magnetization measurements on high quality single crystals of the bilayer perovskite Sr3Ru2O7, which is a close relative of the unconventional superconductor Sr2RuO4. Metamagnetism is observed, and transport and thermodynamic evidence for associated critical fluctuations is presented. These relatively unusual fluctuations might be pictured as variations in the Fermi surface topography itself.

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.

Muscle CT scan findings in McLeod syndrome and chorea-acanthocytosis.

Computed tomography (CT) scans of lower leg muscles reveal a selective pattern of fat infiltration in the posterior compartment with spared gracilis, semitendinosus, and the lateral head of the gastrocnemius in both McLeod syndrome and chorea-acanthocytosis, which are disorders characterized by the presence of circulating acanthocytes. The selectivity of affected muscles indicates that late onset and slowly progressive muscular atrophy in both diseases could be a consequence of primary myopathy. Asymmetrical muscle involvement may be seen during the process of degeneration only in McLeod syndrome, however, and may be helpful in distinguishing this disease from chorea-acanthocytosis.