Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis

Primary distal renal tubular acidosis (dRTA) is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. Kindreds showing either autosomal dominant or recessive transmission are described. Mutations in the chloride-bicarbonate exchanger AE1 have recently been reported in four autosomal dominant dRTA kindreds, three of these altering codon Arg589. We have screened 26 kindreds with primary dRTA for mutations in AE1. Inheritance was autosomal recessive in seventeen kindreds, autosomal dominant in one, and uncertain due to unknown parental phenotype or sporadic disease in eight kindreds. No mutations in AE1 were detected in any of the autosomal recessive kindreds, and analysis of linkage showed no evidence of linkage of recessive dRTA to AE1. In contrast, heterozygous mutations in AE1 were identified in the one known dominant dRTA kindred, in one sporadic case, and one kindred with two affected brothers. In the dominant kindred, the mutation Arg-589/Ser cosegregated with dRTA in the extended pedigree. An Arg-589/His mutation in the sporadic case proved to be a de novo mutation. In the third kindred, affected brothers both have an intragenic 13-bp duplication resulting in deletion of the last 11 amino acids of AE1. These mutations were not detected in 80 alleles from unrelated normal individuals. These findings underscore the key role of Arg-589 and the C terminus in normal AE1 function, and indicate that while mutations in AE1 cause autosomal dominant dRTA, defects in this gene are not responsible for recessive disease.

An impairment in sniffing contributes to the olfactory impairment in Parkinson's disease

Although the presence of an olfactory impairment in Parkinson's disease (PD) has been recognized for 25 years, its cause remains unclear. Here we suggest a contributing factor to this impairment, namely, that PD impairs active sniffing of odorants. We tested 10 men and 10 women with clinically typical PD, and 20 age- and gender-matched healthy controls, in four olfactory tasks: (i) the University of Pennsylvania smell identification test; (ii and iii) detection threshold tests for the odorants vanillin and propionic acid; and (iv) a two-alternative forced-choice detection paradigm during which sniff parameters (airflow peak rate, mean rate, volume, and duration) were recorded with a pneomatotachograph-coupled spirometer. An additional experiment tested the effect of intentionally increasing sniff vigor on olfactory performance in 20 additional patients. PD patients were significantly impaired in olfactory identification (P < 0.0001) and detection (P < 0.007). As predicted, PD patients were also significantly impaired at sniffing, demonstrating significantly reduced sniff airflow rate (P < 0.01) and volume (P < 0.002). Furthermore, a patient's ability to sniff predicted his or her performance on olfactory tasks, i.e., the more poorly patients sniffed, the worse their performance on olfaction tests (P < 0.009). Finally, increasing sniff vigor improved olfactory performance in those patients whose baseline performance had been poorest (P < 0.05). These findings implicate a sniffing impairment as a component of the olfactory impairment in PD and further depict sniffing as an important component of human olfaction.

Functional cell surface expression of the anion transport domain of human red cell band 3 (AE1) in the yeast Saccharomyces cerevisiae.

We expressed the 52-kDa integral membrane domain (B3mem) of the human erythrocyte anion transporter (band 3; AE1) in a protease-deficient strain of the yeast Saccharomyces cerevisiae under the control of the inducible GAL10-CYC1 promoter. Immunoblots of total protein from transformed yeast cells confirmed that the B3mem polypeptide was overexpressed shortly after induction with galactose. Cell surface expression of the functional anion transporter was detected by using a simple transport assay to measure stilbene disulfonate-inhibitable chloride influx into intact yeast cells. The B3mem polypeptide was recycled and degraded by the cells with a half-life of approximately 1-3 hr, which led to a steady-state level of expression in exponentially growing cultures. Our data suggest that 5-10% of total B3mem is functionally active at the cell surface at any one time and that overexpression of this anion transport protein does not interfere with cell growth or survival. This is one of only a few reports of the functional expression of a plasma membrane transport protein in the plasma membrane of yeast cells and to our knowledge is the first report of red cell band 3-mediated anion transport at the plasma membrane of cDNA-transformed cells. The cell surface expression system we describe will provide a simple means for future study of the functional properties of band 3 by using site-directed mutagenesis.

Pacific Coast of Mexico, Central America, and the Region Around the Galapagos Islands Showing Route of the Steamer Albatross, 1891 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Explorations of the U. S. Fish Commission steamer Albatross : Lieut. Comdr. Z. L. Tanner U.S.N. Comdg. : Februrary to April 1891. It was printed for the Museum of Comparative Zoology, Harvard University in 1892. Scale [ca. 1:7,500,000]. Covers the Pacific Coast of Mexico, Central America, and the region around the Galapagos Islands. The image inside the map neatline is georeferenced to the surface of the earth and fit to the 'Mercator' projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as drainage, human settlements, shoreline features, bays, harbors, islands, and more. Relief shown by soundings and bathymetric isolines and tints. Shows the route of the Agassiz-Albatross Cruise 1891. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection and the Harvard University Library as part of the Open Collections Program at Harvard University project: Organizing Our World: Sponsored Exploration and Scientific Discovery in the Modern Age. Maps selected for the project correspond to various expeditions and represent a range of regions, originators, ground condition dates, scales, and purposes.

Galapagos Islands, Ecuador, 1891 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Galapagos Islands : showing exploration of the U.S. Fish Commission steamer "Albatross" Lieut-Comdr. Z. L. Tanner U.S.N. Comdg. February to April 1891. It was printed for the Museum of Comparative Zoology, Harvard University, 1892. Scale [ca. 1:1,400,000]. Covers Galapagos Islands, Ecuador. The image inside the map neatline is georeferenced to the surface of the earth and fit to the 'Mercator' projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows shoreline features, islands and islets, bays, harbors, inlets, points, rocks, bottom types, and more. Relief shown by hachures and spot heights. Depths shown by soundings. Includes note on legend and source. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection and the Harvard University Library as part of the Open Collections Program at Harvard University project: Organizing Our World: Sponsored Exploration and Scientific Discovery in the Modern Age. Maps selected for the project correspond to various expeditions and represent a range of regions, originators, ground condition dates, scales, and purposes.

Serological diagnosis of echinococcosis: the diagnostic potential of native antigens

PURPOSE: Human alveolar (AE) and cystic echinococcosis (CE) caused by the metacestode stages of Echinococcus multilocularis and E. granulosus, respectively, lack pathognomonic clinical signs. Diagnosis therefore relies on the results of imaging and serological studies. The primary goal of this study was to evaluate the efficacy of several easy-to-produce crude or partially purified E. granulosus and E. multilocularis metacestode-derived antigens as tools for the serological diagnosis and differential diagnosis of patients suspicious for AE or CE. METHODS: The sera of 51 treatment-naïve AE and 32 CE patients, 98 Swiss blood donors and 38 patients who were initially suspicious for echinococcosis but suffering from various other liver diseases (e.g., liver neoplasia, etc.) were analysed. RESULTS: According to the results of enzyme-linked immunosorbent assays (ELISA), metacestode-derived antigens of E. granulosus had sensitivities varying from 81 to 97% and >99.9% for the diagnosis of CE and AE, respectively. Antigens derived from E. multilocularis metacestodes had sensitivities ranging from 84 to 91% and >99.9% for the diagnosis of CE and AE, respectively. Specificities ranged from 92 to >99.9%. Post-test probabilities for the differential diagnosis of AE from liver neoplasias, CE from cystic liver lesions, and screening for AE in Switzerland were around 95, 86 and 2.2%, respectively. Cross-reactions with antibodies in sera of patients with other parasitic affections (fasciolosis, schistosomosis, amebosis, cysticercosis, and filarioses) did occur at variable frequencies, but could be eliminated through the use of confirmatory testing. CONCLUSIONS: Different metacestode-derived antigens of E. granulosus and E. multilocularis are valuable, widely accessible, and cost-efficient tools for the serological diagnosis of echinococcosis. However, confirmatory testing is necessary, due to the lack of species specificity and the occurrence of cross-reactions to other helminthic diseases.

Markers for silent atrial fibrillation in esophageal long-term electrocardiography.

PURPOSE Paroxysmal atrial fibrillation (PAF) often remains undiagnosed. Long-term surface ECG is used for screening, but has limitations. Esophageal ECG (eECG) allows recording high quality atrial signals, which were used to identify markers for PAF. METHODS In 50 patients (25 patients with PAF; 25 controls) an eECG and surface ECG was recorded simultaneously. Partially A-V blocked atrial runs (PBARs) were quantified, atrial signal duration in eECG was measured. RESULTS eECG revealed 1.8‰ of atrial premature beats in patients with known PAF to be PBARs with a median duration of 853ms (interquartile range (IQR) 813-1836ms) and a median atrial cycle length of 366ms (IQR 282-432ms). Even during a short recording duration of 2.1h (IQR 1.2-17.2h), PBARs occurred in 20% of PAF patients but not in controls (p=0.05). Left atrial signal duration was predictive for PAF (72% sensitivity, 80% specificity). CONCLUSIONS eECG reveals partially blocked atrial runs and prolonged left atrial signal duration - two novel surrogate markers for PAF.

Electrocardiographic features of disease progression in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is considered a progressive cardiomyopathy. However, data on the clinical features of disease progression are limited. The aim of this study was to assess 12-lead surface electrocardiographic (ECG) changes during long-term follow-up, and to compare these findings with echocardiographic data in our large cohort of patients with ARVC/D. METHODS Baseline and follow-up ECGs of 111 patients from three tertiary care centers in Switzerland were systematically analyzed with digital calipers by two blinded observers, and correlated with findings from transthoracic echocardiography. RESULTS The median follow-up was 4 years (IQR 1.9-9.2 years). ECG progression was significant for epsilon waves (baseline 14% vs. follow-up 31%, p = 0.01) and QRS duration (111 ms vs. 114 ms, p = 0.04). Six patients with repolarization abnormalities according to the 2010 Task Force Criteria at baseline did not display these criteria at follow-up, whereas in all patients with epsilon waves at baseline these depolarization abnormalities also remained at follow-up. T wave inversions in inferior leads were common (36% of patients at baseline), and were significantly associated with major repolarization abnormalities (p = 0.02), extensive echocardiographic right ventricular involvement (p = 0.04), T wave inversions in lateral precordial leads (p = 0.05), and definite ARVC/D (p = 0.05). CONCLUSIONS Our data supports the concept that ARVC/D is generally progressive, which can be detected by 12-lead surface ECG. Repolarization abnormalities may disappear during the course of the disease. Furthermore, the presence of T wave inversions in inferior leads is common in ARVC/D.

Size exclusion chromatogram of the Tannermoor 2009 sample after saltout experiments

Samples from a pristine raised peat bog runoff in Austria, the Tannermoor creek, were analysed for their iron linked to natural organic matter (NOM) content. Dissolved organic carbon < 0.45 µm (DOC) was 41 to 64 mg/L, iron 4.4 to 5.5 mg/L. Samples were analysed applying asymmetric field flow fractionation (AsFlFFF) coupled to UV-Vis absorption, fluorescence and inductively coupled plasma mass spectrometry (ICP-MS). The samples showed an iron peak associated with the NOM peak, one sample exhibiting a second peak of iron independent from the NOM peak. As highland peat bogs with similar climatic conditions and vegetation to the Tanner Moor are found throughout the world, including areas adjacent to the sea, we examined the behaviour of NOM and iron in samples brought to euhaline (35 per mil) conditions with artificial sea salt. The enhanced ionic strength reduced NOM by 53% and iron by 82%. Size exclusion chromatography (SEC) of the samples at sea-like salinity revealed two major fractions of NOM associated with different iron concentrations. The larger one, eluting sharply after the upper exclusion limits of 4000-5000 g/mol, seems to be most important for iron chelating. The results outline the global importance of sub-mountainous and mountainous raised peat bogs as a source of iron chelators to the marine environment at sites where such peat bogs release their run-offs into the sea.

Detrital zircon geochronology data, petrographic point count data and paleocurrent indicator data of Triassic turbidites in the Nanpanjiang Basin, South China

Triassic turbidites of the Nanpanjiang basin of south China represent the most expansive and voluminous siliciclastic turbidite accumulation in south China. The Nanpanjiang basin occurs at a critical junction between the southern margin of the south China plate and the Indochina, Siamo and Sibumasu plates to the south and southwest. The Triassic Yangtze carbonate shelf and isolated carbonated platforms in the basin have been extensively studied, but silicilastic turbidites in the basin have received relatively little attention. Deciphering the facies, paleocurrent indicators and provenance of the Triassic turbidites is important for several reasons: it promises to help resolve the timing of plate collisions along suture zones bordering the basin to the south and southwest, it will enable evaluation of which suture zones and Precambrian massifs were source areas, and it will allow an evaluation of the impact of the siliciclastic flux on carbonate platform evolution within the basin. Turbidites in the basin include the Early Triassic Shipao Formation and the Middle-Late Triassic Baifeng, Xinyuan, Lanmu Bianyang and Laishike formations. Each ranges upward of 700 m and the thickest is nearly 3 km. The turbidites contain very-fine sand in the northern part of the basin whereas the central and southern parts of the basin also commonly contain fine and rarely medium sand size. Coarser sand sizes occur where paleocurrents are from the south, and in this area some turbidites exhibit complete bouma sequences with graded A divisions. Successions contain numerous alternations between mud-rich and sand-rich intervals with thickness trends corresponding to proximal/ distal fan components. Spectacularly preserved sedimentary structures enable robust evaluation of turbidite systems and paleocurrent analyses. Analysis of paleocurrent measurements indicates two major directions of sediment fill. The northern part of the basin was sourced primarily by the Jiangnan massif in the northeast, and the central and southern parts of the basin were sourced primarily from suture zones and the Yunkai massif to the south and southeast respectively. Sandstones of the Lower Triassic Shipao Fm. have volcaniclastic composition including embayed quartz and glass shards. Middle Triassic sandstones are moderately mature, matrix-rich, lithic wackes. The average QFL ratio from all point count samples is 54.1/18.1/27.8% and the QmFLt ratio is 37.8/ 18.1/ 44.1%. Lithic fragments are dominantly claystone and siltstone clasts and metasedimentary clasts such as quartz mica tectonite. Volcanic lithics are rare. Most samples fall in the recycled orogen field of QmFLt plots, indicating a relatively quartz and lithic rich composition consistent with derivation from Precambrian massifs such as the Jiangnan, and Yunkai. A few samples from the southwest part of the basin fall into the dissected arc field, indicating a somewhat more lithic and feldspar-rich composition consistent with derivation from a suture zone Analysis of detrial zircon populations from 17 samples collected across the basin indicate: (1) Several samples contain zircons with concordant ages greater than 3000 Ma, (2) there are widespread peaks across the basin at 1800 Ma and 2500, (3) a widespread 900 Ma population, (3) a widespread population of zircons at 440 Ma, and (5) a larger population of younger zircons about 250 Ma in the southwestern part which is replaced to the north and northwest by a somewhat older population around 260-290 Ma. The 900 Ma provenance fits derivation from the Jiangnan Massif, the 2500, 1800, and 440 Ma provenance fits the Yunkai massif, and the 250 Ma is consistent with convergence and arc development in suture zones bordering the basin on the south or southwest. Early siliciclastic turbidite flux, proximal to source areas impacted carbonate platform evolution by infilling the basin, reducing accommodation space, stabilizing carbonate platform margins and promoting margin progradation. Late arrival, in areas far from source areas caused margin aggradation over a starved basin, development of high relief aggradational escarpments and unstable scalloped margins.