Antibody responses in New World camelids with tuberculosis caused by Mycobacterium microti

Antibody responses in New World camelids (NWC) infected with Mycobacterium microti were studied by two serological methods, multiantigen print immunoassay (MAPIA) and lateral-flow-based rapid test (RT). Serum samples were collected during 2004-2006 from 87 animals including 1 alpaca and 7 llamas with confirmed or suspected M. microti infection, 33 potentially exposed but clinically healthy animals from known infected herds, and 46 control NWC from herds where infection had not been previously diagnosed. The serological assays correctly identified infection status in 97% (MAPIA) or 87% (RT) cases. In three llamas with confirmed M. microti infection and one llama with gross pathology suggestive of disease, for which multiple serum samples collected over time were available, the antibody-based tests showed positive results 1-2 years prior to the onset of clinical signs or being found dead. In MAPIA, MPB83 protein was identified to be an immunodominant serological target antigen recognized in NWC infected with M. microti. With the limited number of animals tested in this study, the serological assays demonstrated the potential for convenient, rapid, and accurate diagnosis of M. microti infection in live llamas and alpacas.

Late-onset posttraumatic septal hematoma and abscess formation in a six-year-old Tamil girl--case report and literature review

Nasal septal hematoma with abscess (NSHA) is an uncommon complication of trauma and studies on children are especially rare. We discuss the case of a 6-year-old girl, who was initially evaluated independently by three doctors for minor nasal trauma but had to be re-hospitalized 6 days later with NSHA. Although septal hematoma had initially been excluded (5, 7 and 24 hours after trauma), a secondary accumulation of blood seems to have occured. Delayed hematoma formation has been described in the orbit as a result of possible venous injuries after endoscopic sinus surgery. However, such an observation is new for septal hematoma in children. Thus, we recommend re-evaluation for septal hematoma 48h to 72h after paediatric nasal trauma. Such a scheduled re-examination offers a chance to treat delayed subperichondral hematoma on time before almost inevitable superinfection leads to abscess formation and destruction of the nasal infrastructure. We suggest that parents should be vigilant for delayed nasal obstruction as possible herald of hematoma accumulation within the first week.

Wavelet-denoising of electroencephalogram and the absolute slope method: a new tool to improve electroencephalographic localization and lateralization

OBJECTIVE: In ictal scalp electroencephalogram (EEG) the presence of artefacts and the wide ranging patterns of discharges are hurdles to good diagnostic accuracy. Quantitative EEG aids the lateralization and/or localization process of epileptiform activity. METHODS: Twelve patients achieving Engel Class I/IIa outcome following temporal lobe surgery (1 year) were selected with approximately 1-3 ictal EEGs analyzed/patient. The EEG signals were denoised with discrete wavelet transform (DWT), followed by computing the normalized absolute slopes and spatial interpolation of scalp topography associated to detection of local maxima. For localization, the region with the highest normalized absolute slopes at the time when epileptiform activities were registered (>2.5 times standard deviation) was designated as the region of onset. For lateralization, the cerebral hemisphere registering the first appearance of normalized absolute slopes >2.5 times the standard deviation was designated as the side of onset. As comparison, all the EEG episodes were reviewed by two neurologists blinded to clinical information to determine the localization and lateralization of seizure onset by visual analysis. RESULTS: 16/25 seizures (64%) were correctly localized by the visual method and 21/25 seizures (84%) by the quantitative EEG method. 12/25 seizures (48%) were correctly lateralized by the visual method and 23/25 seizures (92%) by the quantitative EEG method. The McNemar test showed p=0.15 for localization and p=0.0026 for lateralization when comparing the two methods. CONCLUSIONS: The quantitative EEG method yielded significantly more seizure episodes that were correctly lateralized and there was a trend towards more correctly localized seizures. SIGNIFICANCE: Coupling DWT with the absolute slope method helps clinicians achieve a better EEG diagnostic accuracy.

Parameter-free extraction of the functional network topology from intracranial EEG recordings: a time-resolved study of graph properties in focal onset seizures

Rationale: Focal onset epileptic seizures are due to abnormal interactions between distributed brain areas. By estimating the cross-correlation matrix of multi-site intra-cerebral EEG recordings (iEEG), one can quantify these interactions. To assess the topology of the underlying functional network, the binary connectivity matrix has to be derived from the cross-correlation matrix by use of a threshold. Classically, a unique threshold is used that constrains the topology [1]. Our method aims to set the threshold in a data-driven way by separating genuine from random cross-correlation. We compare our approach to the fixed threshold method and study the dynamics of the functional topology. Methods: We investigate the iEEG of patients suffering from focal onset seizures who underwent evaluation for the possibility of surgery. The equal-time cross-correlation matrices are evaluated using a sliding time window. We then compare 3 approaches assessing the corresponding binary networks. For each time window: * Our parameter-free method derives from the cross-correlation strength matrix (CCS)[2]. It aims at disentangling genuine from random correlations (due to finite length and varying frequency content of the signals). In practice, a threshold is evaluated for each pair of channels independently, in a data-driven way. * The fixed mean degree (FMD) uses a unique threshold on the whole connectivity matrix so as to ensure a user defined mean degree. * The varying mean degree (VMD) uses the mean degree of the CCS network to set a unique threshold for the entire connectivity matrix. * Finally, the connectivity (c), connectedness (given by k, the number of disconnected sub-networks), mean global and local efficiencies (Eg, El, resp.) are computed from FMD, CCS, VMD, and their corresponding random and lattice networks. Results: Compared to FMD and VMD, CCS networks present: *topologies that are different in terms of c, k, Eg and El. *from the pre-ictal to the ictal and then post-ictal period, topological features time courses that are more stable within a period, and more contrasted from one period to the next. For CCS, pre-ictal connectivity is low, increases to a high level during the seizure, then decreases at offset. k shows a ‘‘U-curve’’ underlining the synchronization of all electrodes during the seizure. Eg and El time courses fluctuate between the corresponding random and lattice networks values in a reproducible manner. Conclusions: The definition of a data-driven threshold provides new insights into the topology of the epileptic functional networks.

A new approach to generate a safe double-attenuated Plasmodium liver stage vaccine

Recently it has been shown in rodent malaria models that immunisation with genetically attenuated Plasmodium parasites can confer sterile protection against challenge with virulent parasites. For the mass production of live attenuated Plasmodium parasites for vaccination, safety is a prerequisite. Knockout of a single gene is not sufficient for such a strategy since the parasite can likely compensate for such a genetic modification and a single surviving parasite is sufficient to kill an immunised individual. Parasites must therefore be at least double-attenuated when generating a safe vaccine strain. Genetic double-attenuation can be achieved by knocking out two essential genes or by combining a single gene knockout with the expression of a protein toxic for the parasite. We generated a double-attenuated Plasmodium berghei strain that is deficient in fatty acid synthesis by the knockout of the pdh-e1α gene, introducing a second attenuation by the liver stage-specific expression of the pore-forming bacterial toxin perfringolysin O. With this double genetically attenuated parasite strain, a superior attenuation was indeed achieved compared with single-attenuated strains that were either deficient in pyruvate dehydrogenase (PDH)-E1 or expressed perfringolysin O. In vivo, both single-attenuated strains resulted in breakthrough infections even if low to moderate doses of sporozoites (2,000-5,000) were administered. In contrast, the double genetically attenuated parasite strain, given at moderate doses of 5,000 sporozoites, did not result in blood stage infection and even when administered at 5- to 20-fold higher doses, only single and delayed breakthrough infections were observed. Prime booster immunisation with the double genetically attenuated parasite strain completely protected a susceptible mouse strain from malaria and even a single immunisation conferred protection in some cases and lead to a markedly delayed onset of blood stage infection in others. Importantly, premature rupture of the parasitophorous vacuole membrane by liver stage-specific perfringolysin O expression did not induce host cell death and soluble parasite proteins, which are released into the host cell cytoplasm, have the potential to be processed and presented via MHC class I molecules. This, in turn, might support immunological responses against Plasmodium-infected hepatocytes.

Designing forest biodiversity experiments: general considerations illustrated by a new large experiment in subtropical China

1. Biodiversity-ecosystem functioning (BEF) experiments address ecosystem-level consequences of species loss by comparing communities of high species richness with communities from which species have been gradually eliminated. BEF experiments originally started with microcosms in the laboratory and with grassland ecosystems. A new frontier in experimental BEF research is manipulating tree diversity in forest ecosystems, compelling researchers to think big and comprehensively. 2. We present and discuss some of the major issues to be considered in the design of BEF experiments with trees and illustrate these with a new forest biodiversity experiment established in subtropical China (Xingangshan, Jiangxi Province) in 2009/2010. Using a pool of 40 tree species, extinction scenarios were simulated with tree richness levels of 1, 2, 4, 8 and 16 species on a total of 566 plots of 25.8x25.8m each. 3. The goal of this experiment is to estimate effects of tree and shrub species richness on carbon storage and soil erosion; therefore, the experiment was established on sloped terrain. The following important design choices were made: (i) establishing many small rather than fewer larger plots, (ii) using high planting density and random mixing of species rather than lower planting density and patchwise mixing of species, (iii) establishing a map of the initial ecoscape' to characterize site heterogeneity before the onset of biodiversity effects and (iv) manipulating tree species richness not only in random but also in trait-oriented extinction scenarios. 4. Data management and analysis are particularly challenging in BEF experiments with their hierarchical designs nesting individuals within-species populations within plots within-species compositions. Statistical analysis best proceeds by partitioning these random terms into fixed-term contrasts, for example, species composition into contrasts for species richness and the presence of particular functional groups, which can then be tested against the remaining random variation among compositions. 5. We conclude that forest BEF experiments provide exciting and timely research options. They especially require careful thinking to allow multiple disciplines to measure and analyse data jointly and effectively. Achieving specific research goals and synergy with previous experiments involves trade-offs between different designs and requires manifold design decisions.

The onset of Neoglaciation 6000 years ago in western Mongolia revealed by an ice core from the Tsambagarav mountain range

Glacier highstands since the Last Glacial Maximum are well documented for many regions, but little is known about glacier fluctuations and lowstands during the Holocene. This is because the traces of minimum extents are difficult to identify and at many places are still ice covered, limiting the access to sample material. Here we report a new approach to assess minimal glacier extent, using a 72-m long surface-to-bedrock ice core drilled on Khukh Nuru Uul, a glacier in the Tsambagarav mountain range of the Mongolian Altai (4130 m asl, 48°39.338′N, 90°50.826′E). The small ice cap has low ice temperatures and flat bedrock topography at the drill site. This indicates minimal lateral glacier flow and thereby preserved climate signals. The upper two-thirds of the ice core contain 200 years of climate information with annual resolution, whereas the lower third is subject to strong thinning of the annual layers with a basal ice age of approximately 6000 years before present (BP). We interpret the basal ice age as indicative of ice-free conditions in the Tsambagarav mountain range at 4100 m asl prior to 6000 years BP. This age marks the onset of the Neoglaciation and the end of the Holocene Climate Optimum. The ice-free conditions allow for adjusting the Equilibrium Line Altitude (ELA) and derive the glacier extent in the Mongolian Altai during the Holocene Climate Optimum. Based on the ELA-shift, we conclude that most of the glaciers are not remnants of the Last Glacial Maximum but were formed during the second part of the Holocene. The ice core derived accumulation reconstruction suggests important changes in the precipitation pattern over the last 6000 years. During formation of the glacier, more humid conditions than presently prevailed followed by a long dry period from 5000 years BP until 250 years ago. Present conditions are more humid than during the past millennia. This is consistent with precipitation evolution derived from lake sediment studies in the Altai.

Ultra-low dose - new approaches in menopausal hormone therapy.

Despite increasing life expectancy, the age of onset of natural menopause has not significantly changed in recent decades. Thus, women spend about one-third of their lives in an estrogen-deficient state if untreated. There is a need for appropriate treatment of acute symptoms and prevention of the sequelae of chronic estrogen deficiency. International guidelines call for the use of the lowest effective hormone dosage for vasomotor symptom relief, the major indication for menopausal hormone therapy (MHT). In 2011, an oral continuous combined ultra-low-dose MHT was approved in Switzerland. This publication was elaborated by eight national menopause specialists and intends to review the advantages and disadvantages of ultra-low-dose MHT after the first years of its general use in Switzerland. It concludes that, for many women, ultra-low-dose MHT may be sufficient to decrease vasomotor symptoms, but not necessarily to guarantee fracture prevention.

CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis

Current therapies to treat inflammatory bowel diseases have limited efficacy, significant side effects, and often wane over time. Little is known about the cellular and molecular mechanisms operative in the process of mucosal healing from colitis. To study such events, we developed a new model of reversible colitis in which adoptive transfer of CD4(+)CD45RB(hi) T cells into Helicobacter typhlonius-colonized lymphopenic mice resulted in a rapid onset of colonic inflammation that was reversible through depletion of colitogenic T cells. Remission was associated with an improved clinical and histopathological score, reduced immune cell infiltration to the intestinal mucosa, altered intestinal gene expression profiles, regeneration of the colonic mucus layer, and the restoration of epithelial barrier integrity. Notably, colitogenic T cells were not only critical for induction of colitis but also for maintenance of disease. Depletion of colitogenic T cells resulted in a rapid drop in tumor necrosis factor α (TNFα) levels associated with reduced infiltration of inflammatory immune cells to sites of inflammation. Although neutralization of TNFα prevented the onset of colitis, anti-TNFα treatment of mice with established disease failed to resolve colonic inflammation. Collectively, this new model of reversible colitis provides an important research tool to study the dynamics of mucosal healing in chronic intestinal remitting-relapsing disorders.Mucosal Immunology advance online publication 16 September 2015; doi:10.1038/mi.2015.93.

Assessing the improved discriminatory power of a new biomarker in prognostic models

Although the area under the receiver operating characteristic (AUC) is the most popular measure of the performance of prediction models, it has limitations, especially when it is used to evaluate the added discrimination of a new biomarker in the model. Pencina et al. (2008) proposed two indices, the net reclassification improvement (NRI) and integrated discrimination improvement (IDI), to supplement the improvement in the AUC (IAUC). Their NRI and IDI are based on binary outcomes in case-control settings, which do not involve time-to-event outcome. However, many disease outcomes are time-dependent and the onset time can be censored. Measuring discrimination potential of a prognostic marker without considering time to event can lead to biased estimates. In this dissertation, we have extended the NRI and IDI to survival analysis settings and derived the corresponding sample estimators and asymptotic tests. Simulation studies were conducted to compare the performance of the time-dependent NRI and IDI with Pencina’s NRI and IDI. For illustration, we have applied the proposed method to a breast cancer study.^ Key words: Prognostic model, Discrimination, Time-dependent NRI and IDI ^

Diabetic nephropathy in African-Americans with type 1 diabetes: The new Jersey 725 study

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States. African-Americans and patients with type 1 diabetes (T1D) are at increased risk. We studied the rate and factors that influenced progression of glomerular filtration rate (GFR) in 401 African-American T1D patients who were followed for 6 years through the observational cohort New Jersey 725 study. Patients with ESRD and/or GFR<20 ml/min were excluded. The mean (SD) baseline GFR was 106.8 (27.04) ml/min and it decreased by 13.8 (mean, SD 32.2) ml/min during the 6-year period (2.3 ml/min/year). In patients with baseline macroproteinuria, GFR decreased by 31.8 (39.0) ml/min (5.3 ml/min/year) compared to 8.2 (mean, SD 27.6) ml/min (1.3 ml/min/year) in patients without it (p<0.00001). Six-year GFR fell to <20 ml/min in 5.25% of all patients, but in 16.8% of macroproteinuric patients.^ A model including baseline GFR, proteinuria category and hypertension category, explained 35% of the 6-year GFR variability (p<0.0001). After adjustment for other variables in the model, 6-year GFR was 24.9 ml/min lower in macroproteinuric patients than in those without proteinuria (p=0.0001), and 12.6 ml/min lower in patients with treated but uncontrolled hypertension compared to normotensive patients (p=0.003). In this sample of patients, with an elevated mean glycosylated hemoglobin of 12.4%, glycemic control did not independently influence GFR deterioration, nor did BMI, cholesterol, gender, age at diabetes onset or socioeconomic level.^ Taken together, our findings suggest that proteinuria and hypertension are the most important factors associated with GFR deterioration in African-American T1D patients.^

Onset of long-term cooling of Greenland near the Eocene-Oligocene boundary as revealed by branched tetraether lipids

The Eocene-Oligocene (E-O) boundary interval is considered to be one of the major transitions in Earth's climate, witnessing the first major expansion of the East Antarctic Ice Sheet. However, the extent of the associated climatic cooling, especially for high northern latitude continental landmasses, is poorly constrained. In this study we reconstruct the first mean annual air temperature (MAAT) for the Greenland landmass during the late Eocene and early Oligocene by applying a new proxy based on the distribution of branched tetraether lipids derived from soil bacteria preserved in a marine sediment core from the Greenland Basin. The temperature estimates are compared with a composite continental temperature record based on bio-climatic analysis of pollen assemblages. Both proxies reveal comparable late Eocene MAATs of ~13-15 °C and a gradual long-term cooling of ~3-5 °C starting near the E-O boundary. These data are in agreement with other MAAT reconstructions from northern midlatitude continents and suggest a general cooling of the Northern Hemisphere during the E-O transition.

Neogene and Paleocene-Maestrichtian calcareous nannofossils in sediments of the upper continental rise off New Jersey

Maestrichtian to Holocene calcareous nannofossils from two closely spaced sites on the upper continental rise some 100 miles (161 km) southeast of Atlantic City, New Jersey, were zoned in order to help date a major canyon-cutting event in the late Miocene and to delineate and correlate other hiatuses with seismic stratigraphy. Mid-middle Eocene through middle Miocene sediments (Zones CP14 to CN6) were not recovered in these holes, but nearly all other zones are accounted for. The Eocene section is described in a companion chapter (Applegate and Wise, 1987, doi:10.2973/dsdp.proc.93.118.1987). Nannofossils are generally sparse and moderately preserved in the clastic sediments of Site 604. Sedimentation rates are extremely high for the upper Pleistocene (201 m/m.y. minimum) above a hiatus calculated to span 0.44 to 1.1 Ma. The associated disconformity is correlated with local seismic reflection Horizon Pr . Sedimentation rates continue to be high (93 m/m.y.) down to a second hiatus in the upper Pliocene dated from about 2.4 to 2.9 (or possibly 3.3) Ma. The disconformity associated with this hiatus is correlated with local seismic reflection Horizon P2 and regional Reflector Blue, which can be interpreted to mark either the onset of Northern Hemisphere continental glaciation or circulation changes associated with the closure of the Central American Seaway. Sedimentation rates in the pre-glacial lower Pliocene are only about a third those in the glacial upper Pliocene. A prominent disconformity in the upper Miocene marks a major lithologic boundary that separates Messinian(?) glauconitic claystones above from lower Tortonian conglomeratic debris flows and turbidites below. The debris flows recovered are assigned to nannofossil Zones CN8a and CN7, but drilling difficulties prevented penetration of the bottom of this sequence some 100 m below the terminal depth of the hole. Correlation of the lower bounding seismic reflector (M2/Merlin?) to a drift sequence drilled on the lower rise at DSDP Site 603, however, predicts that the debris flows began close to the beginning of the late Miocene (upper Zone CN6 time) at about 10.5 Ma. The debris flows represent a major canyon-cutting event that we correlate with the beginning of the particularly severe late Miocene glaciations believed to be associated with the formation of the West Antarctic Ice Sheet. The existence of these spectacular debris flows strongly suggest that the late Miocene glacio-eustatic low stand occurred during Vail Cycle TM3.1 (lower Tortonian) rather than during Vail Cycle TM3.2 (Messinian) as originally published. Beneath a set of coalesced regional disconformities centered upon seismic reflection Horizon Au, coccoliths are abundant and in general are moderately preserved at Site 605 in a 619-m carbonate section extending from the middle Eocene Zone CP13b to the upper Maestrichtian Lithraphidites quadratus Zone. Sedimentation rates are 37 m/m.y. in the Eocene down to a condensed interval near the base (Zone CP9). A disconformity is suspected near the Eocene/Paleocene boundary. Sedimentation rates for the upper Paleocene Zone CP8 are similar to those of the Eocene, but Zones CP7 and CP6 lie within another condensed interval. The highest Paleocene rates are 67 m/m.y. down through Zones CP5 and CP4 to a major disconformity that separates the upper Paleocene from the Danian. This hiatus spans about 2.6 m.y. (upper Zone CP3 to lower Zone CP2) and corresponds to the major sea-level drop at the base of Vail Cycle TE2.1. As the most prominent break in this Paleogene section, it may correspond to seismic reflection Horizon A* of the North American Basin. Sedimentation rates from this point to the Cretaceous/Tertiary boundary drop to 11 m/m.y., still high for a Paleocene DSDP section. No major break in deposition could be detected at the Cretaceous/Tertiary boundary.

Onset of south summer snowmelt on Antarctic sea ice between 1988 and 2007

The annual onset of snowmelt on sea ice is essential for climate monitoring since it triggers a decrease in surface albedo that feeds back into a stronger absorption of shortwave radiation - a process known as the snowmelt-albedo feedback - and thus strongly modifies the surface energy balance during summer. Algorithms designed for the detection of snowmelt on Arctic sea ice and based on longterm passive-microwave data revealed the melt season in the Arctic from 1979 to 1998 to be significantly elongated and the onset of melt to be shifted toward earlier dates.

Stable carbon isotope record of benthic foraminifera across the Paleocene-Eocene thermal maximum in the New Jersey Coastal Plain

In the New Jersey Coastal Plain, a silty to clayey sedimentary unit (the Marlboro Formation) represents deposition during the Paleocene-Eocene thermal maximum (PETM). This interval is remarkably different from the glauconitic sands and silts of the underlying Paleocene Vincentown and overlying Eocene Manasquan Formation. We integrate new and published stable isotope, biostratigraphic, lithostratigraphic and ecostratigraphic records, constructing a detailed time frame for the PETM along a depth gradient at core sites Clayton, Wilson Lake, Ancora and Bass River (updip to downdip). The onset of the PETM, marked by the base of the carbon isotope excursion (CIE), is within the gradual transition from glauconitic silty sands to silty clay, and represented fully at the updip sites (Wilson Lake and Clayton). The CIE "core" interval is expanded at the updip sites, but truncated. The CIE "core" is complete at the Bass River and Ancora sites, where the early part of the recovery is present (most complete at Ancora). The extent to which the PETM is expressed in the sediments is highly variable between sites, with a significant unconformity at the base of the overlying lower Eocene sediments. Our regional correlation framework provides an improved age model, allowing better understanding of the progression of environmental changes during the PETM. High-resolution benthic foraminiferal data document the change from a sediment-starved shelf setting to a tropical, river-dominated mud-belt system during the PETM, probably due to intensification of the hydrologic cycle. The excellent preservation of foraminifera during the PETM and the lack of severe benthic extinction suggest there was no extreme ocean acidification in shelf settings.