Multiple Sclerosis Performance Test: validation of self-administered neuroperformance modules.

BACKGROUND AND PURPOSE: The purpose was to determine the test-retest reliability, practice effects, convergent validity and sensitivity to multiple sclerosis (MS) disability of neuroperformance subtests from the patient self-administered Multiple Sclerosis Performance Test (MSPT) designed to assess low contrast vision (Contrast Sensitivity Test, CST), upper extremity motor function (Manual Dexterity Test, MDT) and lower extremity motor function (Walking Speed Test, WST) and to introduce the concept of regression-based norms to aid clinical interpretation of performance scores using the MSPT cognition test (Processing Speed Test, PST) as an example. METHODS: Substudy 1 assessed test-retest reliability, practice effects and convergent validity of the CST, MDT and WST in 30 MS patients and 30 healthy controls. Substudy 2 examined sensitivity to MS disability in over 600 MS patients as part of their routine clinic assessment. Substudy 3 compared performance on the PST in research volunteers and clinical samples. RESULTS: The CST, MDT and WST were shown to be reliable, valid and sensitive to MS outcomes. Performance was comparable to technician-administered testing. PST performance was poorer in the clinical sample compared with the research volunteer sample. CONCLUSIONS: The self-administered MSPT neuroperformance modules produce reliable, objective metrics that can be used in clinical practice and support outcomes research. Published studies which require patient voluntary consent may underestimate the rate of cognitive dysfunction observed in a clinical setting.

Associations of stream geomorphic conditions and prevalence of alternative reproductive tactics among sockeye salmon populations.

In many species, males may exhibit alternative life histories to circumvent the costs of intrasexual competition and female courtship. While the evolution and underlying genetic and physiological mechanisms behind alternative reproductive tactics are well studied, there has been less consideration of the ecological factors that regulate their prevalence. Here, we examine six decades of age composition records from thirty-six populations of sockeye salmon (Oncorhynchus nerka) to quantify associations between spawning habitat characteristics and the prevalence of precocious sneakers known as 'jacks'. Jack prevalence was independent of neutral genetic structure among stream populations, but varied among habitat types and as a function of continuous geomorphic characteristics. Jacks were more common in streams relative to beaches and rivers, and their prevalence was negatively associated with stream width, depth, elevation, slope and area, but positively related to bank cover. Behavioural observations showed that jacks made greater use of banks, wood and shallows than guard males, indicating that their reproductive success depends on the availability of such refuges. Our results emphasize the role of the physical habitat in shaping reproductive tactic frequencies among populations, likely through local adaptation in response to variable fitness expectations under different geomorphic conditions.

Major histocompatibility complex diversity is positively associated with stream water temperatures in proximate populations of sockeye salmon.

Local adaptation to heterogeneous environments generates population diversity within species, significantly increasing ecosystem stability and flows of ecosystem services. However, few studies have isolated the specific mechanisms that create and maintain this diversity. Here, we examined the relationship between water temperature in streams used for spawning and genetic diversity at a gene involved in immune function [the major histocompatibility complex (MHC)] in 14 populations of sockeye salmon (Oncorhynchus nerka) sampled across the Wood River basin in south-western Alaska. The largest influence on MHC diversity was lake basin, but we also found a significant positive correlation between average water temperature and MHC diversity. This positive relationship between temperature and MHC diversity appears to have been produced by natural selection at very local scales rather than neutral processes, as no correlation was observed between temperature and genetic diversity at 90 neutral markers. Additionally, no significant relationship was observed between temperature variability and MHC diversity. Although lake basin was the largest driver of differences in MHC diversity, our results also demonstrate that fine-scale differences in water temperature may generate variable selection regimes in populations that spawn in habitats separated by as little as 1 km. Additionally, our results indicated that some populations may be reaching a maximum level of MHC diversity. We postulate that salmon from populations in warm streams may delay spawning until late summer to avoid thermal stress as well as the elevated levels of pathogen prevalence and virulence associated with warm temperatures earlier in the summer.

Outcomes of mismatched and unrelated donor hematopoietic stem cell transplantation in Fanconi anemia conditioned with chemotherapy only.

Fanconi anemia (FA) is a genomic instability syndrome associated with bone marrow failure, myelodysplastic syndrome (MDS), and/or acute myeloid leukemia (AML) requiring hematopoietic stem cell transplantation (HSCT) to restore normal hematopoiesis. Although low-intensity fludarabine-based preparative regimens without radiation confer excellent outcomes in FA HSCTs with HLA-matched sibling donors, outcomes for FA patients with alternative donors are less encouraging, albeit improving. We present our experience with 17 FA patients who completed mismatched related or unrelated donor HSCT using a non-radiation fludarabine-based preparative regimen at Charité University Medicine Berlin. All patients engrafted; however, one patient had unstable chimerism in the setting of multi-viral infections that necessitated a stem cell boost to revert to full donor chimerism. Forty-seven percent of patients developed grade I acute graft-verus-host disease (aGVHD). No grade II-IV aGVHD or chronic graft-versus-host disease of any severity occurred. At a median follow-up of 30 months, 88 % of patients are alive with normal hematopoiesis. Two patients died of infections 4 months post-transplantation. These results demonstrate that short-term outcomes for FA patients with mismatched and unrelated donor HSCTs can be excellent using chemotherapy only conditioning. Viral reactivation, however, was a major treatment-related complication.

Physical mapping of the holoprosencephaly critical region on chromosome 7q36.

Holoprosencephaly (HPE) is a developmental field defect involving the brain and face. Cytogenetic deletions in patients with HPE have localized one of the HPE genes to chromosomal region 7q36. We have characterized the 7q deletions in thirteen HPE patients. The result is the construction of a high resolution physical map of 7q32-qter. As a first step towards cloning an HPE gene crucial for normal brain development, we have defined the HPE minimal critical region in 7q36 between D7S292 and D7S392.

The Fanconi anaemia group G gene FANCG is identical with XRCC9.

Fanconi anemia (FA) is an autosomal recessive disease with diverse clinical symptoms including developmental anomalies, bone marrow failure and early occurrence of malignancies. In addition to spontaneous chromosome instability, FA cells exhibit cell cycle disturbances and hypersensitivity to cross-linking agents. Eight complementation groups (A-H) have been distinguished, each group possibly representing a distinct FA gene. The genes mutated in patients of complementation groups A (FANCA; refs 4,5) and C (FANCC; ref. 6) have been identified, and FANCD has been mapped to chromosome band 3p22-26 (ref. 7). An additional FA gene has recently been mapped to chromosome 9p (ref. 8). Here we report the identification of the gene mutated in group G, FANCG, on the basis of complementation of an FA-G cell line and the presence of pathogenic mutations in four FA-G patients. We identified the gene as human XRCC9, a gene which has been shown to complement the MMC-sensitive Chinese hamster mutant UV40, and is suspected to be involved in DNA post-replication repair or cell cycle checkpoint control. The gene is localized to chromosome band 9p13 (ref. 9), corresponding with a known localization of an FA gene.

Central European 2018 hot drought shifts scots pine forest to its tipping point.

The occurrence of hot drought, i.e. low water availability and simultaneous high air temperature, represents a severe threat to ecosystems. Here, we investigated how the 2018 hot drought in Central Europe caused a tipping point in tree and ecosystem functioning in a Scots pine (Pinus sylvestris L.) forest in southwest Germany. Measurements of stress indicators, such as needle water potential, carbon assimilation and volatile organic compound (VOC) emissions, of dominant P. sylvestris trees were deployed to evaluate tree functioning during hot drought. Ecosystem impact and recovery were assessed as ecosystem carbon exchange, normalized difference vegetation index (NDVI) from satellite data and tree mortality data. During summer 2018, needle water potentials of trees dropped to minimum values of -7.5 ± 0.2 MPa, which implied severe hydraulic impairment of P. sylvestris. Likewise, carbon assimilation and VOC emissions strongly declined after mid-July. Decreasing NDVI values from August 2018 onwards were detected, along with severe defoliation in P. sylvestris, impairing ecosystem carbon flux recovery in 2019, shifting the forest into a year-round carbon source. A total of 47% of all monitored trees (n = 368) died by September 2020. NDVI recovered to pre-2018 levels in 2019, likely caused by emerging broadleaved understorey species. The 2018 hot drought had severe negative impacts on P. sylvestris. The co-occurrence of unfavourable site-specific conditions with recurrent severe droughts resulted in accelerated mortality. Thus, the 2018 hot drought pushed the P. sylvestris stand towards its tipping point, with a subsequent vegetation shift to a broadleaf-dominated forest.

Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain.

To expand the spectrum of recognition of effector lymphocytes and to redirect them towards predefined targets, we have altered the specificity of human tumor-infiltrating lymphocytes (TIL) through stable modification with chimeric receptor genes consisting of single-chain antibody variable regions linked to the gamma subunit common to the immunoglobulin (Ig)G and IgE Fc receptors. Using either hapten or ovarian carcinoma-specific monoclonal antibodies, we constructed chimeric receptor genes and retrovirally introduced them into CD8+ TIL. Redirected TIL specifically lysed trinitrophenyl-labeled Daudi or a human ovarian carcinoma cell line (IGROV-1), and secreted granulocyte/macrophage colony-stimulating factor upon stimulation with the appropriate antigen. This strategy may allow new approaches towards the adoptive immunotherapy of cancer in humans.

Author Correction: Watershed geomorphology modifies the sensitivity of aquatic ecosystem metabolism to temperature.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Effects of Acid rain on freshwater ecosystems.

Acid-vulnerable areas are more numerous and widespread than believed 7 years ago. Lakes and streams in acid-vulnerable areas of northeastern North America have suffered substantial declines in acid-neutralizing capacity, the worst cases resulting in biological damage. Many invertebrates are very sensitive to acidification, with some disappearing at pH values as high as 6.0. However, the recent rate of acidification of lakes is slower than once predicted, in part the result of decreases in sulfur oxide emissions. A discussion of some of the processes that have contributed to the acidification of lakes as well as those that have protected acid-sensitive freshwaters is presented. The author is in the Department of Fisheries and Oceans, Freshwater Institute, 501 University Crescent, Winnipeg, Manitoba R3T 2N6, Canada.

Eutrophication and recovery in experimental lakes: implications for lake management.

Combinations of phosphorus, nitrogen, and carbon were added to several small lakes in northwestern Ontario, Canada, at rates similar to those in many culturally eutrophied lakes. Phosphate and nitrate caused rapid eutrophication. A similar result was obtained with phosphate, ammonia, and sucrose, but recovery was almost immediate when phosphate additions only were discontinued. When two basins of one lake were fertilized with equal amounts of nitrate and sucrose, and phosphorus was also added to one of the basins, the phosphateenriched basin quickly became highly eutrophic, while the basin receiving only nitrogen and carbon remained at prefertilization conditions. These results, and the high affinity of sediments for phosphorus indicate that rapid abatement of eutrophication may be expected to follow phosphorus control measures.

Mitochondrial polyriboadenylate polymerase: relative lack of activity in hepatomas.

An enzyme that polymerizes adenylate residues from adenosine triphosphate was prepared from rat liver mitochondria and compared to similar preparations from the mitochondria of three hepatomas. Enzyme activity in the hepatomas was only 1 to 2 percent of that in normal liver.

Disruption of the nitrogen cycle in acidified lakes.

Experimental acidification of two small soft-water lakes caused nitrification to cease at pH values of 5.4 to 5.7. The resulting blockage of the nitrogen cycle caused a progressive accumulation of amnonium. When the epermental acidification of one of the lakes was ended and the pH was raised to 5.4, nitrification resumed after a time lag of 1 year.

Natural sources of Acid neutralizing capacity in low alkalinity lakes of the precambrian shield.

A detailed alkalinity budget was constructed for Lake 239 in the Experimental Lakes Area of northwestern Ontario and for three small watersheds in its terrestrial basin. Alkalinity generation in the lake averaged 118 milliequivalents per square meter per year, 4.5 times as high as the areal rate in the terrestrial basin. Although acid deposition in the area is low, only one of the three terrestrial watersheds was a significant source of alkalinity. A second terrestrial watershed yielded very little alkalinity. The third watershed, which contains a wetland, was a sink for, rather than a source of, alkalinity. An analysis of ion budgets for the lake revealed that more than half of the in situ alkalinity production was by biological rather than geochemical processes. The major processes that generated alkalinity were: biological reduction of SO(4)(2-)(53%), exchange of H(+) for Ca(2+) in sediments (39%), and biological reduction of NO(3)(-) (26%). Comparison with experimentally acidified Lake 223 revealed that alkalinity production by sulfate reduction increased in response to increased inputs of sulfuric acid.

Atmospheric carbon dioxide: its role in maintaining phytoplankton standing crops.

The rate of invasion of carbon dioxide into an artificially eutrophic Canadian Shield lake with insufficient internal sources of carbon was determined by two methods: measuring the carbon : nitrogen : phosphorus ratios of seston after weekly additions of nitrogen and phosphorus, and measuring the loss of radon-222 tracer from the epilimnion. Both methods gave an invasion rate of about 0.2 gram of carbon per square meter per day. The results demonstrate that invasion of atmospheric carbon dioxide may be sufficient to permit eutrophication of any body of water receiving an adequate supply of phosphorus and nitrogen.

High concentrations of toxaphene in fishes from a subarctic lake.

Concentrations of toxaphene and other organochlorine compounds are high in fishes from subarctic Lake Laberge, Yukon Territory, Canada. Nitrogen isotope analyses of food chains and contaminant analyses of biota, water, and dated lake sediments show that the high concentrations of toxaphene in fishes from Laberge resulted entirely from the biomagnification of atmospheric inputs. A combination of low inputs of toxaphene from the atmosphere and transfer through an exceptionally long food chain has resulted in concentrations of toxaphene in fishes that are considered hazardous to human health.

Ecosystem experiments.

Experimental manipulations of entire ecosystems have been conducted in lakes, catchments, streams, and open terrestrial and marine environments. Experiments have addressed applied problems of ecosystem management and complex responses of communities and ecosystems to perturbations. In the course of some experiments, environmental indicators and models have been developed and tested. Surprising results with implications for ecological understanding and management are common.

Long-term ecosystem stress: the effects of years of experimental acidification on a small lake.

Experimental acidification of a small lake from an original pH value of 6.8 to 5.0 over an 8-year period caused a number of dramatic changes in the lake's food web. Changes in phytoplankton species, cessation of fish reproduction, disappearance of the benthic crustaceans, and appearance of filamentous algae in the littoral zone were consistent with deductions from synoptic surveys of lakes in regions of high acid deposition. Contrary to what had been expected from synoptic surveys, acidification of Lake 223 did not cause decreases in primary production, rates of decomposition, or nutrient concentrations. Key organisms in the food web leading to lake trout, including Mysis relicta and Pimephales promelas, were eliminated from the lake at pH values as high as 5.8, an indication that irreversible stresses on aquatic ecosystems occur earlier in the acidification process than was heretofore believed. These changes are caused by hydrogen ion alone, and not by the secondary effect of aluminum toxicity. Since no species of fish reproduced at pH values below 5.4, the lake would become fishless within about a decade on the basis of the natural mortalities of the most long-lived species.