Aberrant crossed corticospinal facilitation in muscles distant from a spinal cord injury.

Crossed facilitatory interactions in the corticospinal pathway are impaired in humans with chronic incomplete spinal cord injury (SCI). The extent to which crossed facilitation is affected in muscles above and below the injury remains unknown. To address this question we tested 51 patients with neurological injuries between C2-T12 and 17 age-matched healthy controls. Using transcranial magnetic stimulation we elicited motor evoked potentials (MEPs) in the resting first dorsal interosseous, biceps brachii, and tibialis anterior muscles when the contralateral side remained at rest or performed 70% of maximal voluntary contraction (MVC) into index finger abduction, elbow flexion, and ankle dorsiflexion, respectively. By testing MEPs in muscles with motoneurons located at different spinal cord segments we were able to relate the neurological level of injury to be above, at, or below the location of the motoneurons of the muscle tested. We demonstrate that in patients the size of MEPs was increased to a similar extent as in controls in muscles above the injury during 70% of MVC compared to rest. MEPs remained unchanged in muscles at and within 5 segments below the injury during 70% of MVC compared to rest. However, in muscles beyond 5 segments below the injury the size of MEPs increased similar to controls and was aberrantly high, 2-fold above controls, in muscles distant (>15 segments) from the injury. These aberrantly large MEPs were accompanied by larger F-wave amplitudes compared to controls. Thus, our findings support the view that corticospinal degeneration does not spread rostral to the lesion, and highlights the potential of caudal regions distant from an injury to facilitate residual corticospinal output after SCI

Identification of Gemin5 as a Novel 7-Methylguanosine Cap-Binding Protein

A unique attribute of RNA molecules synthesized by RNA polymerase II is the presence of a 7-methylguanosine (m(7)G) cap structure added co-transcriptionally to the 5' end. Through its association with trans-acting effector proteins, the m(7)G cap participates in multiple aspects of RNA metabolism including localization, translation and decay. However, at present relatively few eukaryotic proteins have been identified as factors capable of direct association with m(7)G.Employing an unbiased proteomic approach, we identified gemin5, a component of the survival of motor neuron (SMN) complex, as a factor capable of direct and specific interaction with the m(7)G cap. Gemin5 was readily purified by cap-affinity chromatography in contrast to other SMN complex proteins. Investigating the underlying basis for this observation, we found that purified gemin5 associates with m(7)G-linked sepharose in the absence of detectable eIF4E, and specifically crosslinks to radiolabeled cap structure after UV irradiation. Deletion analysis revealed that an intact set of WD repeat domains located in the N-terminal half of gemin5 are required for cap-binding. Moreover, using structural modeling and site-directed mutagenesis, we identified two proximal aromatic residues located within the WD repeat region that significantly impact m(7)G association.This study rigorously identifies gemin5 as a novel cap-binding protein and describes an unprecedented role for WD repeat domains in m(7)G recognition. The findings presented here will facilitate understanding of gemin5's role in the metabolism of non-coding snRNAs and perhaps other RNA pol II transcripts

Effects of Extreme Precipitation to the Distribution of Infectious Diseases in Taiwan, 1994–2008

The incidence of extreme precipitation has increased with the exacerbation of worldwide climate disruption. We hypothesize an association between precipitation and the distribution patterns that would affect the endemic burden of 8 infectious diseases in Taiwan, including water- and vector-borne infectious diseases. A database integrating daily precipitation and temperature, along with the infectious disease case registry for all 352 townships in the main island of Taiwan was analysed for the period from 1994 to 2008. Four precipitation levels, <130 mm, 130–200 mm, 200–350 mm and >350 mm, were categorized to represent quantitative differences, and their associations with each specific disease was investigated using the Generalized Additive Mixed Model and afterwards mapped on to the Geographical Information System. Daily precipitation levels were significantly correlated with all 8 mandatory-notified infectious diseases in Taiwan. For water-borne infections, extreme torrential precipitation (>350 mm/day) was found to result in the highest relative risk for bacillary dysentery and enterovirus infections when compared to ordinary rain (<130 mm/day). Yet, for vector-borne diseases, the relative risk of dengue fever and Japanese encephalitis increased with greater precipitation only up to 350 mm. Differential lag effects following precipitation were statistically associated with increased risk for contracting individual infectious diseases. This study’s findings can help health resource sector management better allocate medical resources and be better prepared to deal with infectious disease outbreaks following future extreme precipitation events

New materials and devices for preventing catheter-related infections

Catheters are the leading source of bloodstream infections for patients in the intensive care unit (ICU). Comprehensive unit-based programs have proven to be effective in decreasing catheter-related bloodstream infections (CR-BSIs). ICU rates of CR-BSI higher than 2 per 1,000 catheter-days are no longer acceptable. The locally adapted list of preventive measures should include skin antisepsis with an alcoholic preparation, maximal barrier precautions, a strict catheter maintenance policy, and removal of unnecessary catheters. The development of new technologies capable of further decreasing the now low CR-BSI rate is a major challenge. Recently, new materials that decrease the risk of skin-to-vein bacterial migration, such as new antiseptic dressings, were extensively tested. Antimicrobial-coated catheters can prevent CR-BSI but have a theoretical risk of selecting resistant bacteria. An antimicrobial or antiseptic lock may prevent bacterial migration from the hub to the bloodstream. This review discusses the available knowledge about these new technologies

Chemical Genetics Reveals Bacterial and Host Cell Functions Critical for Type IV Effector Translocation by Legionella pneumophila

Delivery of effector proteins is a process widely used by bacterial pathogens to subvert host cell functions and cause disease. Effector delivery is achieved by elaborate injection devices and can often be triggered by environmental stimuli. However, effector export by the L. pneumophila Icm/Dot Type IVB secretion system cannot be detected until the bacterium encounters a target host cell. We used chemical genetics, a perturbation strategy that utilizes small molecule inhibitors, to determine the mechanisms critical for L. pneumophila Icm/Dot activity. From a collection of more than 2,500 annotated molecules we identified specific inhibitors of effector translocation. We found that L. pneumophila effector translocation in macrophages requires host cell factors known to be involved in phagocytosis such as phosphoinositide 3-kinases, actin and tubulin. Moreover, we found that L. pneumophila phagocytosis and effector translocation also specifically require the receptor protein tyrosine phosphate phosphatases CD45 and CD148. We further show that phagocytosis is required to trigger effector delivery unless intimate contact between the bacteria and the host is artificially generated. In addition, real-time analysis of effector translocation suggests that effector export is rate-limited by phagocytosis. We propose a model in which L. pneumophila utilizes phagocytosis to initiate an intimate contact event required for the translocation of pre-synthesized effector molecules. We discuss the need for host cell participation in the initial step of the infection and its implications in the L. pneumophila lifestyle. Chemical genetic screening provides a novel approach to probe the host cell functions and factors involved in host–pathogen interactions

Type 1 Fimbriae, a Colonization Factor of Uropathogenic Escherichia coli, Are Controlled by the Metabolic Sensor CRP-cAMP

Type 1 fimbriae are a crucial factor for the virulence of uropathogenic Escherichia coli during the first steps of infection by mediating adhesion to epithelial cells. They are also required for the consequent colonization of the tissues and for invasion of the uroepithelium. Here, we studied the role of the specialized signal transduction system CRP-cAMP in the regulation of type 1 fimbriation. Although initially discovered by regulating carbohydrate metabolism, the CRP-cAMP complex controls a major regulatory network in Gram-negative bacteria, including a broad subset of genes spread into different functional categories of the cell. Our results indicate that CRP-cAMP plays a dual role in type 1 fimbriation, affecting both the phase variation process and fimA promoter activity, with an overall repressive outcome on fimbriation. The dissection of the regulatory pathway let us conclude that CRP-cAMP negatively affects FimB-mediated recombination by an indirect mechanism that requires DNA gyrase activity. Moreover, the underlying studies revealed that CRP-cAMP controls the expression of another global regulator in Gram-negative bacteria, the leucine-responsive protein Lrp. CRP-cAMP-mediated repression is limiting the switch from the non-fimbriated to the fimbriated state. Consistently, a drop in the intracellular concentration of cAMP due to altered physiological conditions (e.g. growth in presence of glucose) increases the percentage of fimbriated cells in the bacterial population. We also provide evidence that the repression of type 1 fimbriae by CRP-cAMP occurs during fast growth conditions (logarithmic phase) and is alleviated during slow growth (stationary phase), which is consistent with an involvement of type 1 fimbriae in the adaptation to stress conditions by promoting biofilm growth or entry into host cells. Our work suggests that the metabolic sensor CRP-cAMP plays a role in coupling the expression of type 1 fimbriae to environmental conditions, thereby also affecting subsequent attachment and colonization of host tissues

Locating Temporal Functional Dynamics of Visual Short-Term Memory Binding using Graph Modular Dirichlet Energy

Visual short-term memory binding tasks are a promising early marker for Alzheimer's disease (AD). To uncover functional deficits of AD in these tasks it is meaningful to first study unimpaired brain function. Electroencephalogram recordings were obtained from encoding and maintenance periods of tasks performed by healthy young volunteers. We probe the task's transient physiological underpinnings by contrasting shape only (Shape) and shape-colour binding (Bind) conditions, displayed in the left and right sides of the screen, separately. Particularly, we introduce and implement a novel technique named Modular Dirichlet Energy (MDE) which allows robust and flexible analysis of the functional network with unprecedented temporal precision. We find that connectivity in the Bind condition is less integrated with the global network than in the Shape condition in occipital and frontal modules during the encoding period of the right screen condition. Using MDE we are able to discern driving effects in the occipital module between 100-140ms, coinciding with the P100 visually evoked potential, followed by a driving effect in the frontal module between 140-180ms, suggesting that the differences found constitute an information processing difference between these modules. This provides temporally precise information over a heterogeneous population in promising tasks for the detection of AD

Endocrinologic, neurologic, and visual morbidity after treatment for craniopharyngioma

Craniopharyngiomas are locally aggressive tumors which typically are focused in the sellar and suprasellar region near a number of critical neural and vascular structures mediating endocrinologic, behavioral, and visual functions. The present study aims to summarize and compare the published literature regarding morbidity resulting from treatment of craniopharyngioma. We performed a comprehensive search of the published English language literature to identify studies publishing outcome data of patients undergoing surgery for craniopharyngioma. Comparisons of the rates of endocrine, vascular, neurological, and visual complications were performed using Pearson’s chi-squared test, and covariates of interest were fitted into a multivariate logistic regression model. In our data set, 540 patients underwent surgical resection of their tumor. 138 patients received biopsy alone followed by some form of radiotherapy. Mean overall follow-up for all patients in these studies was 54 ± 1.8 months. The overall rate of new endocrinopathy for all patients undergoing surgical resection of their mass was 37% (95% CI = 33–41). Patients receiving GTR had over 2.5 times the rate of developing at least one endocrinopathy compared to patients receiving STR alone or STR + XRT (52 vs. 19 vs. 20%, χ2P < 0.00001). On multivariate analysis, GTR conferred a significant increase in the risk of endocrinopathy compared to STR + XRT (OR = 3.45, 95% CI = 2.05–5.81, P < 0.00001), after controlling for study size and the presence of significant hypothalamic involvement. There was a statistical trend towards worse visual outcomes in patients receiving XRT after STR compared to GTR or STR alone (GTR = 3.5% vs. STR 2.1% vs. STR + XRT 6.4%, P = 0.11). Given the difficulty in obtaining class 1 data regarding the treatment of this tumor, this study can serve as an estimate of expected outcomes for these patients, and guide decision making until these data are available

Changes in fire regimes since the last glacial maximum: an assessment based on a global synthesis and analysis of charcoal data

Fire activity has varied globally and continuously since the last glacial maximum (LGM) in response to long-term changes in global climate and shorter-term regional changes in climate, vegetation, and human land use. We have synthesized sedimentary charcoal records of biomass burning since the LGM and present global maps showing changes in fire activity for time slices during the past 21,000 years (as differences in charcoal accumulation values compared to pre-industrial). There is strong broad-scale coherence in fire activity after the LGM, but spatial heterogeneity in the signals increases thereafter. In North America, Europe and southern South America, charcoal records indicate less-than-present fire activity during the deglacial period, from 21,000 to ?11,000 cal yr BP. In contrast, the tropical latitudes of South America and Africa show greater-than-present fire activity from ?19,000 to ?17,000 cal yr BP and most sites from Indochina and Australia show greater-than-present fire activity from 16,000 to ?13,000 cal yr BP. Many sites indicate greater-than-present or near-present activity during the Holocene with the exception of eastern North America and eastern Asia from 8,000 to ?3,000 cal yr BP, Indonesia and Australia from 11,000 to 4,000 cal yr BP, and southern South America from 6,000 to 3,000 cal yr BP where fire activity was less than present. Regional coherence in the patterns of change in fire activity was evident throughout the post-glacial period. These complex patterns can largely be explained in terms of large-scale climate controls modulated by local changes in vegetation and fuel load