Neurological update: hereditary neuropathies

In this update, we review the recent discovery of autosomal recessive variants in sorbitol dehydrogenase as one of the commonest and potentially treatable causes of hereditary motor neuropathy and CMT2. We also report on recent therapeutic advances in hereditary neuropathy including the use of lipid nanoparticle sequestered antisense oligonucleotides in CMT1A and lipid nanoparticle delivered CRISPR-Cas9 gene editing in ATTR amyloidosis

Stromelysin-1 Regulates Adipogenesis during Mammary Gland Involution

The matrix metalloproteinase MMP-3/stromelysin-1 (Str1) is highly expressed during mammary gland involution induced by weaning. During involution, programmed cell death of the secretory epithelium takes place concomitant with the repopulation of the mammary fat pad with adipocytes. In this study, we have used a genetic approach to determine the role of Str1 during mammary involution. Although Str1 has been shown to induce unscheduled apoptosis when expressed ectopically during late pregnancy (Alexander, C.M., E.W. Howard, M.J. Bissell, and Z. Werb. 1996. J. Cell Biol. 135:1669–1677), we found that during post-lactational involution, mammary glands from transgenic mice that overexpress the tissue inhibitor of metalloproteinases, TIMP-1 (TO), or mice carrying a targeted mutation in Str1 showed accelerated differentiation and hypertrophy of adipocytes, while epithelial apoptosis was unaffected. These data suggest that matrix metalloproteinases (MMPs) do not induce unscheduled epithelial cell death after weaning, but instead alter the stromal microenvironment. We used adipogenic 3T3-L1 cells as a cell culture model to test the function of MMPs during adipocyte differentiation. Fibroblastic 3T3-L1 progenitor cells expressed very low levels of MMPs or TIMPs. The transcription of a number of MMP and TIMP mRNAs [Str1, MT1-MMP, (MMP-14) collagenase-3 (MMP-13), gelatinase A (MMP-2), and TIMP-1, -2 and -3] was induced in committed preadipocytes, but only differentiated adipocytes expressed an activated MMP, gelatinase A. The addition of MMP inhibitors (GM 6001 and TIMP-1) dramatically accelerated the accumulation of lipid during differentiation. We conclude that MMPs, especially Str1, determine the rate of adipocyte differentiation during involutive mammary gland remodeling

Wnt signaling induces differentiation of progenitor cells in organotypic keratinocyte cultures

BACKGROUND: Interfollicular skin develops normally only when the activity of the progenitor cells in the basal layer is counterbalanced by the exit of cells into the suprabasal layers, where they differentiate and cornify to establish barrier function. Distinct stem and progenitor compartments have been demonstrated in hair follicles and sebaceous glands, but there are few data to describe the control of interfollicular progenitor cell activity. Wnt signaling has been shown to be an important growth-inducer of stem cell compartments in skin and many other tissues. RESULTS: Here, we test the effect of ectopic Wnt1 expression on the behavior of interfollicular progenitor cells in an organotypic culture model, and find that Wnt1 signaling inhibits their growth and promotes terminal differentiation. CONCLUSION: These results are consistent with the phenotypes reported for transgenic mice engineered to have gain or loss of function of Wnt signaling in skin, which would recommend our culture model as an accurate one for molecular analysis. Since it is known that canonical ligands are expressed in skin, it is likely that this pathway normally regulates the balance of growth and differentiation, and suggests it could be important to pathogenesis

Properties of Healthcare Teaming Networks as a Function of Network Construction Algorithms

Network models of healthcare systems can be used to examine how providers collaborate, communicate, refer patients to each other. Most healthcare service network models have been constructed from patient claims data, using billing claims to link patients with providers. The data sets can be quite large, making standard methods for network construction computationally challenging and thus requiring the use of alternate construction algorithms. While these alternate methods have seen increasing use in generating healthcare networks, there is little to no literature comparing the differences in the structural properties of the generated networks. To address this issue, we compared the properties of healthcare networks constructed using different algorithms and the 2013 Medicare Part B outpatient claims data. Three different algorithms were compared: binning, sliding frame, and trace-route. Unipartite networks linking either providers or healthcare organizations by shared patients were built using each method. We found that each algorithm produced networks with substantially different topological properties. Provider networks adhered to a power law, and organization networks to a power law with exponential cutoff. Censoring networks to exclude edges with less than 11 shared patients, a common de-identification practice for healthcare network data, markedly reduced edge numbers and greatly altered measures of vertex prominence such as the betweenness centrality. We identified patterns in the distance patients travel between network providers, and most strikingly between providers in the Northeast United States and Florida. We conclude that the choice of network construction algorithm is critical for healthcare network analysis, and discuss the implications for selecting the algorithm best suited to the type of analysis to be performed.Comment: With links to comprehensive, high resolution figures and networks via figshare.co

Let the sun shine in: effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia, Pennsylvania

BACKGROUND: Streptococcus pneumoniae is a common cause of community acquired pneumonia and bacteremia. Excess wintertime mortality related to pneumonia has been noted for over a century, but the seasonality of invasive pneumococcal disease (IPD) has been described relatively recently and is poorly understood. Improved understanding of environmental influence on disease seasonality has taken on new urgency due to global climate change. METHODS: We evaluated 602 cases of IPD reported in Philadelphia County, Pennsylvania, from 2002 to 2007. Poisson regression models incorporating seasonal smoothers were used to identify associations between weekly weather patterns and case counts. Associations between acute (dayto- day) environmental fluctuations and IPD occurrence were evaluated using a case-crossover approach. Effect modification across age and sex strata was explored, and meta-regression models were created using stratum-specific estimates for effect. RESULTS: IPD incidence was greatest in the wintertime, and spectral decomposition revealed a peak at 51.0 weeks, consistent with annual periodicity. After adjustment for seasonality, yearly increases in reporting, and temperature, weekly incidence was found to be associated with clear-sky UV index (IRR per unit increase in index: 0.70 [95% CI 0.54-0.91]). The effect of UV index was highest among young strata and decreased with age. At shorter time scales, only an association with increases in ambient sulphur oxides was linked to disease risk (OR for highest tertile of exposure 0.75, 95% CI 0.60 to 0.93). CONCLUSION: We confirmed the wintertime predominance of IPD in a major urban center. The major predictor of IPD in Philadelphia is extended periods of low UV radiation, which may explain observed wintertime seasonality. The mechanism of action of diminished light exposure on disease occurrence may be due to direct effects on pathogen survival or host immune function via altered 1,25-(OH)2-vitamin-D metabolism. These findings may suggest less diminution in future IPD risk with climate change than would be expected if wintertime seasonality was driven by temperature

Enhanced immunoprecipitation techniques for the identification of RNA-binding protein partners: IGF2BP1 interactions in mammary epithelial cells

RNA-binding proteins (RBPs) regulate the expression of large cohorts of RNA species to produce programmatic changes in cellular phenotypes. To describe the function of RBPs within a cell, it is key to identify their mRNA-binding partners. This is often done by crosslinking nucleic acids to RBPs, followed by chemical release of the nucleic acid fragments for analysis. However, this methodology is lengthy, which involves complex processing with attendant sample losses, thus large amounts of starting materials and prone to artifacts. To evaluate potential alternative technologies, we tested exclusion-based purification of immunoprecipitates (IFAST or SLIDE) and report here that these methods can efficiently, rapidly, and specifically isolate RBP-RNA complexes. The analysis requires less than 1% of the starting material required for techniques that include crosslinking. Depending on the antibody used, 50% to 100% starting protein can be retrieved, facilitating the assay of endogenous levels of RBPs; the isolated ribonucleoproteins are subsequently analyzed using standard techniques, to provide a comprehensive portrait of RBP complexes. Using exclusion-based techniques, we show that the mRNA-binding partners for RBP IGF2BP1 in cultured mammary epithelial cells are enriched in mRNAs important for detoxifying superoxides (specifically glutathione peroxidase [GPX]-1 and GPX-2) and mRNAs encoding mitochondrial proteins. We show that these interactions are functionally significant, as loss of function of IGF2BP1 leads to destabilization of GPX mRNAs and reduces mitochondrial membrane potential and oxygen consumption. We speculate that this underlies a consistent requirement for IGF2BP1 for the expression of clonogenic activity in vitro

Augmented cognitive behavioral therapy for post stroke depressive symptoms:a randomized controlled trial

Item does not contain fulltextOBJECTIVE: To evaluate the effectiveness of individually tailored cognitive behavioral therapy (CBT) for reducing depressive symptoms with or without anxiety poststroke. DESIGN: Multicenter, assessor-blinded, randomized controlled trial. SETTING: Ambulatory rehabilitation setting. PARTICIPANTS: Patients who had a Hospital Anxiety and Depression Scale-depression subscale (HADS-D) score >7 at least 3 months poststroke (N=61). INTERVENTIONS: Participants were randomly allocated to either augmented CBT or computerized cognitive training (CCT). The CBT intervention was based on the principles of recognizing, registering, and altering negative thoughts and cognitions. CBT was augmented with goal-directed real-life activity training given by an occupational or movement therapist. MAIN OUTCOME MEASURES: HADS-D was the primary outcome, and measures of participation and quality of life were secondary outcomes. Outcome measurements were performed at baseline, immediately posttreatment, and at 4- and 8-month follow-up. Analysis was performed with linear mixed models using group (CBT vs CCT) as the between-subjects factor and time (4 assessments) as the within-subjects factor. RESULTS: Mixed model analyses showed a significant and persistent time effect for HADS-D (mean difference, -4.6; 95% confidence interval, -5.7 to -3.6; P<.001) and for participation and quality of life in both groups. There was no significant group x time effect for any of the outcome measures. CONCLUSIONS: Our augmented CBT intervention was not superior to CCT for the treatment of mood disorders after stroke. Future studies should determine whether both interventions are better than natural history.8 p

Face-to-face: Social work and evil

The concept of evil continues to feature in public discourses and has been reinvigorated in some academic disciplines and caring professions. This article navigates social workers through the controversy surrounding evil so that they are better equipped to acknowledge, reframe or repudiate attributions of evil in respect of themselves, their service users or the societal contexts impinging upon both. A tour of the landscape of evil brings us face-to-face with moral, administrative, societal and metaphysical evils, although it terminates in an exhortation to cultivate a more metaphorical language. The implications for social work ethics, practice and education are also discussed

REPORT OF THE SUNFLOWER WORKING GROUP

Cultivated sunflower (Helianthus annuus) is grown in many temperate, semi-dry regions of the world, often in rotation with small grain cereals such as wheat. The largest areas of sunflower cultivation in the US are in the northern plains (North and South Dakota) and southern, high plains (western Nebraska and Kansas, plus areas of Colorado and Texas) where the growing season is often too dry and/or too short for profitable soybean and corn production. Most commercial sunflower is the oilseed type; in addition, the crop is grown for confectionery seed and is common as an ornamental in home gardens throughout the US. The US is the center of diversity of the ancestral species of cultivated sunflower (Heiser 1954). The crop is capable of hybridizing with its wild progenitor, wild H. annuus, but most crosses with other Helianthus species such as H. petiolaris are unsuccessful or yield infertile F1 progeny (Rieseberg et al. 1999). Cultivated sunflower also occurs as a volunteer weed. Although volunteer domesticated plants can represent a significant portion of the weeds infesting subsequent crops (Auwarter and Nalewaja 1976; Gillespie and Miller 1984), they do not persist for more than one or two years under most cropping systems and are not known to spread. For these reasons, the working group focused on the consequences of gene flow to wild H. annuus. Wild H. annuus is an outcrossing annual that occurs in disturbed sites and is widespread throughout much of the US, reaching its greatest abundance in midwestern states (Heiser 1954). Wild sunflower occurs at elevations ranging from sea level to 3,000 meters and in a variety of habitats that include roadsides, agricultural fields, abandoned fields, construction sites, and rangeland. Populations are typically patchy and ephemeral, relying on the soil seed bank and long-distance dispersal for opportunities to become established in available clearings. This species occurs as a common but manageable weed of wheat, cultivated sunflower, corn, soybean, sugarbeet, sorghum, safflower, and other crops (Al-Khatib et al. 1998; Geir et al. 1996; Irons and Burnside 1982; Schweitzer and Bridge 1982; Teo-Sherrell 1996). Pollen from cultivated sunflower is certain to spread to adjacent wild populations by the movements of foraging insects, especially bees. Commercial sunflower seed companies are required to have 1.6-2.4 km of isolation between hybrid seed production fields and wild sunflower and/or other cultivated sunflower to prevent contamination by “foreign” pollen (e.g., Smith 1978; Schneiter 1997). The extent of pollen movement from the crop to wild sunflowers is greatest at the crop edge, where up to 42% of seeds can be crop-wild hybrids, diminishing to nearly zero at distances of 800-1,000 m (Arias and Rieseberg 1995; Whitton et al. 1997). F1 crop-wild hybrids are fertile and capable of backcrossing with nearby wild plants, but they typically produce fewer flower heads per plant than purely wild genotypes (Snow et al. 1998). Once crop genes enter wild populations, they can spread farther by both pollen and seed dispersal. Seeds can be transported inadvertently by farm equipment and as contaminants of hay, manure, topsoil, and seed lots. Whitton et al. (1997) and Linder et al. (1998) have documented long-term persistence of crop genes in populations of wild sunflower