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Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE.

Abstract Background Ischemic stroke provokes a neuroinflammatory response and simultaneously promotes release of epinephrine and norepinephrine by the sympathetic nervous system. This increased sympathetic outflow can act on β2-adrenergic receptors expressed by immune cells such as brain-resident microglia and monocyte-derived macrophages (MDMs), but the effect on post-stroke neuroinflammation is unknown. Thus, we investigated how changes in β2-adrenergic signaling after stroke onset influence the microglia/MDM stroke response, and the specific importance of microglia/MDM β2-adrenergic receptors to post-stroke neuroinflammation. Methods To investigate the effects of β2-adrenergic receptor manipulation on post-stroke neuroinflammation, we administered the β2-adrenergic receptor agonist clenbuterol to mice 3 h after the onset of photothrombotic stroke. We immunostained to quantify microglia/MDM numbers and proliferation and to assess morphology and activation 3 days later. We assessed stroke outcomes by measuring infarct volume and functional motor recovery and analyzed gene expression levels of neuroinflammatory molecules. Finally, we evaluated changes in cytokine expression and microglia/MDM response in brains of mice with selective knockout of the β2-adrenergic receptor from microglia and monocyte-lineage cells. Results We report that clenbuterol treatment after stroke onset causes enlarged microglia/MDMs and impairs their proliferation, resulting in reduced numbers of these cells in the peri-infarct cortex by 1.7-fold at 3 days after stroke. These changes in microglia/MDMs were associated with increased infarct volume in clenbuterol-treated animals. In mice that had the β2-adrenergic receptor specifically knocked out of microglia/MDMs, there was no change in morphology or numbers of these cells after stroke. However, knockdown of β2-adrenergic receptors in microglia and MDMs resulted in increased expression of TNFα and IL-10 in peri-infarct tissue, while stimulation of β2-adrenergic receptors with clenbuterol had the opposite effect, suppressing TNFα and IL-10 expression. Conclusions We identified β2-adrenergic receptor signaling as an important regulator of the neuroimmune response after ischemic stroke. Increased β2-adrenergic signaling after stroke onset generally suppressed the microglia/MDM response, reducing upregulation of both pro- and anti-inflammatory cytokines, and increasing stroke size. In contrast, diminished β2-adrenergic signaling in microglia/MDMs augmented both pro- and anti-inflammatory cytokine expression after stroke. The β2-adrenergic receptor may therefore present a therapeutic target for improving the post-stroke neuroinflammatory and repair process.

Needle aponeurotomy (NA) and collagenase injections (CI) for treatment of Dupuytren disease are practical and clinically efficient techniques. The purpose of this report is to review the comparative literature and present postprocedure survey data on NA. We reviewed the current literature on treatment of Dupuytren disease with NA and report on direct and indirect comparisons of the 2 treatment options. We also retrospectively identified patients treated with NA for Dupuytren disease, reviewed the demographic details of treatment in the medical records, and solicited patients’ feedback on satisfaction, recurrence, and complications using a phone survey. The results of the survey are discussed in the context of current literature. A total of 250 completed the survey an average of 34 months after treatment. Of those, 178 (71%) were very satisfied or satisfied, 187 (75%) reported some recurrence, and 5% reported a complication. Patients less than 2 years from the procedure were statistically significantly more likely to be satisfied with the procedure and more likely to have it again, and reported less recurrence of disease. Current literature does not clearly suggest a best treatment option for Dupuytren disease. Recent analyses suggest that there is a cost difference, with NA presenting as a more cost-effective option. Survey results demonstrated a low complication rate although the rate of recurrence was high, which was consistent with other studies. Needle aponeurotomy is safe and effective, and results in high patient satisfaction despite a high recurrence rate. Key words: complications, Dupuytren disease, hand surgery, needle aponeurotomy, patient-reported satisfaction, recurrence

One hallmark of human aging is increased brain inflammation represented by glial activation. With age, there is also diminished function of the adaptive immune system, and modest decreases in circulating B- and T-lymphocytes. Lymphocytes traffic through the human brain and reside there in small numbers, but it is unknown how this changes with age. Thus we investigated whether B- and T-lymphocyte numbers change with age in the normal human brain. We examined 16 human subjects in a pilot study and then 40 human subjects from a single brain bank, ranging in age from 44–96 years old, using rigorous criteria for defining neuropathological changes due to age alone. We immunostained post-mortem cortical tissue for B- and T-lymphocytes using antibodies to CD20 and CD3, respectively. We quantified cell density and made a qualitative assessment of cell location in cortical brain sections, and reviewed prior studies. We report that density and location of both B- and T-lymphocytes do not change with age in the normal human cortex. Solitary B-lymphocytes were found equally in intravascular, perivascular, and parenchymal locations, while T-lymphocytes appeared primarily in perivascular clusters. Thus, any change in number or location of lymphocytes in an aging brain may indicate disease rather than normal aging.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.

According to a consensus view in philosophy, “deciding” and “intending” are synonymous expressions. Researchers have recently challenged this view with the discovery of a counterexample in which ordinary speakers attribute deciding without intending. The aim of this paper is to investigate the strengths and limits of this discovery. The result of this investigation revealed that the evidence challenging the consensus view is strong. We replicate the initial finding against consensus and extend it by utilizing several new measures, materials, and procedures. Together this evidence strongly suggests that “deciding” is not synonymous with “intending” in ordinary language and that the consensus view should be rejected.

The general public is subject to triage policies that allocate scarce lifesaving resources during the COVID-19 pandemic, one of the worst public health emergencies in the past 100 years. However, public attitudes toward ethical principles underlying triage policies used during this pandemic are not well understood. Three experiments (preregistered; online samples; N = 1,868; U.S. residents) assessed attitudes toward ethical principles underlying triage policies. The experiments evaluated assessments of utilitarian, egalitarian, prioritizing the worst-off, and social usefulness principles in conditions arising during the COVID-19 pandemic, involving resource scarcity, resource reallocation, and bias in resource allocation toward at-risk groups, such as the elderly or people of color. We found that participants agreed with allocation motivated by utilitarian principles and prioritizing the worst-off during initial distribution of resources and disagreed with allocation motivated by egalitarian and social usefulness principles. At reallocation, participants agreed with giving priority to those patients who received the resources first. Lastly, support for utilitarian allocation varied when saving the greatest number of lives resulted in disadvantage for at-risk or historically marginalized groups. Specifically, participants expressed higher levels of agreement with policies that shifted away from maximizing benefits to one that assigned the same priority to members of different groups if this mitigated disadvantage for people of color. Understanding these attitudes can contribute to developing triage policies, increase trust in health systems, and assist physicians in achieving their goals of patient care during the COVID-19 pandemic.

Abstract Background Sub-Saharan Africa continues to face the highest rate of mortality from diabetes in the world due to limited access to quality diabetes care. We assessed the quality of diabetes care in a rural diabetes clinic in western Kenya. Methods To provide a comprehensive assessment, a set of clinical outcomes, process, and structure metrics were evaluated to assess the quality of diabetes care provided in the outpatient clinic at Webuye District Hospital. The primary clinical outcome measures were the change in HbA1c and point of care blood glucose. In assessing process metrics, the primary measure was the percentage of patients who were lost to follow up. The structure metrics were assessed by evaluating different facets of the operation of the clinic and their accordance with the International Diabetes Federation (IDF) guidelines. Results A total of 524 patients were enrolled into the diabetes clinic during the predefined period of evaluation. The overall clinic population demonstrated a statistically significant reduction in HbA1c and point of care blood glucose at all time points of evaluation after baseline. Patients had a mean baseline HbA1C of 10.2% which decreased to 8.4% amongst the patients who remained in care after 18 months. In terms of process measures, 38 patients (7.3%) were characterized as being lost to follow up as they missed clinic visits for more than 6 months. Through the assessment of structural metrics, the clinic met at least the minimal standards of care for 14 out of the 19 domains recommended by the IDF. Conclusion This analysis illustrates the gains made in various elements of diabetes care quality which can be used by other programs to guide diabetes care scale up across the region.

Candida auris is an emerging fungal pathogen with cases reported in countries around the world and in 19 states within the United States as of August 2020. The CDC has recommended that hospitals perform active surveillance upon admission for patients with the appropriate risk factors. Currently, active surveillance requires that local hospitals send surveillance swabs to a public health laboratory for analysis. In this work, a real-time PCR assay was developed for the specific detection of C. auris from surveillance swabs, blood, and urine to enable rapid detection of this pathogen. The assay uses commercially available primers and reporter probes and it was verified on the LightCycler 480 PCR platform. Contrived specimens and prospectively collected composite groin/axilla surveillance swabs were used to validate the assay. The performance of the PCR assay on surveillance swabs was also compared to a second PCR assay targeting C. auris that was performed at the Minnesota Department of Health–Public Health Laboratory (MDH-PHL). Our PCR assay is able to detect and differentiate C. auris from closely related Candida species such as C. duobushaemulonii, C. haemulonii, and C. pseudohaemulonii on the basis of melting curve temperature differences.

Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood–brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE.

Background: Somatic nerve pain is one of the most common complications following surgery of the foot and ankle but may also arise following traumatic injury or chronic nerve compression. The sural nerve is a commonly affected nerve in the foot and ankle; it is at risk given the proximity to frequently used surgical approaches, exposure to crush injuries, and traction from severe ankle inversion injuries. The purpose of this study is to investigate the outcomes of sural nerve neurectomy with proximal implantation for sural neuromas (SN) and chronic sural neuritis (CSN). Methods: Patients that underwent neurectomy with proximal implantation (20 muscle, 1 adipose tissue) by 2 foot and ankle specialists for isolated SN- and CSN-related pain at a single tertiary institution were included. Demographic data, baseline outcomes including 36-Item Short Form Health Survey (SF-36), Foot and Ankle Ability Measure (FAAM), and visual analog scale (VAS) were recorded. Final follow-up questionnaires using Patient Reported Outcomes Measurement Information System (PROMIS) lower extremity function, pain interference (PI), and neuropathic pain quality, FAAM, and VAS were administered using REDCap. Perioperative factors including neuropathic medications, diagnostic injections, the use of collagen wraps, and perioperative ketamine were collected from the medical record. Descriptive statistics were performed and potential changes in patient-reported outcome measure scores were evaluated using Wilcoxon signed-rank tests. Results: The 21 patients meeting inclusion criteria for this study had a median age of 47 years (interquartile range [IQR], 43-49) and had median follow-up duration of 33.7 months (IQR, 4.5-47.6). Median FAAM activities of daily living score improved from 40.6 (38.7-50.7) preoperatively to 66.1 (53.6-83.3) postoperatively, P =.032. FAAM sports scores improved from 14.1 (7.8-21.9) to 41.1 (25.0-60.9) postoperatively, P =.002. VAS scores improved from a median of 9.0 (8.0-9.0) to 3.0 (3.0-6.0), P <.001. At final follow-up, patients reported PROMIS lower extremity function score median of 43.8 (35.6-54.9), PROMIS neuropathic pain quality score of 54.1 (43.6-61.6), and PROMIS PI of 57.7 (41.1-63.8). Patients with both anxiety and depression reported less improvement in pain and physical. Other perioperative factors lacked sufficient numbers for statistical analysis. Conclusion: Sural nerve neurectomy and proximal implantation (20 muscle, 1 adipose) provided significant improvement in pain and function for patients with sural neuromas and chronic sural neuritis at median follow-up of 33.7 months. Anxiety and depression were associated with significantly poorer outcomes following surgery. Patients with CRPS as well as recent nicotine use tended to report less improvement in pain and worse function after surgery, although this sample size was too limited for statistical analysis of these variables. Further research is needed to identify the ideal surgical candidates and perioperative factors to optimize patient outcomes. Level of Evidence: Level IV, retrospective case series. [ABSTRACT FROM AUTHOR]

Objective and Design. To investigate whether endogenous damage-associated molecular patterns (DAMPs) or alarmins originated from mitochondria or nucleus stimulates inflammatory response in articular chondrocytes to cause chondrolysis which leads to cartilage degradation featured in posttraumatic osteoarthritis (PTOA). Materials. Primary cultures of bovine or human chondrocytes isolated from cartilage of weight-bearing joints. Treatment. Chondrocytes were subjected to mitochondrial DAMPs (MTDs) or HMGB1, a nuclear DAMP (NuD), with or without the presence of an N-terminal 29 kDa fibronectin fragment (Fn-f) or proinflammatory cytokines (IL-1β and TNF-α). Injured cartilage-conditioned culturing medium containing a mixture of DAMPs was employed as a control. After 24 hrs, the protein expression of cartilage degrading metalloproteinases and iNOS in culture medium or cell lysates was examined with Western blotting, respectively. Results. HMGB1 was synergized with IL-1β in upregulating expression of MMP-3, MMP-13, ADAMTS-5, ADAM-8, and iNOS. Moreover, a moderate synergistic effect was detected between HMGB1 and Fn-f or between MTDs and TNF-α on MMP-3 expression. However, when acting alone, MTDs or HMGB1 did not upregulate cartilage degrading enzymes or iNOS. Conclusion. MTDs or HMGB1 could only stimulate inflammatory response in chondrocytes with the presence of cytokines or Fn-f.

This article is intended to help teacher educators, administrators, and mentor teachers envision how to support beginning STEM teachers as they transition from university-based preservice preparation into their first year of classroom teaching in high-need schools. Based on our experiences, and grounded in the associated research and literature, four strategies are developed with accompanying vignettes for how divergent school-based induction and university-based teacher programs can be more seamlessly aligned. (Contains 1 figure and 1 footnote.)

This paper explores both the resonances and the incommensurabilities between the literary discourse developed by the Cuban writers known as the origenistas, on the one hand, and the recent formulations of Franco Moretti and Pascale Casanova on the problem of «world literature», on the other. A conscious effort is made to avoid thinking of origenista discourse as fodder for recent theories issuing from the metropolitan centers, and to think instead of the ways in which recent theoretical developments might contribute to –or fall short of– the poetic imaginary elaborated by the writers associated with the magazine Orígenes (1944-1956). The place of Orígenes in the «world system» of literature, then, is grounded in the poetic imaginary of the origenistas themselves, and the source of theoretical model of world literature thus located in the periphery.

The rates of change in the language status of children with language impairment unaccompanied by other developmental or sensory disorders (primary language disorder) were studied in a longitudinal sample of 196 children who were followed from kindergarten through 4th grade. Previous studies have shown that children with such language impairments have moderate rates of improvement during this age range. Also, those with the most specific deficits have the greatest likelihood of improvement. Cole and colleagues have hypothesized that such results could be due to the effect of regression to the mean (K. Cole, I. Schwartz, A. Notari, P. Dale, & P. Mills, 1995). This study used a baseline measure of language that was independent of the measure used for diagnosis in order to control for factors leading to regression to the mean. Patterns of change using the kindergarten diagnostic measure were compared to those using the baseline measure. Rates of diagnostic change between kindergarten and subsequent observation intervals showed patterns of change similar to those of past research. Comparisons using the baseline measure revealed no significant change in relative language status across the 4-year time period. The results showed that when the conditions for regression to the mean were controlled, the poor language of children with language impairments was very likely to persist during the primary school years.

Focusing on the emergent Chinese and English literacy of a 5-year-old boy from Taiwan, provides insight into the debate within the field of bilingual education as to whether the introduction of literacy in languages with two different writing systems helps or hinders literacy development in both languages. (Author/VWL)

Since the end of the 1990s, unexplained outbreaks of acute encephalitis in children coinciding with litchi harvesting (May–July) have been documented in the Bac Giang Province in northern Vietnam. A retrospective ecologic analysis of data for 2004–2009 involving environmental, agronomic, and climatic factors was conducted to investigate the suspected association between the outbreaks and litchi harvesting. The clinical, biological, and immunologic characteristics of the patients suggested a viral etiology. The ecologic study revealed an independent association between litchi plantation surface proportion and acute encephalitis incidence: Incidence rate ratios were 1.52 (95% CI 0.90–2.57), 2.94 (95% CI 1.88–4.60), and 2.76 (95% CI 1.76–4.32) for second, third, and fourth quartiles, respectively, compared with the lowest quartile. This ecologic study confirmed the suspected association between incidence of acute encephalitis and litchi plantations and should be followed by other studies to identify the causative agent for this syndrome.

Reports on a qualitative study of dyadic discourse between university students of Spanish as a foreign language. Explored the social and cognitive behavior of learners as they participated in second language speaking activities. Repair, as it is formulated in the ethnomethodological approach to conversation analysis provided the lens through which data were examined. (Author/VWL)

This article presents BASE (Big ideas, Analyzing areas of difficulty, creating Strategies and supports, and Evaluating the process), a unit-planning process that teachers have used successfully with ninth-grade nontracked math classes to help secondary students with disabilities and students who are at-risk to be successful in a "reform" math curriculum. (Contains references.) (CR)

Six voluntary continuing-education programs for long-term-care staff on mental health experienced high attrition, attributed to scheduling difficulties and staff turnover. Because attrition affects evaluation and behavioral outcomes, self-contained, short instructional units were recommended. (SK)

Iowa nurses in long-term and home-health-care settings (n=53) were interested in continuing-education programs and teleconferences on the following Alzheimer's disease topics: challenging behaviors, family needs, case management, long-term care services, and new developments. Teleconferences were a viable strategy for isolated rural nurses. (SK)

The current work investigates the effects of a broadly adopted online matchmaking site on the nature and quality of married couples formed. Measures of personality, emotion, interests, values and marital adjustment were collected from a sample of married couples who had been introduced by an online matchmaking service, and from a sample of married couples who had met through unfettered choice. Results showed that couples introduced by the online matchmaking site were more similar, and that such similarity in general using the current measures was a strong predictor of marital adjustment in both online matched and comparison couples. Marriages resulting from the online matchmaking service were observed to have significantly higher scores for marital adjustment. We conclude that online matchmaking services based on predictive inference and proscribed selection can be observed to have a significant and meaningful impact on marital quality.

This study explores the role of the Internet in reconfiguring marriages, introducing couples that meet in person and later marry, through a set of online surveys of married couples in Britain, Australia, and Spain. The study found that a sizeable proportion of online married couples in each country first met their spouse online, usually through an online dating service, chat room or on instant messaging (IM). This was more the case for younger couples. Moreover, the study indicates that meeting online is likely to introduce people to others whom they would not be as likely to meet through other means. The Internet might well open people to more diversity in their choice of a partner, such as by introducing individuals with greater differences in age or education, but with more similar interests and values. These findings are preliminary, but suggestive of significant social trends and indirect implications of social networking in the digital age.