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Introduction: Despite progress in pharmacologic and revascularization therapies, no-option critical limb ischemia poses a major clinical and societal problem. Prior cell-based strategies involved mainly autologous (limited) cell sources., Aim: To evaluate the safety and feasibility of a novel ischemic tissue reparation/regeneration strategy using Wharton's jelly mesenchymal stem/stromal cells (WJMSCs) as an "unlimited" cell source in N-O CLI (first-in-man study, FIM)., Material and Methods: Enrollment criteria included Rutherford-4 to Rutherford-6 in absence of anatomic/technical feasibility for revascularization and adequate inflow via the common femoral artery with patency of at least one below-the-knee artery. 30 × 10 6 WJMSCs were administered intra-arterially and intra-muscularly (50%/50%) over 3-6-week intervals (3-6 administrations). Safety, feasibility and potential signals of efficacy were assessed at 12 and 48 months., Results: Five patients (age 61-71, 60% male, Rutherford-6 20%, Rutherford-5 60%, Rutherford-4 20%) were enrolled. WJMSCs were administered per protocol in absence of administration technique-related adverse events. Hyperemia, lasting 12-24 h, occurred in 4/5 subjects. Transient edema and pain (reactive to paracetamol) occurred in 3 (60%) patients. Amputation-free survival was 80% after 12 and 48 months. In those who avoided amputation, ischemic ulcerations healed and Rutherford stage improved. 4/5 patients were free of resting pain after 3-6 doses., Conclusions: This FIM study demonstrated the safety and feasibility of WJMSCs use in patients with N-O CLI and suggested treatment efficacy with ≥ 3 doses. Our findings provide a basis for a randomized, double-blind clinical trial to assess the efficacy of WJMSC-based therapeutic strategy in N-O CLI patients., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 Termedia Sp. z o. o.)

Critical limb ischemia - an advanced stage of lower extremity arterial disease with presence of rest pain and/or ischemic ulcers - remains an important cause of major amputations and disability in developed societies. Novel treatment strategies are urgently needed to prevent (or delay) amputations in particular for patients in whom effective revascularization is no longer feasible for anatomic and/or technical reasons (no-option critical limb ischemia - N-O CLI). Cellular therapies have been gaining the growing attention of researchers and clinicians in the last two decades. Several cell types have been used in pre-clinical and clinical studies, and a number of mechanisms have been proposed to contribute to vascular reparation and regeneration in N-O CLI. Although early trials suggested clinical improvement with use of cell-based therapies in N-O CLI, meta-analyses that included randomized controlled trials have not provided definitive conclusions. Fundamental limitations have involved poorly defined cell lines/populations, limited numbers of study participants and limited follow-up periods, and enrolling patients "too sick to benefit" (such as those in Rutherford class 6). Recent advances include standardized "unlimited" sources of therapeutic cells and better understanding of mechanisms that may contribute to vascular reparation and regeneration. Furthermore, based on recent pre-clinical and clinical studies, cell-free preparations (such as microvesicle-based) are being increasingly developed along with advanced therapy medical products consisting of engineered cells and pro-angiogenic factors., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 Termedia Sp. z o. o.)

Dysferlin is an integral membrane protein of the transverse tubules of skeletal muscle that is mutated or absent in limb girdle muscular dystrophy 2B and Miyoshi myopathy. Here we examine the role of dysferlin's seven C2 domains, C2A through C2G, in membrane repair and Ca 2+ release, as well as in targeting dysferlin to the transverse tubules of skeletal muscle. We report that deletion of either domain C2A or C2B inhibits membrane repair completely, whereas deletion of C2C, C2D, C2E, C2F or C2G causes partial loss of membrane repair that is exacerbated in the absence of extracellular Ca 2+ . Deletion of C2C, C2D, C2E, C2F or C2G also causes significant changes in Ca 2+ release, measured as the amplitude of the Ca 2+ transient before or after hypo-osmotic shock and the appearance of Ca 2+ waves. Most deletants accumulate in endoplasmic reticulum. Only the C2A domain can be deleted without affecting dysferlin trafficking to transverse tubules, but Dysf-ΔC2A fails to support normal Ca 2+ signalling after hypo-osmotic shock. Our data suggest that (i) every C2 domain contributes to repair; (ii) all C2 domains except C2B regulate Ca 2+ signalling; (iii) transverse tubule localization is insufficient for normal Ca 2+ signalling; and (iv) Ca 2+ dependence of repair is mediated by C2C through C2G. Thus, dysferlin's C2 domains have distinct functions in Ca 2+ signalling and sarcolemmal membrane repair and may play distinct roles in skeletal muscle. KEY POINTS: Dysferlin, a transmembrane protein containing seven C2 domains, C2A through C2G, concentrates in transverse tubules of skeletal muscle, where it stabilizes voltage-induced Ca 2+ transients and participates in sarcolemmal membrane repair. Each of dysferlin's C2 domains except C2B regulate Ca 2+ signalling. Localization of dysferlin variants to the transverse tubules is not sufficient to support normal Ca 2+ signalling or membrane repair. Each of dysferlin's C2 domains contributes to sarcolemmal membrane repair. The Ca 2+ dependence of membrane repair is mediated by C2C through C2G. Dysferlin's C2 domains therefore have distinct functions in Ca 2+ signalling and sarcolemmal membrane repair., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Objective: The present study was designed to examine the impact that walking has on performance in auditory localization, visual discrimination, and aurally aided visual search tasks., Background: Auditory localization and visual search are critical skills that are frequently conducted by moving observers, but most laboratory studies of these tasks have been conducted on stationary listeners who were either seated or standing during stimulus presentation., Method: Thirty participants completed three different tasks while either standing still or while walking at a comfortable self-selected pace on a treadmill: (1) an auditory localization task, where they identified the perceived location of a target sound; (2) a visual discrimination task, where they identified a visual target presented at a known location directly in front of the listener; and (3) an aurally aided visual search task, where they identified a visual target that was presented in the presence of multiple visual distracters either in isolation or in conjunction with a spatially colocated auditory cue., Results: Participants who were walking performed auditory localization and aurally aided visual search tasks significantly faster than those who were standing, with no loss in accuracy., Conclusion: The improved aurally aided visual search performance found in this experiment may be related to enhanced overall activation caused by walking. It is also possible that the slight head movements required may have provided auditory cues that enhanced localization accuracy., Application: The results have potential applications in virtual and augmented reality displays where audio cues might be presented to listeners while walking.

Service members (SMs) who have suffered mild traumatic brain injury due to blast exposure (b/TBI) often report post-concussive symptoms consistent with auditory, visual, or vestibular impairments even when they score within the normal range on traditional clinical tests of sensory function. One possible explanation for this discrepancy is that patients who score in the low normal range in more than one sensory modality may be severely impaired in tasks that require multisensory integration. This study evaluated unimodal and multimodal sensory performance in SMs with b/TBI and healthy controls by having them conduct four tasks while walking or standing in an immersive virtual environment: an Auditory Localization task (AL) where they moved a cursor to the perceived location of a sound; a Visual Discrimination task (VD) where they distinguished between two visual targets; an Aurally-Aided Visual Search Task (AAVS) where they used an auditory cue to locate and identify a visual target hidden in a field of visual distractors; and a Visual-Only Visual Search task (VOVS) where they located and identified a visual target in a field of distractors with no auditory cue. The results show the b/TBI and healthy control groups performed equivalently in the AL and VD tasks, but that the b/TBI group responded roughly 15% slower in the AAVS task and 50% slower in the VOVS task. Walking had no effect on performance in the visual-only tasks, but both groups responded faster while walking in the AL and AAVS tasks without any reduction in accuracy.

Long γ-ray bursts are associated with energetic, broad-lined, stripped-envelope supernovae 1,2 and as such mark the death of massive stars. The scarcity of such events nearby and the brightness of the γ-ray burst afterglow, which dominates the emission in the first few days after the burst, have so far prevented the study of the very early evolution of supernovae associated with γ-ray bursts 3 . In hydrogen-stripped supernovae that are not associated with γ-ray bursts, an excess of high-velocity (roughly 30,000 kilometres per second) material has been interpreted as a signature of a choked jet, which did not emerge from the progenitor star and instead deposited all of its energy in a thermal cocoon 4 . Here we report multi-epoch spectroscopic observations of the supernova SN 2017iuk, which is associated with the γ-ray burst GRB 171205A. Our spectra display features at extremely high expansion velocities (around 115,000 kilometres per second) within the first day after the burst 5,6 . Using spectral synthesis models developed for SN 2017iuk, we show that these features are characterized by chemical abundances that differ from those observed in the ejecta of SN 2017iuk at later times. We further show that the high-velocity features originate from the mildly relativistic hot cocoon that is generated by an ultra-relativistic jet within the γ-ray burst expanding and decelerating into the medium that surrounds the progenitor star 7,8 . This cocoon rapidly becomes transparent 9 and is outshone by the supernova emission, which starts to dominate the emission three days after the burst.

Purpose: Calls for revision in undergraduate medical education frequently cite the importance of integrating basic and clinical sciences and the use of active pedagogies. One under-appreciated approach to accomplishing both is interactive co-teaching, defined as two instructors with complementary expertise engaging students and each other instead of lecturing. This study sought to determine if interactive co-teaching helped students integrate and learn basic and clinical sciences, as well as to explore potential advantages and barriers to co-teaching., Methods: The comparative success of solo- and co-teaching in a microbiology/infectious disease course was determined by surveying student perceptions at the end of the course and examination scores for questions based on either solo- or co-taught content. The advantages and barriers to co-teaching were explored by thematic analysis of student responses to open-ended survey questions., Results: Results suggest that co-teaching supported content integration as a significant majority of students (92%, n=112) reported they understood the connection between basic and clinical sciences better when content was co-taught. In addition, a plurality of students indicated that co-teaching provided a better overall learning experience (81%, n=99), was more engaging (74%, n=90), and made it easier to apply content (74%, n=90). These positive perceptions were reflected in better exam outcomes for materials covered in co-taught over solo-taught sessions., Conclusion: Results suggest students value co-teaching as a means to integrate basic and clinical sciences. However, interactive co-teaching pedagogies require careful planning and collaboration among faculty. Co-teaching requires the commitment of both faculty members to this pedagogy., Competing Interests: Disclosure The authors report no conflict of interest in this work. The authors alone are responsible for the content and writing of the article.

Background: Two dominant themes face medical education: developing integrated curricula and improving the undergraduate medical education (UME) to graduate medical education (GME) transition. An innovative solution to both of these challenges at the Zucker School of Medicine has been the application of the cognitive apprenticeship framework in requiring emergency medical technician (EMT) certification during the first course in medical school as the core on which to build an integrated curriculum and provide entrustable clinical skills., Methods: Beginning with the Class of 2011, student feedback about the short-term impact of the experience was collected annually. In addition, perceptions of near graduates and alumni were surveyed in 2017 to explore the long-term impact of the experience. Theme analysis was conducted via inductive coding., Results: Both first-year and more experienced learners report the value of the EMT curriculum as an integrated component of the first course of medical school. Reported positive long-term impacts included the first-hand observation of social determinants of health and interprofessionalism. Negative comments by early learners focused on course logistics, whereas older learners recalled the variability of clinical experiences during ambulance runs., Conclusions: The integration of the EMT curriculum as a core component of the first course serves multiple purposes: 1) it provides the foundation of a spiral learning approach; 2) it contextualizes the basic sciences within clinical practice; 3) it provides opportunities for students to engage in authentic clinical activities under the guidance of mentors; 4) it introduces students to the interdisciplinary nature of medicine; and 5) it serves as the first entrustable professional activity (EPA) for our students.

In 2014, the USA spent $3 trillion dollars in health care the most per capita in the world. However, the USA lacks universal health coverage, and lags behind other highly developed and wealthy countries in life expectancy (even some "non wealthy" countries have better outcomes). The USA also has deficits in other health outcome measures. Health care costs in the USA continue to rise annually and many patients receive only mediocre care. In addition, clear disparities exist across different communities, socioeconomic groups, and race and ethnicity groups. As a result, individuals with mental illness are at an increased risk of being homeless, committing suicide, and having problems maintaining a job. This paper will address mental health disparities and review the efforts some states are taking to improve the lifesaving services offered to citizens with mental illness, in order for them to recover and reach their full potentials.

The semantic bootstrapping hypothesis proposes that children acquire their native language through exposure to sentences of the language paired with structured representations of their meaning, whose component substructures can be associated with words and syntactic structures used to express these concepts. The child's task is then to learn a language-specific grammar and lexicon based on (probably contextually ambiguous, possibly somewhat noisy) pairs of sentences and their meaning representations (logical forms). Starting from these assumptions, we develop a Bayesian probabilistic account of semantically bootstrapped first-language acquisition in the child, based on techniques from computational parsing and interpretation of unrestricted text. Our learner jointly models (a) word learning: the mapping between components of the given sentential meaning and lexical words (or phrases) of the language, and (b) syntax learning: the projection of lexical elements onto sentences by universal construction-free syntactic rules. Using an incremental learning algorithm, we apply the model to a dataset of real syntactically complex child-directed utterances and (pseudo) logical forms, the latter including contextually plausible but irrelevant distractors. Taking the Eve section of the CHILDES corpus as input, the model simulates several well-documented phenomena from the developmental literature. In particular, the model exhibits syntactic bootstrapping effects (in which previously learned constructions facilitate the learning of novel words), sudden jumps in learning without explicit parameter setting, acceleration of word-learning (the "vocabulary spurt"), an initial bias favoring the learning of nouns over verbs, and one-shot learning of words and their meanings. The learner thus demonstrates how statistical learning over structured representations can provide a unified account for these seemingly disparate phenomena., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: There has been a call for increased integration of basic and clinical sciences during preclinical years of undergraduate medical education. Despite the recognition that clinical simulation is an effective pedagogical tool, little has been reported on its use to demonstrate the relevance of basic science principles to the practice of clinical medicine. We hypothesized that simulation with an integrated science and clinical debrief used with early learners would illustrate the importance of basic science principles in clinical diagnosis and management of patients., Methods: Small groups of first- and second-year medical students were engaged in a high-fidelity simulation followed by a comprehensive debrief facilitated by a basic scientist and clinician. Surveys including anchored and open-ended questions were distributed at the conclusion of each experience., Results: The majority of the students agreed that simulation followed by an integrated debrief illustrated the clinical relevance of basic sciences (mean ± standard deviation: 93.8% ± 2.9% of first-year medical students; 96.7% ± 3.5% of second-year medical students) and its importance in patient care (92.8% of first-year medical students; 90.4% of second-year medical students). In a thematic analysis of open-ended responses, students felt that these experiences provided opportunities for direct application of scientific knowledge to diagnosis and treatment, improving student knowledge, simulating real-world experience, and developing clinical reasoning, all of which specifically helped them understand the clinical relevance of basic sciences., Conclusion: Small-group simulation followed by a debrief that integrates basic and clinical sciences is an effective means of demonstrating the relationship between scientific fundamentals and patient care for early learners. As more medical schools embrace integrated curricula and seek opportunities for integration, our model is a novel approach that can be utilized., Competing Interests: The authors report no conflicts of interest in this work.

Background and Objective: The transfer of acute ischemic stroke (AIS) patients to a comprehensive stroke center (CSC) must be rapid. Delays pose an obstacle to time-sensitive stroke treatments and, therefore, increase the likelihood of exclusion from endovascular stroke therapy. This study aims to evaluate the impact of the Stroke Rescue Program, with its goal of minimizing interfacility transfer delays and increasing the number of transport times completed within 60 minutes., Methods: The Stroke Rescue Program was initiated to facilitate the rapid transfer of AIS patients from regional primary stroke centers (PSCs) to the network's CSC. The transfer process was divided into 3 time elements: transport 1 time (initial phone call from the PSC until emergency medical service [EMS] arrival at the PSC), emergency department (ED) time (EMS PSC arrival to PSC departure), and transport 2 time (PSC departure to CSC arrival). The total transport time target was set at less than 60 minutes. Protocols and procedures were implemented with a focus on decreasing the ED time., Results: Comparing baseline (preimplementation) quarter (n = 21) to postproject quarter (1 year later, n = 31), the percent transported within 60 minutes increased from 62% to 81%. A statistically significant improvement was seen for both median ED time (23 minutes versus 14 minutes; U = 171, P < .01) and median total transport time (56 minutes versus 44 minutes; U = 199, P < .05)., Conclusion: Interfacility transfer protocols minimizing the time paramedics spend in a PSC ED can significantly reduce total transfer time to a comprehensive stroke center., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Head trauma is leading cause of mortality after injuries related with skiing and snowboarding. Wearing a helmet is considered to be a primary method to prevent traumatic brain injuries (TBI) among alpine sports participants. This article, based on literature review, determines the efficacy of helmets and safety of their use. It also presents practical principles of proper helmet fitting. A well proven reduction in the risk of TBI connected with helmet use is reported in the literature, ranging from 22 to 60%. Helmet use does not increase the risk of neck and C-spine injury. There is no good evidence to support the claim that use of helmets increases the risk compensation behaviors among participants. Proper fit includes adequate size, non-attenuated peripheral vision and hearing, well adjusted retention system (chinstrap). This factors may influence both efficacy and safety of helmet use. Helmets are recommended for all skiers and snowboarders.

Objective: The first course of the medical curriculum at the Hofstra North Shore-LIJ School of Medicine, From the Person to the Professional: Challenges, Privileges and Responsibilities, provides an innovative early clinical immersion. The course content specific to the Emergency Medical Technician (EMT) curriculum was developed using the New York State Emergency Medical Technician curriculum. Students gain early legitimate clinical experience and practice clinical skills as team members in the pre-hospital environment. We hypothesized this novel curriculum would increase students' confidence in their ability to perform patient care skills and enhance students' comfort with team-building skills early in their training., Methods: Quantitative and qualitative data were collected from first-year medical students (n=97) through a survey developed to assess students' confidence in patient care and team-building skills. The survey was completed prior to medical school, during the final week of the course, and at the end of their first year. A paired-samples t-test was conducted to compare self-ratings on 12 patient care and 12 team-building skills before and after the course, and a theme analysis was conducted to examine open-ended responses., Results: Following the course, student confidence in patient care skills showed a significant increase from baseline (p<0.05) for all identified skills. Student confidence in team-building skills showed a significant increase (p<0.05) in 4 of the 12 identified skills. By the end of the first year, 84% of the first-year students reported the EMT curriculum had 'some impact' to 'great impact' on their patient care skills, while 72% reported the EMT curriculum had 'some impact' to 'great impact' on their team-building skills., Conclusions: The incorporation of EMT training early in a medical school curriculum provides students with meaningful clinical experiences that increase their self-reported level of confidence in the performance of patient care skills early in their medical education.

Background: Many conditions called "stroke mimics" may resemble acute stroke. The converse of the "stroke mimic" is a presentation suggestive of another condition, which actually represents stroke. These would be "stroke chameleons." The recognition of a chameleon as stroke has implications for therapy and quality of care., Methods: We performed a retrospective chart review, including all cases for 1 year in which patients had a stroke missed on hospital presentation. Initial erroneous diagnoses were compared for all patients correctly admitted with those diagnoses to determine positive predictive value (PPV) for each chameleon., Results: Ninety-four cases were identified as chameleons where brain imaging revealed acute stroke. The common chameleons were initially diagnosed as altered mental status (AMS) (29, 31%), syncope (15, 16%), hypertensive emergency (12, 13%), systemic infection (10, 11%), and suspected acute coronary syndrome (ACS) (9, 10%). The total number of patients who were diagnosed with these conditions over the same year were AMS (393), syncope (326), hypertensive emergency (144), systemic infection (753), and suspected ACS (817) (total N = 2528). For each chameleon diagnosis, the PPV of each presentation for acute stroke was AMS (7%), syncope (4%), hypertensive emergency (8%), systemic infection (1%), and suspected ACS (1%)., Conclusions: Stroke chameleons may result in patients not receiving appropriate care. The largest proportions of chameleons were AMS, syncope, hypertensive emergency, systemic infection, and suspected ACS. Patients diagnosed with hypertensive emergency or AMS had an 8% and 7% chance of having an acute stroke. Physicians should consider stroke in patients with these diagnoses with a lower threshold to obtain neuroimaging with subsequent appropriate management., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.

Background: Intracerebral hemorrhage is associated with a high rate of mortality and functional disability. For most patients, no treatment other than supportive care has been shown to improve outcome. Preliminary studies suggest that recombinant activated factor VII may limit early hematoma growth and improve functional outcome. However, ischemic complications may occur in some patients., Objective: To report a case of severe cerebral ischemic complications associated with the use of recombinant activated factor VII., Design: Case report., Setting: Tertiary care medical center., Patient: We describe a patient with ischemic stroke who developed hemorrhagic conversion following tissue plasminogen activator administration., Interventions: Treatment with recombinant activated factor VII, in addition to standard treatment with cryoprecipitate and platelets., Main Outcome Measure: Brain imaging showing multiple ischemic strokes., Results: The patient subsequently developed multiple acute cerebral infarcts in different vascular distributions., Conclusion: Although the exact relationship between treatment with recombinant activated factor VII and the development of multiple ischemic strokes remains uncertain, this case suggests that a cautious approach to treatment with this agent is warranted until more data are available.

Study Objective: The National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator (rtPA) Stroke Study demonstrated a clinically meaningful and statistically significant benefit of tissue plasminogen activator (tPA). Adjusting for the baseline National Institutes of Health (NIH) Stroke Scale, the benefit of tPA remained. However, other authors suggest that an imbalance in baseline stroke severity between the tPA and placebo groups confounded the results. Another issue that has been raised concerns a possible increase in early mortality for individuals given tPA. In post hoc subgroup analysis, we describe the effect of tPA across a spectrum of time from stroke onset to treatment and stroke severity subgroups. Stroke severity was based on the NIH Stroke Scale. We also compare early mortality (2-week and 30-day) in the tPA and placebo groups., Methods: Using combined data from the 2 NINDS rtPA Stroke Study trials, we performed post hoc subgroup analyses of 3-month favorable outcome (defined by the NIH Stroke Scale, Barthel, Rankin, and Glasgow Outcome Scales). We categorized patients from the trials into onset to treatment (0 to 90 minutes, 91 to 180 minutes) by NIH Stroke Scale (< or =5, 6 to 20, >20) subgroups. Analyses were adjusted for all variables previously shown to be associated with favorable outcome at 3 months. We also compared early mortality within onset-to-treatment subgroups., Results: For all the 12 specified onset-to-treatment-NIH Stroke Scale subgroups, the adjusted odds ratio for a favorable 3-month outcome was greater than 1.0 and favored tPA. We detected no difference in mortality between patients treated with rtPA and those treated with placebo by 2 weeks posttreatment (rtPA=9%, placebo=13%; P =.49) or by 30 days (rtPA=11%, placebo=16%; P =.30)., Conclusion: These are descriptive post hoc subgroup analyses. Using cut points defined in previous critiques of the NINDS trials, these analyses give results consistent with previous NINDS Study Group reports. Baseline NIH Stroke Scale imbalance does not account for the better outcome of rtPA-treated patients.

Background: Quick administration of intravenous recombinant tissue plasminogen activator (rt-PA) after stroke improved outcomes in previous trials. We aimed to analyse combined data for individual patients to confirm the importance of rapid treatment., Methods: We pooled common data elements from six randomised placebo-controlled trials of intravenous rt-PA. Using multivariable logistic regression we assessed the relation of the interval from stroke onset to start of treatment (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant parenchymal haemorrhage., Findings: Treatment was started within 360 min of onset of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was 68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11, and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT decreased (p=0.005). Odds were 2.8 (95% CI 1.8-4.5) for 0-90 min, 1.6 (1.1-2.2) for 91-180 min, 1.4 (1.1-1.9) for 181-270 min, and 1.2 (0.9-1.5) for 271-360 min in favour of the rt-PA group. The hazard ratio for death adjusted for baseline NIHSS was not different from 1.0 for the 0-90, 91-180, and 181-270 min intervals; for 271-360 min it was 1.45 (1.02-2.07). Haemorrhage was seen in 82 (5.9%) rt-PA patients and 15 (1.1%) controls (p<0.0001). Haemorrhage was not associated with OTT but was with rt-PA treatment (p=0.0001) and age (p=0.0002)., Interpretation: The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min. Our results suggest a potential benefit beyond 3 h, but this potential might come with some risks.

Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.

Background and Purpose: Clinicians have tended to view anterior circulation (AC) and posterior circulation (PC) strokes as separate entities, with different underlying pathogenesis, natural histories, and potential responsiveness to interventions such as anticoagulation. We sought to explore differences between AC and PC stroke in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST)., Methods: For patients enrolled in TOAST, prospective clinical information was collected including outcome at 3 months. Data on vascular distribution were obtained from the clinical impression of the investigators. Group comparisons for categorical data were performed using Fisher's exact test. Independent sample t tests and analysis of covariance were used for all continuous data., Results: The analysis included 1,039 patients with AC stroke and 180 patients with PC stroke. There were fewer women in the PC than in the AC groups, but otherwise there were no differences in demographics, risk factors or stroke subtypes between the two groups. Headache (AC 8.7%, PC 15%, p = 0.013) and vomiting (AC 3.5%, PC 17.8%, p < 0.001) were more common among PC patients. Mean baseline National Institutes of Health Stroke Scale (NIHSS) score was lower (less severe) among PC (6.1) than AC patients (9.5; p < 0.001). On univariate analysis, favorable outcome at 3 months was more common for PC patients in both the placebo group (PC 82%, AC 71%, p = 0.04) and heparinoid group (PC 87%, AC 73%, p = 0.005). However, multivariate analysis, controlling for gender, history of previous stroke and baseline NIHSS score, showed no difference in outcome between PC and AC stroke. For favorable outcome, there was no interaction between vascular distribution and treatment category, suggesting that the effect of heparinoid did not differ between PC and AC strokes., Conclusion: Patients with PC stroke seem to have a better long-term outcome than do AC patients, but this difference is no longer apparent when controlling for important prognostic variables. PC patients did not show any particular benefit from anticoagulation, and the efficacy of heparinoid did not vary between AC and PC stroke. While AC and PC patients do differ in some respects, it may be inappropriate to single out PC patients for anticoagulant treatment., (Copyright 2001 S. Karger AG, Basel.)

Objective: The purpose of this study was to define the effects of external beam radiation (EBR) on AlloDerm (LifeCell Corp) through the analysis of graft thickness, fibroblast recellularization, and neovascularization as a function of time., Methods and Material: Thirty-six male Sprague-Dawley rats (n = 36) were randomly assigned to 1 of 4 groups (A, B, C, and D). AlloDerm was implanted subcutaneously into the hind legs of each rat, and 20 Gy of EBR was administered to one side. Grafts harvested 1, 2, 4, and 12 weeks after radiation were subjected to blinded histologic analysis., Results: In groups A, B, and C, the irradiated grafts showed a significant decrease in recellularization versus nonirradiated (P < 0.001). At 12 weeks (group D), recellularization equalized, but neovascularization was significantly less (P = 0.048) in the irradiated group. Graft thickness was unaffected., Conclusions: In the rat model, EBR of the implanted AlloDerm graft hinders recellularization in the early posttreatment period. However, EBR did not adversely affect graft thickness, recellularization or ultimate graft survival.

Our goal was to investigate the postoperative differences in hearing between patients who had their stapedius tendon sacrificed and those whose stapedius tendon was preserved during laser stapes surgery for otosclerosis. To that end, we performed a retrospective review by mailing extensive questionnaires to patients who had been operated on between 1994 and 1997. We also performed routine and special audiometric testing to augment the subjective data. Seventy-nine of 124 questionnaires (64%) were returned. Of the respondents, 75 patients had undergone additional pre- and/or postoperative audiometric testing, including tests to evaluate "hearing in noise" and to determine the "uncomfortable loudness level" (dynamic range). We found no statistically significant differences between the two groups with respect to their subjective responses and their audiologic test results. The responses to the questionnaire indicated that in most cases, hearing was improved by stapes surgery. We conclude that the stapedius tendon should be preserved whenever possible during stapes surgery, provided that it does not jeopardize the exposure or outcome.

Background: In 1995, the two-part National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator Stroke Trial found that patients who were treated with tissue plasminogen activator (t-PA) within three hours after the onset of symptoms of acute ischemic stroke were at least 30 percent more likely than patients given placebo to have minimal or no disability three months after the stroke. It was unknown, however, whether the benefit would be sustained for longer periods., Methods: In the NINDS Trial, a total of 624 patients with stroke were randomly assigned to receive either t-PA or placebo. We collected outcome data over a period of 12 months after the occurrence of stroke. The primary outcome measure was a "favorable outcome," defined as minimal or no disability as measured by the Barthel index, the modified Rankin Scale, and the Glasgow Outcome Scale. We assessed the treatment effect using a global statistic., Results: Using an intention-to-treat analysis for the combined results of the two parts of the trial at 6 months and 12 months, we found that the global statistic favored the t-PA group (odds ratio for a favorable outcome at 6 months, 1.7; 95 percent confidence interval, 1.3 to 2.3; odds ratio at 12 months, 95 percent confidence interval, 1.7; 1.2 to 2.3). The patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at 12 months than were the placebo-treated patients (absolute increase in the proportion with a favorable outcome, 11 to 13 percentage points). There was no significant difference in mortality at 12 months between the t-PA group and the placebo group (24 percent vs. 28 percent, P=0.29). There was no interaction between the type of stroke identified at base line and treatment with respect to the long-term response. The rate of recurrent stroke at 12 months was similar in the two groups., Conclusions: During 12 months of follow-up, the patients with acute ischemic stroke who were treated with t-PA within three hours after the onset of symptoms were more likely to have minimal or no disability, than the patients given placebo. These results indicate a sustained benefit of t-PA for such patients.

A clinical trial is a powerful technique for evaluating the effectiveness of an experimental intervention. The initial stages of planning a clinical trial involve choosing and refining a research question, selecting a study design, and deciding on appropriate statistical tests and sample sizes. The success of the study depends upon how well these issues are thought out in advance, and how they can be put into practice. The protocol is the written document that allows the investigator to communicate details of how the research question will be answered. In the following article, the basic components of the research protocol are described. Issues related to quality control, data entry, and pilot testing are discussed. This is the third in a series of research fundamental concept papers, written by members of the SAEM Research Committee.

This is the second in a series of articles developed by members of the SAEM Research Committee to describe a stepwise approach to the research process. This series is aimed at junior academic emergency physicians (EPs), as well as nonacademic EPs with an interest in the research process. This article describes the development of a testable research hypothesis. While a multitude of sources provide interesting questions for consideration, choosing and refining the research question, so that it can be tested adequately and answered completely, are difficult tasks.

Orbital-sinus foreign bodies traverse the orbit and lay, at least partially, within the paranasal sinuses. Most of these injuries occur as a result of facial trauma. In most cases, history alone is not sufficient to rule out a retained foreign body. Early magnetic resonance imaging is necessary to evaluate the full extent of injury. Since these foreign bodies may cause a severe orbital infection and threaten the patient's vision, surgical removal is recommended. Endoscopic sinus surgery provides a safe and effective approach for extraction of these foreign bodies that can be used alone or in conjunction with other surgical approaches. The case of an orbital-sinus foreign body is presented together with a comprehensive approach for diagnosis and management of this type of injury.

Patients with clinical presentation of deep posterior chronic compartment syndrome (CCS) frequently have symptoms limited to either proximal or distal components of the deep posterior compartment. In this study the posterior aspect of 15 cadaver legs was dissected to document anatomical separations and delineate boundaries, if any, of the deep posterior compartment and to correlate the findings to these patients. Origins of flexor hallucis longus (FHL), flexor digitorum longus (FDL), and tibialis posterior (TP), as well as whether TP existed in its own osseofascial compartment, were noted. Ten specimens had an identifiable distinct layer of tissue separating the deep posterior compartment into two potentially clinically relevant components. Much of this layer was derived from origins of FDL and its anatomical position in relation to the TP muscle. In seven of these cases, FDL had a significant fibular origin in addition to the well-established tibial origin. This essentially compartmentalized the distal third of the tibialis posterior as it descends anterior and medial to FDL in the lower one-third of the leg in five specimens. No cadaver possessed a significant fascial septum encasing TP and separating it from other deep posterior muscles. This study confirms the existence of a proximal and distal sub-compartment of the deep posterior compartment as a variant and supports the most frequent clinical presentation of deep posterior CCS as involving either the distal or proximal deep compartment, rather than the entire deep posterior compartment. The anatomic arrangement of muscles in the deep posterior compartment creates sub-compartments, which may explain the successful outcomes following a deep compartment release limited to symptomatic portion(s) of the deep compartment.

Cigarette smoking and its ramifications are coming under increasing scrutiny in the field of orthopedic surgery. Smoking has been implicated in impeding bone metabolism and fracture repair, and increasing the rate of postoperative infection and the incidence of nonunion. This article reviews the current body of knowledge on these topics, as well as the potential adverse effects of smoking on wound healing and microsurgical procedures. An in-depth discussion on the pathophysiologic mechanisms of nicotine is also included.

Study Objective: To define the extent of immunity against tetanus among patients older than 65 years of age by measuring antitetanus antibody levels., Methods: A convenience sample of 129 patients from an urban comprehensive care geriatric center was studied. Serum was obtained and enzyme-linked immunosorbent assay (ELISA) testing performed. Twenty health care providers, aged 25 to 40 years, were tested for comparison., Results: In 64 (50%) of 129 study patients, antitetanus antibody levels did not reach protective levels. Fifty-four (59%) of 92 women and 10 (27%) of 37 men did not have adequate titers. All 20 health care workers had protective titers., Conclusion: Elderly patients are substantially less likely than young individuals to have adequate immunity against tetanus. Emergency physicians must take this into consideration when evaluating tetanus immunization status in injured elderly patients.

Objective: To determine the time it takes for O2 saturation measured by pulse oximetry to equilibrate after a change is made in supplemental O2 administered by nasal cannula in patients with cardiac and pulmonary disease., Methods: A prospective, observational study of a convenience sample of 51 patients treated in a university-affiliated ED with nasal cannula O2. Patients were placed on and/or subsequently taken off O2 via nasal cannula set at 2 or 4 L/min based on clinical indications. Oxygen saturation was measured at 1-minute intervals over a 30-minute period using finger-probe pulse oximetry. Of the 51 patients in the study, 43 were monitored while O2 treatment was initiated and 18 were monitored when it was discontinued., Results: Most (95%) of the patients placed on O2 attained equilibration of O2 saturation within 3.5 minutes. Most (95%) of the patients taken off supplemental O2 attained equilibration of O2 saturation within 4.5 minutes., Conclusion: The interval to equilibration of O2 saturation in patients receiving O2 by nasal cannula is considerably shorter than the 20-30 minutes generally suggested. Adequacy of O2 supplementation should be assessable much sooner than was previously taught.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat. In this study, we describe the identification and characterization of the gene harbouring this repeat. The SCA1 transcript is 10,660 bases and is transcribed from both the wild type and SCA1 alleles. The CAG repeat, coding for a polyglutamine tract, lies within the coding region. The gene spans 450 kb of genomic DNA and is organized in nine exons. The first seven fall in the 5' untranslated region and the last two contain the coding region, and a 7,277 basepairs 3' untranslated region. The first four non-coding exons undergo alternative splicing in several tissues. These features suggest that the transcriptional and translational regulation of ataxin-1, the SCA1 encoded protein, may be complex.

The gene responsible for spinocerebellar ataxia type 1 (SCA1) has been localized to a 6.7-cM region between the centromeric marker D6S109 and the telomeric marker D6S89. We screened two yeast artificial chromosome (YAC) libraries using sequence-tagged sites at D6S89 and at newly identified markers in 6p22-p23. Fifty YAC clones were identified and 34 insert termini were isolated from some of these YACs for detailed overlap mapping and long-range restriction analysis. A large YAC contig estimated to span 2.5 Mb was developed and genetic analysis in five large SCA1 kindreds using highly informative dinucleotide repeat polymorphisms mapped to this contig allowed the identification of D6S274 as the closest centromeric flanking marker for SCA1. Long-range restriction analysis determined the size for the critical SCA1 region, as defined by the two flanking markers D6S274 and D6S89, to be 1.2 Mb. This region is spanned by a minimum set of four nonchimeric YAC clones. The development of a 2.5-Mb YAC contig in 6p22-p23 provides valuable reagents for characterization of this genomic region and for the cloning of the SCA1 gene.

Study Objective: To determine the safety of lumbar puncture in patients with hemophilia who are pretreated with clotting factor., Design: Retrospective analysis of medical records between 1980 and 1990., Setting: Three hospitals, each serving as a regional hemophilia center., Participants: Thirty-three patients with hemophilia A or B who received one or more lumbar puncture., Intervention: All patients received replacement of deficient factor before the lumbar puncture. Serious post-lumbar puncture complications were defined as motor or sensory deficits, incontinence, or documented intraspinal hemorrhage., Results: Thirty-three patients with hemophilia A or B received a total of 52 lumbar punctures during the study period. Thirty of 33 patients (91%) had severe baseline factor deficiency, two (6%) had moderate deficiency, and one (3%) had mild deficiency. There were no serious complications reported as a result of the lumbar puncture. The 95% confidence interval for the risk of a serious complication was 0% to 5.8%., Conclusion: With adequate factor replacement, a lumbar puncture can be done safely in patients with hemophilia.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder which is genetically linked to the short arm of chromosome 6, telomeric to the human major histocompatibility complex (HLA) and very close to D6S89. Previous multipoint linkage analysis using HLA, D6S89, and SCA1 suggested that SCA1 maps centromeric to D6S89. Data from this study using nine large kindreds indicate a maximum lod score between SCA1 and D6S89 of 67.58 at a maximum recombination fraction of .004. To localize SCA1 more precisely, we identified five dinucleotide polymorphisms near D6S89. Genotypic analyses at these polymorphic loci were carried out in nine multigeneration SCA1 kindreds and in the Centre d'Etude du Polymorphisme Humain reference families. A new marker, AM10GA, demonstrates no recombination with SCA1. The maximum lod score for AM10GA linkage to SCA1 is 42.14 at a recombination fraction of 0. Linkage analysis and analysis of recombination events confirm that SCA1 maps centromeric to D6S89 and establish the following order: CEN-D6S109-AM10GA/SCA1-D6S89-LR40-D6S20 2-TEL.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromosome 6 containing the SCA1 locus was isolated in a yeast artificial chromosome contig and subcloned into cosmids. A highly polymorphic CAG repeat was identified in this region and was found to be unstable and expanded in individuals with SCA1. There is a direct correlation between the size of the (CAG)n repeat expansion and the age-of-onset of SCA1, with larger alleles occurring in juvenile cases. We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat.

200 g of fat in the form of greased wheat bran, was given cows during pasture feeding. For winter feeding on hay and silages the amount was 400 g of greased wheat bran or 400 g of oil in ground rapeseed per day and per animal. Influence of the fat addition on the yield and milk composition was observed in the case of pasture experiment. No such influence was observed in the winter feeding. Addition of fat advantageously influenced the chemical constituents in the cow blood in both experiments.

In 90 cows of black white and red white race, aged 3-9 years and of 450 kg mean body weight fed on food with low level of Ca, P, and Na, several parameters of protein, carbohydrates and lipid liver metabolism before and after supply of special mineral mixtures were evaluated. After the supply the increased concentration of total protein, urea and cholesterol esters and decrease of AspAT, AlAT, and AP activities were recorded in the blood. Cholesterol esters: total cholesterol ratio improved and a slight increase of milk yield and content of fat in milk was observed. Food mineral mixtures favourably influenced the stabilization of liver metabolism.

Highly informative dinucleotide repeat polymorphisms were identified at the T-complex-associated-testes-expressed-1 (TCTE1) locus on human chromosome 6p. Electrophoresis of single-stranded DNA on native gels facilitated the analysis of the dinucleotide polymorphisms. Linkage mapping positions this marker midway between the centromere and HLA with recombination fractions as follows: D6Z1-0.21-TCTE1-0.24-HLA. Two-color fluorescence in situ hybridization places TCTE1 proximal to CRIL171 (D6S19). Together, linkage and in situ hybridization indicate that the order of the loci is D6Z1-D6S4-D6S90-TCTE1-D6S19-D6S29-HL A-telomere. A sequence tagged site (STS) was established, and three yeast artificial chromosome (YAC) clones were identified for the TCTE1 locus.

We studied three large kindreds with the HLA-linked form of spinocerebellar ataxia (SCA1) in order to localize the SCA1 locus on the short arm of chromosome 6 (6p). Two loci containing highly informative dinucleotide repeat sequences were used for linkage analysis. These two loci are D6S89, which is telomeric to the HLA region, and T complex-associated testes-expressed 1 (TCTE1), centromeric to HLA. Pairwise linkage analysis of SCA1 and D6S89 revealed a maximum lod score of 5.86 in the Houston SCA1 (HSCA1) kindred and of 8.08 in the Calabrian SCA1 (SCA1) kindreds, at recombination fractions of .050 and .022, respectively. A maximum pairwise lod score of 4.54 at a recombination frequency of .100 was obtained for SCA1 and TCTE1 in the HSCA1 kindred. No evidence for linkage was detected between TCTE1 and SCA1 in the CSCA1 kindreds. Multilocus linkage analysis of SCA1, HLA, and D6S89 in all three kindreds provided strong evidence for localization of the SCA1 locus telomeric to the HLA regions. However, multilocus linkage analysis of SCA1, HLA, and TCTE1 with HSCA1 family genotypes indicated the possibility of a location of the SCA1 locus centromeric to HLA. An analysis of HSCA1 recombinants in this region of chromosome 6 revealed relatively high recombination frequencies between HLA and each of the other two markers and relatively low frequencies between the latter and SCA1, predicting that the SCA1 locus would tend to segregate away from HLA together with D6S89 or TCTE1, as found with the three-point linkage analyses for this family.(ABSTRACT TRUNCATED AT 250 WORDS)

Eight chromosome 6p markers (MUT, D6S4, D6S5, D6S19, D6S29, PIM, HLA, and F13A) were regionally mapped using somatic cell hybrid deletion cell lines that retained different regions of chromosome 6p. New restriction fragment length polymorphisms were identified at the D6S5 and PIM loci using newly isolated genomic clones at these loci. Genetic linkage among the eight loci was determined using the 40 CEPH reference families. Linkage analyses showed that these loci are in one linkage group spanning 48 cM in males and 128 cM in females. Using both the deletion mapping data and multipoint linkage analyses, chromosomal order for these loci was determined as centromere-(MUT, D6S4)-(D6S5, D6S19)-(D6S29, PIM)-HLA-F13-A-telomere. Analyses of sex-specific recombination frequencies revealed a higher rate of recombination in females in the region between D6S4 and D6S29, while the recombination rate in males was higher for the interval between D6S29 and the HLA loci.

The authors studied the influence of urea added to diet in an amount of 150 grams daily per 1 cow on the function of the liver by means of: determination of the activity of the following enzymes: arginase, ornithin-carbamyl-transferase, leucyloaminopeptidase, gamma-glutamyl-transferase, phosphatase alkaline, determination of the level of total protein, albumins and globulins, urea, sodium and potassium in the serum of dairy cows. No significant changes were found in the activity and in the content of the above mentioned blood constituents. The dose of 150 grams of urea added to diet did not show any disturbances in protein metabolism in the liver and in the health of the cows.

Using Anderson's method for estimation of testosterone level by competitive protein binding, the authors determined plasma testosterone level in young bulls of three breeds: black and white, and red and white lowland. It was found that in bulls of black and white and red and white lowland breed the testosterone level showed great fluctuations without growing tendency. In charolais bulls, in pubescence, testosterone level was low and did not exceed 1 ng/1 ml, but it systematically increased beginning from the 14th month of life. No correlation of testosterone level with protein and energy intake or with sexual activity was observed in adult bulls (breeders) of black and white lowland breed during 12 months of examination.

Cows of the white-black breed from the Sudeten piedmont were divided into two groups: control and experimental. Both groups were fed the same basic fodder, e.g. pasture, green forage of clover and maize, and hay; afterwards they were fed grass silage, hay and beets. Maize forage, containing little fibrin, lot of starch and soluble carbohydrates, was substituted by grass silage with little starch and soluble carbohydrates, but rich in cellulose and hemicelluloses. So, energetic value of the food was different. The chosen chemical indices were estimated during the change of fodder from pasture to winter silage and hay. Cows from the control group were fed additionally, one month before calving, 1 kg of the protein food (bruised barley) without urea, whereas cows from the experimental group were fed additionally with bruised barley, in the amount of 1.5-3 kg, when giving less than 4000 l of milk, and 2.5-4 kg, when giving over 4000 l of milk. The amount of food increased by 0.5 kg every week beginning with smallest dose. This additional feeding had positive influence on the milk production, especially in the 2nd and 3rd month after calving (2.3 kg during 4 months after calving), and improved the effectivity of fertilization after the first insemination. The chemical composition of the milk has not been changed significantly; the total protein and its fraction, levels of urea, Ca, Fe and Mg in the blood plasma have not been changed. Only the level of ketones in blood decreased a little. During the transition period, green forage feeding caused the increase of the glucose level in blood to 60 mg% (50 mg% in winter). Additional energetic feeding of cows before calving improved productivity indices and did not change the internal body balance (homeostasis).

It was compared the effect of different preparations containing urea on the productivity and on the blood content of the biochemical compounds informing about protein synthesis activity in the liver of milk cows. The following preparations were added alternatively to the food to 28 cows in a quantity equal with 150 Gm in the first year and with 200 Gm of pure urea in the second year of experimentation for cow and for day: 1. Melwit--a liquid food supplementation containing 5 per cent of urea, 2. Wałczan--"Sterea"-like preparation with 30 p.c. of urea, 3. Ekstruder--"Golden-Pro"-like preparation with 20 p.c. of urea and 4. BW preparation (concentration) for dairy cows containing only plant protein, without urea. In the plasma of all animals was observed the increase of urea, total protein and albumin content and of the activity of following enzymes: AP, AAP, Arg, LAP, AspAT and of A1AT. The content of total and of direct bilirubin in plasma did not change significantly. All examined compounds did not exceed the physiological range. The greatest changes were observed after feeding with Extruder. The physiological decline of milk production after calving was smallest in group fed with Wałczan (2.4 litres) and greatest in Ekstruder group (4.4 litres) when in Melwit 3.4 and in BW 3.5 litres was noticed. The authors stated that the most suitable form of preparation containing urea was Wałczan in the first place and Melwit in the second.