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Children with ADHD were administered 75 dB of continuous white noise during independent seat work in the classroom and during bedtime in their homes. Compared to baseline all three students exhibit...

International audience; Vascularized composite allografts may be more susceptible to rejection than other types of organ transplants, particularly in sensitized recipients. We describe a successful transatlantic bilateral hand transplant in a 40-year old woman who was highly sensitized to class II HLA antigens including HLA-DPB1 (UNet CPRA = 86%). Prior to transplantation, we selected an upper limb donor based on HLA class II matching and absence of donor specific antibodies, given evidence that class II mismatches are associated with acute cellular rejection in hand transplants. The patient was conditioned using five doses of thymoglobulin, and her immunosuppression included tacrolimus, rapamycin, mycophenolate, and prednisone. Post-transplant, the patient non-DSA anti-HLA antibody levels drastically increased, but only transiently and weak DSAs developed, which became undetectable by two months posttransplant. Following transplantation, periodic biopsies over 6 months indicated no evidence of rejection except for transient Banff grade 1 and one sample with grade 2 acute rejection. There was no evidence of rejection on her recent 1-year follow-up. The patient is currently healthy, has recovered protective sensibility, and is regaining excellent function. This case highlights the importance of pre-transplantation planning, donor selection/compatibility, and ethical considerations in the ultimate success of VCA.

International audience; The developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8 + T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1 + pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8 + T cells, coupled with elevated expression of multiple inhibitory receptors including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD5, and CD160. Genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62L hi TCF-1 + subset and subsequent CD8 + T cell memory. Although central memory phenotype CD8 + T cells were formed in the absence of these cells, subsequent memory CD8 + T cell recall responses were compromised. Together, these results identify an impor tant link between genome integrity maintenance and CD8 + T cell memory. Moreover, the data indicate a role for inhibitory receptors in preserving key memory CD8 + T cell precursors during initial activation and differentiation. Identification of this rare subpopulation within the memory CD8 + T cell precursor pool may help reconcile models of the developmental origin of long-term CD8 + T cell memory.

Introduction The scapula tip free flap has been described for reconstruction of short mandible defects with extensive soft tissue needs. The versatility of this flap has not been extensively described. Methods Retrospective case series of patients who underwent mandibulectomy and reconstruction with the scapula tip free flap from 2005 to 2016. Outcomes include bony union, complications, dental rehabilitation, and donor site morbidity. Results A total of 120 patients were identified. Average harvested bone was 7.7 cm, with 54% undergoing one osteotomy, and 76.7% harvested as a chimeric flap. Radiographically, average inset bone was 6.6 cm. Complete or partial bony union was observed at 74.4% of proximal and 82.6% of distal osteotomies. A 95% of reconstructions met criteria for dental implants. Mean disabilities of the arm, shoulder and hand score was 21.2. Conclusions The scapular tip is an excellent option for reconstruction of segmental mandible defects with the option of osteotomy, excellent bony union rates, low donor site morbidity, and potential for dental rehabilitation.

STUDY DESIGN Retrospective cohort study. OBJECTIVE To evaluate the ability of patient reported outcome measurement information system (PROMIS) assessments to capture disability related to cervical sagittal alignment and secondarily to compare these findings to legacy outcome measures. SUMMARY OF BACKGROUND DATA PROMIS is a validated patient-reported outcome metric that is increasing in popularity due to its speed of administration relative to legacy metrics. The ability of PROMIS to capture disability from sagittal alignment and baseline health status in patients with neck pain has not been investigated. METHODS Patients presenting with a chief complaint of neck pain from December 2016 to July 2017 were included. Demographics and comorbidities were retrospectively collected. All patients prospectively completed the neck disability index (NDI), EQ-5D, visual analog scale (VAS) neck, VAS arm, PROMIS physical function, PROMIS pain intensity, and PROMIS pain interference metrics. Cervical sagittal alignment parameters were measured on standing X-rays. The correlations between outcome measures, health status indexes, psychiatric diagnoses, and sagittal alignment were analyzed. RESULTS Two hundred twenty-six patients were included. The sample was 58.4% female with a mean age of 55.1 years. In patients with neck pain, PROMIS physical function correlated strongly with the NDI (r = -0.763, P

The Press Ganey survey is the most widely used instrument for measuring patient satisfaction. Understanding the factors that influence these surveys may permit better use of survey results and may direct interventions to increase patient satisfaction. Press Ganey Clinician and Group Consumer Assessment of Healthcare Providers and Systems surveys administered to ambulatory spine surgery clinic patients within a large tertiary care network from May 2016 to September 2017 were retrospectively reviewed. Mean comparison testing was performed to measure associations between patient demographics and responses to “overall provider rating” and “recommend this provider's office” survey questions. Mean difference to achieve significance was set at αP P =.001). Those with commercial insurance had significantly lower ratings for recommend this provider's office ( P =.042) and overall provider rating ( P =.022) questions than those with other insurance types. Patients administered the survey on paper had significantly lower ratings than those administered the survey online ( P =.006). Provider ratings were significantly higher when the sex and ethnicity of the patient were concordant with the provider ( P =.021). This study showed that independent, nonmodifiable factors such as age, education level, and survey mode were significantly associated with the satisfaction of ambulatory spine surgery clinic patients. [ Orthopedics . 2019; 42(3):143–148.]

Introduction This study assessed the incidence and risk factors for pseudarthrosis among primary spine fusion patients. Methods Retrospective review of ACS-NSQIP (2005–2013). Differences in comorbidities between spine fusion patients with and without pseudarthrosis (Pseud, N-Pseud) were assessed using chi-squared tests and Independent Samples t-tests. Binary logistic regression assessed patient-related and procedure-related predictors for pseudarthrosis. Results 52,402 patients (57yrs, 53%F, 0.4% w/pseudarthrosis). Alcohol consumption (OR:2.6[1.2–5.7]) and prior history of surgical revision (OR:1.6[1.4–1.8]) were risk factors for pseudarthrosis operation. Pseud patients at higher risk for deep incisional SSI (at 30-days:OR:6.6[2.0–21.8]). Pseud patients had more perioperative complications (avg:0.24 ± 0.43v0.18 ± 0.39,p=0.026). Conclusions Alcoholism and surgical revision are major risk factors for pseudarthrosis in patients undergoing spine fusion.

Patient reported outcomes measurement information system (PROMIS) is a quality of life metric that has gained increased popularity due to computer adaptive testing. Previous studies have shown that PROMIS correlates with Oswestry Disability Index (ODI) in patients with back pain and takes significantly less time to complete. However, the ability of PROMIS to capture disability from spinal malalignment relative to established metrics is unknown. The aim of the present study is to validate the correlation between ODI and PROMIS in patients with back pain, analyze correlations of PROMIS and legacy metrics to sagittal alignment, and identify major drivers of PROMIS scores and ODI in patients with back pain. A retrospective review was conducted of a prospectively collected outcome measures database (PROMIS, ODI, VAS Back, VAS Leg, VAS Neck, and VAS Arm) of spine patients > 18 years. Inclusion criteria for the present study was a chief complaint of back pain and full length weight bearing X-rays within 30 days of health related quality of life (HRQL) completion. Demographic information, radiographic alignment, psychiatric diagnoses, and comorbidities were recorded. PROMIS metrics were correlated to legacy metrics (ODI and VAS). Next, outcome metrics were correlated with sagittal alignment variables T1 Pelvic Angle (TPA), SVA, PT, and PI-LL. Patients were grouped based on the presence of spinal deformity (defined radiographically as any one of SVA > 4 cm, PI-LL > 10°, PT > 20°) and mean HRQL scores were investigated for the adult spinal deformity (ASD) and non-ASD groups. Finally, drivers of PROMIS PF scores and ODI scores were determined using multiple stepwise regression. 150 patients met inclusion criteria including 60 patients with ASD and 90 patients without. For the whole cohort, PROMIS PF correlated with ODI (r = − 0.651, p

Esophagitis, whether caused by acid reflux, allergic responses, graft-versus-host disease, drugs, or infections, is a common condition of the gastrointestinal tract affecting nearly 20% of the US population. The instigating agent typically triggers an inflammatory response. The resulting inflammation is a risk factor for the development of esophageal strictures, Barrett esophagus, and esophageal adenocarcinoma. Research into the pathophysiology of these conditions has been limited by the availability of animal and human model systems. Three-dimensional organotypic tissue culture (OTC) is an innovative three-dimensional multicellular in vitro platform that recapitulates normal esophageal epithelial stratification and differentiation. We hypothesized that this platform can be used to model esophagitis to better understand the interactions between immune cells and the esophageal epithelium. We found that human immune cells remain viable and respond to cytokines when cultured under OTC conditions. The acute inflammatory environment induced in the OTC significantly affected the overlying epithelium, inducing a regenerative response marked by increased cell proliferation and epithelial hyperplasia. Moreover, oxidative stress from the acute inflammation induced DNA damage and strand breaks in epithelial cells, which could be reversed by antioxidant treatment. These findings support the importance of immune cell–mediated esophageal injury in esophagitis and confirms the utility of the OTC platform to characterize the underlying molecular events in esophagitis.

Microvolt t-wave alternans (TWA) is a risk factor for sudden cardiac death but is only discernible on stress ECG using signal processing techniques. This case represents an example of acquired QT interval prolongation and macrovolt TWA leading to torsades de pointes (TdP). 63 year old man with

BACKGROUND CONTEXT Computer adaptive testing facilitates quicker administration of patient-relevant questions. The Patient Reported Outcome Measurement Information System (PROMIS) instruments of Physical Function, Pain Intensity and Pain Interference have been shown to correlate with established patient outcome metrics, though this relationship has yet to be investigated in relation to patient satisfaction. PURPOSE The aim of this study was to study the relationship between PROMIS and VAS scores and patient satisfaction in thoracolumbar patients. STUDY DESIGN/SETTING Retrospective review of single institution clinical data and patient-reported outcome measures. PATIENT SAMPLE A total of 208 spine patients with a thoracolumbar (TL) diagnosis. OUTCOME MEASURES ODI, Visual Analog Scale (VAS) for Back and Leg pain, Scoliosis Research Society 22 (SRS-22); Patient Reported Outcome Measurement Information System (PROMIS). METHODS Inclusion was patients greater than 18 years with a diagnosis related to the thoracolumbar spine (stenosis, disc herniation, low back pain, disc degeneration, spondylolysis most commonly). Bivariate correlations assessed the linear relationships of PROMIS scores (Physical Function, Pain Intensity, and Pain Interference) and ODI with VAS Leg and Back pain scores and patient satisfaction (SRS-22) questions specific to patient satisfaction of their back shape and back management. Linear regression predicted the relationship of PROMIS to VAS and satisfaction outcomes. Statistical significance was set at P RESULTS A total of 208 patients with a thoracolumbar diagnosis were included (age 58.39 ± 73.32 years, 49% female). VAS back pain scores (r=0.673, P CONCLUSIONS VAS Back Pain scores predicted PROMIS Pain Intensity scores as strongly as ODI, though ODI outperformed in predicting PROMIS Physical Function and Pain Interference. Conversely, PROMIS Pain Intensity predicted VAS Back Pain stronger than ODI, though ODI outperformed the other two PROMIS domains. Patients’ satisfaction of the shape of their back and their back management were significantly correlated with PROMIS scores in all three domains.

We evaluated the effects of white noise played through headphones on off-task behavior, percentage of items completed, and percentage of items completed correctly for 3 students with attention deficit hyperactivity disorder (ADHD). Headphones plus white noise were associated with decreases in off-task behavior relative to baseline and headphones-only (no white noise) control conditions. Little change in academic responding occurred across conditions for all participants.

BACKGROUND CONTEXT Recent research has identified increased C2-T3 angle as a risk factor for persistent sagittal malalignment following thoracolumbar surgery. Despite this, no ideal cervicothoracic alignment thresholds exist in the literature. As several studies have demonstrated a clear relationship between the normal aging spine and sagittal spinal alignment, such ideal-alignment thresholds should also account for patient age. PURPOSE This study proposes age-specific cervicothoracic alignment targets using previously published age-specific normative Neck Disability Index (NDI) values. STUDY DESIGN/SETTING Single center retrospective review. PATIENT SAMPLE A total of 223 patients with available biplanar full-body stereographic x-rays. OUTCOME MEASURES C2-T3 lordosis; Neck Disability Index score. METHODS Patients >18 years with cervical sagittal vertical axis RESULTS Overall, 223 patients (50±20years, 65% F) met inclusion criteria, presenting with a mean sagittal vertical axis (SVA) of 17.8±47.7 mm, cervical SVA 19.8±11.2 mm, T1 Slope-C2-C7 lordosis 24.7°±16.2°, and C2-T3 of 2.1°±16.5°. At baseline, increased C2-T3 angle was significantly correlated with both NDI score (r=0.266, p 75 years: 27.8. Liner regression analysis showed a significant relationship between NDI score, age, and baseline cervicothoracic alignment, as assessed by C2-T3 angle (r=0.497, p 75 years: 6.7°. CONCLUSIONS Significant relationships exist between age, neck disability, and cervicothoracic alignment, suggesting broad measurements across the cervicothoracic junction may be clinically relevant in predicting postoperative outcomes of surgical spine deformity patients. Taking into account patient age and USA-normative values of neck disability, this study offers a set of ideal age-adjusted alignment targets for C2-T3. By proposing a set of normative, age-specific cervicothoracic alignment targets, this study better facilitates individual optimization of surgical planning.

BACKGROUND CONTEXT Patient satisfaction is an important metric in value-based care systems. The Press Ganey Associates survey is the most widely used instrument for measuring patient satisfaction. Understanding the factors that influence these surveys may help to better utilize survey results and direct interventions to increase patient satisfaction. PURPOSE To determine if nonmodifiable demographic factors influence spine patient satisfaction scores on the Press Ganey CG-CAHPS survey. STUDY DESIGN/SETTING Retrospective review of satisfaction surveys. PATIENT SAMPLE A total of 1,400 spine surgery ambulatory clinic patients in one tertiary care network. OUTCOME MEASURES Press Ganey CG-CAHPS satisfaction surveys. METHODS Press Ganey CG-CAHPS surveys administered to ambulatory spine surgery clinic patients within a large tertiary care network from 05/2016 to 09/2017 were retrospectively reviewed. Mean comparison testing was performed to measure associations between patient demographics and survey responses to “overall provider rating” and “recommend this provider office” questions. Mean difference to achieve significance was set at α RESULTS A total of 1,400 survey responses from the offices of 11 orthopedic spine surgeons were included. Patients aged 18-34 had significantly lower responses to the “overall doctor rating” question than older patients (p CONCLUSIONS This study demonstrates that independent, nonmodifiable factors such as age, education level, survey mode, and insurance type influence satisfaction. It also suggests that patients may be more satisfied when they align with the gender and ethnicity of the provider.

Autism is a low-incidence disability that is complex to assess and for which rates continue to increase. Assessment options for autism are reviewed and presented in the context of recent research and a comprehensive, multidisciplinary assessment model. The model involves three levels that yield data progressing from more subjective and general to more objective and specific. Each level provides unique information critical to verifying eligibility, planning instruction, and monitoring progress. Because of the complexity of autism, a systematic and comprehensive assessment approach is critical to reducing error in decisions regarding eligibility and treatment.

Purpose: To compare high-order aberrations in patients who had cataract surgery and implantation of different types of intraocular lenses (IOLs). Setting: Sir Charles Gairdner Hospital and Lions Eye Institute, University of Western Australia, Perth, Australia. Methods: Fifty eyes of 48 patients were included in this study. The optical aberrations were measured with the Hartmann-Shack wavefront sensor (Zyoptix, Bausch & Lomb) before and after surgery using a 5.0 mm wavefront aperture diameter for all comparisons. The eyes were divided into 4 groups according to the type of IOL (material and curvature). A fifth group of 10 eyes of 6 elderly patients with normal crystalline lenses had the same examination. Results: There was no statistical difference in high-order aberrations between the 2 acrylic IOL groups with different curvatures ( P >.05) or between the silicone and poly(methyl methacrylate) (PMMA) IOL groups ( P >.05). However, the measured high-order aberrations were significantly higher (3rd through 5th order) in the 2 acrylic IOL groups than in the PMMA and silicone IOL groups ( P Conclusions: An increase in IOL high-order aberrations contributed to the decline in retinal image quality. An IOL modifies the entire aberration pattern of the eye. There was a statistically significant increase in aberrations in patients with an acrylic IOL compared to those with a silicone or PMMA IOL. The exact mechanism is uncertain. Further study is required to optimize IOL design.

Thirty students with profound mental retardation (age range: 3-5 to 19-11) and 30 healthy, full-term infants (5-8 months) were shown 12 stimuli, three times each. Four patterned stimuli were presented one to a card and each pattern appeared in black-and-white, black-and-yellow, and red-and-yellow. Both groups looked significantly longer at face patterns than other patterns. Students with profound mental retardation looked longer at black-and-white patterns than other color combinations. Infants looked longer at red and yellow cards than did students with profound mental retardation. The measurement method was practical, reliable, and sensitive to both within and between group differences. Results from this assessment method may help determine the most salient visual stimuli for evoking active-alert states for students with profound mental retardation. Individual variability was evident in the data, which demonstrates the importance of examining preferences for each individual when planning intervention. Implications for future research and intervention are discussed.

As adults with congenital heart disease (CHD) grow older, preoperative screening for coronary artery disease (CAD) may be indicated prior to CHD surgery. Data regarding the indications for preoperative CAD screening in this population are limited. Current practice is to follow guidelines for patients with valvular heart disease; however, the risk for CAD in certain congenital heart diagnoses may be higher than the general population. This study aimed to assess the results of preoperative CAD screening in patients prior to CHD surgery.Retrospective study.Single tertiary center.Patients ≥35 years that had CHD surgery from 1/1/2007 to 5/1/2017.Data regarding CAD risk factors and preoperative CAD screening results were obtained. Prevalence and risk factors for CAD were analyzed, along with their relationship to perioperative outcomes.A total of 73 patients underwent CAD screening with either cardiac catheterization (56%) or computed tomography angiography (34%) prior to CHD surgery. Overall 16 (22%) patients were found to have CAD. Only two patients had severe coronary stenosis and underwent coronary bypass grafting at time of CHD surgery. Patients with CAD were more likely to be older and have history of hypertension, dyslipidemia, and tobacco smoking. CHD diagnosis was not significantly associated with presence of CAD.CAD is common in asymptomatic older patients referred for screening prior to CHD surgery; however, severe CAD requiring concomitant coronary intervention is uncommon. Preoperative CAD screening should be based on age and traditional CAD risk factors, rather than underlying CHD.

Purposes of the study were to determine the type and format of information pediatricians receive from schools regarding diagnosis and treatment of Attention Deficit-Hyperactivity Disorder (ADHD), their preferences for this information, and their opinions on referral rates and treatment. Results from a random sample of members of the American Academy of Pediatrics indicate that for both diagnostic and treatment information, significant discrepancies exist between what pediatricians prefer and the information schools always or usually provide. The majority of pediatricians believe schools overrefer and over one-third believe parents overrefer for ADHD. Pediatricians recommend behavior management at home and school more often than stimulant medication. To improve referral, diagnosis, and treatment, discussion of discrepancies in expectations between school psychologists and pediatricians could be helpful. Additional training in some areas for both groups also may be beneficial. ********** Attention-Deficit Hyperactivity Disorder (ADHD) is a major clinical and public health problem, affecting approximately 3% to 5% of school-age children (American Psychiatric Association, 1994). In a survey of school children in Maryland, Safer and Malever (2000) found that about 3% were on medication for ADHD. Because many children diagnosed with ADHI) are not on medication, these data suggest that more than 3% of children are diagnosed with the condition. ADHD is one of the most common reasons for referrals to clinics for pediatrics, family practice, neurology, and child psychiatry (Biederman, Faraone, Keenan, Knee, & Tsuang, 1990). Historically, the most favored treatment option for children with ADHD has been stimulant medication. Stimulants have been shown to have beneficial effects including improving attention, reducing disruptive and impulsive behavior, and increasing compliance with instructions from adults (Brown & Sawyer, 1998). However, the medications are not without side effects, some of which include insomnia, irritability, and loss of appetite. The use of stimulants for ADHD has increased considerably over the years. A recent study examining frequency of use from 1991 to 1995 indicates that the most prominent use of methylphenidate (Ritalin) is with students from 5 through 14 years of age; the largest increase in use occurred for students from 15 through 19 years. Even with children as young as 2 to 4 years of age there has been a substantial increase (Zito et al., 2000). Results of a large, multisite, multimodal treatment study for ADHD suggest that for 7to 9-year-olds medication monitored monthly with teacher input is more effective than behavior treatment in treating ADHD symptoms. However, to obtain some important outcomes such as improved family interaction and academic performance, a combination of medication and behavior treatment is needed (The MTA Cooperative Group, 1999a, 1999b). Misperceptions and inaccurate interpretation of the results of this study have occurred and the results have raised important issues needing further research, especially with regard to diagnosis (Carey, 2000). The American Academy of Pediatrics (AAP; 1987) noted that the use of medication should not be the first approach for ADHD; further, the AAP recommended that medication should not be considered a complete treatment program (AAP, 1996). Likewise, in their position statement on ADHD, the National Association of School Psychologists (NASP; 1995) strongly recommended that when medication is a consideration: (a) instructional and behavioral interventions should be used before beginning medication trials, (b) behavioral data should be collected for baseline conditions and during medication trials to evaluate medication effects, and (c) communication among school, home, and medical personnel should stress mutual problem solving and cooperation. …

Calls for change in the role of school psychologists have appeared in the literature over a period of nearly 50 years. Evidence of change exists for some outstanding individual school psychologists and in a number of model programs, but not on a widespread basis. This paper discusses ideas for role change that have appeared rather consistently in the literature: an emphasis on indirect service, application of the science of psychology, an emphasis on prevention, systematic evaluation of services, involvement of various stakeholders, and consideration of diversity from a broad perspective. Hopefully the 21st century will bring more widespread implementation of these ideas because there is likely to be an even greater need for such services in the schools. © 2000 John Wiley & Sons, Inc.

Purpose: An animal model of glaucoma is necessary for the study of its pathogenesis and treatment. The purpose of this study was to create open-angle glaucoma using a laser in rabbits. Methods: The trabecular meshwork of anaesthetized, adult, pigmented and albino rabbits was ablated internally using a diode laser via a gonioscopy lens, or externally through the limbus. In albino rabbits we used Chinese ink to pigment the angle and methylcellulose to open the iridocorneal angle. The eyes were examined weekly and histological assessment was performed. Results: The success rate of intra-ocular hypertension was low (15%) and a result of synechial angle closure. A narrow angle prevented access of the laser beam to the trabecular meshwork and promoted damage to the ciliary processes located on the posterior iris. Conclusions: Due to the unique anatomy of the rabbit eye, laser-induced glaucoma is difficult to achieve. To create a successful model it is necessary to widen the iridocorneal angle, selectively damage the trabecular meshwork and reduce inflammation.

Ratings by 23 parents and 21 regular education teachers on the Social Skills Rating Scale (SSRS) for elementary-age students who were blind were compared to ratings for the SSRS sighted norm group. No significant differences were found in the overall ratings of social skills or on the Self-Control or Responsibility subscales, but several important differences were noted on the Assertion and Cooperation subscales. Students who were blind were rated as less academically competent and higher on problem behaviors than the sighted norm group, even though stereotypical behaviors were not assessed by the SSRS. Implications for instruction are discussed.

The investigational biotherapeutic agent, B43(anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin, has shown substantial anti-leukemic activity in SCID mouse models of human B-lineage leukemia and lymphoma. In this report, we describe the results of a comprehensive preclinical toxicity study which determined the toxicity profile of B43-PAP in BALB/c mice. Administration of un-conjugated B43 monoclonal antibody was not associated with any toxicity, whereas B43-PAP caused dose-limiting and cardiac and renal toxicities which were fatal. In addition, B43-PAP also caused multifocal skeletal myofiber necrosis, which was associated with abnormal gait and lethargy. Notably, parenteral administrations of methylprednisolone, pentoxyphylline, or dopamine were able to markedly reduce B43-PAP related toxicity. This study provides a basis for further evaluation of the toxicity of B43-PAP in monkeys and humans.

The molecular pathogenesis of colitis-associated colorectal cancer (CAC) has been suggested to involve oxidative stress-induced DNA damage, resulting in mutations of tumor-suppressor genes and activation of pro-oncogenic pathways. However, the exact relationship between inflammation and colorectal cancer is not well understood due to the lack of a human model system that not only recapitulates in vivo growth/differentiation patterns, but also can be easily manipulated. In order to gain insight into the mechanism of colitis-associated colorectal cancer, we explored human intestinal enteroids as an ex vivo model to study the interaction of intestinal epithelial cells with immune cells under inflammatory conditions. Human intestinal crypts were isolated from adult intestinal tissue and grown in Matrigel culture to form enteroids. To model inflammation, we incorporated MHC-mismatched human peripheral blood mononuclear cells (PBMCs) into the Matrigel. TH1 immune response was induced by a cocktail of cytokines including IL-2, IL-7 and IL-15. A TH1 response was confirmed by the production of pro-inflammatory cytokines INFγ and TNFα over the course of 6-day treatment with the cytokine cocktail. Several cytokines related to TH1 and TH2 responses were induced. Interestingly, co-culture with human intestinal enteroids significantly enhanced the level of pro-inflammatory cytokines INFγ, IL-6 and TNFα, anti-inflammatory cytokine IL-10, as well as TH2 cytokine IL-13. Immunophenotyping of PBMCs shows that both CD4+ T cells (10-30%) and CD8+ T cells (1-10%) were activated upon TH1 induction. In addition, the percentage of activated CD8+ T cells was much higher in co-culture than in PBMC alone controls. Moreover, the cytokine cocktail dramatically induced the production of INFγ by purified CD4+ or CD8+ T cells but only when in co-culture with enteroids and not when cultured alone. In the enteroids, the TH1 response significantly inhibited cell proliferation and increased the apoptosis of epithelial cells when in co-culture only. Increased γH2AX (DNA damage marker) and impaired integrity of intestinal enteroids were also observed when in co-culture with the TH1 response. Cell-cell contact between enteroids and immune cells is required for these effects. Moreover, the TH1 response increases the mRNA levels of GRP78 (master regulator of ER stress) and Nrf2 (regulator of oxidative stress); decreases the mRNA level of Lgr5 [marker of active intestinal stem cells (ISCs)], but has no obvious effect on Bmi1 (marker of quiescent ISCs) in co-culture. Taken together, our data provide insight into the interaction of intestinal epithelial cells with immune cells at the molecular and cellular levels and establish this approach as a viable model for exploring the mechanism of CAC. Future studies will examine specifically for oxidative DNA damage and the effects of specific tumor suppressor inactivation on epithelial cell responses. Citation Format: Fang Wang, Dorottya Laczkó, Mary Ann Crissey, Gary Falk, Bradley Johnson, Anil Rustgi, John Lynch. Modeling the effects of inflammatory stress on human intestinal epithelial cells in 3D enteroid co-culture system. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4253.

The survey reported on in this paper replicated and modified Levine's (1974) nationwide survey of the psychological services provided for deaf and hard of hearing students. The purpose of our survey was to up date the information in light of the requirements of PL 94-142 (1975) and current practice. We noted several changes in practice since the first survey, but unfortunately, little change has taken place in many important areas. We suggest possible areas for expanding the role of school psychologists and discuss implications for training.

This study examined the effect of a parent training program and its two components on the development of 48 graduates of neonatal intensive care units. When the infants were 6 months of age, infants whose parents participated in either of the treatment groups that included the parent education class scored higher on the Bayley Mental Scale than the other groups of infants. All treatment group parents were rated by the babies' physicians as providing better nutrition for their infants. The developmental assessment component of the training program was not found to enhance infant mental development. Implications for intervention, program development, and research are presented.

SummaryTwo cytochrome P450 2C9 (CYP2C9) polymorphisms, CYP2C9*2 and *3, metabolize warfarin inefficiently. We assessed the extent to which these polymorphisms explain very low warfarin dose requirements and hemorrhagic complications after excluding non-genetic determinants of warfarin dosing. In this retrospective observational study, 73 patients with stable warfarin doses for ≥1 month and International Normalized Ratios (INR) of 2.0–3.0 were enrolled from our Anticoagulation Clinic. Seventeen patients required ≤2 mg (low-dose), 41 required 4–6 mg (moderate-dose), and 15 required ≥10 mg (high-dose) of daily warfarin. CYP2C9 genotyping was assessed by PCR amplification and restriction enzyme digestion analysis of DNA isolated from circulating leukocytes. The CYP2C9 polymorphisms independently predicted low warfarin requirements after adjusting for Body Mass Index, age, acetaminophen use, and race (OR 24.80; 95% CI 3.83–160.78). At least one polymorphism was present in every patient requiring ≤1.5 mg of daily warfarin, and 88%, 37%, and 7% of the low-, moderate-, and high-dose groups, respectively. All homozygotes and compound-heterozygotes for the variant alleles were in the low-dose group. Rates of excessive (INR>6.0) anticoagulation (and bleeding) were 4.5 (6.0), 7.9 (7.9), and 14.7 (0) per 100 patient-years in the wild-types, heterozygotes, and compound heterozygotes/homozygotes, respectively. In conclusion, CYP2C9*2 or *3 compound heterozygotes and homozygotes have low warfarin requirements even after excluding liver disease, excessive alcohol or acetaminophen consumption, low body weight, advancing age, and drug interactions. These polymorphisms increase the rate of excessive anticoagulation, but this risk does not appear to be associated with higher bleeding rates when anticoagulation status is closely monitored.

Werner Syndrome (WS) is a human genetic disorder with many features of premature aging. The gene defective in WS ( WRN ) has been cloned and encodes a protein homologous to several helicases, including Escherichia coli RecQ, the human Bloom syndrome protein (BLM), and Saccharomyces cerevisiae Sgs1p. To better define the function of WRN protein we have determined its subcellular localization. Indirect immunofluorescence using polyclonal anti-human WRN shows a predominant nucleolar localization. Studies of WRN mutant cells lines confirmed the specificity of antibody recognition. No difference was seen in the subcellular localization of the WRN protein in a variety of normal and transformed human cell lines, including both carcinomas and sarcomas. The nucleolar localization of human WRN protein was supported by the finding that upon biochemical subcellular fractionation, WRN protein is present in an increased concentration in a subnuclear fraction enriched for nucleolar proteins. We have also determined the subcellular localization of the mouse WRN homologue (mWRN). In contrast to human WRN protein, mWRN protein is present diffusely throughout the nucleus. Understanding the function of WRN in these organisms of vastly differing lifespan may yield new insights into the mechanisms of lifespan determination.

Two teaching strategies, delayed-prompting (Touchette, 1971) and fading (Egeland, 1975), were compared for teaching the most easily confused letters and numbers to preschoolers. One group of children received training using delayed prompting with a fixed delay, a second group with a fading procedure; third served as the control group that received no training. A derived progress score on the training stimuli was calculated by subtracting errors on a pretest from errors on the post-test Analysis of these results indicated a significant difference between the delayed-prompting group and the control group only. The delayed-prompting group showed greater progress. During training, subjects in the fading group met criterion on an average of 4.33 stimuli and the subjects in the delayed-prompting group met criterion on an average of 3.23 stimuli. However, on a criterion test and a posttest given 1 week later, the fading group made significantly more errors than the delayed-prompting group.

The importance of involving parents as active participants in the process of infant assessment is discussed. Presented are techniques for facilitating this involvement which can maximize the possibility that parents will follow through on educational plans. Use of this type of assessment is a form of intervention.

The effects of token rewards on the WISC-R performance of white, first, second, fourth, and fifth grade students of low-socioeconomic-status were examined. Twenty control subjects (10 first- and second-graders, 10 fourth- and fifth-graders) were administered the IQ test according to standardized procedures. An experimental group of 20 subjects (10 first- and second-graders, 10 fourth- and fifth-graders) earned tokens immediately following each correct response on the WISC-R. Upon completion of testing, tokens were exchangeable for a variety of items costing less than $3.00. The results indicated that the experimental group scored significantly higher (mean = 108) than the control group (mean = 102). A significant difference was also found for grade level, the first- and second-graders scoring higher (mean = 107) than the fourth- and fifth-graders (mean = 102). The implications for future research are discussed.

This study investigated the effect of three parent-education methods for use with mothers in maternity wards. The three methods were videotapes and a handbook, videotapes only, and handbook only. The two groups who received the videotapes performed better on a posttest than two no-treatment control groups. No differences were evident between the videotapes and handbook group and the videotapes-only group. The handbook-only condition was better than only one of the control groups. Usefulness of the program, problems encountered, and future research needs are discussed.

We measured hematocrit and serum albumin concentration at birth and red blood cell and plasma volume soon after birth in prematurely born infants with erythroblastosis fetalis of varying severity and examined the realtionships between these variables and the presence and severity of hydrops fetalis. Blood volumes in most of these infants were similar to the established normals for newborn infants without erythroblastosis. There was no simple association between blood volume and the presence of hydrops. Nonhydropic and severely hydropic infants had, on the average, similar and normal blood volumes, while mildly hydropic infants had low blood volumes. Anemia correlated fairly well with severity of hydrops but almost a quarter of the infants with severe hydrops were only mildly anemic. Red blood cell volume decreased and plasma volume increased proportionally with the degree of anemia at birth. Thus, hydropic infants with severe anemia had large plasma volumes while those with milder anemia did not. On the other hand, hypoalbuminemia was common and correlated closely with severity of hydrops. We suggest that hydrops results at least in part from low plasma colloid osmotic pressure due to hypoalbuminemia.

The authors evaluated the incidence and type of technical problems associated with blind insertion of intrapleural catheters placed in 21 anesthetized patients and then injected in a double-blind fashion with 0.5% bupivacaine (1.5 mg/kg) or isotonic saline. The patients' chests were then opened, catheter positions located, and the lungs inspected. Eleven of the catheters were located with the tips intrapleurally, three extrapleurally, and seven actually in lung tissue. Eight patients had holes in the lung surface. Three patients had a pneumothorax, two of which were under tension. Plasma bupivacaine levels reached maximal concentrations at about 20 minutes in those with intrapleurally placed catheters, but not until 60 minutes when the catheter had actually penetrated the lung. Significant variations in plasma bupivacaine levels were achieved when the catheter entered lung tissue, with potentially toxic levels in one patient. To evaluate intraoperative analgesic effects, all patients were given a standard anesthetic with isoflurane, oxygen, and a muscle relaxant. There was no significant difference in isoflurane requirement between the groups who had bupivacaine v saline injected into their intrapleural catheters before surgery. It is concluded that blind insertion of intrapleural catheters can be hazardous, especially if followed by positive-pressure ventilation. In addition, catheter placement in lung tissue, which was not uncommon, delays the time for peak plasma concentrations and may increase risk of toxicity. Intrapleural bupivacaine was not found to be a useful adjunct to general anesthesia during thoracotomies.

Telomeres protect against chromosomal damage. Accelerated telomere loss has been associated with premature aging syndromes such as Werner's syndrome and Dyskeratosis Congenita, while, progressive telomere loss activates a DNA damage response leading to chromosomal instability, typically observed in cancer cells and senescent cells. Therefore, identifying mechanisms of telomere length maintenance is critical for understanding human pathologies. In this paper we demonstrate that mitochondrial dysfunction plays a causal role in telomere shortening. Furthermore, hnRNPA2, a mitochondrial stress responsive lysine acetyltransferase (KAT) acetylates telomere histone H4at lysine 8 of (H4K8) and this acetylation is associated with telomere attrition. Cells containing dysfunctional mitochondria have higher telomere H4K8 acetylation and shorter telomeres independent of cell proliferation rates. Ectopic expression of KAT mutant hnRNPA2 rescued telomere length possibly due to impaired H4K8 acetylation coupled with inability to activate telomerase expression. The phenotypic outcome of telomere shortening in immortalized cells included chromosomal instability (end-fusions) and telomerase activation, typical of an oncogenic transformation; while in non-telomerase expressing fibroblasts, mitochondrial dysfunction induced-telomere attrition resulted in senescence. Our findings provide a mechanistic association between dysfunctional mitochondria and telomere loss and therefore describe a novel epigenetic signal for telomere length maintenance.