Heparanase and Type 1 Diabetes.

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing beta cells in pancreatic islets. The degradation of the glycosaminoglycan heparan sulfate (HS) by the endo-ß-D-glycosidase heparanase plays a critical role in multiple stages of the disease process. Heparanase aids (i) migration of inflammatory leukocytes from the vasculature to the islets, (ii) intra-islet invasion by insulitis leukocytes, and (iii) selective destruction of beta cells. These disease stages are marked by the solubilization of HS in the subendothelial basement membrane (BM), HS breakdown in the peri-islet BM, and the degradation of HS inside beta cells, respectively. Significantly, healthy islet beta cells are enriched in highly sulfated HS which is essential for their viability, protection from damage by reactive oxygen species (ROS), beta cell function and differentiation. Consequently, mouse and human beta cells but not glucagon-producing alpha cells (which contain less-sulfated HS) are exquisitely vulnerable to heparanase-mediated damage. In vitro, the death of HS-depleted mouse and human beta cells can be prevented by HS replacement using highly sulfated HS mimetics or analogues. T1D progression in NOD mice and recent-onset T1D in humans correlate with increased expression of heparanase by circulating leukocytes of myeloid origin and heparanase-expressing insulitis leukocytes. Treatment of NOD mice with the heparanase inhibitor and HS replacer, PI-88, significantly reduced T1D incidence by 50%, impaired the development of insulitis and preserved beta cell HS. These outcomes identified heparanase as a novel destructive tool in T1D, distinct from the conventional cytotoxic and apoptosis-inducing mechanisms of autoreactive T cells. In contrast to exogenous catalytically active heparanase, endogenous heparanase may function in HS homeostasis, gene expression and insulin secretion in normal beta cells and immune gene expression in leukocytes. In established diabetes, the interplay between hyperglycemia, local inflammatory cells (e.g. macrophages) and heparanase contributes to secondary micro- and macro-vascular disease. We have identified dual activity heparanase inhibitors/HS replacers as a novel class of therapeutic for preventing T1D progression and potentially for mitigating secondary vascular disease that develops with long-term T1D.

Use of standard laboratory methods to obviate routine dithiothreitol treatment of blood samples with daratumumab interference.

CONCLUSIONS: Daratumumab is an antibody currently used in the treatment of patients with refractory multiple myeloma. Blood samples from patients being treated with daratumumab may show panreactivity during pre-transfusion testing. To facilitate the provision of blood components for such patients, it is recommended that a baseline phenotype or genotype be established prior to starting treatment with daratumumab. If patient red blood cells (RBCs) require phenotyping after the start of daratumumab treatment, dithiothreitol (DTT) treatment of the patient's RBCs should be performed. The medical charts of four patients treated with daratumumab were reviewed. The individual number of doses ranged from 1 to 14; patient age ranged from 55 to 78 years; two men and two women were included in the review. Type and screen data were obtained from samples collected over 33 encounters with a range of 1 to 13 encounters per patient. All samples were tested initially by automated solid-phase testing. Any reactivity with solid phase led to tube testing with either low-ionic-strength saline, polyethylene glycol, or both. If incubation failed to eliminate the reactivity, the sample was sent to a reference laboratory for DTT treatment and phenotyping. Of the 33 samples tested, 23 (69.7%) samples had reactivity in solid-phase testing. In 8 of the 10 samples that did not react in solid-phase, testing was conducted more than four half-lives after the last dose of daratumumab. Of the 23 that had reactivity in solid-phase, 16 (69.6%) samples demonstrated loss of reactivity using common laboratory methods. For the seven patients whose sample reactivity was not initially eliminated, six were provided with phenotypically matched blood based on prior molecular testing. Only one sample was sent out for DTT treatment. These results suggest that daratumumab interference with pre-transfusion testing can be addressed using common laboratory methods. This finding could save time and money for laboratories that do not have DTT available.

Outcome Measures for the Evaluation of Treatment Response in Hidradenitis Suppurativa for Clinical Practice: A HiSTORIC Consensus Statement.

Importance: Although several clinician- and patient-reported outcome measures have been developed for trials in hidradenitis suppurativa (HS), there is currently no consensus on which measures are best suited for use in clinical practice. Identifying validated and feasible measures applicable to the practice setting has the potential to optimize treatment strategies and generate generalizable evidence that may inform treatment guidelines. Objective: To establish consensus on a core set of clinician- and patient-reported outcome measures recommended for use in clinical practice and to establish the appropriate interval within which these measures should be applied. Evidence Review: Clinician- and patient-reported HS measures and studies describing their psychometric properties were identified through literature reviews. Identified measures comprised an item reduction survey and subsequent electronic Delphi (e-Delphi) consensus rounds. In each consensus round, a summary of outcome measure components and scoring methods was provided to participants. Experts were provided with feasibility characteristics of clinician measures to aid selection. Consensus was achieved if at least 67% of respondents agreed with use of a measure in clinical practice. Findings: Among HS experts, response rates for item reduction, e-Delphi round 1, and e-Delphi round 2 surveys were 76.4% (42 of 55), 90.5% (38 of 42), and 92.9% (39 of 42), respectively; among patient research partners (PRPs), response rates were 70.8% (17 of 24), 100% (17 of 17), and 82.4% (14 of 17), respectively. The majority of experts across rounds were practicing dermatologists with 18 to 19 years of clinical experience. In the final e-Delphi round, most PRPs were female (12 [85.7%] vs 2 males [11.8%]) and aged 30 to 49 years. In the final e-Delphi round, HS experts and PRPs agreed with the use of the HS Investigator Global Assessment (28 [71.8%]) and HS Quality of Life score (13 [92.9%]), respectively. The most expert-preferred assessment interval in which to apply these measures was 3 months (27 [69.2%]). Conclusions and Relevance: An international group of HS experts and PRPs achieved consensus on a core set of HS measures suitable for use in clinical practice. Consistent use of these measures may lead to more accurate assessments of HS disease activity and life outcomes, facilitating shared treatment decision-making in the practice setting.

Circulating platelet-neutrophil aggregates characterize the development of type 1 diabetes in humans and NOD mice.

Platelet-neutrophil aggregates (PNAs) facilitate neutrophil activation and migration and could underpin the recruitment of neutrophils to the pancreas during type 1 diabetes (T1D) pathogenesis. PNAs, measured by flow cytometry, were significantly elevated in the circulation of autoantibody-positive (Aab+) children and new-onset T1D children, as well as in pre-T1D (at 4 weeks and 10-12 weeks) and T1D-onset NOD mice, compared with relevant controls, and PNAs were characterized by activated P-selectin+ platelets. PNAs were similarly increased in pre-T1D and T1D-onset NOD isolated islets/insulitis, and immunofluorescence staining revealed increased islet-associated neutrophil extracellular trap (NET) products (myeloperoxidase [MPO] and citrullinated histones [CitH3]) in NOD pancreata. In vitro, cell-free histones and NETs induced islet cell damage, which was prevented by the small polyanionic drug methyl cellobiose sulfate (mCBS) that binds to histones and neutralizes their pathological effects. Elevated circulating PNAs could, therefore, act as an innate immune and pathogenic biomarker of T1D autoimmunity. Platelet hyperreactivity within PNAs appears to represent a previously unrecognized hematological abnormality that precedes T1D onset. In summary, PNAs could contribute to the pathogenesis of T1D and potentially function as a pre-T1D diagnostic.

Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes.

Heparan sulfate proteoglycans (HSPGs) consist of a core protein with side chains of the glycosaminoglycan heparan sulfate (HS). We have previously identified (i) the HSPGs syndecan-1 (SDC1), and collagen type XVIII (COL18) inside mouse and human islet beta cells, and (ii) a critical role for HS in beta cell survival and protection from reactive oxygen species (ROS). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress contributes to oxidative stress and type 2 diabetes (T2D) by depleting beta cell HSPGs/HS. A rapid loss of intra-islet/beta cell HSPGs, HS and heparanase (HPSE, an HS-degrading enzyme) accompanied upregulation of islet ER stress gene expression in both young T2D-prone db/db and Akita Ins2WT/C96Y mice. In MIN6 beta cells, HSPGs, HS and HPSE were reduced following treatment with pharmacological inducers of ER stress (thapsigargin or tunicamycin). Treatment of young db/db mice with Tauroursodeoxycholic acid (TUDCA), a chemical protein folding chaperone that relieves ER stress, improved glycemic control and increased intra-islet HSPG/HS. In vitro, HS replacement with heparin (a highly sulfated HS analogue) significantly increased the survival of wild-type and db/db beta cells and restored their resistance to hydrogen peroxide-induced death. We conclude that ER stress inhibits the synthesis/maturation of HSPG core proteins which are essential for HS assembly, thereby exacerbating oxidative stress and promoting beta cell failure. Diminished intracellular HSPGs/HS represent a previously unrecognized critical link bridging ER stress, oxidative stress and beta cell failure in T2D.

Expanding pediatric orthopaedic trauma volume at a pediatric level 1 trauma hospital.

BACKGROUND: Trauma continues to be the leading cause of morbidity and mortality among children. There is a perception among pediatric orthopaedists that the volume of pediatric orthopaedic trauma care is increasing. We hypothesized that the change in trauma volume was greater than the local and regional population change. METHODS: This retrospective analysis (1996 to 2006) of our institution's trauma registry analyzed changes in general trauma and orthopaedic trauma admissions, surgical volumes, patient and population demographics, and hospital reimbursement. RESULTS: For the decade, the local pediatric population increased annually by only 2% to 3%. During that same period, there was an increase in the proportion of patients treated from outside the immediate county, from 13% in 1996 to 28% in 2006. Total general trauma patient admissions increased at an average of 10% per year from 1996 to 2006, whereas total orthopaedic trauma admissions and orthopaedic trauma admissions requiring operative treatment increased by an annual average of 18%. Orthopaedic trauma admissions as a percentage of total trauma admissions steadily increased from 26% in 1996 to 45% in 2006. During 2005 and 2006, an average total of 1216 orthopaedic trauma cases per year were performed generating an average 10,465 work relative value units per year. Between 1996 and 2005, the hospital's gross charges for pediatric orthopaedic trauma increased by an average of 26% annually; however, the percentage of total charges collected decreased from 67% in 1999 to 28% in 2005. CONCLUSIONS: Pediatric orthopaedic trauma at this level 1 trauma center increased dramatically and more rapidly than the local population over the last decade, increasing the demand for physician and hospital resources. Physicians, hospitals, and the communities they serve face financial and logistical problems of providing care for an expanding volume of pediatric orthopaedic trauma patients with decreasing reimbursements, changing referral patterns and a decreasing population of pediatric orthopaedic specialists. Care of the pediatric orthopaedic trauma patient could become a national crisis. LEVEL OF EVIDENCE: Economic analysis-level III.

Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans.

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intra-islet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxide-induced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D.

Effective interventions for lifestyle change after myocardial infarction or coronary artery revascularization.

PURPOSE: This science clinical paper reviews medical literature and examines interventions that are currently used to assist patients in achieving lifestyle change after myocardial infarction or coronary artery revascularization. Interventions that focused on both provider- and patient-implemented strategies were included. The effectiveness of these interventions to significantly reduce coronary heart disease risk factors was explored. DATA SOURCES: Original longitudinal research studies or reviews indexed in PubMed between 1999 and 2004 were included. Eight studies were identified that met the inclusion criteria and presented successful interventions to increase participants' adherence to recommended lifestyle changes. CONCLUSIONS: Current strategies for achieving recommended risk factor reductions include frequent follow-up, intensive diet changes, individualized and group exercise, coaching, group meetings, education on lifestyle modification and behavior change, and formal cardiac rehabilitation programs. IMPLICATIONS FOR PRACTICE: Nurse Practitioners can help close the gap between evidence-based recommendations and clinical practice by implementing education programs in their practices and in the community. Recommendations include frequent follow-up visits, negotiating personalized treatment plans, and a general emphasis on therapeutic lifestyle change as an essential component of the treatment plan.

Spiritual care practices of nurse practitioners in federally designated nonmetropolitan areas of North Carolina.

PURPOSE: The purpose of this study was to explore if and then how nurse practitioners (NPs) living in federally designated nonmetropolitan areas of North Carolina integrated spiritual care into their practices. Participants identified the frequency in which they utilize spiritual care practices, specific spiritual interventions, and their definitions of spiritual care. DATA SOURCES: A sample of 101 NPs was chosen through systematic sampling from 507 eligible NPs. Each participant was mailed a demographic data sheet and the Nurse Practitioner Spiritual Care Perspective Survey (NPSCPS). The NPSCPS was modified from the Oncology Nurse Spiritual Care Perspective Scale developed by Taylor and colleagues. Of the 101 mailings, 65 were returned and included in the analysis. CONCLUSIONS: Although most of the NPs in this study felt that spiritual care was an important part of nursing practice, 73% did not routinely provide spiritual care to their patients. Barriers and limitations to the provision of spiritual care must be explored. IMPLICATIONS FOR PRACTICE: As providers of holistic care, NPs should be proficient and comfortable in providing spiritual care to their patients. Educational programs should provide NPs and NP students with knowledge and skills to provide spiritual care.

Porcine endogenous retrovirus encodes xenoantigens involved in porcine cellular xenograft rejection by mice.

BACKGROUND: Identification of the antigens that stimulate transplant rejection can help develop graft-specific antirejection strategies. The xenoantigens recognized during rejection of porcine cellular xenografts have not been clearly defined, but it has been assumed that major histocompatibility complex (MHC) xenoantigens are involved. METHODS: The role of porcine endogenous retrovirus (PERV) as a source of xenoantigens was examined. The authors used morphometry to compare the kinetics of swine leukocyte antigen (SLA) pig thyroid xenograft rejection in control mice and mice immunized with PERV PK15 cells (porcine kidney epithelial cells), PERV SLA pig peripheral blood lymphocytes (PBL), PERV virions purified from PK15 cells, and PERV or PERV A pseudotypes produced from infected human 293 cells. The tempo of rejection for cellular xenografts of PERV A pseudotype-producing human 293 cells, uninfected human 293 cells, and PK15 cells in PERV-preimmunized and control mice was also compared. RESULTS: Mice immunized with PK15 cells rejected pig thyroid xenografts significantly faster at day 5 than control mice and mice immunized with pig PBL. This correlated with the amount of PERV RNA and virions produced, but not with the amount of SLA class I MHC expressed by PK15 cells. Immunization of mice with PERV virions purified from porcine PK15 cells and with PERV virions or PERV A pseudotypes produced by human 293 cells also induced accelerated xenograft rejection by 5 days. Accelerated rejection induced by virus pretreatment was CD4 T-cell dependent and restricted to PERV-expressing cellular xenografts of porcine or nonporcine origin. CONCLUSIONS: PERV acts as a significant source of xenoantigens that target porcine cellular xenografts for rejection.

Prevalence of hypertension in a sample of Black American adults using JNC 7 classifications.

High blood pressure is a major health problem, particularly among Black Americans, and many Black Americans are unaware that they have the disease. In 2003, new guidelines (JNC 7) were created for classifying blood pressure including a category designated as "pre-hypertension." We examined the prevalence of hypertension based on JNC 7 guidelines in Black Americans from the study of Everyday Life for Black American Adults: Stress, Emotional and Cardiovascular Responses. In this study, 211 (N = 211) participants had no history of hypertension and were not taking anti-hypertensive medications. Demographic factors were also explored in relationship to the JNC 7 classifications. Using JNC 7, only 28.9% of the participants had normal blood pressures. Of those with abnormal blood pressures, 37.8% were pre-hypertensive. Surprisingly, there was a high prevalence of hypertension, which might be explained by a lack of awareness of their disease status, lack of desire to acknowledge it, or fear of having a disease. The pre-hypertension category allows for earlier identification of those at risk for developing hypertension so that early interventions can deter its debilitating effects.

Everyday life for black american adults: stress, emotions, and blood pressure.

The purpose of this study was to examine the stress process in Black Americans by exploring chronic stress, emotions, age, body mass index, and blood pressure within the context of gender and socioeconomic position (SEP). The convenience sample of middle-class Black Americans ( N = 211) ranged from ages 25 to 79 years. A sociopsychophysiological model of everyday life for Black American adults was tested using structural equation modeling. The model explained 27% of the variance in systolic and 17% of the variance in diastolic blood pressure. SEP had a significant effect on chronic stress, and chronic stress had a significant effect on negative affect. Although men had lower negative affect scores than women, men's diastolic blood pressures were on average 4 mm Hg higher than women's. These findings are useful to the development and implementation of interventions to eliminate health disparities and improve years of healthy life for Black Americans.

Video recording of emergency department trauma resuscitations.

Although hospitals are faced with the challenges of appropriately informing the public regarding health care and protecting the privacy of patients, a comprehensive policy concerning videotaping of trauma resuscitations can be developed to comply with regulatory bodies. Video recording of trauma team resuscitations can be utilized as an effective quality improvement tool to evaluate trauma team performance, psychomotor skills and techniques, and to identify educational needs related to specific trauma populations. Video recording of Trauma resuscitations is an effective tool for improving trauma team performance by educating clinical staff regarding roles and responsibilities.

Intraoperative monitoring technician: a new member of the surgical team.

As surgery needs have increased, the traditional surgical team has expanded to include personnel from radiology and perfusion services. A new surgical team member, the intraoperative monitoring technician, is needed to perform intraoperative monitoring during procedures that carry a higher risk of central and peripheral nerve injury. Including the intraoperative monitoring technician on the surgical team can create challenges, including surgical delays and anesthesia care considerations. When the surgical team members, including the surgeon, anesthesia care provider, and circulating nurse, understand and facilitate this new staff member's responsibilities, the technician is able to perform monitoring functions that promote the smooth flow of the surgical procedure and positive patient outcomes.

Performance evaluation for diversity programs.

This policy paper addresses the problem of underrepresentation of minorities in the health care professions. Projections are that by 2050 minorities will represent 49% of the U.S. population. Several notable reports suggest that the health care of underrepresented minorities is improved when providers of similar ethnic and racial backgrounds provide the care. However, minority representation in the health care professions has not kept pace with the increase of minorities in the population. A variety of groups (federal, state, private, and health professional educational institutions) have provided billions of dollars toward increasing the number of underrepresented minority health care providers. However, the effectiveness of these programs is not readily evident. Therefore, we recommend comprehensive evaluations of programs funded to increase diversity in the health professions and the development of a Minority Health Care Professionals Center to assume accountability for monitoring programs that receive funding to increase the number of underrepresented minority health care providers.