Bioactive hydrogels with enhanced initial and sustained cell interactions.

The highly tunable properties of poly(ethylene glycol) (PEG)-based hydrogel systems permit their use in a wide array of regenerative medicine and drug delivery applications. One of the most valuable properties of PEG hydrogels is their intrinsic resistance to protein adsorption and cell adhesion, as it allows for a controlled introduction of desired bioactive factors including proteins, peptides, and drugs. Acrylate-PEG-N-hydroxysuccinimide (Acr-PEG-NHS) is widely utilized as a PEG linker to functionalize bioactive factors with photo-cross-linkable groups. This enables their facile incorporation into PEG hydrogel networks or the use of PEGylation strategies for drug delivery. However, PEG linkers can sterically block integrin binding sites on functionalized proteins and reduce cell-material interactions. In this study we demonstrate that reducing the density of PEG linkers on protein backbones during functionalization results in significantly improved cell adhesion and spreading to bioactive hydrogels. However, this reduction in functionalization density also increases protein loss from the matrix over time due to ester hydrolysis of the Acr-PEG-NHS linkers. To address this, a novel PEG linker, acrylamide-PEG-isocyanate (Aam-PEG-I), with enhanced hydrolytic stability was synthesized. It was found that decreasing functionalization density with Aam-PEG-I resulted in comparable increases in cell adhesion and spreading to Acr-PEG-NHS systems while maintaining protein and bioactivity levels within the hydrogel network over a significantly longer time frame. Thus, Aam-PEG-I provides a new option for protein functionalization for use in a wide range of applications that improves initial and sustained cell-material interactions to enhance control of bioactivity.

Development of a biostable replacement for PEGDA hydrogels.

The exceptional tunability of poly(ethylene glycol) (PEG) hydrogel chemical, mechanical, and biological properties enables their successful use in a wide range of biomedical applications. Although PEG diacrylate (PEGDA) hydrogels are often used as nondegradable controls in short-term in vitro studies, it is widely acknowledged that the hydrolytically labile esters formed upon acrylation of the PEG diol make them susceptible to slow degradation in vivo. A PEG hydrogel system that maintains the desirable properties of PEGDA while improving biostability would be valuable in preventing degradation-related failure of gel-based devices in long-term in vivo applications. To this end, PEG diacrylamide (PEGDAA) hydrogels were synthesized and characterized in quantitative comparison to traditional PEGDA hydrogels. It was found that PEGDAA hydrogel modulus and swelling can be tuned over a similar range and to comparable degrees as PEGDA hydrogels with changes in macromer molecular weight and concentration. Additionally, PEGDAA cytocompatibility, low cell adhesion, and capacity for incorporation of bioactivity were analogous to that of PEGDA. In vitro hydrolytic degradation studies showed that the amide-based PEGDAA had significantly increased biostability relative to PEGDA. Overall, these findings indicate that PEGDAA hydrogels are a suitable replacement for PEGDA hydrogels with enhanced hydrolytic resistance. In addition, these studies provide a quantitative measure of the hydrolytic degradation rate of PEGDA hydrogels which was previously lacking in the literature.

The future of nursing: community health's network approach.

This bimonthly department, sponsored by the American Organization of Nurse Executives (AONE), presents information to assist nurse leaders in shaping the future of healthcare through creative and innovative leadership. The strategic priorities of AONE anchor the editorial content. They reflect contemporary healthcare and nursing practice issues that challenge nurse executives as they strive to meet the needs of patients.

Supporting cancer patients and their carers: the contribution of art therapy and clinical psychology.

The value of various types of psychosocial support for people with cancer is now becoming well established. Typically the term 'psychosocial' includes: counselling and psychotherapy, cognitive behaviour therapy, education and information, and social support. The research literature sometimes fails to clarify the exact nature of the different approaches and their relative efficacy. Inevitably, even within a specific type of therapeutic approach, there is variation owing to the professional background and skills of different practitioners. This article describes the relative contributions made by an art psychotherapist and a clinical psychologist working together in a cancer and palliative care service in Wales. The referrals come from the same sources and tend to be for similar types of problem. The assessment and formulation processes are also broadly similar. Interventions, however, are markedly different. These are described in some detail through case study examples.

Supporting cancer patients and their carers: the contribution of art therapy and clinical psychology.

The value of various types of psychosocial support for people with cancer is now becoming well established. Typically the term 'psychosocial' includes: counselling and psychotherapy, cognitive behaviour therapy, education and information, and social support. The research literature sometimes fails to clarify the exact nature of the different approaches and their relative efficacy. Inevitably, even within a specific type of therapeutic approach, there is variation owing to the professional background and skills of different practitioners. This article describes the relative contributions made by an art psychotherapist and a clinical psychologist working together in a cancer and palliative care service in Wales. The referrals come from the same sources and tend to be for similar types of problem. The assessment and formulation processes are also broadly similar. Interventions, however, are markedly different. These are described in some detail through case study examples.

Pilot experience with continuous infusion alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia.

We evaluated the activity and tolerability of alemtuzumab given as a continuous infusion for 7 d followed by subcutaneous administration for 11 wk as salvage therapy for 10 patients with fludarabine-refractory chronic lymphocytic leukemia. The continuous infusion of alemtuzumab was well tolerated. The typical infusion reaction seen with intravenous alemtuzumab was abolished. Two patients achieved a partial response with an overall response rate of 20%. Alemtuzumab levels were measured in four patients and detectable levels were obtained in three. Clinical activity needs to be confirmed in a larger patient population.

Nursing guidelines for managing infections in patients with chronic lymphocytic leukemia.

Infections are a primary cause of death in patients with chronic lymphocytic leukemia (CLL). Such individuals are particularly susceptible to infectious complications stemming from immune deficits associated with the primary disease process and with immunosuppression secondary to treatment. Although the recent availability of new treatment modalities and more aggressive therapies are improving outcomes for patients with CLL, standardized approaches are needed so that nurses can monitor for and manage infections. The aim is overall reduction in morbidity and mortality, as well as improvement in quality of life. The current pharmacologic therapies for CLL are alkylating agents, purine nucleoside analogs, monoclonal antibodies, and combinations of those therapies, which may present their own unique risks for and different spectra of infectious events. This article provides an overview of the known risks for developing infections in CLL, as well as nursing guidelines for monitoring and managing patients with CLL.

Chronic Wound Dressings Based on Collagen-Mimetic Proteins.

Objective: Chronic wounds are projected to reach epidemic proportions due to the aging population and the increasing incidence of diabetes. There is a strong clinical need for an improved wound dressing that can balance wound moisture, promote cell migration and proliferation, and degrade at an appropriate rate to minimize the need for dressing changes. Approach: To this end, we have developed a bioactive, hydrogel microsphere wound dressing that incorporates a collagen-mimetic protein, Scl2GFPGER, to promote active wound healing. A redesigned Scl2GFPGER, engineered collagen (eColGFPGER), was created to reduce steric hindrance of integrin-binding motifs and increase overall stability of the triple helical backbone, thereby resulting in increased cell adhesion to substrates. Results: This study demonstrates the successful modification of the Scl2GFPGER protein to eColGFPGER, which displayed enhanced stability and integrin interactions. Fabrication of hydrogel microspheres provided a matrix with adaptive moisture technology, and degradation rates have potential for use in human wounds. Innovation: This collagen-mimetic wound dressing was designed to permit controlled modulation of cellular interactions and degradation rate without impact on other physical properties. Its fabrication into uniform hydrogel microspheres provides a bioactive dressing that can readily conform to irregular wounds. Conclusion: Overall, this new eColGFPGER shows strong promise in the generation of bioactive hydrogels for wound healing as well as a variety of tissue scaffolds.

Continued high-risk sexual behaviour among HIV-positive people in Wales.

The study objective was to investigate self-reported sexual practices among HIV-positive people in Wales in order to estimate the extent of unprotected sex and to develop services that assist positive people reduce the risk of sexual spread of HIV. A cross-sectional postal questionnaire survey was conducted between February and July 1999 at all open-access HIV outpatient facilities in Wales. All HIV-positive people attending during the study period were invited to enroll in the study. Data were obtained on 104/141 (74%) enrolled patients including 70 (67%) homo/bisexual men. Most (79/104, 76%) were sexually active and 42% (33/79) had casual partners. One in six (13/79, 16.5%) sexually active people reported unprotected high-risk sex with HIV-negative or unknown status partners, the majority (9/13, 69%) of whom were male homosexuals. It is important that health professionals specifically address issues of sexual behaviour with HIV positive people during consultation. A renewed safer sex campaign targeting men who have sex with men is urgently needed.

Endothelial cell response to chemical, biological, and physical cues in bioactive hydrogels.

The highly tunable biological, chemical, and physical properties of bioactive hydrogels enable their use in an array of tissue engineering and drug delivery applications. Systematic modulation of these properties can be used to elucidate key cell-material interactions to improve therapeutic effects. For example, the rate and extent of endothelialization are critical to the long-term success of many blood-contacting devices. To this end, we have developed a bioactive hydrogel that could be used as coating on cardiovascular devices to enhance endothelial cell (EC) adhesion and migration. The current work investigates the relative impact of hydrogel variables on key endothelialization processes. The bioactive hydrogel is based on poly(ethylene glycol) (PEG) and a streptococcal collagen-like (Scl2-2) protein that has been modified with integrin α1ß1 and α2ß1 binding sites. The use of PEG hydrogels allows for incorporation of specific bioactive cues and independent manipulation of scaffold properties. The selective integrin binding of Scl2-2 was compared to more traditional collagen-modified PEG hydrogels to determine the effect of integrin binding on cell behavior. Protein functionalization density, protein concentration, and substrate modulus were independently tuned with both Scl2-2 and collagen to determine the effect of each variable on EC adhesion, spreading, and migration. The findings here demonstrate that increasing substrate modulus, decreasing functionalization density, and increasing protein concentration can be utilized to increase EC adhesion and migration. Additionally, PEG-Scl2-2 hydrogels had higher migration speeds and proliferation over 1 week compared with PEG-collagen gels, demonstrating that selective integrin binding can be used to enhance cell-material interactions. Overall, these studies contribute to the understanding of the effects of matrix cues on EC interactions and demonstrate the strong potential of PEG-Scl2-2 hydrogels to promote endothelialization of blood-contacting devices.

Managing hypersensitivity to asparaginase in pediatrics, adolescents, and young adults.

Hypersensitivity reactions to chemotherapeutic drugs have been documented for numerous cancer therapies. Clinical hypersensitivity to Escherichia coli asparaginase has been reported to range from 0% to 75%. Throughout the United States, nurses assume frontline responsibility for the assessment of asparaginase-related hypersensitivity reactions. It is essential that nurses educate themselves on the signs and symptoms of asparaginase-related hypersensitivity reactions as well as current supportive care approaches. The purpose of this review is to summarize acute lymphoblastic leukemia and the role of asparaginase and the pathology of allergic reactions. We will also update nurses on the differences in asparaginase preparations including dosing, half-life, rates of hypersensitivity, and routes of administration. A summary of current management and supportive care strategies will be provided as will a discussion of the relationship between allergy, antibodies, and asparaginase activity.

Self-administered, subcutaneous alemtuzumab to treat residual disease in patients with chronic lymphocytic leukemia.

BACKGROUND: Alemtuzumab is highly effective at treating chronic lymphocytic leukemia (CLL) in bone marrow, which is the usual site of residual disease after fludarabine-based treatment. Eliminating residual disease potentially is associated with longer remission and overall survival. The authors of this report evaluated the ability of subcutaneous alemtuzumab to treat residual disease. METHODS: Patients in partial remission (PR), nodular PR (nPR), or complete remission (CR) who had disease in bone marrow established by 2-color flow cytometry analysis were enrolled and received alemtuzumab 30 mg subcutaneously 3 times weekly for 4 weeks, and patients had the option to self-administer alemtuzumab. Responders were patients in PR who converted to an nPR or a CR, patients in nPR who converted to a CR, and patients in CR who had no evidence of disease on 2-color flow cytometry analysis after treatment. RESULTS: There were 31 patients enrolled, of whom 29 were evaluable, and there were 23 responders (4 of 4 patients who achieved a CR, 8 of 9 patients who achieved an nPR, and 11 of 16 patients who achieved a PR. Nonresponders had significantly lower plasma alemtuzumab levels at the end of treatment. Furthermore, higher plasma alemtuzumab levels at the end of treatment were correlated with a longer response duration. Compared with the results from an historic group that received intravenous alemtuzumab for residual disease, there was a trend toward a higher response rate but a shorter response duration with subcutaneous alemtuzumab. CONCLUSIONS: The current results demonstrated that self-administered, subcutaneous alemtuzumab was safe and active for residual disease and that plasma alemtuzumab levels and real-time minimal residual disease evaluation are important endpoints to monitor in future alemtuzumab consolidation trials.

Soft tissue infections and emergency department disposition: predicting the need for inpatient admission.

OBJECTIVES: Little empiric evidence exists to guide emergency department (ED) disposition of patients presenting with soft tissue infections. This study's objective was to generate a clinical decision rule to predict the need for greater than 24-hour hospital admission for patients presenting to the ED with soft tissue infection. METHODS: This was a retrospective cohort study of consecutive patients presenting to a tertiary care hospital ED with diagnosis of nonfacial soft tissue infection. Standardized chart review was used to collect 29 clinical variables. The primary outcome was >24-hour hospital admission (either general admission or ED observation unit), regardless of initial disposition. Patients initially discharged home and later admitted for more than 24 hours were included in the outcome. Data were analyzed using classification and regression tree (CART) analysis and multivariable logistic regression. RESULTS: A total of 846 patients presented to the ED with nonfacial soft tissue infection. After merging duplicate records, 674 patients remained, of which 81 (12%) required longer than 24-hour admission. Using CART, the strongest predictors of >24-hour admission were patient temperature at ED presentation and mechanism of infection. In the multivariable logistic regression model, initial patient temperature (odds ratio [OR] for each degree over 37 degrees C = 2.91, 95% confidence interval [CI] = 1.65 to 5.12) and history of fever (OR = 3.02, 95% CI = 1.41 to 6.43) remained the strongest predictors of hospital admission. Despite these findings, there was no combination of factors that reliably identified more than 90% of target patients. CONCLUSIONS: Although we were unable to generate a high-sensitivity decision rule to identify ED patients with soft tissue infection requiring >24-hour admission, the presence of a fever (either by initial ED vital signs or by history) was the strongest predictor of need for >24-hour hospital stay. These findings may help guide disposition of patients presenting to the ED with nonfacial soft tissue infections.

Low serum albumin level is associated with cytomegalovirus reactivation in patients with chronic lymphoproliferative diseases treated with alemtuzumab (Campath-1H)-based therapies.

BACKGROUND: Alemtuzumab (Campath-1H), a monoclonal antibody that targets the CD52 antigen, has been approved for the treatment of fludarabine-refractory chronic lymphocytic leukemia. However, the profound immunosuppression caused by alemtuzumab has been associated with infectious complications. METHODS: The authors report on the incidence and risk factors for development of symptomatic cytomegalovirus reactivation in 113 patients with chronic lymphoproliferative disorders who received alemtuzumab-based therapy. Kaplan-Meier methods were applied to generate survival curves, and the log-rank test was used to assess the difference between groups; in addition, univariate and multivariate Cox proportional hazards models were used to estimate the hazard ratio of death including 95% confidence intervals. RESULTS: Cytomegalovirus reactivation was diagnosed in 25 patients (22%), and most of those patients responded to antiviral therapy. Nine additional patients had asymptomatic cytomegalovirus viremia. CONCLUSIONS: With appropriate therapy, most patients achieved clearance of cytomegalovirus viremia. Low serum albumin was the only factor associated significantly with symptomatic cytomegalovirus reactivation.

Activity of alemtuzumab in patients with CD52-positive acute leukemia.

BACKGROUND: Alemtuzumab is a humanized monoclonal antibody directed against the cell surface antigen CD52 and has demonstrated activity in chronic lymphocytic leukemia and other CD52-positive lymphoproliferative disorders. Because CD52 also is expressed on acute leukemic blasts, the authors investigated the safety and efficacy of alemtuzumab in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). METHODS: Fifteen patients with CD52-positive (> or = 20%), recurrent or refractory acute leukemia (9 patients with AML and 6 patients with ALL) received alemtuzumab at a dose of 30 mg intravenously given 3 times a week (dose escalation during Week 1) for a total of 4 to 12 weeks. RESULTS: The median age of the patients was 39 years (range, 18-71 years). Patients had received a median of 3 prior therapies (range, 1-5 prior therapies). Two patients (13%) achieved a bone marrow complete response and 1 patient achieved a substantial reduction in bone marrow blasts. No complete remissions were observed. Ten patients developed disease progression while on study. Alemtuzumab was myelosuppressive in nearly all patients. Infusion-related toxicities were common, but usually did not exceed Grade 2 (according to the National Cancer Institute Common Toxicity Criteria). Infectious episodes occurred in 13 patients (87%) and included pneumonia (6 patients), bacteremia (11 patients), fungemia (2 patients), and cytomegalovirus reactivation (2 patients). CONCLUSIONS: Single-agent alemtuzumab was found to have limited activity in recurrent or refractory acute leukemia. An evaluation in patients with a better prognosis, in combination with other agents or as part of consolidation therapy, is warranted.

Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia.

BACKGROUND: The objective of this study was to investigate the efficacy and safety of alemtuzumab, the humanized anti-CD52 monoclonal antibody, in patients with B-cell chronic lymphocytic leukemia and residual disease after chemotherapy. METHODS: Forty-one patients received alemtuzumab 3 times weekly for 4 weeks. The first 24 patients received 10 mg per dose, and the next 17 patients received 30 mg. All patients received infection prophylaxis during therapy and for 2 months after treatment. RESULTS: The overall response rate was 46%, including 39% of patients who received the 10 mg dose and responded versus 56% of the patients who received the 30 mg dose. The major reason for failure to respond was the presence of adenopathy. Residual bone marrow disease cleared in most patients, and 11 of 29 patients (38%) achieved a molecular disease remission. The median time to disease progression had not been reached in responders with a median follow-up of 18 months. Six patients remained in disease remission between 24-38 months after therapy. Infusion-related events were common with the initial doses, but all such events were NCI Common Toxicity Criteria Grade 1-2. Infections were reported to occur in 15 patients (37%), and 9 of these infections were reactivation of cytomegalovirus. Three patients developed Epstein-Barr virus positive, large cell lymphoma. Two patients had spontaneous resolution of the lymphoma and, in one patient, the lymphoma resolved after treatment with cidofovir and immunoglobulin. CONCLUSIONS: Alemtuzumab produced significant responses in patients with residual disease after chemotherapy. Bone marrow disease was eradicated more frequently than lymph node disease, and molecular disease remissions were achieved. A randomized trial comparing alemtuzumab with observation after chemotherapy is indicated.