Lenalidomide: an immunomodulatory drug

Lenalidomide (CC-5013; Revlimid) represents one compound in a category of new medications known as immunomodulatory drugs. These compounds are thalidomide derivatives. Through relatively minor structural modifications, the potency of the medication is improved compared with the parent compound, and the side-effect profile has changed considerably. The neurologic toxicity and pro-thrombotic effects of thalidomide are reduced in the structural analog, although concerns regarding pro-thrombotic effects are still present when lenalidomide is combined with dexamethasone. Data supporting lenalidomide's use in myelodysplastic syndrome and multiple myeloma has been published over the past several years and presented at the May 2005 meeting of the American Society of Clinical Oncology. Further trials are ongoing for many other malignancies. This report will review the preclinical and clinical results of the investigations with this exciting new therapeutic, its toxicities and future prospects.     

Organizational systems to support publicly funded tobacco treatment services

BACKGROUND: Professional societies and government organizations have promoted guidelines and best practices that encourage clinicians to routinely integrate cessation counseling into patient encounters. While research in health maintenance organizations has demonstrated that the development and maintenance of office systems do enable clinicians' smoking-cessation services, little is known about the adoption of system strategies in diverse organizations serving disadvantaged populations. METHODS: Data were collected via face-to-face interviews from November 2001 to October 2002 using a standardized systems assessment checklist at service delivery sites of 83 funded community health service agencies, which included hospitals, community health centers, and other organizations (e.g., substance abuse, mental health, and multiservice). The content of the structured assessment reflected system elements with proven effectiveness that have been included in guidelines and best practices recommendations. Detailed information was collected on the implementation strategies. RESULTS: This study found considerable attention to systems that support cessation services in diverse healthcare organizations, but much remains to be done. There is a wide diversity of implementation strategies employed, with varied degrees of sophistication. CONCLUSIONS: A major challenge is to develop systems capable of providing population-based feedback to, and between, providers, which will enable further quality improvement efforts.     

Determinants of patient and surgeon perspectives on maximum acceptable waiting times for hip and knee arthroplasty

OBJECTIVES: Lengthy waiting times for hip and knee arthroplasty have raised concerns about equitable and timely access to care. The Western Canada Waiting List project has developed priority criteria scores linked to maximum acceptable waiting times (MAWT) for different levels of priority. Our study purpose was to assess the determinants of patient- and surgeon-rated MAWT, and to test whether the anticipated waiting time has an independent influence after adjusting for age, sex and patient urgency. A second aim was to compare MAWT, waiting time and anticipated waiting time for different levels of urgency assessed using the priority criteria score. METHODS: Orthopaedic surgeons assessed 233 consecutive patients waiting for arthroplasty in terms of their urgency (assessed using the priority criteria score and a visual analogue scale), MAWT and anticipated waiting time. Patient data included urgency (assessed by a visual analogue scale), MAWT and the Western Ontario McMaster Osteoarthritis index. We used hierarchical linear regression to test the models. RESULTS: After adjusting for age and sex, urgency (assessed by priority criteria score and visual analogue scale) and anticipated waiting time accounted for 40% of the variance in surgeon MAWT. The patient model accounted for 30% of the variance in patient MAWT. Older patients preferred signficantly shorter MAWTs (P <0.05). Anticipated waiting time added significantly to both the surgeon and patient MAWT models (R(2) change 0.11 and 0.07, respectively). Actual waiting time was weakly correlated with urgency assessed using the priority criteria score (r = -0.25, P <0.0001). CONCLUSIONS: Patients' and surgeons' views are critical to a fair process of establishing MAWT for elective procedures. Anticipated waiting time may influence the perspectives on MAWT and must be considered in their interpretation.     

The effect of different stages of neuromuscular block on the bispectral index and the bispectral index-XP under remifentanil/propofol anesthesia

Facial electromyographic activity and neuromuscular block could influence bispectral index (BIS) depth of anesthesia monitoring. In this study we examined, in 30 patients undergoing general surgical procedures, the effect of different stages of neuromuscular block on BIS monitoring and compared the conventional A-2000 BIS trade mark (BIS(3.4)) with the new BIS-XP trade mark (BIS(XP)). At deep surgical anesthesia BIS(3.4) of approximately 40, under a propofol 3.61 microg/mL target-controlled infusion and a 0.15-0.3 microg. kg(-1). min(-1) remifentanil infusion, mivacurium 0.15 mg/kg was administered. The onset of neuromuscular block triggered a brief transient odd divergence in response that manifested as a BIS(3.4) increase from 43 +/- 4 to 49 +/- 7 (P = 0.007) and a BIS(XP) decline from 41 +/- 3 to 35 +/- 3 (P = 0.003) at 1 +/- 0.2 min. Then, 2.5 +/- 1 min after mivacurium administration, both monitors returned to baseline values of 43 +/- 5 and 40 +/- 4, respectively. After that, BIS(3.4) and BIS(XP) did not significantly change during complete neuromuscular block or during various levels of neuromuscular recovery. At all phases, BIS(XP) was significantly lower than BIS(3.4). Our study indicated that the BIS(3.4)/BIS(XP) bias and the wide limits of agreement do not allow values given by the two monitors to be used interchangeably.     

A study of age-related IgE pathophysiological changes

The literature on immunosenescence has focused mainly on T cell impairment. However, it is well known that B function is also profoundly affected. In particular, several studies have shown age-related changes in immunoglobulin serum levels. Concerning allergic diseases, the incidence of onset of allergic symptoms, as well as their severity, seems to decrease with age. So, the decline of onset of allergic symptoms observed in ageing might result from a decrease of serum total IgE due to an unbalance of cytokines and soluble factors involved in its production. To gain insight into the mechanisms of age related incidence of onset of allergic symptoms, as well as their severity, in this study we have evaluated in a sample of young (12 females and 15 males, range 20-64 years) and old (42 females and 20, males range 70-93 years) individuals serum values of IgE and sCD23 and in vitro Type 2 cytokine production. Total serum IgE levels were quantified by CAP-system fluorescence enzyme immunoassay. Serum CD23 levels were measured by a sandwich enzyme-linked immunoassay. Enzyme immunoassay tests have been used to quantify IL-4, IL-10 and IL-13 on mitogen-stimulated cultures. Serum total IgE and sCD23 in the two groups of young and old subjects were not significantly different. No detectable levels of IL-4, IL-10 and IL-13 were observed in supernatants from unstimulated cultures in all the subjects tested. After 48 h stimulation with PHA, cytokine amounts became detectable in all subjects. However, the values of the cytokines under study were not significantly different between young and old subjects. In our study, we have not been able to show no impairment in the afferent (type 2 cytokine production) and in the central (serum IgE and sCD23 levels) branch of allergic responses. Previous studies have shown that the efferent branch, at least studied as basophil releasability and bronchial responsiveness, is not impaired in elderly. In conclusion, as suggested from the present and previous papers it is questionable whether there is sufficient information to validate the statement that the incidence of allergic diseases decreases with age.     

Psychosocial adjustment of patients and caregivers prior to allogeneic bone marrow transplantation

There are many studies that examine the psychosocial adjustment of survivors of bone marrow transplantation (BMT). On the other hand, there are relatively few studies that examine the psychosocial adjustment of patients prior to BMT, and even fewer that focus on the psychosocial adjustment of the patient's caregiver. The purpose of the present study was to assess performance status and psychosocial adjustment to illness, mood and stress response of patients and caregivers prior to admission for allogeneic BMT. Forty patients and their 39 caregivers were assessed using standardized measures. One-fourth of the patients reported clinical levels of psychosocial maladjustment on the Psychosocial Adjustment to Illness Scale and had greater adjustment problems than BMT survivors. Approximately one-third (35%) and one-quarter (23%) of the patients reported significant symptoms of intrusive and avoidance stress responses, respectively on the Impact of Events Scale. Caregivers reported more impairments in family relationships than patients, but overall reported similar distress to that of patients. Information about the pre-BMT process appears to be critical to understanding the psychosocial impact that BMT can have on patients and their caregivers.     

In vitro treatment with interleukin-2 normalizes type-1 cytokine production by lymphocytes from elderly

The term immunosenescence is taken to mean the deterioration of immune function seen in elderly, which is manifested in increased susceptibility to infectious diseases, neoplasias, and autoimmune diseases. It is only recently that we have begun to understand the cellular and molecular changes involved. Of special interest in this regard are observations of a decline in synthesis of Type-1 cytokines which predisposes to diminished cell mediated immunity. We have evaluated the production of type 1 cytokines in old and young donors either in presence or in absence of recombinant interleukin-2 (rIL-2). Lymphocytes were stimulated with plastic bound anti-CD3 and after 48 h the supernatants were harvested and stored at-70 °C until assay. Type 1 cytokine, i.e.IL-12 and interferon-γ (IFN-γ) production by anti-CD3 stimulated lymphocytes from old subjects was significantly reduced when compared to that from young ones. This impaired production was reversed by adding rIL-2 in the culture medium. In previous studies on aged subjects, we have been able to demonstrate that in vitro treatment with rIL-2 completely restores proliferative responses and partially rescues the increased apoptosis of T cell cultures. Present and previous results suggest that rIL-2 completely restores Type 1 responses by overcoming the well known costimulation deficit of aged lymphocytes.