Edith Burns

Familial Occurrence of Hypersensitivity to Phenytoin

PURPOSE Therapy with anticonvulsants such as phenytoin, phenobarbital, and carbamazepine can be complicated by severe hypersensitivity reactions. Previous work has suggested that the predisposition to such reactions is based on an inherited abnormality in the detoxification of reactive metabolites of the drugs. However, there are no reports of familial occurrence of the reactions in the literature. In the current study, we examined a family in which three siblings developed hypersensitivity reactions to phenytoin, confirming the inheritance of a predisposition to the reactions. Detoxification of reactive metabolites of the anticonvulsants was studied in cells from the patients and their siblings. PATIENTS AND METHODS Three siblings from a family of 12 siblings developed hypersensitivity reactions to phenytoin characterized by fever, rash, lymphadenopathy, and anicteric hepatitis. All recovered completely after discontinuation of treatment. One sibling tolerated phenobarbital without toxic sequelae. Peripheral blood mononuclear cells from the three patients and five additional siblings who had never taken anticonvulsants were exposed to oxidative metabolites of phenytoin, phenobarbital, and carbamazepine generated by a hepatic microsomal drug-metabolizing system in vitro. The toxicity of metabolites in the cells from the siblings was compared with that in cells from control subjects. RESULTS Cells from each of the patients who had experienced a hypersensitivity reaction exhibited increased toxicity from metabolites of phenytoin and carbamazepine, while the cellular response to metabolites of phenobarbital was within normal limits. Cells from four of the other siblings showed an abnormal response to phenytoin metabolites, while cells from the final sibling detoxified phenytoin metabolites normally. CONCLUSION Our observations on the patients confirm the inherited nature of phenytoin hypersensitivity reactions in vivo. In vitro studies demonstrated abnormal metabolite detoxification in the patients and several of their siblings. The detoxification defect included metabolites of phenytoin and carbamazepine but not of phenobarbital. A family history of a drug hypersensitivity reaction should alert physicians to the probability of a markedly increased risk of an adverse reaction in family members. In vitro assays to confirm adverse reaction risks may ultimately be able to provide individualized risk assessment for patients who must take anticonvulsants.

Using the common sense model to design interventions for the prevention and management of chronic illness threats: From description to process

In this article, we discuss how one might use the common sense model of self-regulation (CSM) for developing interventions for improving chronic illness management. We argue that features of that CSM such as its dynamic, self-regulative (feedback) control feature and its system structure provide an important basis for patient-centered interventions. We describe two separate, ongoing interventions with patients with diabetes and asthma to demonstrate the adaptability of the CSM. Finally, we discuss three additional factors that need to be addressed before planning and implementing interventions: (1) the use of top-down versus bottom-up intervention strategies; (2) health care interventions involving multidisciplinary teams; and (3) fidelity of implementation for tailored interventions.

Age-related decline in immunity: implications for vaccine responsiveness

Aging is associated with declines in immune system function, or ‘immunosenescence’, leading to progressive deterioration in both innate and adaptive immunity. These changes contribute to the decreased response to vaccines seen in many older adults, and morbidity and mortality from infection. Infections (e.g., influenza, pneumonia and septicemia) appear among the top ten most-common causes of death in adults in the USA aged 55 years and older. As immunosenescence has gathered more attention in the scientific and healthcare communities, investigators have demonstrated more links between immunosenescent changes and morbidity and mortality related to infections and declining vaccine responses. This review summarizes the recent literature on age-dependent defects in adaptive and innate immunity, data linking these defects to poor vaccine response and morbidity and mortality, current recommendations for vaccinations and potential strategies to improve vaccine efficacy in older adults.

Does patient blood glucose monitoring improve diabetes control: a systematic review of the literature

OBJECTIVE The purpose of this systematic review was 2-fold: first, to perform a comprehensive review of relevant studies on the impact of self-monitoring of blood glucose (SMBG) on HbA1c levels for patients with type 2 diabetes mellitus and, second, to explore mediators and moderators within a self-regulation framework. DATA SOURCES Five databases-Medline, PsychInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing & Allied Health Literature (CINAHL)-were searched. STUDY SELECTION Cross-sectional, longitudinal, and randomized control trials from 1990 to 2006, which included patients with type 2 diabetes not on insulin, were reviewed. In total, 6,769 studies were screened for inclusion, 89 were retrieved for detailed analysis, and 29 met criteria for inclusion in the review. DATA EXTRACTION Data on the impact of SMBG on HbA1c, potential mediators and moderators, study design and participants, and limitations of each study were retrieved. DATA SYNTHESIS Twenty-nine studies were included in this review: 9 cross-sectional studies, 9 longitudinal studies, and 11 randomized controlled trials. Evidence from the cross-sectional and longitudinal studies was inconclusive. Evidence from randomized controlled trials suggests that SMBG may lead to improvements in glucose control. Very few studies examined potential mediators or moderators of SMBG on HbA1c levels. CONCLUSIONS SMBG may be effective in controlling blood glucose for patients with type 2 diabetes. There is a need for studies that implement all the components of the process for self-regulation of SMBG to assess whether patient use of SMBG will improve HbA1c levels.

Immunodeficiency of Aging

SummaryAging is associated with declines in multiple areas of immune function, but to date no single mechanism has emerged as being responsible for all the observed changes. Many changes occur at different rates within individuals as well as between individuals. With advancing age there is a concomitant increase in the incidence of many infections and cancers. It is being increasingly acknowledged that autoimmune processes play a proinflammatory role in the development of many pathological conditions, such as atherosclerosis. However, direct causal relationships between specific changes in immunity and the occurrence of specific diseases are rare. There is accumulating epidemiological, in vivo and in vitro evidence to support many such direct relationships in both animals and humans. It is likely that the mechanisms underlying age-related changes in immunity are multifactorial, with both genetic and environmental factors playing a significantrole. Despite the current lack of unifying theories, much active and exciting work is proceeding in the area of immune stimulation. Studies describing age-related changes in immunity, as well as the testing of interventions to reverse these changes, will continue to fill the gaps in our knowledge, leading to a more comprehensive understanding of immunosenescence.

Effects of Aging on Immune Function

A variety of changes are observed in the immune system in both animals and humans with increasing age. There is a decline in the functional capacity of the cell populations that mount generalized and focused immune responses, and decreasing production and response of these cells to regulatory signals and proteins. These changes translate into less effective innate and adaptive immune responses, increased reactivity against self-antigens in vivo, and an increased incidence of infection. There may also be an increased risk of mortality. The mechanisms underlying age-related changes in immune function are not fully understood, but are likely to be multifactorial, including environmental and behavioral factors that affect over-all immune function from the molecular level to that of the entire organism.

Hospital stay amongst patients undergoing major elective colorectal surgery: predicting prolonged stay and readmissions in NHS hospitals

Aim  Reduced hospital stay confers clinical and economic benefits for patients and healthcare providers. This article examines the length of stay and consequent bed resource usage of patients undergoing elective excisional colorectal surgery in English NHS trusts.

Aging, Immunity, and Cancer

BACKGROUND The prime function of the immune system is to protect the entire organism from a variety of insults and illnesses, including the development of cancer. The question of how age-related declines in immune function contribute to an increasing incidence of malignancies continues to be a focus of discussion and speculation. METHODS The recent literature from the National Library of Medicine database (1990 through the present) was searched for articles using the medical subject headings (MeSH terms) of aging, immunity, cancer, senescence, and apoptosis. Bibliographies of articles retrieved were also scanned. RESULTS Data from in vitro and in vivo animal and human studies demonstrate clear age-related alterations in both the cellular and humoral components of the immune system, but there is little evidence supporting direct causal links between immune senescence and most malignancies. CONCLUSIONS Senescent decline in immune surveillance leads to the accumulation of cellular and DNA mutations that could be a significant factor in the development of malignancy and programmed cell death or apoptosis observed in the elderly.

Immunology and Infectious Disease

Immunologic function declines with age. Indeed, most physiologic functions decline with age. Why, then, has so much attention been given to the study of immunologic changes in elderly humans and laboratory animals? Immunologic function probably is the most intensively studied physiologic process in gerontology. Part of the reason has to do with the rapid growth in all aspects of immunologic research in the past 3 decades. In addition, immunocytes (lymphocytes, monocytes, and polymorphonuclear leukocytes) are the most easily obtained tissue specimens in humans. A tube of venous blood provides the immunologist with millions of cells with which to study antibody production, cytotoxicity, proliferation, migration, and other characteristics that are necessary for the continued health and survival of an organism.

Decreased specific antibody synthesis in old adults: Decreased potency of antigen-specific B cells with aging

The rise in rates of infection in adults over the age of 60 is accompanied by a decreased ability of older adults to make specific immune responses after immunization with a variety of specific antigens (Ag). This investigation delineates age-related changes in Ag-specific humoral immunity, comparing adults over age 60 to young adults aged 18-40, using tetanus toxoid (TT) as an immunologic probe. A culture system which does not require TT booster immunizations of study subjects was used to induce in vitro specific antibody responses. The amount of anti-TT antibody (Ab) produced in serum and in culture was measured by a TT-specific enzyme-linked immunosorbent assay (ELISA). The numbers of anti-TT Ab-secreting B cells were measured by a TT-specific ELISA-plaque assay. The TT-specific responses of old subjects were significantly less than that seen for young control subjects in the following measures: (1) serum anti-TT Ab titers (mean +/- S.E. log 2 titer = 3.3 +/- 1.1 vs. 9.5 +/- 1.4, P less than 0.01); (2) anti-TT Ab produced by peripheral blood lymphocytes (PBL) in cultures stimulated with TT (6 +/- 2.1 ng/ml vs. 22 +/- 8.4 ng/ml, P less than 0.01); (3) numbers of anti-TT Ab secreting B cells per million cells cultured (6.7 +/- 3.4 vs. 26.6 +/- 7.6, P less than 0.001) and (4) mean ng Ab secreted per anti-TT Ab-secreting B cell (0.6 +/- 0.4 ng vs. 12.7 +/- 7.8 ng, P less than 0.01). This study shows that both decreased numbers of Ag-specific immune B cells and decreased potency on a per cell basis contribute to the impaired immune responses to immunizations in older adults.