Ro (SSA) and La (SSB) antibodies

Summary This review traces the historical development of information regarding the Ro (SSA) and La (SSB) autoantibody systems over the past twenty years. Clinical and serologic findings are integrated with fundamental observations in this rapidly expanding area of research. Retrospective analysis of the physicochemical properties of the antigens and the cellular staining characteristics of antibodies to these antigens suggest that SjD and Ro and SSA, as well as SjT and La, SSB, and Ha antigens probably are similar macromolecules. The immunologic identity of Ro with SSA and La with SSB and Ha has been established previously. Antibodies to these antigens are directed against macromolecules containing small RNA nucleotides.Antibodies to the Ro (SSA)-La(SSB) antigen system commonly are detected in the sera of patients with systemic lupus erythematosus and Sjögren's syndrome and appear to be of diagnostic significance. These antibodies occur in up to one quarter of patients with systemic lupus erythematosus (SLE) without the sicca complex, but also in patients with ANA negative SLE who have a prominent photosensitive dermatitis and may have serious renal disease, subacute cutaneous SLE, and in infants and mothers of infants with neonatal SLE. Thus, these antibody systems form a serologic link between many unusual connective tissue diseases and systemic SLE.Antibodies to Ro (SSA)-La(SSB) are associated not only with Sjögren's syndrome occurring alone, but also with Sjögren's syndrome occurring in the setting of other connective tissue diseases including SLE and rheumatoid arthritis. Anemia, leukopenia, and thrombocytopenia, as well as hyperglobulinemia and the presence of rheumatoid factor, cryoglobulins, and antibodies to nuclear antigens are associated significantly with Ro positivity in Sjögren's syndrome patients. There is a striking association of vasculitis in the clinical setting of Sjögren's syndrome with the presence of antibodies to Ro (SSA). In addition to peripheral nerve involvement, unusual central nervous system manifestations as well as myositis occur in these Ro(SSA) positive Sjögren's syndrome patients. Deposition of immunoglobulin and complement within vessel walls of kidney and muscle from Ro positive patients with Sjögren's syndrome suggests a possible role for immune complex deposition in the pathogenesis of the vasculitis.Supported by National Institutes of Health grant 5ROI-AM-25650-03 and Research Career Development Award 5-KO-4-AM-00524-02     

Pharmacology and physiology of ovine corticosteroid receptors

The aim of these studies was to characterize the ovine corticosteroid receptors (MR, mineralocorticoid receptors and GR, glucocorticoid receptors) in ovine hippocampus and brainstem. Adrenal-intact and adrenalectomized ewes were studied; adrenalectomized ewes were killed 47 +/- 9 h after steroid withdrawal, when symptoms of hypotension and/or hyperkalemia became evident. RT-PCR, immunoblotting and pharmacologic studies indicated the presence of both MR and GR in hippocampus and brainstem. Competitive binding studies using 3H-cortisol in brain tissue showed that the ovine MR binds cortisol, aldosterone and progesterone with equal affinity. Differences in receptor availability in intact and adrenalectomized ewes, along with determination of the binding affinity (K(d)) of MR and GR, suggested that MR occupancy is about 90%, whereas GR occupancy is about 30%, in normal animals. There was a significant increase in protein level of MR in brainstem, and the appearance of a higher molecular weight band for MR in hippocampus following steroid withdrawal, however no significant change in mRNA was detected by semiquantitative RT-PCR for either MR or GR in hippocampus or brainstem following steroid withdrawal. These studies suggest that physiological ligands of MR in the sheep brain include progesterone and cortisol, and that, as in other species, affinity of MR for cortisol is greater than that of GR.     

Idiopathic cholangiopathy in a biliary cast syndrome necessitating liver transplantation following head trauma

The development of total biliary casts is very unusual, especially in patients who have not undergone liver transplantation. The aetiology of these casts is uncertain but several factors are believed to play a role, including periods of fasting, haemolysis, cholangitis and recent surgery. Resultant bile stasis and/or gallbladder hypocontractility promote sludge and subsequent stone formation. Here we present the case of a previously well 66-year-old woman who developed a total biliary cast several weeks after being involved in a road traffic accident during which she sustained head injuries but no obvious liver insult. This cast was removed at laparotomy but the patient had resultant diffuse biliary tree abnormalities and persistent cholestasis and subsequently required a liver transplant. The possible aetiologies of biliary cast formation and subsequently cholangiopathy necessitating transplantation in this patient are described.     

Organ-specific models of Streptococcus pneumoniae disease

The variability of the course of infection by Streptococcus pneumoniae is well known but poorly understood. Most animal models of pneumonia, sepsis or meningitis have been forced to use site-specific bacterial inoculation to mimic localized human infection. This study examined the differences in the progression of disease-causing strains D39 (serotype 2), A66.1 (serotype 3) and TIGR4 (serotype 4) using isolates transformed with the Gram-positive lux transposon cassette, Tn4001 luxABCDE Km(r). Expression of the lux operon results in bioluminescence, permitting the detection of the bacteria within a living animal while using a CCD camera. Mice infected intranasally with A66.1 developed only pneumonia, those challenged with D39 experienced high-grade sepsis, while TIGR4 infection resulted in low-grade pneumonia and bacteremia ultimately progressing to meningitis. Quantitative analysis of bacterial titers confirmed these patterns, which were consistent across different lineages of mice. Mice anesthetized with ketamine and xylazine developed more severe forms of the disease compared with isoflurane. These studies unambiguously characterize 3 distinct models of the natural course of pneumococcal infection. Mapping these models provides a framework for detailed molecular modeling of pneumococcal virulence determinants at specific stages of disease.     

Survivorship care in breast cancer: Perceptions of patients and primary care physicians

Objective

To compare the perceptions of breast cancer survivors and primary care physicians (PCPs) about PCPs’ ability to deliver survivorship care in breast cancer.

Design

Mailed survey.

Setting

British Columbia.

Participants

A total of 1065 breast cancer survivors who had completed treatment of nonmetastatic breast cancer within the previous year, and 587 PCPs who had patients with nonmetastatic breast cancer discharged to their care within the preceding 18 months.

Main outcome measures

Breast cancer survivors’ and PCPs’ confidence ratings of PCPs’ ability to deliver the following aspects of care: screening for recurrence; managing osteoporosis, lymphedema, endocrine therapy, menopausal symptoms, and anxiety about or fear of recurrence; and providing nutrition and exercise counseling, sex and body image counseling, and family counseling. Response options for each question included low, adequate, or good. Responses were summarized as frequencies and compared using χ² tests.

Results

Response rates for breast cancer survivors and PCPs were 47% and 59%, respectively. Responses were statistically different in all categories (P < .05). Both groups were most confident in the ability of PCPs to screen for recurrence, but breast cancer survivors were 10 times as likely to indicate low confidence (10% of breast cancer survivors vs 1% of PCPs) in this aspect of care. More breast cancer survivors (23%) expressed low confidence in PCPs’ ability to provide counseling about fear of recurrence compared with PCPs (3%). Aspects of care in which both breast cancer survivors and PCPs were most likely to express low confidence included sex and body image counseling (35% of breast cancer survivors vs 26% of PCPs) and family counseling (33% of breast cancer survivors vs 24% of PCPs). Primary care physicians (24%) described low confidence in their ability to manage lymphedema.

Conclusion

Breast cancer survivors and PCPs are reasonably confident in a PCP-based model of survivorship care. Primary care physicians are confident in their ability to manage physical effects related to breast cancer, with the exception of lymphedema. Low confidence ratings among both groups in psychosocial aspects of care suggest an area for improvement.     

The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo

Naturally occurring CD4(+)CD25(hi)Foxp3(+) Tregs (nTregs) are highly proliferative in blood. However, the kinetics of their accumulation and proliferation during a localized antigen-specific T cell response is currently unknown. To explore this, we used a human experimental system whereby tuberculin purified protein derivative (PPD) was injected into the skin and the local T cell response analyzed over time. The numbers of both CD4(+)Foxp3(-) (memory) and CD4(+)Foxp3(+) (putative nTreg) T cells increased in parallel, with the 2 populations proliferating at the same relative rate. In contrast to CD4(+)Foxp3(-) T cell populations, skin CD4(+)Foxp3(+) T cells expressed typical Treg markers (i.e., they were CD25(hi), CD127(lo), CD27(+), and CD39(+)) and did not synthesize IL-2 or IFN-gamma after restimulation in vitro, indicating that they were not recently activated effector cells. To determine whether CD4(+)Foxp3(+) T cells in skin could be induced from memory CD4(+) T cells, we expanded skin-derived memory CD4(+) T cells in vitro and anergized them. These cells expressed high levels of CD25 and Foxp3 and suppressed the proliferation of skin-derived responder T cells to PPD challenge. Our data therefore demonstrate that memory and CD4(+) Treg populations are regulated in tandem during a secondary antigenic response. Furthermore, it is possible to isolate effector CD4(+) T cell populations from inflamed tissues and manipulate them to generate Tregs with the potential to suppress inflammatory responses.     

Dextrin–rhEGF conjugates as bioresponsive nanomedicines for wound repair

Growth factors are known to act in concert to promote wound repair, but their topical application rarely leads to a significant clinical improvement of chronic wounds due to premature inactivation in wound environment. The aim of this study was to synthesise a polymer–growth factor conjugate and investigate whether the novel concept called Polymer-masking-UnMasking-Protein Therapy (PUMPT) might be used to generate bioresponsive polymer therapeutics as nanomedicines able to promote tissue repair. Succinoylated dextrin ( 85,000 g/mol;  19 mol% succinoylation), and rhEGF were chosen as a first model combination. The conjugate synthesised contained  16%wt rhEGF and < 1% free protein. It exhibited increased stability towards proteolytic degradation by trypsin and the clinically relevant enzyme neutrophil elastase. The dextrin component was degraded on addition of α-amylase leading to sustained release of free rhEGF over time (52.7% release after 168 h). When biological activity was assessed (± α-amylase) in proliferation assays using epidermoid carcinoma (HEp2) cells and HaCaT keratinocytes, as anticipated, polymer conjugation reduced rhEGF bioactivity (p = 0.0035). However, exposure to physiological concentrations of α-amylase triggered dextrin degradation and this led to protein unmasking with restoration of bioactivity to the level seen for unmodified rhEGF. Indeed, prolongation of HEp2 proliferation was observed over 8 days. The inability of dextrin, succinoylated dextrin or α-amylase alone to induce proliferative effects, and the ability of α-amylase-exposed dextrin–rhEGF to induce phosphorylation of the epidermal growth factor receptor (EGFR) in HEp2 cells confirmed a mechanism of action by stimulation of classical signal transduction pathways. These observations suggest that this dextrin–rhEGF, and other dextrin-growth factor conjugates have potential for further development as bioresponsive nanomedicines for tissue repair.     

Evidence-based practice and the road to Magnet status

Conducting research and using evidence-based practice play a major role in achieving Magnet status, the sought-after recognition awarded by the American Nurses Credentialing Center to healthcare institutions that exhibit nursing excellence. The authors present a synopsis of a conference sponsored by a Sigma Theta Tau International consortium in which a panel of nurse leaders distinguishes between research and evidence-based practice and discusses strategies to achieve both in the journey to Magnet status.     

Cancer information needs of people with intellectual disability: A review of the literature

The lifespan of people with an intellectual disability has increased significantly in recent years; however, this has resulted in a rising incidence of age-related illnesses including cancer. The World Health Organisation has expressed concern as evidence suggests prevalence rates for cancer are increasing for this group. The needs of people with a cancer diagnosis and an intellectual disability are beginning to be highlighted; however, there appears to be a substantial dearth of services including appropriate cancer information. This presents alarming obstacles and barriers to high-quality cancer care impacting on treatment, management and overall survival rates for this client group. Furthermore, a number of policy and research reports directed at the health needs of people with an intellectual disability have continually highlighted the need for accessible information and effective communication. Having access to cancer information should be considered a crucial part of providing optimum holistic care for this client group. Cancer professionals should assess the unique information needs of people with an intellectual disability as mainstream information does not meet their requirements. Furthermore, health professionals working in intellectual disability settings must also address their knowledge and information deficits in this regard. This paper presents a review of the literature with a specific focus on the cancer information needs of people with an intellectual disability.