Reducing mortality in severe sepsis: the Surviving Sepsis Campaign

This article traces the history and evolution of the Surviving Sepsis Campaign as a public health initiative through its several stages of development. The literature that has characterized clinical experiences with interventions related to the campaign is reviewed and conclusions discussed.     

Magnetic resonance imaging assessment of spinal inflammation in patients treated for ankylosing spondylitis

OBJECTIVE: To compare different magnetic resonance imaging (MRI) based algorithms for assessment of spinal inflammation in patients with ankylosing spondylitis (AS) being treated with disease modifying drugs. METHODS: Eleven patients (10 men, 1 woman) who fulfilled modified New York diagnostic criteria and had severe disease [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) > 4] were given intravenous infusion of infliximab (Remicade, 5 mg/kg) for 96 weeks. Whole-spine MRI was done at 0, 24, and 54 weeks. Measurements of the Ankylosing Spondylitis Spinal MRI Activity Score (ASspiMRI), paravertebral inflammatory lesion count (pILC), contrast:noise ratio (CNR) measurements of defined inflammatory lesions, and other scores together with C-reactive protein concentration were made at each visit. Examinations were anonymized and randomly presented twice to 2 radiologists. The significance of any changes in scores, their correlation with the BASDAI, and interobserver and intraobserver correlations were calculated. RESULTS: The mean (+/- SD) BASDAI improved from 7.2 (+/- 1.5) to 1.3 (+/- 0.9) after 54 weeks (p < 0.001), and the ASspiMRI score improved from 12.0 (+/- 8.0) to 0.2 (+/- 0.5) (p < 0.001). Correlations between ASspiMRI score and BASDAI were 0.831, 0.746, and 0.369 (p < 0.001 each). The pILC improved significantly (p < 0.01). CNR showed no correlation with any clinical score. CONCLUSION:The ASspiMRI score performed best for assessment and quantification of spinal inflammation and disease activity in patients with AS, but should also quantify paravertebral inflammatory lesions, since we could show that this will significantly improve its correlation to clinical scores and increase its sensitivity to mild inflammatory processes.     

Autoimmune conditions and chronic infections in chronic lymphocytic leukemia patients at diagnosis are associated with unmutated IgVH genes

Few data are available concerning the prevalence of autoimmune disease or chronic infections in chronic lymphocytic leukemia patients at diagnosis as well as their clinical outcome. We studied the frequency of such chronic conditions in relation to prognostic markers. A history of autoimmune disease or chronic infection was found in 21% of 186 chronic lymphocytic leukemia patients (12% in autoimmune diseases, 9% in chronic infections). Patients with a history of chronic stimulation were more likely to have unmutated IgV(H) genes (p<0.002), unfavorable or intermediate risk cytogenetics (11q, 17p deletions, trisomy 12) (p<0.001), and higher CD38 expression (p=0.004). Autoimmune conditions (n=22) were characterized by female predominance (55.0%) with a high frequency of unmutated IgV(H) (53,8%). Median time to first treatment was 83 months for the chronic stimulation group compared to 128 months for the non-chronic stimulation group (n.s.). Patients suffering from chronic conditions at chronic lymphocytic leukemia diagnosis are likely to have poor prognostic markers, particularly unmutated IgV(H) genes.     

The physical challenges of early breastfeeding

Breastfeeding rates have recently increased in the United States and Canada and a majority of women now initiate breastfeeding. Feminist scholarship on breastfeeding has addressed a variety of issues related to women's breastfeeding experiences but has tended to ignore or downplay the potentially physically challenging aspects of early breastfeeding. This study, based on semi-structured, in-depth interviews with 52 women from Canada and the United States conducted at approximately one month postpartum, examines women's experiences of pain and discomfort associated with breastfeeding. The findings demonstrate that many women experienced pain and discomfort and that they were generally surprised by the extent, intensity and duration of discomfort and pain, which ranged from mild to severe. Several women indicated that the physical impact of breastfeeding affected their relationship with their baby; others indicated that they became hesitant to continue the practice due to feelings of physical vulnerability, pain and/or discomfort. Lastly, women's experiences of the physical implications of breastfeeding were influenced in part by assistance provided by health care practitioners, in both positive and negative ways. The practice of breastfeeding has the potential to challenge women's physicality. Feminist scholars addressing the topic of breastfeeding, women's postpartum health, and embodiment must more directly and comprehensively account for the potentially negative physical implications and demands associated with early breastfeeding.     

Cutaneous sensitivity to ultraviolett light and chemical irritants

Summary This investigation examines the relationship between the sun sensitivity of human skin and its response to chemical irritants. Forty-four Caucasoid subjects with normal back skin were studied. The minimal erythema dose (MED) was determined with the sunburning spectrum of a high-pressure mercury lamp. Cutaneous irritability was quantified using a series of seven irritants of different chemical structure, solubility, and concentrations. The response was either expressed as a threshold value of exposure time (ammonium hydroxide, sodium hydroxide) or was graded after a standard exposure in intensity of whealing (dimethyl sulphoxide) or erythema (sodium lauryl sulphate, quaternium 1, croton oil, kerosene).A significant correlation between the MED and the response to all seven primary irritants was found. The relationship was better for water-soluble irritants than for lipid-soluble ones. Despite marked individual variations the determination of the MED is suggested as a valuable tool in identifying hyperirritable skin. Skin typing based on complexion and sunburn history proved to be less reliable.Supported by the Ministerium für Wissenschaft und Forschung, Nordrhein-Westfalen     

The intracellular 52-kd Ro/SSA autoantigen in keratinocytes is up-regulated by tumor necrosis factor alpha via tumor necrosis factor receptor I

OBJECTIVE: Previous studies have shown that the nuclear Ro/SSA autoantigens involved in photosensitive cutaneous lupus manifestations are regulated by ultraviolet B (UVB) irradiation. UVB exposure triggers the release of tumor necrosis factor alpha (TNFalpha) from keratinocytes in the epidermis and from mast cells in the dermis. The present study aimed to characterize the effect of TNFalpha on messenger RNA (mRNA) and protein expression of the intracellular 52-kd Ro/SSA autoantigen in primary human keratinocytes and to elucidate the TNFalpha receptor (TNFR) signaling pathways mediating this effect. METHODS: Expression of 52-kd Ro/SSA mRNA in primary human keratinocytes was investigated by quantitative real-time polymerase chain reaction (LightCycler system) using GAPDH as the housekeeping gene. Expression of 52-kd Ro/SSA protein was studied by flow cytometry after staining intracellular protein with IgG purified from an anti-52-kd Ro/SSA-positive serum. TNFR function was assessed by culturing cells in the presence and absence of neutralizing antibodies directed against the TNFR subunits TNFRI and TNFRII. RESULTS: TNFalpha-induced up-regulation of 52-kd Ro/SSA mRNA expression peaked at 4 hours, followed by up-regulation of intracellular 52-kd Ro/SSA protein expression at 24 hours, independently of apoptosis. Between different donors, a high variability of both constitutive expression levels and TNFalpha-induced changes in 52-kd Ro/SSA mRNA and protein expression was observed. The up-regulatory effect of TNFalpha on 52-kd Ro/SSA mRNA and protein expression was inhibited by anti-TNFRI antibodies but enhanced by anti-TNFRII antibodies. CONCLUSION: The finding that TNFalpha up-regulates 52-kd Ro/SSA expression in keratinocytes via TNFRI suggests that it may play a role in the pathogenesis of anti-Ro/SSA-associated cutaneous lupus erythematosus.     

The effects of supra-normal protein C levels on markers of coagulation, fibrinolysis and inflammation in a human model of endotoxemia

The protein C pathway serves as a modulating system with both anti-inflammatory and anticoagulant properties and is intimately involved in the pathophysiology of inflammation and sepsis. Treatment with recombinant human activated protein C (rhAPC) can reduce the mortality of severe sepsis.We investigated whether an elevation of plasma protein C levels to supra-normal levels by infusion of a protein C zymogen concentrate has an effect on coagulation, protein C activation or inflammation in a human endotoxemia model. Eleven healthy male volunteers were enrolled in a double-blind, placebo-controlled two-way cross-over trial. Ten minutes after infusion of 2ng/kg endotoxin each volunteer received either placebo or a plasma-derived protein C zymogen concentrate (Ceprotin, Baxter) (150 U/kg as a slow bolus infusion followed by 30 U/kg/h continuous infusion until 4 hours after LPS-infusion). Protein C antigen and activity increased 4- to 5-fold after infusion of the concentrate. APC was generated during endotoxin-induced inflammation in the placebo (1.6 fold increase) and the protein C period (4.0-fold increase). The increase of APC levels correlated with the TNF-alpha and IL-6 release in both periods (r = 0.65-0.68; p < 0.05) and paralleled the protein C antigen and activity levels in the period with supranormal protein C levels. Supra normal protein C levels resulted in slightly, although non-significant, lower tissue factor mRNA expression and thrombin generation (TAT, F1+2). Systemic inflammation (TNF-alpha, IL-6) was not influenced by protein C zymogen concentrate administration. Infusion of protein C zymogen was safe and no adverse effects occurred. The increase of protein C levels several fold above the normal range resulted in a proportional increase of the APC levels, but had no major anticoagulant, anti-inflammatory or profibrinolytic effects. Low grade endotoxemia itself induces significant protein C activation, which correlates with the TNF release.     

Blood transfusions, HIV and legal liability in South Africa

This article deals with the legislation, regulations and clinical guidelines regulating blood transfusions in South Africa. Although these are aimed at protecting both the recipients and donors of blood, the risk of HIV infected blood being donated and transfused is on the increase, due to inter alia, the high prevalence of HIV infection among the South African population. The article discusses, in the absence of strict liability in South Africa, the possible legal liability of blood services, medical practitioners, the Department of Health, and the blood donor when a recipient of blood is infected. The need for informed consent by both the recipient and the donor is also discussed, as well as the legal repercussions where informed consent is lacking.     

Elevated levels of interleukin-18 predict the development of type 2 diabetes: results from the MONICA/KORA Augsburg Study, 1984-2002

We investigated prospectively the association between serum levels of interleukin (IL)-18 and the risk of type 2 diabetes in a case-cohort study conducted in middle-aged men and women who represented 7,936 participants of the three MONItoring of trends and determinants in CArdiovascular disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) surveys. Levels of IL-18 were measured in stored samples of 527 case subjects with incident type 2 diabetes and 1,698 noncase subjects. Elevated levels of IL-18 were associated with a significantly increased risk of type 2 diabetes after adjustment for age, sex, survey, BMI, systolic blood pressure, ratio of total cholesterol to HDL cholesterol, physical activity, alcohol intake, smoking status, and parental history of diabetes. Hazard ratios and 95% confidence intervals comparing quartile extremes were 1.73 (1.25-2.40). Further adjustment for C-reactive protein and IL-6 had no impact on the observed associations. However, the risk of developing type 2 diabetes was highest among subjects with elevated levels of both IL-18 and CRP or IL-18 and IL-6, respectively. In conclusion, elevated levels of IL-18 are associated with a considerably increased risk of type 2 diabetes. This association is independent of a generalized proinflammatory state, but subjects with elevated levels of several inflammatory markers seem to be particularly prone to develop type 2 diabetes.