Dose-time considerations of head and neck squamous cell carcinomas treated with irradiation

The dose-time factors in the external beam treatment of 473 patients with squamous cell carcinoma of the pharyngeal wall, vocal cord, pyriform sinus or supraglottic larynx were considered. The effect of overall treatment time on the tumor response was quantified by estimating the increment in dose per day needed to achieve a constant rate of local control, that is, the dose required to counterbalance the effect of growth of the tumor during irradiation. The estimated increment in isoeffect dose per day varies between sites, however, the increments, although estimated with considerable uncertainty, are in general larger than 1 Gy per day. These estimates are consistent with accelerated tumor clonogen repopulation during irradiation.     

Smoking and roentgenographic opacities in US Navy asbestos workers

The US Navy's Asbestos Medical Surveillance Program monitors civilian and military employees with current or historical exposure to asbestos. The prevalence of definite radiologic parenchymal abnormalities (ILO category greater than or equal to 1/0) was 3.10 percent for 32,233 smokers vs 1.09 percent for 13,414 nonsmokers. The age-adjusted prevalence ratio was 2.23. The difference in prevalence between smokers and nonsmokers persisted in all age groups studied and was greatest among the oldest employees. These findings in a large population suggest that parenchymal opacifications alone will not reliably differentiate between the impacts of asbestos exposure and smoking in patients who face both risks.     

Decreased blood dendritic cell counts in type 1 diabetic children

In this study DC numbers, phenotype and DC responses to the Toll-like receptor (TLR)-3 ligand, poly I:C, were examined in new-onset Type 1 diabetes (T1D) patients (ND) and in established T1D patients (ED). Absolute blood myeloid DC (MDC) and plasmacytoid DC (PDC) numbers were decreased in ND and ED patients compared to age-matched controls. The decrease in MDC and PDC counts was less evident in patients with a combination of T1D and coeliac disease (CD) or CD alone. The age-dependent decline in blood DC numbers, found in control children, was not evident in ND patients, such that 2-10 years old ND children had similar MDC and PDC numbers to 15-17 years old controls. In ED patients the t-score of MDC and PDC numbers related to the age of diagnosis but not to disease duration. Blood DC in T1D patients were not distinguished from those of controls by the levels of HLA-DR, CD40 and CD86 expression or the percentage of DC expressing cytokines, IL-12, IL-10, IL-6 and TNF-alpha, in responses to poly I:C. If low DC numbers are shown to contribute to the autoimmunity in T1D, interventions aimed to increase DC numbers may mitigate against beta-cell loss.     

Vascular delivery of c-myc antisense from cationically modified phosphorylcholine coated stents

c-Myc is involved in the formation of neointimal hyperplasia. We investigated in vitro, ex vivo and in vivo release of antisense c-myc from cationically modified phosphorylcholine-coated stents, as well as the effects on c-Myc expression and neointima formation in a porcine coronary stent model. In vitro experiments were performed to determine optimal loading of stents with antisense. Stents loaded with labelled antisense were deployed in porcine arteries ex vivo and in vivo. Antisense was detected in the vessel wall directly surrounding the stent of pig carotid and coronary artery up to 48 h after stent deployment. Nuclear uptake was observed in endothelial and vascular smooth muscle cells. Labelled antisense within peripheral tissues in vivo was <1.0% of that within stented arterial segments. Control and antisense loaded stents implanted into 10 pig coronary arteries and analysed at 28 days post-stenting showed that lumen area within the antisense stents was significantly increased (i.e. 30.5% greater, P<0.01), whilst both neointimal area and neointimal thickness were significantly reduced (17.5% and 19.5%, respectively, P<0.01) compared to control stents. Cationically modified phosphorylcholine coated stent-based delivery of c-myc antisense is feasible with minimal systemic delivery and is associated with a reduction of in-stent neointimal hyperplasia in pig coronary arteries.     

ICOS is required for the generation of both central and effector CD4+ memory T‐cell populations following acute bacterial infection

Interactions between ICOS and ICOS ligand (ICOSL) are essential for the development of T follicular helper (Tfh) cells and thus the formation and maintenance of GC reactions. Given the conflicting reports on the requirement of other CD4⁺ T‐cell populations for ICOS signals, we have employed a range of in vivo approaches to dissect requirements for ICOS signals in mice during an endogenous CD4⁺ T‐cell response and contrasted this with CD28 signals. Genetic absence of ICOSL only modestly reduced the total number of antigen‐specific CD4⁺ T cells at the peak of the primary response, but resulted in a severely diminished number of both T central memory and T effector memory cells. Treatment with blocking anti‐ICOS mAb during the primary response recapitulated these effects and caused a more substantial reduction than blocking CD28 signals with CTLA4Ig. During the memory phase of the response further signals through ICOS or CD28 were not required for survival. However, upon secondary challenge only Tfh cell expansion remained heavily ICOS‐dependent, while CD28 signals were required for optimal expansion of all subsets. These data demonstrate the importance of ICOS signals specifically for memory CD4⁺ T‐cell formation, while highlighting the potential of therapeutically targeting this pathway.     

IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs

The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22–blocking agents in B-cell–mediated autoimmune conditions.Tertiary lymphoid organs (TLOs) are organized clusters of immune cells that preferentially form in autoimmune diseases such as Sjogren’s syndrome and Hashimoto thyroiditis (1). TLOs’ cellular compartments, spatial organization, vasculature, and function are similar to those of secondary lymphoid organs (SLOs), providing a local hub for autoreactive B-cell proliferation and affinity maturation. TLOs appear to contribute to disease progression and to the emergence of malignant B clones responsible for lymphoma development (2). Within TLOs, the ectopic expression of lymphoid chemokines has been shown to correlate with the size or degree of organization of lymphoid aggregates and with the production of autoantibodies (3, 4). In the case of malignant transformation, lymphoid chemokine expression increases during disease progression (5). The pathways regulating chemokine expression in SLOs during embryonic life have been largely described and mainly involve the engagement of lymphotoxin β receptor on a family of gp38⁺ lymphoid tissue-organizer stromal cells (6). At sites of TLO formation, lymphotoxin and lymphotoxin-producing cells appear to be dispensable for the early production of lymphoid chemokines required during SLO formation, raising the possibility that signals other than lymphotoxin can regulate the formation of TLOs, stimulating the production of lymphoid chemokines during inflammation (7, 8). Some of these signals have been identified in the family of the IL-23/IL-17 cytokines (9), but other cytokines have been advocated in TLO formation; thus different molecules may play differential roles depending on site and nature of the etiological agent (10).IL-22, a member of the IL-10 cytokine superfamily, regulates mucosal responses to danger and wound healing (11). IL-22 promotes tissue repair, inducing epithelial cell proliferation and survival, in both physiological and pathological conditions (12–15). Recently, an association between IL-22 expression and autoimmune B-cell activation has been proposed (16). In Sjogren’s syndrome, serum levels of IL-22 correlate with clinical manifestations including autoantibody production (17). Furthermore, B-cell–depleting treatment modulates salivary gland expression of IL-22, thus suggesting a potential functional relationship between IL-22 expression, B-cell infiltration, and local pathology (18). Previously we have demonstrated that direct cannulation of murine salivary glands with a replication-deficient adenovirus induces the formation of organized T-cell and B-cell aggregates, local expression of lymphoid chemokines, and the enzyme aicda [activation-induced cytidine deaminase (AID)] required for affinity maturation and isotype switching in B cells (19). Exploiting this model, we tested the hypothesis that IL-22 is involved in the generation of a humoral response within the TLOs (19). Here we demonstrate that early expression of IL-22 is instrumental for lymphoid chemokine production by stromal cells that, in turn, regulates B-cell aggregation. This work highlights a novel role for IL-22 in lymphoid chemokine expression and provides a mechanistic link between deranged mucosal responses and autoantibody production.     

Prevalence of metabolic syndrome in Chinese women and men: a systematic review and meta-analysis of data from 734 511 individuals

Background

The prevalence of metabolic syndrome is growing because of increasing rates of obesity and sedentary lifestyle. Metabolic syndrome is one of the most important risk factors associated with diabetes, cardiovascular disease, and all-cause mortality. Few studies have examined its sex-specific prevalence in China across time. We compared the prevalences and temporal trends of metabolic syndrome in Chinese women and men.

Antibody levels to hepatitis E virus in North Carolina swine workers,non-swine workers,swine, and murids

In a cross-sectional serosurvey, eastern North Carolina swine workers (n = 165) were compared with non-swine workers (127) for the presence of antibodies to hepatitis E virus as measured by a quantitative immunoglobulin enzyme-linked immunosorbent assay. Using a cutoff of 20 Walter Reed U/ml, swine-exposed subjects had a 4.5-fold higher antibody prevalence (10.9%) than unexposed subjects (2.4%). No evidence of past clinical hepatitis E or unexplained jaundice could be elicited. Swine (84) and mice (61), from farm sites in the same region as exposed subjects, were also tested. Antibody prevalence in swine (overall = 34.5%) varied widely (10.0-91.7%) according to site, but no antibody was detected in mice. Our data contribute to the accumulating evidence that hepatitis E may be a zoonosis and specifically to the concept of it as an occupational infection of livestock workers.     

Metabolic, respiratory and haematological adjustments of the little pocket mouse to circadian torpor cycles.

Metabolic, respiratory and haematological parameters were investigated for the Little Pocket mouse during circadian torpor cycles. The rate of O2 consumption decreased from 7.04 to 0.05 ml O2.g-1.hr-1, with a corresponding decrease in respiratory minute volume from 49.4 to 0.9 ml.min-1 during torpor at an ambient temperature of 10 C. No changes in haemoglobin concentration (19.7 g/100 ml), haematocrit (54%), red blood corpuscle count (12.4 10(6)/microliter), mean corpuscular volume (43.6 micrometer3), mean corpuscular haemoglobin content (16.2 pg), mean corpuscular haemoglobin concentration (37.4%) and [2,3-DPG] (9.6 mumol/g Hb) were observed during torpor cycles. The half saturation tension of P. longimembris haemoglobin was 41 mm Hg (37 C, pH = 7.28) and 19.7 mm Hg (10 degrees C, pH = 7.51). The effect of temperature on P50 was deltalog P50/ C = +0.0106 (pH = 7.4). Venous blood parameters were: euthermic mice (37 C); PCO2 = 36.8 mm Hg, PO2 = 49.5 mm Hg, pH = 7.28, [HCO-3] = 17.3 mmol/l; torpid mice (10 C); PCO2 = 14.6, PO2 = 35.7 pH = 7.51, [HCO-3] = 18.8. These data indicate a new, relatively acidotic acid-base status during torpor, characterised by a higher H+/ OH- ratio. The respiratory sensitivity to inspired CO2 of pocket mice was, despite their being semi-fossorial, typical of other mammals. High concentrations of CO2 did not induce, or facilitate, entry into torpor.