Glucan phosphate potentiates endotoxin-induced interferon-gamma expression in immunocompetent mice, but attenuates induction of endotoxin tolerance.

Glucan phosphate has been shown to enhance antimicrobial immunity in a variety of experimental models. However, the mechanisms by which glucans enhance resistance to infection remain largely unknown. Interferon-gamma (IFN-gamma) is a key regulator of both innate and acquired immunity. Suppression of IFN-gamma production is a prominent feature of the altered immune response that follows major trauma or sepsis. The present studies were designed to determine the effect of glucan phosphate on IFN-gamma expression in normal mice and endotoxin [lipopolysaccharide (LPS)]-tolerant mice. The model of LPS tolerance was used because it results in patterns of cytokine expression similar to those commonly observed following severe trauma or sepsis. Glucan treatment potentiated LPS-induced IFN-gamma expression in control mice. The induction of LPS tolerance resulted in marked suppression of LPS-induced IFN-gamma production. However, co-administration of glucan with LPS, during the tolerance induction phase, attenuated the LPS-tolerant response. Interleukin-12 (IL-12) and IL-18 are important mediators of LPS-induced IFN-gamma production. LPS-induced IL-12 p40 mRNA expression was increased in the spleens of glucan-treated mice compared with controls. Induction of LPS tolerance caused marked suppression of IL-12 production, a response that was attenuated by glucan treatment. IL-18 was constitutively expressed in both control and LPS-tolerant mice, and LPS-induced serum levels of IL-18 were increased in mice treated with glucan. T cells isolated from glucan-treated mice exhibited increased IFN-gamma expression in response to IL-12 and IL-18, as well as increased expression of the IL-12 and IL-18 receptors. The ability of glucan to potentiate IFN-gamma expression in control mice provides a potential mechanism by which glucan enhances antimicrobial immunity. The ability of glucan to attenuate suppressed IFN-gamma expression in LPS-tolerant mice denotes its potential benefit for the treatment of trauma and sepsis-induced immunosuppression.     

Persistent Dysphagia after Head and Neck Radiotherapy: A Common and Under-reported Complication with Significant Effect on Non-cancer-related Mortality

AimsDysphagia is a well-recognised acute complication after radiotherapy. However, knowledge about the long-term prevalence and effect remains limited. The aims of this study were to determine the prevalence, severity, morbidity, time course and reporting patterns of dysphagia symptoms after head and neck radiotherapy.Materials and methodsAn observational cross-sectional study was conducted in a large consecutive series of head and neck cancer patients. All patients in the St George Hospital Cancer Care database who had received head and neck radiotherapy with curative intent 0.5–8 years previously and recorded as being alive were surveyed using the Sydney Swallow Questionnaire (SSQ). Case notes were reviewed to determine the level of awareness of swallowing dysfunction in all patients, as well as the causes of mortality in the 83 deceased patients.ResultsThe mean follow-up at the time of survey was 3 years after radiotherapy (range 0.5–8 years). Of the 116 patients surveyed by questionnaire, the response rate was 72% (83). Impaired swallowing (SSQ score > 234) was reported by 59% of patients. Dysphagia severity was not predicted by tumour site or stage, nor by the time since therapy, age, gender or adjuvant chemotherapy. Review of the hospital medical records and cancer database revealed that cancer accounted for 55% of deaths and aspiration pneumonia was responsible for 19% of non-cancer-related deaths. Of those with abnormal SSQ scores, only 47% reported dysphagia during follow-up clinic visits.ConclusionsPersistent dysphagia is a prevalent, under-recognised and under-reported long-term complication of head and neck radiotherapy which currently cannot be predicted on the basis of patient, tumour or treatment characteristics. Aspiration pneumonia is an important contributor to non-cancer-related mortality in these patients. These data highlight the need for closer monitoring of swallow dysfunction and its sequelae in this population.     

Complementary and Integrative Medicine in Hematologic Malignancies: Questions and Challenges

Hematologic malignancies represent 9.7% of all cancers, making them the fourth most common type of cancer in the United States. The aggressive and complex treatments administered in hematologic malignancies result in a high burden of psychological needs. Complementary and integrative medicine (CIM) is becoming one of the options that patients use to address their distress during and after cancer treatments. It is not clear whether appropriate CIM can relieve distress in patients affected by these malignancies. This review covers the potential benefits of CIM as relates to nutrition, nutritional supplements, exercise, circadian rhythm, methods for reducing distress during bone marrow aspiration, massage therapy, and acupuncture, in treating patients with hematological malignancies. This review may provide a framework to enhance patient-doctor dialogue regarding CIM use in hematologic malignancies.     

Loss of p16 in recurrent malignant mixed müllerian tumors of the uterus

Uterine malignant mixed müllerian tumors (MMMTs) are rare and highly aggressive malignancies with poor clinical prognoses. We examined for differences in the oncoprotein profiles of primary versus recurrent MMMTs. Five cases of recurrent uterine MMMT were examined by paraffin immunohistochemistry for the expression of p53, p16, P-cadherin, and Cerb-B2. P16, p53, and P-cadherin were each expressed in 100%, 80%, and 60% of the primary cases, respectively. Three cases expressed all three oncoproteins. All five cases were negative for Cerb-B2. No difference in antigen expression was seen in the epithelial versus sarcomatous components. Primary and recurrent tumors were concordant for p53, P-cadherin, and Cerb-B2. However, three cases of recurrent tumors were negative for p16 expression. P53, p16, and P-cadherin are common tumor suppressor genes expressed in uterine MMMT. Interestingly, p16 protein expression was lost in some cases of MMMTs when they recurred. This suggests that the oncoprotein and possibly genetic profile of p16 changes over time. We did not observe any difference in antigen expression between areas of epithelial or sarcomatous differentiation, which would support a single pluripotential malignant clone in the histogenesis of these tumors.     

Signal pathways mediating oxytocin stimulation of prostaglandin synthesis in select target cells

A major action of oxytocin is to stimulate prostaglandin production in reproductive tissues. The two major enzyme systems involved are cytosolic phospholipase A₂ (cPLA₂), which catalyses the formation of arachidonic acid from membrane glycerophospholipids, and prostaglandin endoperoxide-H synthases-1 and -2, which allow conversion of arachidonic acid to prostaglandins. During gestation, the concentrations of all three enzymes rise in the rabbit amnion. Agonists, including oxytocin, increase cPLA₂ activity, in part, by elevating intracellular Ca²⁺ concentration, which causes cPLA₂ to be translocated from the cytosol to intracellular membrane binding sites. Cytosolic PLA₂ is then activated by a mitogen-activated protein kinase (MAPK)-dependent step. Our studies have elucidated signal pathways involved in oxytocin-stimulated prostaglandin output in both rabbit amnion cells and Chinese hamster ovary cells stably transfected with the rat oxytocin receptor. The two cell types are alike with respect to oxytocin-stimulated intracellular Ca²⁺ transients, mediation via G_q, and the specific MAPK that catalyses the phosphorylation of cPLA₂. However, they differ with respect to the mechanisms of upregulation of key enzymes involved in prostaglandin E₂ synthesis. These findings illustrate the tiers of complementary mechanisms involved in oxytocin stimulation of prostaglandin E₂, and the extent of the diversity in the cellular signalling pathways involved.