The effect of cefodizime on phagocyte function in non-patient volunteers and patients with chronic renal failure

Cefodizime has previously been shown to possess a number of immunomodulating properties in vivo and in vitro using several different test systems. Since most in vitro studies have been performed with cells from normal individuals, we first investigated whether cells from chronic renal failure patients would respond in vitro to cefodizime in the same way as healthy subjects. Subsequently, we investigated the effect of cefodizime (10 gover 10 days in 2-g doses) on phagocyte function ex vivo in an open study of 26 chronic renal failure patients and 16 healthy subjects. Polymorphonuclear leukocytes were tested for their ability to polarize in response to cefodizime and/or f-met-leu-phe peptide. Polymorphonuclear leukocytes and monocytes were tested for their ability to produce chemiluminescence on stimulation with either phagocytic (zymosan) or soluble phorbol myristate acetate stimuli. Phagocyte and lymphocyte membrane receptor expression was compared after exposure to cefodizime. Exposure to cefodizime in vitro causes a significant increase in polarization of polymorphonuclear leukocytes from both normal individuals and renal failure patients (bothP<0.001). It also caused increased chemotaxis and chemokinesis in a modified Boyden chamber assay. Cefodizime did not affect lucigenin-enhanced chemiluminescence and there were only minor effects on cell membrane antigen levels. In the ex vivo study there was a significant increase in polymorphonuclear leukocyte polarization (P<0.001) attributable to cefodizime, but other investigations showed no significant differences. The results suggest that cefodizime may act as a mild priming agent for some functions, particularly chemotaxis.     

Plasma Cytokine Levels are Related to Brain Volumes in HIV-infected Individuals

HIV-infected individuals frequently exhibit brain dysfunction despite antiretroviral treatment. The neuropathological mechanisms underlying these abnormalities remain unclear, pointing to the importance of identifying biomarkers sensitive to brain dysfunction. We examined 74 medically stable HIV-infected individuals using T1-weighted MRI. Volumes of the cortical grey matter (GM), white matter (WM), caudate, putamen, globus pallidus, thalamus, hippocampus, amygdala, and ventricles were derived using automated parcellation. A panel of plasma cytokines was measured using multiplexed bead array immunoassay. A model selection algorithm was used to select the combination of clinical and cytokine markers that best predicted each brain volumetric measure in a series of linear regression models. Higher CD4 nadir, shorter HIV infection duration, and antiretroviral treatment were significantly related to higher volumes of the putamen, thalamus, hippocampus, and WM. Older age was related to lower volumes in most brain regions and higher ventricular volume. Higher IFN-γ, MCP-1, and TNF-α were related to higher volumes of the putamen, pallidum, amygdala, GM, and WM. Higher IL-1β, IL-6, IL-16, IL-18, IP-10, MIP-1β, and SDF-1α were related to lower volumes of the putamen, pallidum, thalamus, hippocampus, amygdala, GM, and WM; and higher ventricular volume. The current findings provide evidence linking smaller brain volumes to HIV disease history, antiretroviral treatment, and advanced age. Cytokine markers, especially IL-6 and IL-16, showed robust association with brain volumes even after accounting for other clinical variables, demonstrating their utility in examining the mechanisms of HIV-associated brain abnormalities.     

Body temperature and cardiac changes induced by peripherally administered oxytocin,vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats

Background and Purpose

There is current interest in oxytocin (OT) as a possible therapeutic in psychiatric disorders. However, the usefulness of OT may be constrained by peripheral autonomic effects, which may involve an action at both OT and vasopressin V_1A receptors. Here, we characterized the cardiovascular and thermoregulatory effects of OT, vasopressin (AVP) and the non-peptide OT receptor agonist WAY 267,464 in rats, and assessed the relative involvement of the OT and V_1A receptors in these effects.

Experimental Approach

Biotelemetry in freely moving male Wistar rats was used to examine body temperature and heart rate after OT (0.01 – 1 mg kg⁻¹; i.p.), AVP (0.001 – 0.1 mg kg⁻¹; i.p.) or WAY 267,464 (10 and 100 mg kg⁻¹; i.p.). The actions of the OT receptor antagonist Compound 25 (C25, 5 and 10 mg kg⁻¹) and V_1A receptor antagonist SR49059 (1 and 10 mg kg⁻¹) were studied, as well as possible V_1A receptor antagonist effects of WAY 267,464.

Key Results

OT and AVP dose-dependently reduced body temperature and heart rate. WAY 267,464 had similar, but more modest, effects. SR49059, but not C25, prevented the hypothermia and bradycardia induced by OT and AVP. WAY 267,464 (100 mg·kg⁻¹) prevented the effects of OT, and to some extent AVP.

Conclusions and Implications

Peripherally administered OT and AVP have profound cardiovascular and thermoregulatory effects that appear to principally involve the V_1A receptor rather than the OT receptor. Additionally, WAY 267,464 is not a simple OT receptor agonist, as it has functionally relevant V_1A antagonist actions.     

Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis

Anti-neutrophil cytoplasmic antibody–associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCA-negative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.     

Reliability and validity of The Awareness of Social Inference Test (TASIT): A clinical test of social perception

Purpose.?The Awareness of Social Inference Test (TASIT) is an audiovisual tool designed for the clinical assessment of social perception with alternate forms for re-testing. Part 1 assesses emotion recognition, Parts 2 and 3 assess the ability to interpret conversational remarks meant literally (i.e., sincere remarks and lies) or non-literally (i.e., sarcasm) as well as the ability to make judgments about the thoughts, intentions and feelings of speakers. This paper aims to examine TASIT's reliability and validity.

Method.?Some 32 adults with severe, chronic brain injuries were administered Form A twice, one week apart. 38 adults with brain injuries were readministered alternate forms over a period of 5 – 26 weeks. Construct validity was examined in subsets of a sample of 116 adults with brain injuries by relating TASIT performance to standard tests of neuropsychological function and specific social perception measures.

Results.?Test-retest reliability ranged from 0.74 – 0.88. Alternate forms reliability ranged from 0.62 – 0.83. TASIT performance was associated with face perception, information processing speed and working memory. Socially relevant new learning and executive tasks were significantly associated with TASIT performance whereas non-social tasks showed little association. Social perception tasks such as Ekman photos and theory of mind stories were also associated.

Conclusions.?TASIT has adequate psychometric properties as a clinical test of social perception. It is not overly prone to practice effects and is reliable for repeat administrations. Performance on TASIT is affected by information processing speed, working memory, new learning and executive functioning, but the uniquely social material that comprises the stimuli for TASIT will provide useful insights into the particular difficulties people with clinical conditions experience when interpreting complex social phenomena.     

Transparency and accountability in mass media campaigns about organ donation: a response to Morgan and Feeley

We respond to Morgan and Feeley’s critique on our article “Mass Media in Organ Donation: Managing Conflicting Messages and Interests.” We noted that Morgan and Feeley agree with the position that the primary aims of media campaigns are: “to educate the general public about organ donation process” and “help individuals make informed decisions” about organ donation. For those reasons, the educational messages in media campaigns should not be restricted to “information from pilot work or focus groups” but should include evidence-based facts resulting from a comprehensive literature research. We consider the controversial aspects about organ donation to be relevant, if not necessary, educational materials that must be disclosed in media campaigns to comply with the legal and moral requirements of informed consent. With that perspective in mind, we address the validity of Morgan and Feeley’s claim that media campaigns have no need for informing the public about the controversial nature of death determination in organ donation. Scientific evidence has proven that the criteria for death determination are inconsistent with the Uniform Determination of Death Act and therefore potentially harmful to donors. The decision by campaign designers to use the statutory definition of death without disclosing the current controversies surrounding that definition does not contribute to improved informed decision making. We argue that if Morgan and Feeley accept the important role of media campaigns to enhance informed decision making, then critical controversies should be disclosed. In support of that premise, we will outline: (1) the wide-spread scientific challenges to brain death as a concept of death; (2) the influence of the donor registry and team-huddling on the medical care of potential donors; (3) the use of authorization rather than informed consent for donor registration; (4) the contemporary religious controversy; and (5) the effects of training desk clerks as organ requestors at the Department of Motor Vehicles offices. We conclude that organ donation is a medical procedure subject to all the ethical obligations that the medical profession must uphold including that of transparency and truthfulness.     

Are informal carers and community care workers effective in managing malnutrition in the older adult community? A systematic review of current evidence

Background

Enhancing the effectiveness of the community and aged care workforce to prevent malnutrition and functional decline is important in reducing hospital and aged care facility demand.

Objective

To investigate the impact of nutrition-related interventions delivered to or by informal carers and non-clinical community care workers on malnutrition-related health outcomes of community-dwelling older adults (≥65years).

Methods

Intervention studies were searched for using six electronic databases for English-language publications from January 1980 to 30 May 2012.

Results

Nine studies were eligible for inclusion. The strength and quality of the evidence was moderate (six studies with level II intervention evidence, five with positive quality). Types of interventions used were highly varied. The majority of interventions were delivered to informal carers (6 studies), with three of these studies also involving older adult care recipients. Five interventions were targeted at identifying, preventing and/or treating malnutrition specifically (two positive quality, three neutral quality, n=2368). As a result of these interventions, nutritional status improved or stabilized (two positive quality, two neutral quality, n=2333). No study reported an improvement in functional status but two successfully prevented further decline in their participants (two neutral quality, n=1097).

Conclusion

Interventions targeted at identifying, preventing and/or treating malnutrition were able to improve or prevent decline in nutritional and functional status, without increasing informal carer burden. The findings of this review support the involvement of non-clinical community care workers and informal carers as part of the nutritional care team for community-dwelling older adults.     

Working Sensitively with Child Sexual Abuse Survivors: What Female Child Sexual Abuse Survivors Want from Health Professionals

Adult survivors of child sexual abuse are high users of health and mental health services. Health professionals are well placed to improve health outcomes for them by delivering positive interventions post-abuse. The current study explored female child sexual abuse survivors' opinions on how health professionals could work better with child sexual abuse survivors. Sixty-one women, from 22–65 years old, who had been sexually abused before the age of 16 years, completed postal questionnaires in late 2004. A model was developed to guide the development of knowledge, skills, and practices for working more sensitively with child sexual abuse survivors. The model consisted of six chronological training steps: (1) knowledge on effects of child sexual abuse; (2) establishing the relationship with child sexual abuse survivors; (3) asking about child sexual abuse; (4) responding to disclosure; (5) sensitive provision of medical examinations; and (6) follow-up post examination. A systematic approach to training is proposed to assist with improving delivery of services sensitive to child sexual abuse survivor needs.     

Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin

BACKGROUND: Human papillomaviruses (HPVs) are found in normal skin and in benign and malignant skin conditions. Epidermodysplasia verruciformis (EV) HPV types are those most plausibly linked to the development of squamous cell carcinomas of the skin. OBJECTIVES: To assess the risk of nonmelanoma skin cancer (NMSC) associated with the presence of EV HPV in normal skin in immunocompetent (IC) individuals and renal transplant recipients (RTRs). METHODS: Using a degenerate and nested polymerase chain reaction technique, HPV DNA was sought in 124 normal skin samples from sun-exposed and nonsun-exposed sites, from 39 IC individuals and 38 RTRs, both with and without NMSC. Data were analysed using the Mantel-Haenszel test and by logistic regression analysis. RESULTS: HPV DNA was detected in 58/67 (87%) and 20/57 (35%) samples from renal transplant and IC patients, respectively. There was no difference in either the prevalence or spectrum of HPV types found in sun-exposed and nonsun-exposed normal skin. However, there was significant association between NMSC and the presence of EV HPV DNA. Multivariate analysis provided an odds ratio of 6.41 (95% confidence interval 1.79-22.9) for the association of EV HPV DNA in normal skin (irrespective of site) and NMSC status, even after stratifying for patient group and adjusting for the clustering effect of multiple sampling. Conversely, there was no association between skin cancer status and the presence of cutaneous or mucosal HPV types in either sun-exposed or nonsun-exposed skin. CONCLUSIONS: HPV DNA is widespread in normal adult skin, particularly in transplant patients. In our study, the presence of EV but not cutaneous HPV DNA in normal skin was significantly associated with NMSC status and may prove to be of predictive value for skin cancer risk. These data provide reason to focus on EV HPV types as causal agents in skin cancer.