Regulation of stimulated integrin surface expression in human neutrophils by tyrosine phosphorylation

The control of the adhesive properties of human neutrophils is an essential element of their defense function. One level at which this control is exerted involves the upregulation of the surface expression of beta 2-integrins. In this study, we have examined the potential involvement of tyrosine phosphorylation in the latter process. Two inhibitors of tyrosine kinases with differing modes of action, erbstatin and herbimycin A, were found to inhibit the expression of CD11b and CD18 stimulated by chemotactic factors (fMet-Leu-Phe or leukotriene B4) or growth factors (tumor necrosis factor alpha). This inhibition was not shared by an inactive analog of erbstatin or by the protein kinase C inhibitor Ro 31-8330. Erbstatin also inhibited the unveiling of activation-specific neoepitopes detected by antibody CBRM1/5. Pretreatment of neutrophils (but not of endothelial cells) with erbstatin inhibited the stimulation of neutrophils' adherence to endothelial cells induced by fMet-Leu-Phe. Augmentation of tyrosine phosphorylation by inhibiting tyrosine phosphatases using hydroperoxyvanadate led to an increased surface expression of CD11b and CD18 and enhanced the adhesion of neutrophils to endothelial cells. Finally, the leumedin NPC 15669, which had previously been shown to inhibit stimulated CD11b expression and neutrophil adherence to endothelial cells and to exhibit anti-inflammatory properties in various in vivo models of inflammation, inhibited the stimulation of tyrosine, phosphorylation induced by fMet-Leu-Phe. Taken together, these data establish a strong correlation between tyrosine phosphorylation and integrin upregulation in stimulated human neutrophils.     

Patterns of hematopoietic chimerism following bone marrow transplantation for childhood acute lymphoblastic leukemia from volunteer unrelated donors

Hematopoietic chimerism was analyzed in serial bone marrow samples taken from 28 children following T-cell depleted unrelated donor bone marrow transplants (UD BMT) for acute lymphoblastic leukemia (ALL). Chimeric status was determined by polymerase chain reaction (PCR) of simple tandem repeat (STR) sequences (maximal sensitivity, 0.1%). At least two serial samples were examined in 23 patients. Of these, two had evidence of complete donor engraftment at all times and eight showed stable low level mixed chimerism (MC) (<1% recipient hematopoiesis). All 10 of these patients remain in remission with a minimum follow-up of 24 months. By contrast, 13 patients demonstrated a progressive return of recipient hematopoiesis. Five of these relapsed (4 to 9 months post BMT), one died of cytomegalovirus pneumonitis and seven remain in remission with a minimum follow-up of 24 months. Five children were excluded from serial analysis as two serial samples were not collected before either relapse (3) or graft rejection (2). We conclude that as with sibling transplants, ex vivo T depleted UD BMT in children with ALL is associated with a high incidence of MC. Stable donor engraftment and low level MC always correlated with continued remission. However, detection of a progressive return of recipient cells did not universally correlate with relapse, but highlighted those patients at greatest risk. Serial chimerism analysis by PCR of STRs provides a rapid and simple screening technique for the detection of relapse and the identification of patients with progressive MC who might benefit from detailed molecular analysis for minimal residual disease following matched volunteer UD BMT for childhood ALL.     

Establishing a Research Agenda on Mobile Health Technologies and Later-Life Pain Using an Evidence-Based Consensus Workshop Approach

The rapid growth of mobile health (mHealth) devices holds substantial potential for improving care and care outcomes in all patient populations, including older adults with pain. However, existing research reflects a substantial gap in knowledge about how to design, evaluate, and disseminate devices to optimally address the many challenges associated with managing pain in older persons. Given these knowledge gaps, we sought to develop a set of practice-based research priorities to facilitate innovation in this field. We employed the Cornell Research-Practice Consensus Workshop Model, an evidence-based approach to generating research priorities. Sixty participants attended the conference, where stakeholder groups included older adults with pain and their caregivers, behavioral and social scientists, healthcare providers, pain experts, and specialists in mHealth and health policy. Participants generated 13 recommendations classified into 2 categories: 1) implications for designing research on mHealth among older adults (eg, conduct research on ways to enhance accessibility of mHealth tools among diverse groups of older adults with pain, expand research on mHealth sensing applications), and 2) implementation of mHealth technology into practice and associated regulatory issues (eg, promote research on ways to initiate/sustain patient behavior change, expand research on mHealth cybersecurity and privacy issues).

Practice-Based Research Priorities for Palliative Care: Results From a Research-to-Practice Consensus Workshop

We employed the research-to-practice consensus workshop (RTP; workshops held in New York City and Tompkins County, New York, in 2013) model to merge researcher and practitioner views of translational research priorities in palliative care. In the RTP approach, a diverse group of frontline providers generates a research agenda for palliative care in collaboration with researchers. We have presented the major workshop recommendations and contrasted the practice-based research priorities with those of previous consensus efforts. We uncovered notable differences and found that the RTP model can produce unique insights into research priorities. Integrating practitioner-identified needs into research priorities for palliative care can contribute to addressing palliative care more effectively as a public health issue.Over the past 2 decades, palliative care has become established as a promising approach for addressing the needs of individuals with life-threatening illnesses from a holistic, interdisciplinary perspective. For this project, we defined palliative care as an approach that improves the quality of life of patients and families facing the problems encountered in life-threatening illness by preventing and relieving suffering. Core components of palliative care include providing relief from pain and other distressing symptoms, affirming dying as a normal process, integrating psychological and spiritual aspects of care, enhancing the quality of life of patients, and offering support systems to patients and their families to help them live as fully as possible until death occurs.Research suggests that palliative care results in positive patient outcomes, greater patient and family satisfaction, and significant cost savings.1,2 The American Public Health Association, the World Health Organization, and the Institute of Medicine3–6 have identified the development of a robust palliative care delivery system as a key public health issue because of the documented ability of palliative care to deliver effective and efficient patient- and symptom-focused care to a growing population in need.In its 2013 report the American Public Health Association specifically detailed the public health implications of palliative care, acknowledged the growing burden of advanced chronic illness and disease in older adults, and recommended key steps to address the problem. This policy statement called for federal, state, and local efforts to promote effective symptom management in populations with serious illness or at the end of life. Other recommended initiatives included the development of a palliative care workforce, educational programs to improve uptake and use of palliative and hospice care, and research funding to support the expansion of palliative care initiatives. Achieving these goals will require moving beyond traditional medical practices to include both policies and initiatives at the public health level.Despite the potential of palliative care to address the mental and physical health needs of individuals with advanced illness, significant knowledge gaps impede its reach and effectiveness. Reports from scientific bodies and consensus workshops have highlighted weaknesses in the literature and called for more research on palliative care and improved research methods.7–10 Thus, although both interest in and demand for palliative care are increasing, reviews of the knowledge base continue to lament the lack of research on many key issues.11,12Especially urgent is a research agenda that fits most closely with the needs of providers who deliver palliative care. The systematic engagement of community practitioners in a consensus process can lead to particularly useful and actionable recommendations for research,13–15 which are greatly needed at this stage in the development of the field. Therefore, to shed new light on research priorities in palliative care, we used a structured, participatory method designed to solicit practitioner input on research priorities: the research-to-practice consensus workshop (RTP) model.16We employed the RTP approach to identify knowledge gaps and types of studies that should be conducted to improve providers’ ability to deliver palliative care most effectively. This model harnesses practice wisdom by engaging clinicians, agency staff, and other practitioners with researchers in a process of articulating and refining research questions and research priorities that honors scientific expertise and practice wisdom.     

Pilot clinical trial of intravenous doxycycline versus placebo for rheumatoid arthritis

OBJECTIVE: To screen for potential efficacy and assess the feasibility of intravenous (IV) doxycycline as a treatment for rheumatoid arthritis (RA). METHODS: The study was a (stratified, block) randomized, double blind, 12 week, pilot trial of IV doxycycline 300 mg/day versus identical appearing IV placebo given over 2 h for 14 days. The primary comparison was to a hypothesized placebo rate of 20% as described by Paulus. If a total of 14 consecutive subjects receiving doxycycline treatment did not respond, it would be considered futile to proceed to a Phase III trial. We planned a placebo group of 14 subjects to verify the placebo response rate and estimate sample size required for a definitive Phase III trial, if such a trial was warranted based on the pilot study. American College of Rheumatology (ACR) RA response criteria were used. After 23 subjects entered, the study was closed due to recruitment difficulties. RESULTS: At baseline, mean (SD) tender joint count was 37 (11.9), swollen joint count 30 (9.6), morning stiffness 317 (319) min, and erythrocyte sedimentation rate 72 mm/h (27.5). Randomization resulted in 10 subjects receiving doxycycline and 13 receiving placebo. Treatment was stopped in 8 subjects: in 6, treatment was ineffective (one taking doxycycline, 5 placebo), and in 2, rashes occurred (one taking doxycycline, one placebo). Only one subject met ACR response criteria in the doxycycline group and none in the placebo group. Having no responders in the placebo group was consistent with placebo response rate of 20% or less. Several patients required peripherally inserted central catheters for venous access. CONCLUSION: The efficacy of IV doxycycline as a treatment for RA could not be ruled out. However, as the proportion of responders was small, it is unlikely that potential efficacy of IV doxycycline would outweigh potential disadvantages of IV administration.     

Major salivary gland function in primary Sj?gren's syndrome and its relationship to clinical features

Unstimulated and stimulated salivary secretions of both the parotid and submandibular/sublingual glands were studied in 64 patients with primary Sj?gren's syndrome to define further salivary changes in this disorder. The stimulated flows of the submandibular/sublingual glands were below normal in 56 of 64 patients, while stimulated parotid flows were decreased in only 35. Compositional changes of the submandibular saliva paralleled changes of parotid saliva, and these data suggest that ductal electrolyte resorption is altered in the glands of patients. Finally, stimulated parotid flow rates correlated inversely with focus scores of the minor salivary gland biopsies.     

Lupus nephritis: association between serology and renal biopsy measures

The relationship between serologic tests and renal histologic change over time was examined in 55 patients with lupus nephritis. After a median interval of 40 months on various immunosuppressive drug regimens, C3 complement levels were improved in 78% of patients and anti-DNA levels were improved in 85%. Comparison of initial and followup renal pathology showed that the activity index of the biopsy improved in 82%, while the chronicity index worsened in 71% of patients. Normalization of C3, but not anti-DNA levels, was associated with a lowering of the activity index on repeat biopsy. Prolonged depression of serum C3 levels was associated with a trend (p = 0.066) towards worsening of the chronicity index, but the change in chronicity index showed no relationship to the duration of elevated anti-DNA. Our studies indicate that abnormal levels of C3 complement are predictive of the degree of persistently active glomerular disease, but that duration of abnormal C3 or anti-DNA are less consistent predictors of the acquisition of chronic, irreversible renal lesions.     

Involvement of guanine nucleotide binding proteins in neutrophil activation and priming by GM-CSF

Pre-incubation of human neutrophils with pertussis toxin significantly inhibited the neutrophil-directed biologic actions of granulocyte- macrophage colony-stimulating factor (GM-CSF) in three separate assays: the induction of c-fos mRNA, the enhancement of both platelet- activating factor-induced mobilization of intracellular calcium, and stimulation of leukotriene synthesis by the calcium ionophore A23187. Cholera toxin did not have an effect on the latter two assays. Pre- treatment of human neutrophils with pertussis toxin did not affect the binding of GM-CSF to its surface receptor. These results provide the first evidence that a pertussis toxin substrate plays an important mediatory role in the mechanism of action of GM-CSF.     

Human papillomavirus and oral disease – emerging evidence: a review

Human papillomavirus (HPV) infections have received considerable attention in recent years. Of the 120 or so known types of the virus, some cause a variety of benign wart‐like lesions of the skin and genital and oral mucosae, whilst others are aetiologically associated with cervical and anogenital cancers. Recent epidemiologic evidence suggests that HPV may also be an independent risk factor for oropharyngeal cancer. In this context it has been suggested that HPV virus may modulate the process of carcinogenesis in some tobacco and alcohol induced oropharyngeal cancers and act as the primary oncogenic agent for inducing carcinogenesis among non‐smokers. Dental practitioners have a major role in detecting all lesions of the oral mucosa caused, or possibly caused, by HPV. This paper briefly reviews the current state of knowledge of molecular and clinical aspects of HPV infections of the oral mucosa.