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Neutrophils are traditionally considered short‐lived, circulating innate immune cells that are rapidly recruited to sites of inflammation in response to infectious and inflammatory stimuli. Neutrophils efficiently internalize, kill or entrap pathogens, but their effector molecules may cause collateral tissue damage. More recently, it has been appreciated that neutrophils can also influence adaptive immunity. Lymph nodes (LNs) are immune cell‐rich secondary lymphoid organs that provide an ideal platform for cellular interaction and the integration of immunological information collected from local tissues. A variety of peripheral stimuli promote neutrophil migration to draining LNs via blood or lymphatics, utilizing differing molecular cues depending on the site of entry. Within LNs, neutrophils interact with other innate and adaptive cells. Crosstalk with subcapsular sinus macrophages contributes to the control of pathogen spread beyond the LN. Neutrophils can influence antigen presentation indirectly by interacting with DCs or directly by expressing major histocompatibility complex (MHC) and costimulatory molecules for antigen presentation. Interactions between neutrophils and adaptive lymphocytes can alter B‐cell antibody responses. Studies have shown conflicting results on whether neutrophils exert stimulatory or inhibitory effects on other LN immune cells, with stimulus‐specific and temporal differences in the outcome of these interactions. Furthermore, neutrophils have also been shown to traffick to LNs in homeostasis, with a potential role in immune surveillance, antigen capture and in shaping early adaptive responses in LNs. Understanding the mechanisms underpinning the effects of neutrophils on LN immune cells and adaptive immunity could facilitate the development of neutrophil‐targeted therapies in inflammatory diseases., In addition to their role in pathogen defence, neutrophils can also influence adaptive immune responses. Neutrophils can traffick to lymph nodes, at baseline and following inflammatory stimuli, to interact with other lymph node immune cells to shape innate and adaptive immune responses.

Significance IgG antibodies are a key component of adaptive humoral immunity but can cause organ damage if they bind self-antigen, as occurs in the autoimmune disease systemic lupus erythematosus (SLE). Many of the proinflammatory effects of IgG are mediated by ligating Fcγ receptors (FcγRs) expressed by tissue-resident leukocytes such as macrophages. One of the most serious complications of SLE is kidney inflammation: lupus nephritis. Here we show that IgG ligation of FcγRs on macrophages in the kidney leads to a change in their metabolism, resulting in a switch toward glycolysis. Administration of a glycolysis inhibitor attenuated IgG-associated kidney macrophage activation, proinflammatory cytokine secretion, and kidney inflammation. Therefore, manipulating macrophage metabolism may be a useful therapeutic strategy in lupus nephritis., IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.

Infection or vaccination leads to the development of germinal centers (GCs) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. We followed the migratory pathways of B cells emerging from germinal centers (BEM) and found that many migrated into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From there, B cells may exit the lymph node to enter distant tissues. Some BEM cells interacted with and took up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibited the recycling of BEM cells and resulted in less efficient adaption to antigenic variation. Our findings suggest that the recycling of BEM cells, that transport antigen and that contain the genetic code for B cell receptor variants, may support affinity maturation to antigenic drift.

Neutrophils play an important role in the lung tumour microenvironment. We hypothesised that radiolabelled neutrophils coupled to single-photon emission CT (SPECT) may non-invasively quantify neutrophil uptake in tumours from patients with non-small cell lung cancer. We demonstrated increased uptake of radiolabelled neutrophils from the blood into tumours compared with non-specific uptake using radiolabelled transferrin. Moreover, indium-111-neutrophil activity in the tumour biopsies also correlated with myeloperoxidase (MPO)-positive neutrophils. Our data support the utility of imaging with In-111-labelled neutrophils and SPECT-CT to quantify neutrophil uptake in lung cancer.

Vedolizumab is a humanized monoclonal antibody that binds to the human a4β7 integrin and is approved for use in inflammatory bowel diseases. We describe a patient with severe, refractory erosive gingivostomatitis, which appeared a few days after the first dose of vedolizumab and resolved after discontinuation of the drug. We believe the gingivostomatitis to be a direct side effect of vedolizumab, rather than an extraintestinal manifestation of the underlying inflammatory bowel diseases. The clinicians need to be aware of this adverse event, which could be mistakenly considered as an extraintestinal manifestation of inflammatory bowel diseases.

Summary Macrophages play a central role in intestinal immunity, but inappropriate macrophage activation is associated with inflammatory bowel disease (IBD). Here, we identify granulocyte-macrophage colony stimulating factor (GM-CSF) as a critical regulator of intestinal macrophage activation in patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis. We find that GM-CSF drives the maturation and polarization of inflammatory intestinal macrophages, promoting anti-microbial functions while suppressing wound-healing transcriptional programs. Group 3 innate lymphoid cells (ILC3s) are a major source of GM-CSF in intestinal inflammation, with a strong positive correlation observed between ILC or CSF2 transcripts and M1 macrophage signatures in IBD mucosal biopsies. Furthermore, GM-CSF-dependent macrophage polarization results in a positive feedback loop that augmented ILC3 activation and type 17 immunity. Together, our data reveal an important role for GM-CSF-mediated ILC-macrophage crosstalk in calibrating intestinal macrophage phenotype to enhance anti-bacterial responses, while inhibiting pro-repair functions associated with fibrosis and stricturing, with important clinical implications., Graphical Abstract, Highlights • ILCs are a major source of GM-CSF, a critical regulator of gut inflammatory macrophages • GM-CSF promotes ILC-macrophage crosstalk and augments type 17 and barrier immunity • GM-CSF-induced macrophages are protective during infection but drive inflammatory colitis • GM-CSF suppresses wound-healing macrophage response associated with intestinal fibrosis, Castro-Dopico et al. identify GM-CSF as a major upstream regulator of intestinal inflammatory macrophages, with ILC-derived GM-CSF polarizing macrophages toward a glycolytic, anti-microbial phenotype while suppressing wound-healing, pro-fibrotic activity. GM-CSF initiates further ILC-macrophage crosstalk, amplifying ILC3 activation and type 17 immunity.

Significance The classical view of neutrophils is as circulating phagocytes that are recruited to tissues following infection or injury. Here we show that neutrophils were present in mouse and human lymph nodes in the absence of perturbation. Lymph node neutrophils were phenotypically distinct, with increased expression of major histocompatibility complex II, and predominantly localized to the interfollicular zone, where CD4 T lymphocytes are activated. Neutrophils trafficked into lymph nodes via blood and lymphatic vessels, and were capable of rapidly carrying systemically acquired, IgG antibody-opsonized cargo to lymph nodes. These data support a novel role for neutrophils in homeostatic immune surveillance, sampling circulating antigens and delivering them to lymph nodes, with the potential to activate adaptive immunity., Neutrophils play a key role in innate immunity. As the dominant circulating phagocyte, they are rapidly recruited from the bloodstream to sites of infection or injury to internalize and destroy microbes. More recently, neutrophils have been identified in uninfected organs, challenging the classical view of their function. Here we show that neutrophils were present in lymph nodes (LNs) in homeostasis. Using flow cytometry and confocal imaging, we identified neutrophils within LNs in naive, unchallenged mice, including LNs draining the skin, lungs, and gastrointestinal tract. Neutrophils were enriched within specific anatomical regions, in the interfollicular zone, a site of T cell activation. Intravital two-photon microscopy demonstrated that LN neutrophils were motile, trafficked into LNs from both blood and tissues via high endothelial venules and afferent lymphatics, respectively, and formed interactions with dendritic cells in LNs. Murine and human LN neutrophils had a distinct phenotype compared with circulating neutrophils, with higher major histocompatibility complex II (MHCII) expression, suggesting a potential role in CD4 T cell activation. Upon ex vivo stimulation with IgG immune complex (IC), neutrophils up-regulated expression of MHCII and costimulatory molecules and increased T cell activation. In vivo, neutrophils were capable of delivering circulating IC to LNs, suggesting a broader functional remit. Overall, our data challenge the perception that neutrophil patrol is limited to the circulation in homeostasis, adding LNs to their routine surveillance territory.

IntroductionRadionuclides for leucocyte kinetic studies have progressed from non-gamma emitting cell-labelling radionuclides through gamma emitting nuclides that allow imaging of leucocyte kinetics, to the next goal of positron emission tomography (PET).Sources of dataMostly the authors’ own studies, following on from studies of the early pioneers.Areas of controversyFrom early imaging studies, it appeared that the majority of the marginated granulocyte pool was located in the lungs. However, later work disputed this by demonstrating the exquisite sensitivity of granulocytes to ex vivo isolation and labelling, and that excessive lung activity is artefactual.Areas of agreementFollowing refinement of labelling techniques, it was shown that the majority of marginated granulocytes are located in the spleen and bone marrow. The majority of leucocytes have a pulmonary vascular transit time only a few seconds longer than erythrocytes. The minority showing slow transit, ~5% in healthy persons, is increased in systemic inflammatory disorders that cause neutrophil priming and loss of deformability. Using a range of imaging techniques, including gamma camera imaging, whole-body counting and single photon-emission computerized tomography, labelled granulocytes were subsequently used to image pulmonary trafficking in lobar pneumonia, bronchiectasis, chronic obstructive pulmonary disease and adult respiratory distress syndrome.Growing pointsMore recently, eosinophils have been separated in pure form using magnetic bead technology for the study of eosinophil trafficking in asthma.Areas timely for developing researchThese include advancement of eosinophil imaging, development of monocyte labelling, development of cell labelling with PET tracers and the tracking of lymphocytes.

Background Decreases in circulating neutrophils (polymorphonuclear leukocytes, PMNs) have been reported in patients treated with the anti-interleukin-6 receptor (IL-6R) antibody tocilizumab (TCZ); the mechanism for this is unclear. We hypothesize that TCZ reduces circulating neutrophils by affecting margination and / or bone marrow trafficking without affecting neutrophil function or apoptosis. Materials and methods 18 healthy subjects were randomized to single intravenous dose of TCZ 8 mg/kg (n = 12) or placebo (n = 6) on day 0. On day 4, each subject had autologous indium-111-labeled neutrophils re-injected, and their kinetics quantified with longitudinal profiling in a whole body gamma-counter. TCZ-treated subjects were divided into two groups according to the extent of reduction in neutrophil count. Results Mean day 4 neutrophil counts, as % baseline, were 101.9%, 68.3% and 44.2% in the placebo, TCZ-PMN-’high’ and TCZ-PMN-’low’ groups, respectively (p < 0.001). Following TCZ, neutrophil function, activation and apoptosis ex vivo were all unaffected. In vivo, there were no differences in early blood recovery or margination to liver / spleen and bone marrow; however, later neutrophil re-distribution to bone marrow was markedly reduced in the TCZ-PMN-low group (peak pelvic count as % day 4 count on: day 5, 188% placebo vs 127% TCZ-PMN-low, p < 0.001; day 10, 180% placebo vs 132% TCZ-PMN-low, p < 0.01), with a trend towards higher liver / spleen neutrophil retention. Conclusions We have demonstrated for the first time in humans that IL-6R blockade affects neutrophil trafficking to the bone marrow without influencing neutrophil functional capacity. This article is protected by copyright. All rights reserved.

Monilethrix is a rare genodermatosis characterized by a hair shaft dysplasia responsible for hypotrichosis. We report the case of a child with monilethrix with no associated cases in the family. Trichoscopy facilitated the diagnosis. A 2-year-old boy presented with diffuse alopecia and persistent fragile hair for several months. Clinical examination revealed alopecia with hairs broken several millimeters from the scalp. Trichoscopy revealed zones of dystrophic constriction of the hair shaft, separated at regular intervals by elliptical nodes of normal thickness, giving a "necklace" appearance. The diagnosis of monilethrix was made on the basis of these specific features. The diagnosis of monilethrix was more difficult to establish in our patient owing to the absence of any familial cases.

Idiopathic hypertrophic pachymeningitis is a rare inflammatory condition with diffuse thickening of the dura mater, which may cause a compressive effect or vascular compromise. We report on a 28-year-old Chinese woman with a history of granulomatous mastitis 7 years previously and oligomenorrhoea, headache, blurred vision, and raised prolactin level 2 years previously, that was diagnosed as prolactinoma and treated conservatively with bromocriptine. However, she had recurrent bilateral vision loss when the bromocriptine was stopped. Her symptoms were resolved by high-dose steroid injection but remained steroid-dependent. Serial magnetic resonance imaging scan showed progressive diffuse thickening of the pachymeningitis with disappearance of pituitary apoplexy. Lumbar puncture showed lymphocytosis with no organisms. Open biopsy of the meninges was performed and histology showed features of inflammatory infiltrates and vasculitis. This is an unusual presentation of a rare condition in this age-group, with co-existing granulomatous mastitis and chronic otitis media, and is a diagnostic challenge mimicking pituitary macroadenoma and meningioma in initial magnetic resonance imaging scans.

Objective. We previously showed that DU significantly increased global and hand disability with a significant impact on activities of daily living (ADLs) and work disability. This study aims to evaluate the impact of digital ulcer (DU) healing on disability and daily activity limitations in SSc. Methods. From January 2008 and June 2009, we prospectively evaluated 189 SSc patients for DU history, disability, employment and occupational status during meetings of the French SSc Patient Association (n = 86, 45.5%) or during hospitalization (n = 103, 54.5%)1. Among the 60 patients with at least one active DU at baseline (M0), 40 patients were followed longitudinally over 6 (3) months. These patients were evaluated for DU history, global and hand disability, health-related quality of life (HRQoL), daily activity limitation and employment status. Results. The median (IQR) age was 57.5 (43.5-68) years and the median (IQR) disease duration was 8.3 (3-16.5) years. Twenty-two (55%) patients had diffuse SSc and 34 (85%) were females. At baseline, a mean of 2.9 (2.8) DU per patient was reported. Thirty-three (82.5%) patients had ischaemic DU, 7 (17.5%) patients had >1 DU associated with calcinosis and 13 (32.5%) patients had mechanical DU. Thirteen (32.5%) patients had >4 DU at baseline. Among the 40 patients, 16 (40%) patients showed complete ulcer healing. In these patients with DU, the presence of calcinosis was associated with a lower probability of healing (P = 0.03). Comparison between healed and no-healed DU patients showed an improvement of hand disability provided by an improvement of the Cochin Hand Function score (P = 0.05)) and a trend towards HAQ domain dressing and grooming (P = 0.06) between M0 and M6 (3) visit in healed patients but not in no-healed patients. Concerning HRQoL, there were no difference for Mental and Physical component Scores of SF-36 but significant improvement of Bodily Pain score (P = 0.04) and Physical Role score (P = 0.05) between M0 and M6 (3) visit in patients with healed DU. The absence of healing was associated with significantly decreased work productivity (P = 0.05), whereas the performance in ADL was not significantly decreased (P = 0.15). Patients who were on sick-leave and who received some help for household tasks at the time of active DU were more likely to heal. Conclusion. For the first time, we provide prospective data with evidence that DU healing is associated with an improvement in hand function. Sick leave was associated with better healing of DU

Objective: To identify nailfold videocapillaroscopic features and other clinical risk factors for new digital ulcers (DUs) during a 6-month period in patients with systemic sclerosis (SSc). Methods: In this multicenter, prospective, observational cohort study, the videoCAPillaroscopy (CAP) study, we evaluated 623 patients with SSc from 59 centers (14 countries). Patients were stratified into 2 groups: a DU history group and a no DU history group. At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and assessment of demographic characteristics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression (MLR) analyses. Results: Of the 468 patients in the DU history group (mean ± SD age 54.0 ± 13.7 years), 79.5% were female, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by MLR in the DU history group included the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs (categorized as 0, 1, 2, or ≥3), and the presence of critical digital ischemia. The receiver operating characteristic (ROC) of the area under the curve (AUC) of the final MLR model was 0.738 (95% confidence interval [95% CI] 0.681–0.795). Internal validation through bootstrap generated a ROC AUC of 0.633 (95% CI 0.510–0.756). Conclusion: This international prospective study, which included detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc, identified the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs at enrollment, and the presence of critical digital ischemia at enrollment as risk factors for the development of new DUs. © 2016, American College of Rheumatology

In contrast with bone metastasis, acrometastases are uncommon and are associated with advanced cancer. We report the cases of two patients with atypical lesions of the fingers in a context of cancer, in which biopsies confirmed a metastasis. Patients died rapidly before treatment was initiated. We discuss the characteristics of these atypical metastatic sites, associated with a generally poor prognosis.

OBJECTIVES: To determine the mechanism and epidemiology of paediatric finger injuries in Hong Kong during 2003-2005 and 2010-2012. DESIGN: Comparison of two case series. SETTING: University-affiliated teaching hospital, Hong Kong. PATIENTS: A retrospective study of two cohorts of children (age, 0 to 16 years) admitted to Prince of Wales Hospital with finger injuries during two 3-year periods. Comparisons were made between the two groups for age, involved finger(s), mechanism of injury, treatment, and outcome. Telephone interviews were conducted for parents of children who sustained a crushing injury of finger(s) by door. RESULTS: A total of 137 children (group A) were admitted from 1 January 2003 to 31 December 2005, and 109 children (group B) were admitted from 1 January 2010 to 31 December 2012. Overall, the mechanisms and epidemiology of paediatric finger injuries were similar between groups A and B. Most finger injuries occurred in children younger than 5 years (group A, 55%; group B, 75%) and in their home (group A, 67%; group B, 69%). The most common mechanism was crushing injury of finger by door (group A, 33%; group B, 41%) on the hinge side (group A, 63%; group B, 64%). The right hand was most commonly involved. The door was often closed by another child (group A, 37%; group B, 23%) and the injury often occurred in the presence of adults (group A, 60%; group B, 56%). Nailbed injury was the commonest type of injury (group A, 31%; group B, 49%). Fractures occurred in 24% and 49% in groups A and B, respectively. Traumatic finger amputation requiring replantation or revascularisation occurred in 12% and 10% in groups A and B, respectively. CONCLUSIONS: Crushing injury of finger by door is the most common mechanism of injury among younger children and accounts for a large number of hospital admissions. Serious injuries, such as amputations leading to considerable morbidity, can result. Crushing injury of finger by door occurs even in the presence of adults. There has been no significant decrease in the number of crushing injuries of finger by door in the 5 years between the two studies despite easily available and affordable preventive measures. It is the authors' view that measures aimed at promoting public awareness and education, and safety precautions are needed. Language: en

Post-transplant cutaneous lymphomas are rare. Cutaneous T-cell lymphomas account for 30% of these lymphomas. The clinical appearance of the skin lesions is identical to cutaneous lymphomas observed in non-immunosuppressed patients, with infiltrated plaques, nodular and ulcerated tumors, but with an increased frequency of erythroderma. Standard histology and immunohistochemistry are also consistent with the features of mycosis fungoides and CD30+ cutaneous lymphomas observed in the general population. However, the pronostic differs from the usually favourable outcome of cutaneous T-cell lymphomas, as 8 out of the 13 patients of our series died, in less than 1 year for 6 of them. This unfavourable course appears to be the same as that observed for systemic T-cell lymphoma in transplant recipients. In contrast to post-transplant B-cell lymphomas (systemic and primary cutaneous), the link to a virus has not been demonstrated. The prognosis is also less favourable for post-transplant cutaneous T-cell lymphomas than for post-transplant cutaneous B-cell lymphomas.

What do you see Walt Whitman? Who are they you salute, and that one after another salute you? ... I see the curious rapid change of the light and shade, I see distant lands, as real and near to the inhabitants of them as my land is to me ... All you continentals of Asia, Africa, Europe, Australia, indifferent of place! All you on the numberless islands of the archipelagoes of the sea! And you of centuries hence when you listen to me! And you each and everywhere whom I specify not, but include just the same! Health to you! good will to you all, from me and America sent! Each of us inevitable, Each of us limitless--each of us with his or her rights upon the earth, Each of us allow'd the eternal purports of the earth, Each of us here as divinely as any is here. --From Walt Whitman, "Salut Au Monde" In July 2001, Veronica Makowsky invited us to guest-edit a special issue of MELUS in celebration of Katharine Dealy Newman's life and work. We knew then already that our festschrift for Newman would have to be more than just a miscellaneous volume to honor the memory of the woman who had played a more crucial role than any other individual in bringing MELUS--and MELUS--into existence in the early 1970s. Imbued strongly with what we know today as the MELUS mission, Katharine herself would have liked such a celebration to be more than a compendium of her life and achievements. So we decided in our Call to spread our net as wide as possible to attract scholarly fish of all hues, and see what we could gather. Our Call stated in part, "Our objective in bringing out this special number is to preserve and expand Newman's legacy by attempting a retrospective evaluation of the role played by MELUS during the past three decades in the ongoing re-definition of American Literature by taking stock of developments in ethnic and cultural studies since the 1960s." We welcomed especially essays on pedagogy, canon, theory, and ethnic literary studies as a "discipline," as well as others on the role of anthologies and critical editions in transforming curriculum. We had also hoped to include some new interpretations of by-now canonical ethnic American authors or texts, as well as some pieces dedicated to the recovery of lost, neglected, and forgotten figures or texts. As our table of contents indicates, we have every reason to be happy with the wide-ranging response from our fellow scholars. To be sure, like the persona in that elusive Emerson poem, "Days," we might acknowledge the understandable gap between what one wishes for and what one actually receives. And yet, this gathering of essays by Americanists from around the globe, seasoned and emerging scholars as well as graduate students still discovering their voices, represents some of the most exciting scholarship in US literary studies on issues of canon and context, pedagogy and theory, race and ethnicity, gender and sexuality, nation and diaspora, individual and group identity. We are especially pleased to include quite a few international scholars: from Ireland, Germany, India, Italy, Poland, and Israel. We expect that this collection as a whole, and through its individual essays, will raise new debate and discussion, and for us, that is indeed the best measure of how we might remember Newman and honor her legacy. In relation to the many shared spaces and intersections among the interconnected and overlapping areas of American Studies and Cultural Studies, multi-ethnic literary studies as a field--in tandem with African American literary studies--is now so vast that it would be foolhardy for any one volume to cover all its subsets systematically and exhaustively. While limited in many ways by what we could accept from the submissions we received--or at times, what we could nudge or commission into being to fill up some lacunae--we were attentive to the need to cover a wide and suggestive range of issues in relation to the multiple ethnicities and historical experiences that make up the United States and the Americas beyond. …

In hybrid environments, where real and virtual overlap, participants naturally see, touch, and manipulate the object at hand.

Background andobjectivesThecalcimimeticcinacalcet reduced therisk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients. Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified. ResultsOlderpatients hadhigher baselineprevalenceof diabetesmellitusandCV comorbidity. Annualizedrates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. Conclusions In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone. Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.07730814

Phacoemulsification is the main gold standard for cataract operation in the developed world together with foldable intraocular lens (IOL) implantation by injection, allowing for stable wound construction and less postoperative astigmatism. It is a safe procedure with high success rate with the advancement in machines, improvement of IOL injection systems and further maturation of surgeons' techniques. Despite the large number of operations performed every day, foldable IOL injection leading to an intra-stromal corneal track is a very rare complication. We report a case of this unusual finding in a 70-year-old gentleman who has undergone cataract operation in November 2011 in our hospital and will review on the complications related to foldable IOL injection.

Background The treatment of stage I Merkel cell carcinoma (MCC) usually includes wide local excision (WLE) combined with irradiation of the tumor bed (ITB). No randomized study has ever been conducted in MCC. The purpose of this study was to assess the efficacy and safety of prophylactic adjuvant radiotherapy on the regional nodes. Patients and methods In this randomized open controlled study, patients for a stage I MCC treated by WLE and ITB were randomly assigned to regional adjuvant radiotherapy versus observation. Overall survival (OS) and probability of regional recurrence (PRR) were primary end points. Progression-free survival (PFS) and tolerance of irradiation were secondary end points. Results Eighty-three patients were included before premature interruption of the trial, due to a drop in the recruitment mainly due to the introduction of the sentinel node dissection in the management of MCC. No significant improvement in OS (P = 0.989) or PFS (P = 0.4) could be demonstrated after regional irradiation, which, however, significantly reduced the PRR (P = 0.007) with 16.7% regional recurrence rate in the observation arm versus 0% in the treatment arm. The treatment was well tolerated. Conclusion The adjuvant regional irradiation significantly decreased the PRR in MCC, but benefit in survival could not be demonstrated.

To evaluate the effect of quaternary nicotinamide pendant groups on gene delivery properties, a series of poly(amido amine) (co)polymers were synthesized by Michael addition polymerization of N, N'-cystaminebisacrylamide with variable ratios of 1-(4-aminobutyl)-3-carbamoylpyridinium (Nic-BuNH(2)), and tert-butyl-4-aminobutyl carbamate (BocNH-BuNH(2)), yielding poly(amido amine)s (NicX-NHBoc) with X=0, 10, 30, and 50 % of quaternary nicotinamide groups in the polymer side chains. Deprotection of the pendant Boc-NH groups afforded an analogous series of polymers (NicX-NH(2)) with higher charge density (due to the presence of protonated primary amino groups in the side chains) and subsequent acetylation yielded a series of polymers (NicX-NHAc) of lower hydrophobicity than the Boc-protected polymers. The polymers with the Boc-protected or the acetylated amino groups showed high buffer capacity in the range pH 5.1-7.4, which is a property that can contribute to endosomal escape of polyplexes. The presence of quaternary nicotinamide groups has distinct beneficial effects on the gene vector properties of these polymers. The polymers containingor=30 % of quaternary nicotinamide groups in their side chains condense DNA into small, nanosized particles (or=200 nm) with positive surface charge (or=+15 mV). Fluorescence experiments using ethidium bromide as a competitor showed that the quaternary nicotinamide groups intercalate with DNA, contributing to a more intimate polymer-DNA binding and shielding. Polyplexes of nicotinamide-functionalized poly(amido amine)s NicX-NHBoc and NicX-NHAc, formed at 12/1 polymerDNA mass ratio, efficiently transfect COS-7 cells with efficacies up to four times higher than that of PEI (Exgen 500), and with essentially absence of cytotoxicity. NicX-NH(2) polymers, possessing protonated primary amino groups in their side chains, have a higher cytotoxicity profile under these conditions, but at lower 3/1 polymer-DNA mass ratio also these polymers are capable of efficient transfection, while retaining full cell viability.

A new cationic biodegradable polyphosphazene was developed, bearing both pendant primary and tertiary amine side groups, poly(2-dimethylaminoethylamine-co-diaminobutane)phosphazene (poly(DMAEA-co-BA)phosphazene). PEG and PEG-folate were coupled to polyplexes based on this poly(DMAEA-co-BA)phosphazene, leading to small (size 100 and 120 nm, respectively) and almost neutral particles. In vitro tissue culture experiments showed a low cytotoxicity of both uncoated and coated polyplexes. However, the PEG coated polyplexes showed a 2-fold lower transfection activity in OVCAR 3 cells as compared to the uncoated polyplexes. On the other hand, the PEG-folate coated polyplexes had a 3-fold higher transfection than the PEGylated polyplexes. When free folate was added to the transfection medium, only the transfection activity of the targeted polyplexes was reduced, indicating internalization of the targeted PEG polyplexes via the folate receptor. Confocal laser scanning microscopy confirmed a lower binding and uptake of the PEGylated polyplexes by OVCAR-3 cells when compared to uncoated and folate-PEGylated polyplexes. While uncoated polyplexes induced aggregation of erythrocytes at polymer concentrations of 0.09 μg/mL, the PEGylated systems could be incubated at ten times higher concentration before aggregation occurred indicating excellent shielding of the surface charge of the polyplexes by grafting of PEG. In conclusion, the targeted delivery of poly(DMAEA-co-BA)phosphazene bases polyplexes and their improved compatibility with erythrocytes makes them interesting for in vivo applications.

The ability to efficiently produce hundreds of proteins in parallel is the most basic requirement of many aspects of proteomics. Overcoming the technical and financial barriers associated with high throughput protein production is essential for the development of an experimental platform to query and browse the protein content of a cell (e.g. protein and antibody arrays). Proteins are inherently different one from another in their physicochemical properties; therefore, no single protocol can be expected to successfully express most of the proteins. Instead of optimizing a protocol to express a specific protein, we used sequence analysis tools to estimate the probability of a specific protein to be expressed successfully using a given protocol, thereby avoiding a priori proteins with a low success probability. A set of 547 proteins, to be used for antibody production and selection, was expressed in Escherichia coli using a high throughput protein production pipeline. Protein properties derived from sequence alone were correlated to successful expression, and general guidelines are given to increase the efficiency of similar pipelines. A second set of 68 proteins was expressed to investigate the link between successful protein expression and inclusion body formation. More proteins were expressed in inclusion bodies; however, the formation of inclusion bodies was not a requirement for successful expression.

Introduction and objectives Tuberculosis (TB) has re-emerged as an important public health problem in the UK. Subsequent to the publication of ‘Stopping Tuberculosis in England: An Action Plan from the Chief Medical Officer’ in 2004, the London TB Metrics was produced, against which the performance of local TB services can be measured. This audit recorded relevant aspects of diagnosis and management of all adult TB patients in a local district hospital TB clinic, and compared them against the Metric targets. Methods Eight of the nine Metric indices were selected (neonatal BCG vaccination coverage excluded). Data were collected on all adult patients seen in an outpatient TB clinic in 2008 and compared against targets set in the London TB Metrics. Results 73 adults (35 males, 38 females) were diagnosed, of which 38 (49.4%) were pulmonary cases. 69 patients (94.5%) were offered an HIV test; 63 patients attended for testing, with two patients testing positive for HIV. Abstract P57 Table 1 summarises results achieved. Discussion We have audited performance of a local TB clinic against targets set in the London TB Metrics. Achieving a microbiological diagnosis in 65% is difficult as patients are often already on treatment before referred into the service. Changes were instituted in laboratory workflow patterns to improve sputum smear result availability within one working day, increasing to 93.8% in the first 2 months of 2010. Conclusion The London TB Metrics targets are achievable (seven of eight targets met) and provide an audit tool that may facilitate improvements in the standard of TB care.

Smoking is associated with many diseases and remains a major cause of mortality. The Million Women Study is a large UK prospective cohort study of women born in the second quarter of the 20th century, collecting data for a broad range of health issues. Women were recruited and sent questionnaires that included lifestyle factors …

A set of 1438 human exons was subjected to nested PCR. The initial success rate using a standard PCR protocol required for ligation-independent cloning was 83.4%. Logistic regression analysis was conducted on 27 primer- and template-related characteristics, of which most could be ignored apart from those related to the GC content of the template. Overall GC content of the template was a good predictor for PCR success; however, specificity and sensitivity values for predicted outcome were improved to 84.3 and 94.8%, respectively, when regionalized GC content was employed. This represented a significant improvement in predictability with respect to GC content alone (P < 0.001; chi(2)) and is expected to increase in relative sensitivity as template size increases. Regionalized GC was calculated with respect to a threshold of 61% GC content and a sliding window of 21 bp across the target sequence. Fine-tuning of PCR conditions is not practicable for all target sequences whenever a large number of genes of different lengths and GC content are to be amplified in parallel, particularly if total open reading frame or domain coverage is essential for recombinant protein synthesis. Thus, the present method is proposed as a means of grouping subsets of genes possessing potentially difficult target sequences so that PCR conditions can be optimized separately in order to obtain improved outcomes.

Objective. To assess the effect of oral treatment with micronized purified flavonoid fraction (MPFF) on leg ulcer healing. Design. Meta-analysis of randomised prospective studies using MPFF in addition to conventional treatment. Materials and methods. Five prospective, randomised, controlled studies in which 723 patients with venous ulcers were treated between 1996 and 2001 were identified. Conventional treatment (compression and local care) in addition to MPFF was compared to conventional treatment plus placebo in two studies (NZ309), or with conventional treatment alone in three studies (NZ414). The primary end point was complete ulcer healing at 6 months. Results. At 6 months, the chance of healing ulcer was 32% better in patients treated with adjunctive MPFF than in those managed by conventional therapy alone (RRR: 32%; CI, 3‐70%). This difference was present from month 2 (RRR: 44%; CI, 7‐94%), and was associated with a shorter time to healing (16 versus 21 weeks; PZ0.0034). The main benefit of MPFF was present in the subgroup of ulcers between 5 and 10 cm 2 in area (RRR: 40%; CI, 6‐87%), and those present for 6‐12 months duration (RRR: 44%; CI, 6‐97%). Conclusion. These results confirm that venous ulcer healing is accelerated by MPFF treatment. MPFF might be a useful adjunct to conventional therapy in large and long standing ulcers.