Identification of a Disease-Associated Network of Intestinal Immune Cells in Treatment-Naive Inflammatory Bowel Disease.

Chronic intestinal inflammation underlies inflammatory bowel disease (IBD). Previous studies indicated alterations in the cellular immune system; however, it has been challenging to interrogate the role of all immune cell subsets simultaneously. Therefore, we aimed to identify immune cell types associated with inflammation in IBD using high-dimensional mass cytometry. We analyzed 188 intestinal biopsies and paired blood samples of newly-diagnosed, treatment-naive patients (n=42) and controls (n=26) in two independent cohorts. We applied mass cytometry (36-antibody panel) to resolve single cells and analyzed the data with unbiased Hierarchical-SNE. In addition, imaging-mass cytometry (IMC) was performed to reveal the spatial distribution of the immune subsets in the tissue. We identified 44 distinct immune subsets. Correlation network analysis identified a network of inflammation-associated subsets, including HLA-DR+CD38+ EM CD4+ T cells, T regulatory-like cells, PD1+ EM CD8+ T cells, neutrophils, CD27+ TCRγδ cells and NK cells. All disease-associated subsets were validated in a second cohort. This network was abundant in a subset of patients, independent of IBD subtype, severity or intestinal location. Putative disease-associated CD4+ T cells were detectable in blood. Finally, imaging-mass cytometry revealed the spatial colocalization of neutrophils, memory CD4+ T cells and myeloid cells in the inflamed intestine. Our study indicates that a cellular network of both innate and adaptive immune cells colocalizes in inflamed biopsies from a subset of patients. These results contribute to dissecting disease heterogeneity and may guide the development of targeted therapeutics in IBD.

Snapshots of Iron Speciation: Tracking the Fate of Iron Nanoparticle Drugs via a Liquid Chromatography-Inductively Coupled Plasma-Mass Spectrometric Approach.

Nanomedicines are nanoparticle-based therapeutic or diagnostic agents designed for targeted delivery or enhanced stability. Nanotechnology has been successfully employed to develop various drug formulations with improved pharmacokinetic characteristics, and current research efforts are focused on the development of new innovator and generic nanomedicines. Nanomedicines, which are often denoted as complex or nonbiological complex drugs, have inherently different physicochemical and pharmacokinetic properties than conventional small molecule drugs. The tools necessary to fully evaluate nanomedicines in clinical settings are limited, which can hamper their development. One of the most successful families of nanomedicines are iron-carbohydrate nanoparticles, which are administered intravenously (IV) to treat iron-deficiency anemia. In the U.S., the FDA has approved six distinct iron-carbohydrate nanoparticles but only one generic version (sodium ferric gluconate for Ferrlecit). There is significant interest in approving additional generic iron-carbohydrate drugs; however, the lack of a direct method to monitor the fate of the iron nanoparticles in clinical samples has impeded this approval. Herein we report a novel liquid chromatography-inductively coupled plasma-mass spectrometry (LC-ICP-MS) method that allows for the direct quantification of the iron-carbohydrate drugs in clinical samples, while simultaneously measuring the speciation of the iron released from the nanoparticles in biological samples. To our knowledge, this is the first time that iron nanoparticles have been observed in clinical samples, opening the door for direct pharmacokinetic studies of this family of drugs. This method has potential applications not only for iron-nanoparticle drugs but also for any nanomedicine with an inorganic component.

The Cost of Self-Reported Penicillin Allergy: A Systematic Review.

BACKGROUND: Patients who report a penicillin (PCN) allergy receive suboptimal antibiotic therapy compared with patients not reporting an allergy. However, a majority of patients who report PCN allergy are not truly allergic on confirmatory testing. Ruling out PCN allergy by testing may improve clinical and economic outcomes for patients with reported allergies requiring antibiotic therapy. OBJECTIVE: The objective of this study was to summarize clinical and economic outcomes associated with PCN allergy and provide recommendations for future cost-effectiveness analyses for PCN allergy testing. METHODS: A literature search was conducted using SCOPUS, EMBASE, and PubMed, including all articles published any date through April 25, 2017 (PROSPERO Registration number 42017064112). A total of 1518 abstracts were found during the initial search with 96 duplicates, for a total of 1422 articles for screening. Thirty articles were included for qualitative synthesis and full data extraction. RESULTS: The majority of the studies included had an observational design focusing on inpatient admissions. The most frequently measured outcome in the context of PCN allergy was optimizing antibiotic therapy. Patients with PCN allergy were found to have direct drug costs during inpatient admission ranging from no difference to an additional $609/patient compared with patients without PCN allergy. Outpatient prescription costs were estimated from $14 to $193/patient higher for PCN allergic patients. Total inpatient costs were less for patients without PCN allergy with average savings from $1145 to $4254/patient. CONCLUSIONS: Evaluations of clinical and economic outcomes of PCN allergy are primarily observational and focus on inpatient populations. Long-term relationships between PCN allergy and clinical and economic outcomes are unknown.

BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION ASSOCIATED WITH RENAL CANCER: THE IMPORTANCE OF INDOCYANINE GREEN ANGIOGRAPHY AND EARLY DIAGNOSIS.

PURPOSE: To report a case of bilateral diffuse uveal melanocytic proliferation associated with renal carcinoma and to illustrate the importance of ancillary examinations to early diagnosis and treatment. DESIGN: Clinical case report. METHODS: A 56-year-old man reported a 3-day history of visual impairment and scotoma in the right eye. An ophthalmoscopic examination, visual field test, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography, and systemic evaluation were performed. RESULTS: Fundus examination showed multiple nevus-like uveal pigmented lesions bilaterally. Optical coherence tomography showed a subfoveal serous retinal detachment and focal loss of the retinal pigment epithelium with adjacent areas of retinal pigment epithelial thickening in the right eye, explaining the scotoma on the visual field examination. Indocyanine green angiography showed multiple round areas of hypofluorescence corresponding to the nevus-like pigmented tumors seen on funduscopy, and retinal pigment epithelium damage corresponding to hypoautofluorescence on fundus autofluorescence imaging and window defects points seen on fluorescein angiography bilaterally. After bilateral diffuse uveal melanocytic proliferation diagnosis, a systemic workup showed clear cell carcinoma in the left kidney. Owing to the tumoral size, chemotherapy was administered. CONCLUSION: Renal carcinoma associated with bilateral diffuse uveal melanocytic proliferation is rare, and the patterns observed in the ancillary examinations, including indocyanine green angiography, are useful for early-stage diagnosis and immediate referral for systemic investigation and treatment.

Randomized Comparison of Surveillance Intervals in Familial Colorectal Cancer.

PURPOSE: Colonoscopic surveillance is recommended for individuals with familial colorectal cancer (CRC). However, the appropriate screening interval has not yet been determined. The aim of this randomized trial was to compare a 3-year with a 6-year screening interval. PATIENTS AND METHODS: Individuals between ages 45 and 65 years with one first-degree relative with CRC age < 50 years or two first-degree relatives with CRC were selected. Patients with zero to two adenomas at baseline were randomly assigned to one of two groups: group A (colonoscopy at 6 years) or group B (colonoscopy at 3 and 6 years). The primary outcome measure was advanced adenomatous polyps (AAPs). Risk factors studied included sex, age, type of family history, and baseline endoscopic findings. RESULTS: A total of 528 patients were randomly assigned (group A, n = 262; group B, n = 266). Intention-to-treat analysis showed no significant difference in the proportion of patients with AAPs at the first follow-up examination at 6 years in group A (6.9%) versus 3 years in group B (3.5%). Also, the proportion of patients with AAPs at the final follow-up examination at 6 years in group A (6.9%) versus 6 years in group B (3.4%) was not significantly different. Only AAPs at baseline was a significant predictor for the presence of AAPs at first follow-up. After correction for the difference in AAPs at baseline, differences between the groups in the rate of AAPs at first follow-up and at the final examination were statistically significant. CONCLUSION: In view of the relatively low rate of AAPs at 6 years and the absence of CRC in group A, we consider a 6-year surveillance interval appropriate. A surveillance interval of 3 years might be considered in patients with AAPs and patients with ≥ three adenomas.

Guidelines-based diagnostic process does increase hospital delay in a cohort of colorectal cancer patients: a population-based study.

This is an investigation of factors determining hospital delay until treatment in an unrestricted population of colorectal cancer patients in the western part of the Netherlands. All patients with newly diagnosed colon (n=2146) and rectal carcinoma (n=1036) in the period 2006-2008 were included in analyses of inhospital delay (first hospital visit until first treatment >35 days). One-third of all patients were also available for analyses of prehospital delay (enrollment until first hospital visit >7 days). Patient, tumour and process factors predicting delay were examined in logistic regression models. The median prehospital and inhospital time intervals were 2 days [(p25-p75) 0-16] and 32 days (17-49), respectively, for colon cancer patients and 7 days (1-21) and 43 days (33-60) for rectal cancer patients. After adjustment for patient and tumour factors, colon and rectal cancer patients with first hospital visit before histological confirmation of cancer, complete diagnostic assessment or discussed in a multidisciplinary meeting had a higher probability of increased inhospital delay. Furthermore, first hospital visit before histological confirmation of cancer was associated with decreased prehospital delay in colon and rectal cancer patients. A guidelines-based diagnostic process (considered high quality of care) and multidisciplinary collaboration were associated with increased hospital delay in colorectal cancer patients.

Effects of prophylactic and therapeutic paracetamol treatment during vaccination on hepatitis B antibody levels in adults: two open-label, randomized controlled trials.

UNLABELLED: Worldwide, paracetamol is administered as a remedy for complaints that occur after vaccination. Recently published results indicate that paracetamol inhibits the vaccination response in infants when given prior to vaccination. The goal of this study was to establish whether paracetamol exerts similar effects in young adults. In addition, the effect of timing of paracetamol intake was investigated. In two randomized, controlled, open-label studies 496 healthy young adults were randomly assigned to three groups. The study groups received paracetamol for 24 hours starting at the time of (prophylactic use) - or 6 hours after (therapeutic use) the primary (0 month) and first booster (1 month) hepatitis B vaccination. The control group received no paracetamol. None of the participants used paracetamol around the second booster (6 months) vaccination. Anti-HBs levels were measured prior to and one month after the second booster vaccination on ADVIA Centaur XP. One month after the second booster vaccination, the anti-HBs level in the prophylactic paracetamol group was significantly lower (p = 0.048) than the level in the control group (4257 mIU/mL vs. 5768 mIU/mL). The anti-HBs level in the therapeutic paracetamol group (4958 mIU/mL) was not different (p = 0.34) from the level in the control group. Only prophylactic paracetamol treatment, and not therapeutic treatment, during vaccination has a negative influence on the antibody concentration after hepatitis B vaccination in adults. These findings prompt to consider therapeutic instead of prophylactic treatment to ensure maximal vaccination efficacy and retain the possibility to treat pain and fever after vaccination. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN03576945.

Cholesterol and synaptic compensatory mechanisms in Alzheimer's disease mice brain during aging.

Research into the development of Alzheimer's disease (AD) provides increasing evidence that vascular risk factors, including high serum cholesterol, might influence the progression of cognitive impairment and neural degeneration. In this study, we investigated the effects of high dietary cholesterol intake and the cholesterol-lowering liver X receptor-agonist T0901317 on capillary density, amyloid-ß deposition, and presynaptic boutons in the hippocampus of adult (8 months) and aged (15 months) AßPPswe-PS1dE9 and wild-type mice to elucidate how cholesterol may affect neurodegenerative processes in aging and AD. Our results show increased number of presynaptic boutons in 15-month-old AßPP-PS1 mice compared to age-matched wild-type animals, but no difference at 8 months of age. High cholesterol intake accelerated this response by increasing the amount of presynaptic boutons at 8 and 15 months of age, while T0901317 intake decreased the amount of presynaptic boutons in 15-month-old AßPP-PS1 mice. These findings suggest a synaptic compensatory response to maintain connectivity during aging. We hypothesize that high cholesterol intake may cause impaired cerebral blood flow inducing ischemia, fortifying the above mentioned hypothesis of a compensatory mechanism. Contrarily, cholesterol-lowering agents may positively influence cerebral circulation, thereby diminishing aggravation of AD-like pathology.

Idiopathic macular telangiectasia. 2006.

OBJECTIVES: To review the frequency and nature of idiopathic macular telangiectasia and to classify the disorders based on new clinical and imaging observations. METHODS: A combined retrospective and prospective analysis of newly diagnosed patients seen over a period of 3 years. Patients were identified based on the Gass-Blodi classification and were studied with biomicroscopy, fluorescein angiography, and optical coherence tomography. RESULTS: Ten patients associated with aneurysmal telangiectasia (Gass-Blodi group 1) and 26 patients with perifoveal telangiectasia (Gass-Blodi group 2) were recruited. None with occlusive telangiectasia (Gass-Blodi group 3) were identified. New observations based on clinical, fluorescein angiographic, and optical coherence tomographic findings were made. CONCLUSIONS: Our series was similar to that in the Gass-Blodi study in terms of frequency. New observations in groups 1 and 2 have expanded our knowledge of the clinical spectrum of these disorders. A simplified classification termed idiopathic macular telangiectasia with 2 distinct types (type I, or aneurysmal telangiectasia, and type II, or perifoveal telangiectasia) was proposed to produce a better understanding of the entities and to enhance teaching and research. The third type, occlusive telangiectasia, has been omitted from our classification based on its rarity and presence of capillary nonperfusion rather than macular telangiectasia as the primary abnormality.

ATM gene variants in patients with idiopathic perifoveal telangiectasia.

PURPOSE: To investigate the prevalence of sequence variants in the ATM gene and to determine the frequency of major age-related macular degeneration (AMD)-associated variants in CFH, CFB, and 10q26 loci in patients with idiopathic perifoveal telangiectasia (IPT). METHODS: Thirty patients with diagnoses of IPT underwent standard ophthalmologic evaluation that included visual acuity testing, fundus photography, and fluorescein angiography. DNA was screened for variations in the ATM gene by a combination of denaturing high-performance liquid chromatography and direct sequencing. Major AMD-associated alleles in CFH, CFB, and 10q loci were screened by PCR-restriction fragment-length polymorphism. RESULTS: Nineteen female and 11 male patients (average age, 59 years) with a median visual acuity of 20/50 were evaluated. Six patients were of Asian-Indian origin, one was Hispanic, and 23 were of European-American ancestry. Nine of 30 (30%) patients had diabetes mellitus, 18 of 30 (60%) patients had hypertension, and 12 of 30 (40%) patients had a history of smoking. Screening of the ATM gene revealed a null allele in 2 of 23 (8.7%) patients of European ancestry, previously disease-associated missense alleles in 4 of 23 (17.4%) patients, and common missense alleles in 7 of 23 (30.4%) patients. No variants were identified in the ATM gene in patients of Asian or Hispanic origin. Frequencies of major AMD-associated alleles in CFH, CFB, and 10q loci in the IPT cohort were similar to those in the ethnically matched general population. CONCLUSIONS: At least 26%, and maybe up to 57%, of IPT patients of European-American descent carried possibly disease-associated ATM alleles. Vascular risk factors such as hypertension, diabetes, and smoking may be associated with the pathogenesis of the disease.

Eradication of Helicobacter pylori infection favourably affects altered gastric mucosal MMP-9 levels.

BACKGROUND: Helicobacter pylori gastritis is recognized as an important pathogenetic factor in peptic ulcer disease and gastric carcinogenesis, and is accompanied by strongly enhanced gastric mucosal matrix metalloproteinase-9 (MMP-9) levels. AIM: This study was performed to investigate whether H. pylori-affected gastric mucosal MMP-2 and MMP-9 levels are reversible by successful treatment of the infection. PATIENTS AND METHODS: Fifty-eight patients with H. pylori-associated gastritis were treated with a combination regimen of acid inhibitory therapy and antibiotics for 14 days. The levels and isoforms of MMP-2 and MMP-9 were measured by semiquantitative gelatin-zymography, bioactivity assay and enzyme-linked immunosorbent assay in gastric mucosal biopsy homogenates. RESULTS: Latent, active, and total MMP-9 levels decreased consistently and significantly by successful H. pylori eradication, in antrum as well as corpus mucosa, compared with those prior to treatment, irrespective of the therapy regimen used. The elevated levels remained unchanged, however, when treatment failed. MMP-2 levels did not show major alterations after H. pylori therapy. CONCLUSION: Elevated MMP-9 levels in H. pylori-infected gastric mucosa are reversible by eradication of the infection. No major changes in mucosal MMP-2 levels were observed by H. pylori eradication.

Idiopathic macular telangiectasia.

OBJECTIVES: To review the frequency and nature of idiopathic macular telangiectasia and to classify the disorders based on new clinical and imaging observations. METHODS: A combined retrospective and prospective analysis of newly diagnosed patients seen over a period of 3 years. Patients were identified based on the Gass-Blodi classification and were studied with biomicroscopy, fluorescein angiography, and optical coherence tomography. RESULTS: Ten patients associated with aneurysmal telangiectasia (Gass-Blodi group 1) and 26 patients with perifoveal telangiectasia (Gass-Blodi group 2) were recruited. None with occlusive telangiectasia (Gass-Blodi group 3) were identified. New observations based on clinical, fluorescein angiographic, and optical coherence tomographic findings were made. CONCLUSIONS: Our series was similar to that in the Gass-Blodi study in terms of frequency. New observations in groups 1 and 2 have expanded our knowledge of the clinical spectrum of these disorders. A simplified classification termed idiopathic macular telangiectasia with 2 distinct types (type I, or aneurysmal telangiectasia, and type II, or perifoveal telangiectasia) was proposed to produce a better understanding of the entities and to enhance teaching and research. The third type, occlusive telangiectasia, has been omitted from our classification based on its rarity and presence of capillary nonperfusion rather than macular telangiectasia as the primary abnormality.

A novel instrument for assessing the retinal red reflex for non-ophthalmic health professionals.

BACKGROUND: The direct ophthalmoscope is the standard instrument for assessing retinal red reflexes when screening for cataract, however, it is expensive and often not available to non-ophthalmic health professionals. The pen torch ophthalmoscope is a new economic alternative for this purpose. This study aimed to determine its accuracy in assessing retinal red reflexes and to compare it to the direct ophthalmoscope. It is anticipated that this instrument will be useful in detecting both congenital and adult type cataracts. METHODS: Eighteen health professionals evaluated the retinal red reflexes of 68 subjects at the Dunedin Hospital Eye Clinic with both the direct ophthalmoscope and the pen torch ophthalmoscope. Three groups of seven, six and five observers assessed both eyes of 24, 21 and 23 subjects, respectively, resulting in 1,574 examinations. RESULTS: Compared to the direct ophthalmoscope, the pen torch ophthalmoscope exhibited lower sensitivity (68 per cent versus 75 per cent), but higher specificity (72 per cent versus 63 per cent) and lower over-referral (false positive) rates by nine per cent. The positive predictive value in respect to identifying for cataract was better for the pen torch ophthalmoscope (71 per cent) than for the direct ophthalmoscope (66 per cent), while the negative predictive value was slightly worse (70 per cent and 73 per cent, respectively). When compared to the direct ophthalmoscope, 15/18 observers felt the pen torch ophthalmoscope was accurate enough, one felt it was just as good and two did not respond. CONCLUSIONS: This pilot study demonstrates that the pen torch ophthalmoscope is comparable to the direct ophthalmoscope in detecting abnormal retinal red reflexes in adults with cataracts. At six per cent of the cost of a direct ophthalmoscope, it may appeal to non-ophthalmic health professionals in developed and developing countries. It may also increase the frequency of screening for cataract in children and adults. Further development and study of this pen torch ophthalmoscope prototype is warranted.

Analysis of New Zealand's research productivity in ophthalmology and vision science: 1993-2002.

AIM: To assess New Zealand's research productivity in the area of ophthalmology and vision science over the decade 1993-2002. METHODS: New Zealand-based researchers involved in ophthalmology or vision science research, including ophthalmologists, optometrists and vision scientists were identified via professional colleges, universities and electronic databases. Peer-reviewed publications by these authors were identified by both searching electronic databases (MEDLINE/Pubmed) and personal communication with individual researchers. RESULTS: Eighty-five New Zealand-based researchers involved in ophthalmology or vision science research published 446 articles in 84 scientific journals during the 10-year period. The cohort consisted of 59 ophthalmologists and 26 other researchers based in a diverse range of ophthalmology, optometry and university departments. Significant collaboration was observed between groups within New Zealand and with international institutions. Comparing ophthalmologists and 'other' researchers, ophthalmologists produced 69% of all ophthalmology and vision science research publications and those classified as 'active ophthalmologist researchers' published an average of 11 (range 5-55) papers each during this decade, compared to eight (range 5-25) for the group 'other active researchers'. This was also reflected in the high productivity rate by ophthalmologists of 277 publications per 1000. Publications were identified in a wide range of journals with the majority in top 20-ranked ophthalmology journals. The trend over the decade highlighted an increase in number of scientific publications, from 43 per annum in 1993, to 68 per annum in 2002. CONCLUSIONS: Despite a relatively small and geographically isolated population, New Zealand ophthalmology and vision science research is highly active and collaborative, with significantly increased research productivity during the period 1993-2002. The present study is the first to document these trends and provides strong evidence to justify continued support for ophthalmology and vision science research in New Zealand.

Castleman's disease of the lacrimal gland.

Castleman's disease, also known as angiofollicular lymphoid hyperplasia, is a lymphoproliferative disorder that is generally benign. The lesions most commonly originate in the lymph nodes of the mediastinum. The second documented case of Castleman's disease of the lacrimal gland is reported in an 84-year-old woman who presented with an 8-year history of a left upper lid mass. This was excised via a lateral orbitotomy, and a diagnosis of Castleman's disease was made histologically. Relevant images of the clinical findings and histology are shown.