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Microplastics are ubiquitous emerging contaminants found in every habitat surveyed, building upon international databases globally. Costs and accessibility often correlate to few deep sea sediment surveys, restricting the number of stations within a given sampling area. An extensive survey of the Porcupine Seabight, Porcupine Bank, the Goban Spur, and south-western canyons resulted in identifying microplastics in deep sea sediment surface layers from 33 of the 44 stations sampled (75%), with a total of 83 particles (74 synthetic and 9 natural) recorded. No microplastic hotspots were identified, and abundances (kg d.w.

This paper explores the rise of fertility apps and what data-sharing in this arena can mean for app users. The paper offers a brief background of some available fertility apps, how they work and wh...

Background Recurrence-free patients after esophageal cancer surgery face long-term nutritional consequences, occurring in the context of an exaggerated postprandial gut hormone response. Acute gut hormone suppression influences brain reward signaling and eating behavior. This study aimed to suppress gut hormone secretion and characterize reward responses and eating behavior among postesophagectomy patients with unintentional weight loss. Methods This pilot study prospectively studied postoperative patients with 10% or greater body weight loss (BWL) beyond 1 year who were candidates for clinical treatment with long-acting octreotide (LAR). Before and after 4 weeks of treatment, gut hormone secretion, food cue reactivity (functional magnetic resonance imaging), eating motivation (progressive ratio task), ad libitum food intake, body composition, and symptom burden were assessed. Results Eight patients (7 male, age: mean ± SD 62.8 ± 9.4 years, postoperative BWL: 15.5 ± 5.8%) participated. Octreotide LAR did not significantly suppress total postprandial plasma glucagon-like peptide-1 response at 4 weeks (P = .08). Postprandial symptom burden improved after treatment (Sigstad score median [range]: 12 [2-28] vs 8 [3-18], P = .04) but weight remained stable (pre: 68.6 ± 12.8 kg vs post: 69.2 ± 13.4 kg, P = .13). There was no significant change in brain reward system responses, during evaluation of high-energy or low-energy food pictures, nor their appeal rating. Moreover, treatment did not alter motivation to eat (P = .41) nor ad libitum food intake(P = .46). Conclusion The protocol used made it feasible to characterize the gut-brain axis and eating behavior in this cohort. Inadequate suppression of gut hormone responses 4 weeks after octreotide LAR administration may explain the lack of gut-brain pathway alterations. A higher dose or shorter interdose interval may be required to optimize the intervention.

Measurement of glycated haemoglobin (HbA1c) has been utilised in assessing long-term control of blood glucose in patients with diabetes, as well as diagnosing diabetes and identifying patients at increased risk of developing diabetes in the future. HbA1c reflects the level of blood glucose to which the erythrocyte has been exposed during its lifespan, and there are a number of clinical situations affecting the erythrocyte life span in which HbA1c values may be spuriously high or low and therefore not reflective of the true level of glucose control. In the present case series, we describe the particulars of three patients with diabetes who had spuriously low HbA1c levels as a result of dapsone usage. Furthermore, we discuss the limitations of HbA1c testing and the mechanisms by which it may be affected by dapsone in particular. Learning points: Various conditions and medications can result in falsely low HbA1c. Dapsone can lead to falsely low HbA1c by inducing haemolysis and by forming methaemoglobin. Capillary glucose measurement, urine glucose measurements and fructosamine levels should be used as alternatives to HbA1c for monitoring glycaemic control if it was falsely low or high. Patient Demographics: Adult, Female, Male, Other, Ireland Clinical Overview: Pancreas, Diabetes, Insulin, Diabetes mellitus type 1, Diabetes mellitus type 2, Anaemia, Haemolysis*, Methemoglobinemia*, Dermatitis herpetiformis*, Coeliac disease*, Hyperglycaemia, Hypoglycaemia, Urticarial rash*, Granuloma Diagnosis and Treatment: Diabetes mellitus type 1, Diabetes mellitus type 2, Haemolysis*, Methemoglobinemia*, Coeliac disease, Dermatitis herpetiformis*, Polydipsia, Polyuria, Weight loss, Hypoglycaemia, Hyperglycaemia, Rash, Anaemia, Haemoglobin A1c, Fructosamine*, Glucose (blood), GADA, Methaemoglobin*, Haptoglobin*, Mean corpuscular volume*, Haemoglobin , Bilirubin, Reticulocyte count*, Lactate dehydrogenase, Antibiotics, Dapsone*, Metformin, Gliclazide, Sulphonylureas, Dapagliflozin, SGLT2 inhibitors, Insulin Publication Details: Unusual effects of medical treatment, September, 2019 Background HbA1c reflects the level of blood glucose to which the erythrocyte has been exposed during its lifespan, and there are a number of clinical situations affecting the erythrocyte life span in which HbA1c values may be spuriously high or low and therefore not reflective of the true level of glucose control. In the present case series, we describe the particulars of three patients with diabetes who had spuriously low HbA1c levels as a result of dapsone usage. Furthermore, we discuss the limitations of HbA1c testing and the mechanisms by which it may be affected by dapsone in particular.

Patient: Male, 32-year-old Final Diagnosis: Granulomatous amebic encephalitis Symptoms: — Medication:— Clinical Procedure: — Specialty: — Objective: Challenging differential diagnosis Background: Acanthamoeba are free-living amoebae with potential to infect immunocompromised hosts. The mortality rate of granulomatous amebic encephalitis (GAE) due to Acanthamoeba exceeds 90% and there are currently no reports of survival of this infection in recipients of hematopoietic stem cell transplant. Case Report: We report herein the case of a 32-year-old man presenting to our service with abrupt neurological deterioration and seizures 5 months after allogeneic stem cell transplantation for Hodgkin lymphoma. Clinical and imaging findings were non-specific at presentation. Multiple circumscribed, heterogenous, mass-like lesions were identified on MRI. Brain biopsy was performed and revealed multiple cysts and trophozoites suggesting a diagnosis of granulomatous amebic encephalitis. PCR testing confirmed Acanthamoeba. Treatment with miltefosine, metronidazole, azithromycin, fluconazole, pentamidine isethionate, and co-trimoxazole was instituted and the patient survived and shows continued improvement with intensive rehabilitation. Conclusions: We report the first successful outcome in this setting. The diagnosis would have been missed on cerebrospinal fluid analysis alone, but was rapidly made by histological analysis of brain biopsy. This diagnostically challenging infection is likely under-recognized. Early brain biopsy and commencement of a prolonged miltefosine-containing anti-ameba regimen can be curative.

Patients with type 2 diabetes are at higher risk for periodontal disease and diabetic foot ulcer infections (DFUIs), the latter of which are predominantly caused by staphylococcal bacteria. Staphylococci have also been detected in the mouth, nose and gums (the oro-nasal cavity) of patients with periodontal disease and can move between the mouth and nose. The present study investigated if the oro-nasal cavity and/or periodontal pockets in diseased gum tissue can provide a microbial reservoir for DFUIs. Eighteen patients with type 2 diabetes and at least three natural teeth (13 patients with ulcers and five patients without ulcers) underwent non-invasive microbiological sampling of periodontal pocket, oro-nasal, skin and ulcer sites. Staphylococci were recovered using selective chromogenic agar, definitively identified and subjected to DNA microarray profiling, whole-genome sequencing and core-genome multilocus sequence typing (cgMLST). Staphylococcus aureus and Staphylococcus epidermidis were recovered from both the oro-nasal and ulcer sites of 6/13 and 5/13 patients with ulcers, respectively. Molecular typing based on the staphylococcal protein A (spa) gene and DNA microarray profiling indicated that for each patient investigated, S. aureus strains from oro-nasal and ulcer sites were identical. Comparative cgMLST confirmed that isolates from multiple anatomical sites of each individual investigated grouped into closely-related, patient-distinct clusters (Clusters 1-7). Isolates belonging to the same cluster exhibited an average of 2.9 allelic differences (range 11). In contrast, reference genomes downloaded from GenBank selected as representatives of each sequence type identified in the present study exhibited an average of 227 allelic differences from the most closely related isolate within each cluster.

Activated fibroblasts are considered major drivers of fibrotic disease progression through the production of excessive extracellular matrix (ECM) in response to signals from damaged epithelial and inflammatory cells. Nevertheless, epithelial cells are capable of expressing components of the ECM, cross-linking enzymes that increase its stability and are sensitive to factors involved in the early stages of fibrosis. We therefore wanted to test the hypothesis that epithelial cells can deposit ECM in response to stimulation in a comparable manner to fibroblasts. We performed immunofluorescence analysis of components of stable, mature extracellular matrix produced by primary human renal proximal tubular epithelial cells and renal fibroblasts in response to cytokine stimulation. Whilst fibroblasts produced a higher basal level of extracellular matrix components, epithelial cells were able to deposit significant levels of fibronectin, collagen I, III and IV in response to cytokine stimulation. In response to hypoxia, epithelial cells showed an increase in collagen IV deposition but not in response to the acute stress stimuli aristolochic acid or hydrogen peroxide. When epithelial cells were in co-culture with fibroblasts we observed significant increases in the level of matrix deposition which could be reduced by transforming growth factor beta (TGF-β) blockade. Our results highlight the role of epithelial cells acting as efficient producers of stable extracellular matrix which could contribute to renal tubule thickening in fibrosis., Summary: Using an immunofluorescence extracellular matrix, we show that epithelial cells can deposit extracellular matrix components in a comparable manner to fibroblasts highlighting their role as potential targets in fibrotic disease.

Patients with type 2 diabetes are at higher risk for periodontal disease and diabetic foot ulcer infections (DFUIs), the latter of which are predominantly caused by staphylococcal bacteria. Staphylococci have also been detected in the mouth, nose and gums (the oro-nasal cavity) of patients with periodontal disease and can move between the mouth and nose. The present study investigated if the oro-nasal cavity and/or periodontal pockets (PPs) in diseased gum tissue can provide a microbial reservoir for DFUIs. Eighteen patients with type 2 diabetes and at least three natural teeth (13 patients with ulcers and 5 patients without ulcers) underwent non-invasive microbiological sampling of PP, oro-nasal, skin and ulcer sites. Staphylococci were recovered using selective chromogenic agar, definitively identified and subjected to DNA microarray profiling, whole-genome sequencing and core-genome multilocus sequence typing (cgMLST). Staphylococcus aureus and Staphylococcus epidermidis were recovered from both the oro-nasal and ulcer sites of 6/13 and 5/13 patients with ulcers, respectively. Molecular typing based on the staphylococcal protein A (spa) gene and DNA microarray profiling indicated that for each patient investigated, S. aureus strains from oro-nasal and ulcer sites were identical. Comparative cgMLST confirmed that isolates from multiple anatomical sites of each individual investigated grouped into closely related, patient-distinct clusters (Clusters 1–7). Isolates belonging to the same cluster exhibited an average of 2.9 allelic differences (range 0–11). In contrast, reference genomes downloaded from GenBank selected as representatives of each sequence type identified in the present study exhibited an average of 227 allelic differences from the most closely related isolate within each cluster.

Background: Radioiodine (RAI) is widely used for the treatment of hyperthyroidism. Most patients respond to RAI therapy with a normalization of TFTs and improvement in clinical symptoms within 4-8 weeks. Hypothyroidism may occur from 4 weeks on, with 40% of patients being hypothyroid by 8 weeks and >80% by 16 weeks. American thyroid association guidelines recommend testing for free T4, total T3, and TSH within the first 1-2 months after RAI. Biochemical monitoring should be continued at 4- to 6-week intervals for 6 months, or until the patient becomes hypothyroid and stable on thyroid replacement therapy. Our local protocol is to monitor thyroid function more frequently and earlier, week 1,3,6,9,12,24 post RAI therapy to avoid any delay in starting treatment if required. Methods: 79 patients with hyperthyroidism underwent definiive treatment with RAI between January 2012 and June 2017. Monitoring of thyroid function tests were examined retrospectively to determine timing of initiation of treatment for either hypothyroidism or persistent hyperthyroidism post RAI. Results: Treatment started for both hypothyroidism and persistent hyperthyroidism in 47/79 patients, 41 developed hypothyroidism while 6 became hyperthyroid. 19/41 developed hypothyroidism within 9 weeks post RAI, while 9/41 developed hypothyroid within 3 weeks post RAI. Median time to commence treatment was 13.6 weeks. Conclusion: Frequent early monitoring of thyroid function tests post RAI may avoid delay in starting treatment for patients developing either hypo- or hyperthyroidism.

Coronary Artery Bypass Grafting (CABG) surgery is identified in case reports as a rare cause of pituitary apoplexy, postulated to be caused by sustained hypotension due to intraoperative extracorporeal circulation. This typically presents with acute neurological manifestations and evidence of pituitary infarction on Magnetic Resonance Imaging (MRI). Here, we present a case of panhypopituitarism without apoplexy weeks after CABG, which presented with nonspecific signs and without definite neuroimaging abnormalities. SM, a 57 year old man with Type 1 Diabetes underwent elective CABG. His initial postoperative course was uneventful. On review at 4 weeks, his sternotomy wound was slow to heal. At 6 weeks, there was wound dehiscence and he was admitted for management of this. He noted a number of significant hypoglycaemic events over the preceding 10 days, despite a 30% reduction in daily insulin over that period. On readmission sodium was reduced at 118mmol/L – normal 6 weeks prior. This was felt to be SIADH secondary to infection, supported by raised urinary sodium and low plasma osmolality. Fluid restriction, however, led to no improvement. He continued to experience hypoglycaemia and erratic glycemic control. Persistent hypotension was then noted, though initially attributed to diuretics. Thyroid function showed low T4 and TSH levels. Panhypopituitarism was confirmed with markedly low Growth Hormone, IGF-1, Prolactin, FSH, LH and 8am cortisol. Adrenal response was absent on short Tetracosactide testing. MRI pituitary was unremarkable. Anterior Pituitary Hormone replacement with Levothyroxine, Hydrocortisone and Somatropin was commenced. Blood pressure improved and electrolytes normalised. 1 year later, SM’s pituitary hormones were maintained within normal ranges with exogenous replacement. However, glycemic control has been challenging, due to loss of counterregulatory hormonal responses to hypoglycaemia. Panhypopituitarism is rarely reported after CABG and mostly involves apoplexy or infarction of a pre-existing pituitary adenoma, with characteristic findings on neuroimaging. These cases relate to alterations in blood flow through the pituitary on ‘bypass’ and highlight the intrinsic vulnerability of the pituitary vasculature. This case is unusual in a number of respects - presentation weeks after surgery with nonspecific findings - poor wound healing and decreased insulin requirements, rather than acute neurological manifestations postoperatively. Previous reports have demonstrated pre-existing pituitary adenomas or evidence of pituitary infarction on MRI. Despite clear biochemical Panhypopituitarism, the MRI here shows a normal gland. Finally, this case reiterates the need for vigilance for subtle and delayed manifestations of pituitary dysfunction post Cardiac Surgery with intervention, prior to life threatening overt glucocorticoid deficiency.

Background: RAI is used as definitive treatment for hyperthyroidism, but administered activities vary between institutions. We used a fixed activity of RAI therapy for Grave’s disease (GD) and toxic multinodular goitre (TMNG), and calculated activity for toxic adenoma (TA). We reviewed treatment outcomes at one year. Methods: Thyroid function tests 1 year post RAI were reviewed retrospectively to asess outcome for 79 hyperthyroid patients divided into 3 etiological groups: those with GD treated with 200MBq, TMNG treated with 400 MBq and TA treated with calculated activity (50-434 MBq), between January 2012 and June 2017. 24 hour isotope uptake results were examined retrospectively to assess relationship to clinical outcome. Results: 48/79 patients had GD (60.8%%), 16/79 TMNG (20.2%) and 15/79 TA (19%). Patients with GD were younger (median 46 years) compared to those with TMNG and TA (median 62 and 59 years respectively). There were more females in both groups (85.5% female in GD, 93.7% in TMNG and 83.3% in TA). At one year post-RAI, more patients with GD were rendered hypothyroid 28/48 compared to TMNG and TA (62.5% vs. 18.75% vs. 53.33%) and fewer patients with GD were rendered euthyroid (25% vs. 46.6% vs. 53.3%) or had persistent hyperthyroidism compared to those with TMNG/TA (12.5% vs. 0% vs. 0%). 12/28 patients with GD who developed hypothyroidism had 24 hour uptake >60% and all patients with 24 hour uptake >60% became hypothyroid in GD and TMNG groups. Conclusion: We used low activity RAI (200 MBq) as treatment for GD, an activity below international recommendations, with comparable outcomes and cure rate 87.5%. All patients with 24 hour uptake >60% in GD and TMNG group developed hypothyroidism post RAI indicating that lower activity RAI should be considered to reduce risk of hypothyroidism.

Objective: For radioactive Iodine-131 (131I) treatments of thyroid diseases, increased efficacy has been reported for personalized dosimetry treatments. The measurement of Iodine-131 thyroid uptake (131IU) is required in these cases. This study aims to investigate whether 99mTc thyroid uptake (99mTcU) may be used in place of 131IU for implementing personalised treatments. Methods: A retrospective study of 152 benign thyroid disease 131I treatments was carried out during 2012–2020; 117 treatments were for female patients while 35 were for male patients diagnosed with either Graves’ disease, multinodular goitre or toxic nodules. Results: A statistically significant correlation was found between 131IU and 99mTcU data, with the data more correlated for male than female patients (r = 0.71 vs 0.38, p-value < 0.001). Patient age and time difference between the two respective uptake measurements significantly influenced the uptake correlation in females but not for the male cohort, although there was no significant difference between the parameters across gender. Thyroid diagnosis and hormone levels showed a significant correlation with uptakes in both genders. Estimating 131IU based on 99mTcU was shown to be predictive for male but not in female patients (R2 = 91% vs 16%). Conclusion: Estimating 131IU based on 99mTcU is not recommended for females at our centre. Males reported good correlation, but a larger sample would be needed for validation. Advances in knowledge: The initial findings showed a significant gender difference in benign thyroid uptake parameters at our centre, highlighting the potential need for gender consideration when planning 131IU patient management and when reporting studies results.

Prolonged exposure to antigens can lead to a state of reduced T cell responsiveness termed exhaustion. Restoring T cell functions from this state of reduced functionality by, for example, blockade of inhibitory immune checkpoints is now an established therapeutic modality with lasting impact on survival for some patients. Modelling human T cell exhaustion and its reversal in vitro can be challenging in medium or high-throughput assays. We have therefore sought to develop and characterize an in vitro model of T cell exhaustion using human T cells. Long-term (14-day) prolonged stimulation of human T cells in vitro led to both an up-regulation of established exhaustion markers PD-1, LAG-3 and TIM-3, and a lack of responsiveness to subsequent stimulation with human allogeneic monocyte-derived dendritic cells (DCs) as assessed by, for instance, IFNγ and TNFα production. Subsequent addition of blocking antibodies against PD-1 (pembrolizumab and nivolumab) led to a robust reversal of exhausted state by, for instance, restoration of cytokine secretion. The magnitude and nature of the response also correlated with the response of dissociated cells from lung and colon carcinomas. This response also showed greater sensitivity to PD-1 blockade compared to freshly isolated T cells or when using PBMCs stimulated with a pool of EBV peptides. By performing intracellular cytokine staining of human exhausted T cells stimulated with allogeneic dendritic cells, we further noted that PD-1 blockade using either pembrolizumab or nivolumab increased the percentage of cells producing IFNγ suggesting a greater responding pool of T cells. However, whilst the levels of the IFNγ in the supernatants of the exhausted T cell/allogeneic dendritic cell cultures was fully restored when compared to ‘fresh' T cell/allogeneic dendritic cell cultures, the percentage of IFNγ+ cells was not, nor was it fully restored by the inclusion of PMA/ionomycin. Taken together, this would suggest that PD-1 blockade induces responding cells to produce more IFNγ. We suggest that this chronic activation model of human T cell exhaustion with a robust assay window, and responsive to the clinically validated anti-PD-1 antibodies, nivolumab and pembrolizumab, may provide a platform for the discovery of new immuno-oncology therapeutics as well as the assessment of differences in mechanism of action between them. Citation Format: Omar S. Qureshi, Alexander Roberts, Lindsay Bentley, Tina Tang, Fay Stewart, Graham Wallace, Alison Cooper, Aaron Scott, David Thickett, Babu Naidu, Thomas Pinkney, Graham Taylor, Kristian Brock, Louise Healy, Zania Stamataki, Catherine Brady, S J. Curnow, John Gordon, Nicholas M. Barnes. A robust enhancement of cytokine production in a human chronic activation model of T cell exhaustion in vitro through blockade of PD-1/PDL-1 interactions using pembrolizumab or nivolumab; correlation with dissociated tumor immune cell responses [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3274.

Scope: Chronic inflammation and hypoadiponectinemia are characteristics of obesity-induced insulin resistance (IR). The effect of an anti-inflammatory nutrition supplement (AINS) on IR and adiponectin biology in overweight adolescents was investigated. The secondary objective was to examine the extent to which individuals’ biomarker profiles, derived from baseline phenotypes, predicted response or not to the AINS. Additionally, the impact of DNA methylation on intervention efficacy was assessed. Methods and results: Seventy overweight adolescents (13–18 years) were recruited to this randomized controlled crossover trial. Participants received an AINS (long chain n-3 PUFA, vitamin C, α-tocopherol, green tea extract, and lycopene) and placebo for 8 weeks each. Homeostatic model assessment (HOMA)-IR, adiponectin, inflammatory profiles, and DNA methylation were assessed. HOMA-IR was unchanged in the total cohort. High-molecular-weight (HMW) adiponectin was maintained following the AINS while it decreased over time following the placebo intervention. HOMA-IR decreased in 40% of subjects (responders) following the AINS. Responders’ pretreatment phenotype was characterized by higher HOMA-IR, total and LDL cholesterol, but similar BMI in comparison to nonresponders. HMW adiponectin response to the AINS was associated with bidirectional modulation of adipogenic gene methylation. Conclusion: The AINS modulated adiponectin biology, an early predictor of type 2 diabetes risk, was associated with bidirectional modulation of adipogenic gene methylation in weight-stable overweight adolescents. HOMA-IR decreased in a sub-cohort of adolescents with an adverse metabolic phenotype. Thus, suggesting that more stratified or personalized nutrition approaches may enhance efficacy of dietary interventions.

The aims of this study were to examine the relationship between admission blood glucose and mortality in a large, unselected cohort of acutely ill medical patients and to assess the impact of diabetes on this relationship.We studied the broad pattern of acute medical admissions over an eight year period and the impact of admission serum glucose on in-hospital mortality. Significant predictors of outcome, including acute illness severity and co-morbidity, were entered into a multivariate regression model, adjusting the univariate estimates of the glycaemic status on mortality.There were 45,068 consecutive acute medical emergency admissions between 2005 and 2012. The normoglycaemic (4.0 ≤7.0 mmol/l) cohort (86%) had a 3.9% in-hospital mortality. Both hypoglycaemia (OR: 3.23: 95% CI: 2.59-4.04; p0.001) and hyperglycaemia (OR: 2.1; 95% CI: 1.9-2.4; p0.001) predicted an increased risk of an in-hospital death. Neither of these increased risks were fully adjusted nor explained by a highly predictive outcome model, using multiple acute illness parameters. Hyperglycaemia did not carry similar adverse prognostic implications for patients with diabetes.In patients without diabetes, an abnormal serum glucose is independently predictive of an increased mortality among the broad cohort of acute emergency medical patients. Similar disturbances of glucose homeostasis for patients with diabetes do not confer equivalent adverse prognostic implications.

Phosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating cellular survival, development, and function. Expression of the PI3K δ isoform is largely restricted to leukocytes and it plays a key role in immune cell development and function. Seletalisib is a novel small-molecule inhibitor of PI3K δ that was evaluated in biochemical assays, cellular assays of adaptive and innate immunity, and an in vivo rat model of inflammation. Our findings show that seletalisib is a potent, ATP-competitive, and selective PI3K δ inhibitor able to block protein kinase B (AKT) phosphorylation following activation of the B-cell receptor in a B-cell line. Moreover, seletalisib inhibited N -formyl peptide–stimulated but not phorbol myristate acetate–stimulated superoxide release from human neutrophils, consistent with a PI3K δ -specific activity. No indications of cytotoxicity were observed in peripheral blood mononuclear cells (PBMCs) or other cell types treated with seletalisib. Findings from cellular assays of adaptive immunity demonstrated that seletalisib blocks human T-cell production of several cytokines from activated T-cells. Additionally, seletalisib inhibited B-cell proliferation and cytokine release. In human whole blood assays, seletalisib inhibited CD69 expression upon B-cell activation and anti-IgE-mediated basophil degranulation. Seletalisib showed dose-dependent inhibition in an in vivo rat model of anti-CD3-antibody-induced interleukin 2 release. Collectively, these data characterize seletalisib as a selective PI3K δ inhibitor and potential therapeutic candidate for the treatment of B-cell malignancies and autoimmune diseases driven by dysregulated proinflammatory cytokine secretion.

Pancreatic neuroendocrine tumors (NETs) are extremely rare, and although insulinomas are the commonest, less than 10% of insulinomas are malignant. Most patients with insulinomas present with neuroglycopenic symptoms and weight gain attributable to insulin excess. Here, we report a case where a 67-year-old lady with a background history of type 2 diabetes mellitus and breakthrough hyperinsulinism who presented with coma. The biochemical profile revealed features typical of insulinoma, and CT and endosonography confirmed a pancreatic tumor with large volume right-sided liver metastases (biopsy confirming a neuroendocrine tumor). The patient underwent successful one-step RO surgical resection, distal pancreatectomy, splenectomy, and right hepatectomy, and 9 months postoperatively, she remains free of recurrent disease. She remains a diabetic.

At IAPM 2017 an overview of the dosimetry protocol for outpatient I-131 therapy which was in the process of being implemented in St. James’s Hospital was presented. A year on, 25 patients have now been treated using dosimetry, and here we present an overview of our experience and treatment outcomes for this small cohort.

Hyperprolactinemia is a commonly encountered disorder that suppresses both male and female gonadal function. The etiology includes pituitary tumors, hypothalamic or pituitary stalk lesions, drugs and hypothyroidism. In women, the hyperprolactinemic syndrome is characterized by menstrual disorders with or without galactorrhea, while men present with hypogonadism and related symptoms. Occasionally, a pituitary macroadenoma may be associated with pressure symptoms and/or hypopituitarism. Clinically, the most important cause of hyperprolactinemia is a prolactin-secreting pituitary adenoma. The majority of patients with prolactinomas are successfully managed medically with dopamine agonists such as cabergoline or bromocriptine. Misdiagnosis of hyperprolactinemia owing to immunoassay interference by a biologically minimally active form of prolactin termed macroprolactin is common in laboratory medicine . Alhough the etiology of macroprolactinemia is unclear, the condition is commonly associated with the presence of circulating antiprolactin antibodies. In the absence of specific testing, macroprolactin represents a diagnostic pitfall resulting in misdiagnosis and mismanagement of patients. This review examines the investigation and treatment of hyperprolactinemia in the broadened context of screening for macroprolactin and the consequences of failure to identify its presence.

The EANM Guidelines for Dosimetry for Benign thyroid diseases [1] recommend two or more uptake measurements to estimate the residence time of I-131 in the thyroid, which when combined with the mass of the gland can be used to calculate the treatment activity. The guidelines also outline methods to estimate residence time using one early or one late uptake assessment, with subsequent loss of accuracy. The workup for therapy in our centre includes thyroid ultrasound and an I-131 uptake measurement. For patients with a solitary toxic nodule the uptake measurement combined with nodule size have been used to determine treatment activity. Patients with Grave’s disease and multinodular goitre were previously treated with fixed activities. Following a review of the treatment outcome for 130 patients we present a retrospective analysis which demonstrates that these fixed activities resulted in estimated thyroid doses which ranged over an order of magnitude. Subsequently we present our initial experiences of adopting the EANM Dosimetry guidelines using a minimum of two uptake measurements. For therapies such as I-131 therapy with high success rates (85%–90% in our centre), it has been difficult to justify the use of dosimetry in the past. However with the imminent implementation of the 97/43/EURATOM and to optimise the therapeutic benefit to the patient, it is essential that we begin to utilize available dosimetry techniques.

We present a rare case of an insulin-like growth factor-2 (IGF-2)-secreting tumour of the thorax. This patient demonstrated the combination of fasting hypoglycaemia and impaired glucose tolerance on oral glucose tolerance testing, which has not been previously described in this condition. A review of the literature of IGF-2-secreting intrathoracic tumours is presented here.

Background COPD patients have increased numbers of macrophages and neutrophils in the lungs. Interleukin-6 (IL-6) trans-signaling via its soluble receptor sIL-6R, governs the influx of innate immune cells to inflammatory foci through regulation of the chemokine CCL3. We hypothesized that there would be enhanced levels of IL-6, sIL-6R and CCL3 in COPD sputum. Methods 59 COPD patients, 15 HNS and 15 S underwent sputum induction and processing with phosphate buffered saline to obtain supernatants for IL-6, sIL-6R and CCL3 analysis. Cytoslides were produced for differential cell counting and immunocytochemistry (COPD; n = 3) to determine cell type surface expression of the CCL3 receptors CCR5 and CCR1. Results COPD patients expressed higher levels (p

Pneumomediastinum and epidural pneumatosis are rare complications of diabetic ketoacidosis (DKA). These result from the emesis and hyperventilation associated with DKA which lead to alveolar rupture and air escape into the mediastinal and epidural spaces. These complications are often asymptomatic and resolve with the correction of the underlying metabolic abnormality. Oesophageal contrast studies are only required if oesophageal perforation is suspected in patients presenting with persistent vomiting and chest pain. We report the rare association of pneumomediastinum and epidural pneumatosis complicating DKA in a 19-year-old female patient.

T helper-type 17 (Th17) cells are proinflammatory CD4+ cells characterized by Interleukin-17 (IL-17) production. Evidence suggests cytokines produce by Th17s, including IL-17, are involved in rheumatoid arthritis (RA) pathogenesis [1]. Lipopolysaccharide (LPS)-stimulated monocytes promote CD4+ cell differentiation into Th17 cells, producing IL-17 in vitro[2].

We report a case of a 37-year-old man, with a background of a rare polyglandular autoimmune syndrome and achalasia, who developed an oesophageal tumour. Both autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or type I polyglandular syndrome and achalasia confer increased risk of development of oesophageal squamous cell carcinoma.Despite having had multiple endoscopic examinations and dilatations in the recent past, this patient presented with dysphagia, and on endoscopy, he was found to have a mid-oesophageal tumour. A multidisciplinary team approach was vital in his management as careful monitoring of underlying disorders including Addison's disease and hypoparathyroidism were challenging during neoadjuvant chemoradiotherapy and in the perioperative period.He made an uneventful recovery after a three-stage oesophagectomy, and histologically, he had a complete pathological response.To our knowledge, this is the first successful outcome of a patient with APECED and oesophageal carcinoma in the literature.

The insulin tolerance test (ITT) is the gold standard for assessment of ACTH and GH reserve in patients with suspected hypopituitarism. It is labor intensive and costly.The objective of the study was to determine whether use of the overnight metyrapone test (OMT) and plasma IGF-I sd scores (SDS) could provide a cost-effective alternative to the ITT.This was a retrospective chart review.The study was conducted at a teaching hospital.Charts from 100 patients with organic pituitary disorders were reviewed. All underwent the OMT unless 0900 h plasma cortisol was less than 80 or greater than 450 nmol/liter when ACTH deficiency or ACTH sufficiency, respectively, was diagnosed. Patients were considered GH deficient if the age-related IGF-I SDS was less than -3 or if they had three or more other pituitary hormone deficiencies. Patients were considered GH sufficient if age-related IGF-I SDS was greater than the 95th centile established from patients with known GH deficiency. Thirty-three underwent an ITT.The proportion of patients in whom ACTH and GH reserve could be assessed using OMT/IGF-I SDS was measured. The concordance with results was obtained from ITT.Fifty-five patients were ACTH sufficient and 45 were ACTH deficient. Twenty-one were GH sufficient and 33 were GH deficient based on IGF-I SDS and other pituitary hormone deficiencies, whereas 46 could not be classified. There was near-uniform concordance between OMT/IGF-I SDS and ITT. Initial investigation using OMT/IGF-I SDS resulted in a significant cost saving.ACTH and GH reserve can be accurately and cost-effectively investigated using OMT/IGF-I SDS in approximately 50% of patients with organic pituitary disorders.

Measurement of prolactin is one of the most commonly undertaken hormonal investigations in evaluating patients with reproductive disorders. Hyperprolactinemia is found in up to 17% of such cases. Diagnostic evaluation of hyperprolactinemia is difficult but is facilitated by a logical approach where a thorough patient history is obtained, secondary causes of hyperprolactinemia are excluded, and the limitations of current prolactin assays are appreciated. Once hyperprolactinemia has been confirmed, attempts to establish the underlying cause can start. Given current workloads, laboratories rely on automated platforms to measure prolactin, most of which employ two-site immunoassay sandwich methods. Although generally robust and reliable, such immunoassays are susceptible to interference, and good collaboration between clinicians and the laboratory helps to minimize problems. A major challenge facing laboratories is correct differentiation of patients with true hyperprolactinemia from those with macroprolactinemia. Macroprolactin is a high-molecular-mass, biologically inactive form of prolactin that is detected to varying degrees by all prolactin immunoassays. Conservative estimates suggest that the presence of macroprolactin leads to misdiagnosis in as many as 10% of all reported instances of biochemical hyperprolactinemia. In the absence of specific testing, macroprolactin represents a diagnostic pitfall that results in the misdiagnosis and mismanagement of large numbers of patients.