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Σάββατο 4 Νοεμβρίου 2017

Metastatic non-small cell lung carcinoma a mimic of primary breast carcinoma—case series and literature review

Abstract

Metastatic tumors to the breast are rare but constitute a major diagnostic dilemma. Of these, non-mammary carcinomatous metastases to the breast are particularly challenging and, without a clinical history, may be extremely difficult to distinguish from primary breast carcinoma (PBC). We specifically studied metastatic tumors of pulmonary origin, as the lung is one of the major primary sites for carcinomatous metastasis to breast. Sixteen metastatic lung tumors to the breast were identified in our archives between 1996 and 2017 including 12 non-small cell lung carcinomas (NSCLC), one large-cell neuroendocrine, one atypical carcinoid, and two small-cell carcinomas. Adenocarcinoma was the most frequent amongst the NSCLCs (11/14). We retrieved the clinical information of these cases and reviewed the pathological characteristics to provide practical tools for pathologists to aid in their identification. Even in the absence of a clinical history of lung cancer, metastatic pulmonary adenocarcinoma to the breast should be considered in at least one of the following scenarios: (1) single or multiple well-circumscribed lesions of the breast that lack an in situ component and that are accompanied by distant metastases but negative axillary lymph nodes, (2) breast tumors that are triple negative yet not high-grade, or (3) breast tumors presenting as stage 4 disease and/or having an unusually aggressive clinical course on standard breast therapy. Accurate and timely diagnosis of these tumors is mandatory because of treatment and prognostic implications.



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Population Pharmacokinetics of Fosdagrocorat (PF-04171327), a Dissociated Glucocorticoid Receptor Agonist, in Patients With Rheumatoid Arthritis

Abstract

Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF-04171327), with active DAGR metabolite PF-00251802 (Metabolite-1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite-1 and its active metabolite PF-04015475 (Metabolite-2) in patients with moderate to severe RA enrolled in a 12-week, phase II, randomized, double-blind study (NCT01393639). A simultaneous fit of a two-compartment model for Metabolite-1 and a one-compartment model for Metabolite-2 provided an adequate fit to the data. Significant covariates included weight, with an additional female effect on clearance of Metabolite-1 (∼26%) and Metabolite-2 (∼33%) compared with males. Age influenced clearance of Metabolite-1. In combination, age, weight, and sex predicted >twofold differences in area under the concentration–time curve of Metabolite-1 at the extremes.



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Negative selection, epitope mimicry and autoimmunity

Noel R Rose

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On Denny-Brown’s ‘spastic dystonia’ - what is it and what causes it?

There has been considerable debate in the scientific literature in recent years regarding the proper definition of spasticity (Biering-Sorensen et al. 2006; Burridge et al. 2005; Gracies 2005a, 2005b; Lorentzen et al. 2010; Malhotra et al. 2008; Pandyan et al. 2005; Sheean 2002). Much of this debate stems from documented differences in the understanding of which clinical signs define spasticity as well as a presumed variability in the clinical use of the term (Pandyan et al.2005a; 2005b). Without a clear consensus of what we understand by ́spasticitý there is a risk that research in the field remains confused and potentially leads to misunderstandings and wrong treatment decisions in the clinic.

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Sera from Visceral Leishmaniasis Patients Display Oxidative Activity and Affect the TNF-α Production by Macrophages In Vitro

Mammalian protection against leishmanial infection depends on the development of an effective immune response. Zoonotic visceral leishmaniasis (ZVL) patients are usually unable to mount an effective immune response against the parasite and indeed appear to be severely immunosuppressed. This suppression has strong nonspecific and specific components mediated by serum factors and leishmanicidal activity of infected macrophages, respectively. The lipid profile has been shown to be altered in ZVL patients' sera. This work aimed at (i) determining the HDL, Apo A1, LDL, and VLDL concentrations in ZVL patients' sera; (ii) investigating the oxidative effect of ZVL patients' sera on the β-carotene matrix; (iii) measuring IL-10, IL-6, IL-12p40, and tumour necrosis factor-α (TNF-α) concentrations in the macrophage cultures, to which 10% of ZVL patients' serum had been added. Levels of HDL, LDL fraction, and apolipoprotein A1 in ZVL patients' sera were lower than those of healthy individuals' sera, except for the mean level of VLDL. The matrix of β-carotene and linoleic acid system was oxidized in the presence of ZLV patients' sera. The presence of ZVL patients' sera did not modify the cytokine production of IL-6, IL-12p40, and IL-10 by human macrophages in vitro but TNF-α production was altered, probably due to lack of macrophage stimulation by lipoprotein.

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Invitro Evaluation of Torin2 and 2, 6-Dihydroxyacetophenone in Colorectal Cancer Therapy

Abstract

Colorectal cancer (CRC) is one of the most prevalent cancers diagnosed worldwide. Despite recent advances, resistance to cytotoxic and targeted therapy remains one of the greatest challenges in long-term management of colorectal cancer therapy. Recently established role of mTOR signaling in proliferation of CRC has incited for evaluation of mTOR kinase specific inhibitors in CRC therapy. Second generation mTOR kinase inhibitors including Torin2 has demonstrated efficient anticancer properties against variety of cancers and are in various stages of drug development. The time and financial constraints concomitant from discovery to development of efficient chemical inhibitors has redirected attention towards investigation of wide spread naturally occurring largely inexpensive compounds for their therapeutic potential. One such naturally occurring compound acetophenone derivative polyphenolic compound 2, 6-Dihydroxyacetophenone (DHAP) inhibits cell growth in different conditions. We investigated anticancer properties of both Torin2 and DHAP against colorectal cancer in HCT8 cell lines. Both Torin2 and DHAP inhibited growth of CRC cells at different concentrations by restricting multiple cellular functions e.g., cell cycle progression, cell migration and induced apoptosis. Treatment of HCT8 cells with natural compound DHAP resulted in reduced expression of mTOR pathway specific genes p70S6K1 and AKT1. In silico docking studies showed affinity of DHAP to mTOR kinase like Torin2. Taken together, our result vouches for role of Torin2 in CRC therapy and recommends DHAP an mTOR inhibitor, as a potential lead in the development of new therapeutic regimes against colorectal cancer.



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Diagnostic dilemmas in chronic inflammatory bowel disease

Abstract

Histopathological assessment of biopsy and resection specimens of chronic inflammatory bowel disease (CIBD), or possible CIBD, forms a significant component of the routine workload in most tissue pathology laboratories. In this review, we have chosen selected areas of particular diagnostic difficulty in CIBD pathology, providing key advice for pathology reporting. Those mimics of CIBD which have the greatest potential for misdiagnosis are discussed, particularly the wide range of infectious colitides which represent possible diagnostic pitfalls. The most important distinguishing features between the two main forms of CIBD, ulcerative colitis and Crohn's disease, are addressed, first in relation to resection specimens, and then with emphasis on features which may also be diagnostically useful in endoscopic biopsy material. The importance of assessment of the index endoscopic specimen is stressed, before treatment has been instigated, along with careful correlation with clinical and endoscopic features. Problems in the assessment of post-surgical CIBD specimens are described and then the role of upper gastrointestinal pathology specimens in diagnosing both Crohn's disease and ulcerative colitis, with increased recognition of upper gastrointestinal tract involvement in the latter condition. Finally, with recent developments in endoscopic surveillance techniques and local excision options, modern approaches to reporting and managing neoplasia complicating CIBD are reviewed.



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A case of lymphangioma-like mesenteric cysts diagnosed as adenocarcinoma of possible pancreatic origin on EUS-FNA



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Best practices for online Canadian prenatal health promotion: A public health approach

Publication date: Available online 4 November 2017
Source:Women and Birth
Author(s): Rebecca A. Chedid, Rowan M. Terrell, Karen P. Phillips
BackgroundPrenatal health promotion provides information regarding pregnancy risks, protective behaviours and clinical and community resources. Typically, women obtain prenatal health information from health care providers, prenatal classes, peers/family, media and increasingly, Internet sites and mobile apps. Barriers to prenatal health promotion and related services include language, rural/remote location, citizenship and disability. Online public health platforms represent the capacity to reach underserved women and can be customised to address the needs of a heterogeneous population of pregnant women.AimCanadian government-hosted websites and online prenatal e-classes were evaluated to determine if accessible, inclusive, comprehensive and evidence-based prenatal health promotion was provided.MethodsUsing a multijurisdictional approach, federal, provincial/territorial, municipal and public health region-hosted websites, along with affiliated prenatal e-classes, were evaluated based on four criteria: comprehensiveness, evidence-based information, accessibility and inclusivity.FindingsOnline prenatal e-classes, federal, provincial/territorial and public health-hosted websites generally provided comprehensive and evidence-based promotion of essential prenatal topics, in contrast to municipal-hosted websites which provided very limited prenatal health information. Gaps in online prenatal health promotion were identified as lack of French and multilingual content, targeted information and representations of Indigenous peoples, immigrants and women with disabilities.ConclusionCanadian online prenatal health promotion is broadly comprehensive and evidence-based, but fails to address the needs of non-Anglophones and represent the diverse population of Canadian pregnant women. It is recommended that agencies enhance the organisation of website pregnancy portals/pages and collaborate with other jurisdictions and community groups to ensure linguistically accessible, culturally-competent and inclusive prenatal online resources.



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Sagittal Plane Kinematic Gait Analysis in C57BL/6 Mice Subjected to MOG35-55 Induced Experimental Autoimmune Encephalomyelitis

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Kinematic gait analysis in the sagittal plane yields highly precise information about how movement is executed. We describe the application of these techniques to identify gait deficits for mice subjected to autoimmune-mediated demyelination. These methods may also be used to characterize gait deficits for other mouse models featuring impaired locomotion.

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Computational Lipidomics of the Neuronal Plasma Membrane

Membrane lipid composition varies greatly within submembrane compartments, different organelle membranes, and also between cells of different cell stage, cell and tissue types, and organisms. Environmental factors (such as diet) also influence membrane composition. The membrane lipid composition is tightly regulated by the cell, maintaining a homeostasis that, if disrupted, can impair cell function and lead to disease. This is especially pronounced in the brain, where defects in lipid regulation are linked to various neurological diseases.

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Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota

Objective

Gastric carcinoma development is triggered by Helicobacter pylori. Chronic H. pylori infection leads to reduced acid secretion, which may allow the growth of a different gastric bacterial community. This change in the microbiome may increase aggression to the gastric mucosa and contribute to malignancy. Our aim was to evaluate the composition of the gastric microbiota in chronic gastritis and in gastric carcinoma.

Design

The gastric microbiota was retrospectively investigated in 54 patients with gastric carcinoma and 81 patients with chronic gastritis by 16S rRNA gene profiling, using next-generation sequencing. Differences in microbial composition of the two patient groups were assessed using linear discriminant analysis effect size. Associations between the most relevant taxa and clinical diagnosis were validated by real-time quantitative PCR. Predictive functional profiling of microbial communities was obtained with PICRUSt.

Results

The gastric carcinoma microbiota was characterised by reduced microbial diversity, by decreased abundance of Helicobacter and by the enrichment of other bacterial genera, mostly represented by intestinal commensals. The combination of these taxa into a microbial dysbiosis index revealed that dysbiosis has excellent capacity to discriminate between gastritis and gastric carcinoma. Analysis of the functional features of the microbiota was compatible with the presence of a nitrosating microbial community in carcinoma. The major observations were confirmed in validation cohorts from different geographic origins.

Conclusions

Detailed analysis of the gastric microbiota revealed for the first time that patients with gastric carcinoma exhibit a dysbiotic microbial community with genotoxic potential, which is distinct from that of patients with chronic gastritis.



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Monitoring the estimated glomerular filtration rate (eGFR) in patients with small-cell lung cancer during chemotherapy: equations based on serum creatinine or cystatin C?

Abstract

Background

This study compared the differences between the estimated glomerular filtration rate (eGFR) calculated by several equations based on serum creatinine (Scr) and cystatin C (CysC) concentrations for monitoring renal function in patients with small-cell lung cancer (SCLC) during chemotherapy.

Methods

Seventy-one patients with SCLC were retrospectively analyzed. The eGFR before and after each chemotherapy cycle was calculated by the following equations: the chronic kidney disease epidemiology collaboration (CKD-EPI) equation, the modification of diet in renal disease (MDRD) equation, the Cockcroft–Gault (CG) equation, and five CysC-based equations. The patients were compared among the different eGFR groups.

Results

The mean decreases in eGFRCKD-EPI (−2.25 ± 9.89 ml/min/1.73 m2) between each treatment cycle were more significant than the decreases in eGFRCG (−0.46 ± 10.17 ml/min/1.73 m2), eGFRMDRD (−0.48 ± 9.79 ml/min/1.73 m2), and five calculated eGFRCysC (p < 0.05). Single-/multiparameter analyses showed that patients with a higher body mass index (BMI >23) and receiving more treatment cycles (>3) were at increased risk for developing renal impairment with an eGFR less than 60 ml/min/1.73 m2 during chemotherapy.

Conclusions

The eGFR calculated by the CKD-EPI equation changed more significantly between each chemotherapy cycle than did the eGFR from the other equations based on Scr or CysC in patients with SCLC. Oncologists should pay more attention to the renal function of specific patient groups during treatment.



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Computational Lipidomics of the Neuronal Plasma Membrane

Membrane lipid composition varies greatly within submembrane compartments, different organelle membranes, and also between cells of different cell stage, cell and tissue types, and organisms. Environmental factors (such as diet) also influence membrane composition. The membrane lipid composition is tightly regulated by the cell, maintaining a homeostasis that, if disrupted, can impair cell function and lead to disease. This is especially pronounced in the brain, where defects in lipid regulation are linked to various neurological diseases.

http://ift.tt/2ziwWgl

Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro

Summary

Aim

The aim of this study was to study potential cytochrome P450 induction by dicloxacillin.

Methods

We performed an open-label randomized two-phase 5-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1g dicloxacillin three times daily for 10 days. Plasma and urine was collected over 24 hours and the concentration of all five drugs and their primary metabolites was determined using a LC-MS/MS method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48h and changes in gene expression and enzyme activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 was investigated. Activation of nuclear receptors by dicloxacillin was assessed using luciferase assays.

Results

Ten days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0-24h of omeprazole (CYP2C19) (geometric mean ratio (GMR) [95% confidence interval (CI)]: 0.33 [0.24-0.45]), tolbutamide (CYP2C9) (GMR [95% CI]: 0.73 [0.65-0.81]) and midazolam (CYP3A4) (GMR [95% CI]: 0.54 [0.41-0.72]). Additionally, other relevant pharmacokinetic parameters were affected indicating induction of CYP2C and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed statistically significant dose-dependent increase in P450 expression and activity by dicloxacillin, caused by activation of pregnane X receptor.

Conclusions

Dicloxacillin is an inducer of CYP2C- and CYP3A-mediated drug metabolism and we recommend caution when prescribing dicloxacillin to users of drugs with a narrow therapeutic window.



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Chemotherapy-related anemia



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Cross-modal integration of polyphonic characters in Chinese audio-visual sentences: a MVPA study based on functional connectivity

Abstract

This study aimed to investigate the functional connectivity in the brain during the cross-modal integration of polyphonic characters in Chinese audio-visual sentences. The visual sentences were all semantically reasonable and the audible pronunciations of the polyphonic characters in corresponding sentences contexts varied in four conditions. To measure the functional connectivity, correlation, coherence and phase synchronization index (PSI) were used, and then multivariate pattern analysis was performed to detect the consensus functional connectivity patterns. These analyses were confined in the time windows of three event-related potential components of P200, N400 and late positive shift (LPS) to investigate the dynamic changes of the connectivity patterns at different cognitive stages. We found that when differentiating the polyphonic characters with abnormal pronunciations from that with the appreciate ones in audio-visual sentences, significant classification results were obtained based on the coherence in the time window of the P200 component, the correlation in the time window of the N400 component and the coherence and PSI in the time window the LPS component. Moreover, the spatial distributions in these time windows were also different, with the recruitment of frontal sites in the time window of the P200 component, the frontal-central-parietal regions in the time window of the N400 component and the central-parietal sites in the time window of the LPS component. These findings demonstrate that the functional interaction mechanisms are different at different stages of audio-visual integration of polyphonic characters.



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Altered neurofilament protein expression in the lateral vestibular nucleus in Parkinson’s disease

Abstract

A major cause of morbidity in Parkinson's disease (PD) is postural instability. The neuropathology underlying postural instability is unknown. Postural control is mediated by Deiters' neurons of the lateral vestibular nucleus (LVN), which are the brainstem origin of descending vestibulospinal reflexes. Deiters' neurons express the cytostructural protein, non-phosphorylated neurofilament protein (NPNFP). In PD, reduced expression of NPNFP in substantia nigra (SN) neurons is believed to contribute to dysfunction. It was the aim of this study to determine if there is altered expression of NPNFP in the LVN in PD. We immunolabeled NPNFP in brainstem sections of six aged controls (mean age 92 yo) and six PD donors (mean age 83 yo). Our results show there was a ~ 50% reduction in NPNFP-positive Deiters' neurons compared to controls (13 ± 2.0/section vs 25.7 ± 3.0/section; p < 0.01, repeated measures ANOVA). In contrast, there was no difference in NPNFP-positive counts in the facial nucleus between control and PD. The normalized intensity of NPNFP labeling in LVN was also reduced in PD (0.87 ± 0.05 vs 1.09 ± 0.03; p < 0.01). There was a 35% concurrent reduction in NPNFP-positive neuropil in PD relative to controls (p < 0.01). We also show there was an 84% increase (p < 0.05) in somatic lipofuscin in PD patients compared to control. Lipofuscin aggregation has been shown to increase not only with age but also with neurodegeneration. Furthermore, decreased NPNFP intensity was strongly correlated with increasing lipofuscin autofluorescence across all cases (R 2 = 0.81, p < 0.01). These results show two alterations in cellular content with PD, reduced expression and intensity of NPNFP and increased lipofuscin aggregation in Deiter's neurons. These changes may contribute to degeneration of postural reflexes observed in PD.



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Development of finger force coordination in children

Abstract

Coordination is often observed as body parts moving together. However, when producing force with multiple fingers, the optimal coordination is not to produce similar forces with each finger, but rather for each finger to correct mistakes of other fingers. In this study, we aim to determine whether and how this skill develops in children aged 4–12 years. We measured this sort of coordination using the uncontrolled manifold hypothesis (UCM). We recorded finger forces produced by 60 typically developing children aged between 4 and 12 years in a finger-pressing task. The children controlled the height of an object on a screen by the total amount of force they produced on force sensors. We found that the synergy index, a measure of the relationship between "good" and "bad" variance, increased linearly as a function of age. This improvement was achieved by a selective reduction in "bad" variance rather than an increase in "good" variance. We did not observe differences between males and females, and the synergy index was not able to predict outcomes of upper limb behavioral tests after controlling for age. As children develop between the ages of 4 and 12 years, their ability to produce negative covariation between their finger forces improves, likely related to their improved ability to perform dexterous tasks.



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Music-related reward responses predict episodic memory performance

Abstract

Music represents a special type of reward involving the recruitment of the mesolimbic dopaminergic system. According to recent theories on episodic memory formation, as dopamine strengthens the synaptic potentiation produced by learning, stimuli triggering dopamine release could result in long-term memory improvements. Here, we behaviourally test whether music-related reward responses could modulate episodic memory performance. Thirty participants rated (in terms of arousal, familiarity, emotional valence, and reward) and encoded unfamiliar classical music excerpts. Twenty-four hours later, their episodic memory was tested (old/new recognition and remember/know paradigm). Results revealed an influence of music-related reward responses on memory: excerpts rated as more rewarding were significantly better recognized and remembered. Furthermore, inter-individual differences in the ability to experience musical reward, measured through the Barcelona Music Reward Questionnaire, positively predicted memory performance. Taken together, these findings shed new light on the relationship between music, reward and memory, showing for the first time that music-driven reward responses are directly implicated in higher cognitive functions and can account for individual differences in memory performance.



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The effect of hand position on perceived finger orientation in left- and right-handers

Abstract

In the absence of visual feedback, the perceived orientation of the fingers is systematically biased. In right-handers these biases are asymmetrical between the left and right hands in the horizontal plane and may reflect common functional postures for the two hands. Here we compared finger orientation perception in right- and left-handed participants for both hands, across various hand positions in the horizontal plane. Participants rotated a white line on a screen optically superimposed over their hand to indicate the perceived position of the finger that was rotated to one of seven orientations with the hand either aligned with the body midline, aligned with the shoulder, or displaced by twice the shoulder-to-midline distance from the midline. We replicated the asymmetric pattern of biases previously reported in right-handed participants (left hand biased towards an orientation ~30° inward, right hand ~10° inward). However, no such asymmetry was found for left-handers, suggesting left-handers may use different strategies when mapping proprioception to body or space coordinates and/or have less specialization of function between the hands. Both groups' responses rotated further outward as distance of the hand from the body midline increased, consistent with other research showing spatial orientation estimates diverge outward in the periphery. Finally, for right-handers, precision of responses was best when the hand was aligned with the shoulder compared to the other two conditions. These results highlight the unique role of hand dominance and hand position in perception of finger orientation, and provide insight into the proprioceptive position sense of the upper limbs.



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How effector-specific is the effect of sequence learning by motor execution and motor imagery?

Abstract

The aim of the present study was twofold. First, we wanted to examine how effector specific the effect of sequence learning by motor execution is, and second, we wanted to compare this effect with learning by motor imagery. We employed a Go/NoGo discrete sequence production task in which in each trial a spatial sequence of five stimuli was presented. After a Go signal the corresponding spatial response sequence had to be executed, while after a NoGo signal, the response sequence had to be mentally imagined. For the training phase, participants were divided into two groups. In the index finger group, participants had to respond (physically or mentally) with the left or right index finger, while in the hand group they had to respond with four fingers of the left or right hand. In a final test phase both execution modes were compared and all trials had to be executed. Response times and the percentage of correct responses were determined to establish learning effects. Results showed that sequence learning effects as assessed in the test phase were independent of the effector used during the training phase. Results revealed the presence of aspecific learning effects in the case of learning a required motor task with an index finger, but sequence-specific learning effects, both due to motor execution and to motor imagery, were not effector specific.



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Cancer-Specific Survival Stratification Derived from Tumor Expression of Tissue Inhibitor of Metalloproteinase-2 in Non-Metastatic Renal Cell Carcinoma

Abstract

Degradation of the extracellular matrix is a prerequisite for the processes of cancer cell invasion and metastasis. The purpose of our study was to assess the association of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9) and their inhibitors (TIMP-1 and TIMP-2) with renal cell carcinoma (RCC) progression and cancer-specific survival (CSS), using immunohistochemical analysis of 60 formalin-fixed, paraffin-embedded sections of tumor tissue and normal tissue near the tumor from surgical T1-3bN0 M0 RCC specimens. Significant overexpression of MMP-2 in tumor and normal tissue was correlated with advanced stages, tumor size, sarcomatous differentiation and clinical symptoms. Overall survival was 31.7% (55.2% M0, 9.7% M1) and CSS 56.7% (100% M0, 16.1% M1) with a follow-up of 76 (5–230) months. Fuhrman grade [HR 2.87 (95% CI: 1.28–6.45); p = 0.01], tumor size [HR 1.13 (95% CI: 1.03–1.26); p = 0.009] and low TIMP-2 expression [HR 0.35 (95% CI: 0.16–0.78); p = 0.01] were independent predictive factors of CSS and stratified the patients into three groups with different rates of 10-year CSS; [100%, 73.9% and 20.5% for the good, intermediate and poor prognosis group respectively (p = 0.000006)] . This study offers strong evidence that TIMP-2 expression in tumor tissue may play a crucial role in progression and poor prognosis in human localized and locally advanced RCC.



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Stain-free Histopathology of Basal Cell Carcinoma by Dual Vibration Resonance Frequency CARS Microscopy

Abstract

Basal cell carcinoma (BCC) is the most common malignancy in Caucasians. Nonlinear microscopy has been previously utilized for the imaging of BCC, but the captured images do not correlate with H&E staining. Recently, Freudiger et al. introduced a novel method to visualize tissue morphology analogous to H&E staining, using coherent anti-Stokes Raman scattering (CARS) technique. In our present work, we introduce a novel algorithm to post-process images obtained from dual vibration resonance frequency (DVRF) CARS measurements to acquire high-quality pseudo H&E images of BCC samples. We adapted our CARS setup to utilize the distinct vibrational properties of CH3 (mainly in proteins) and CH2 bonds (primarily in lipids). In a narrowband setup, the central wavelength of the pump laser is set to 791 nm and 796 nm to obtain optimal excitation. Due to the partial overlap of the excitation spectra and the 5–10 nm FWHM spectral bandwidth of our lasers, we set the wavelengths to 790 nm (proteins) and 800 nm (lipids). Nonresonant background from water molecules also reduces the chemical selectivity which can be significantly improved if we subtract the DVRF images from each other. As a result, we acquired two images: one for "lipids" and one for" proteins" when we properly set a multiplication factor to minimize the non-specific background. By merging these images, we obtained high contrast H&E "stained" images of BBC's. Nonlinear microscope systems upgraded for real time DVRF CARS measurements, providing pseudo H&E images can be suitable for in vivo assessment of BCC in the future.



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Possible Predictive Markers of Response to Therapy in Esophageal Squamous Cell Cancer

Abstract

The aim of the present study was to investigate the relationship between the intensity of biomarker expression and the response to radiochemotherapy in patients with advanced esophageal squamous cell cancer (ESCC). Ninety-two patients with locally advanced ESCC were examined retrospectively. Pre-treatment tumor samples were stained for proteins SOUL, Hsp 16.2, Growth Hormone-Releasing Hormone Receptor (GHRH-R) and p-Akt using immunhistochemistry methods. Kaplan-Meier curves were used to show the relationship between intensity of expression of biomarkers and clinical parameters and 3-year OS. A significant correlation was found between high intensity staining for Hsp 16.2, p-Akt and SOUL and poor response to NRCT. Application of a higher dose of radiation and higher dose of cisplatin resulted in better clinical and histopathological responses, respectively. Among the clinical parameters, the localization of the tumor in the upper-third of the esophagus and less than 10% weight loss were independent prognostic factors for increased 3-year OS. Hsp16.2, p-Akt and SOUL are predictors of negative response to NRCT, therefore these biomarkers may become promising targets for therapy. Furthermore, level of expression of p-Akt, weight loss and the localization of the tumor are significant factors in the prediction of OS in ESCC.



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Efficacy and safety in older patient subsets in studies of endocrine monotherapy versus combination therapy in patients with HR+/HER2− advanced breast cancer: a review

Abstract

Purpose

Prospective information regarding the tolerability and efficacy of endocrine therapy (ET) alone and in combination with targeted agents in older patients in the metastatic setting is limited. This review summarizes available trial data in this population.

Methods

We searched PubMed for Phase 2 or 3 trials with age-stratified patient cohorts (≥ 65 vs. < 65 years in most studies) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer treated with ET ± targeted agents.

Results

We identified 19 studies reporting 10 clinical trials. Efficacy was similar in age-stratified subsets. There was a reduced disease progression risk for ET + everolimus, palbociclib, or ribociclib versus ET alone. In the first-line setting, median progression-free survival (mPFS) in older patients was 8.5, 26.2 months, and not reached with letrozole + temsirolimus, palbociclib, and ribociclib, respectively, and in younger patients was 9.0, 18.8 months, and not reached, respectively. In the second-line setting, older patients had mPFS of 6.8 and 9.9 months with everolimus + exemestane and palbociclib + fulvestrant, respectively, and younger patients had mPFS of 8.1 and 9.5 months, respectively. Tolerability was worse for combination therapy versus monotherapy. No age-related differences in discontinuations were observed for CDK4/6 inhibitors, although a higher rate of treatment discontinuation was observed for patients ≥ 70 years receiving everolimus + exemestane. Adverse event rates were similar in age-stratified subsets.

Conclusions

ET + CDK4/6 or mTOR inhibitors are likely safe and effective in older patients with HR+, HER2− advanced breast cancer.



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Vertically arrayed stimuli and responses: transfer of incompatible spatial mapping to Simon task occurs regardless of response-device orientation

Abstract

Conde et al. (Exp Brain Res 233:3313–3321, 2015) found that the Simon effect for vertically arrayed stimuli and responses was reduced after 100 prior practice trials with an incompatible mapping of the stimulus locations and responses. This finding was contrary to Vu's (Mem Cognit 35:1463–1471, 2007) finding of no transfer effect with 72 trials of prior practice. Conde et al. proposed that the different results were due to their responses being coded as top and bottom in the frontal plane, whereas Vu's were coded as far and near in the transverse plane. We conducted four experiments to test this possibility in which participants responded with keypresses using their thumbs on a numeric keypad held vertically (upright in the frontal plane) or horizontally (flat in the transverse plane). Experiment 1 showed that, without any prior practice, a similar sized Simon effect was obtained when the response device was oriented in the transverse plane as when it was oriented in the frontal plane. In Experiments 2 and 3 participants performed with the same device orientation in the incompatible practice and Simon transfer tasks, with orientation manipulated between-subjects in the former and within-subjects in the latter. The Simon effect was reduced in both cases, with no significant difference in transfer effect for transverse and frontal planes. In Experiment 4, the device orientation differed between the incompatible practice and Simon transfer tasks, and the Simon effect was reduced similarly across both response-device orientations. Thus, the differences between Conde et al.'s and Vu's findings cannot be attributed to the response-device orientation. Our results are consistent with the view that people code response locations in the transverse plane as top and bottom, rather than far and near, in agreement with the terminology of "top row" and "bottom row" for computer keyboards.



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Seizure Triggered by Sick Sinus Syndrome

Sick sinus syndrome (SSS) is a dysfunction of sinoatrial node resulting in symptomatic bradycardia or sinus pauses causing decreased cardiac output with cerebral hypoperfusion and usually presents as syncope, presyncope or fatigue. The occurrence of a seizure is very rare. A 69-year-old man suffered two episodes of generalised tonic–clonic seizures. MRI and electroencephalogram failed to reveal the cause of seizures. In the emergency room, he experienced presyncope simultaneous to bradycardia and sinus pauses. He was stabilised with atropine and dopamine infusion and underwent definitive therapy with a permanent dual-chamber pacemaker with complete symptom resolution. Diagnostic confounders include convulsive syncope and ictal bradycardia. Syncope may be accompanied by myoclonic jerks (convulsive syncope), but postictal confusion is absent. Bradycardia may be seen during the postictal period (ictal bradycardia syndrome), but protracted sinus dysfunction is not present. Hypoperfusion due to significant SSS triggered seizures in this patient who may have an underlying predisposition.



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Metastatic melanoma: a rare cause of central airway obstruction

A middle-aged woman with recurrent malignant melanoma presented initially with massive left pleural effusion. There was a complete obliteration of the left main bronchus on flexible bronchoscopy caused by a mass. Serial cryo-debulking of the tumour was done under rigid bronchoscopy; however, the outcome was not favourable due to the aggressive tumour growth. Vemurafenib was planned after thoracic radiation. She was not keen for the biologics treatment due to financial constraints. We report a case of central airway obstruction due to recurrent aggressive melanoma. More evaluations are needed on the role of interventional pulmonologist for bronchoscopic debulking of this rapidly growing tumour as well as the role of biological agents in treating such cases.



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A rare localised nasal CD30+ primary cutaneous T-cell lymphoma following liver transplantation

Cutaneous T-cell post-transplant lymphoproliferative disorder (PTLD) is a rare clinical presentation that can potentially turn aggressive in solid-organ transplant recipients if not detected and intervened on early. We encountered a rare case of rapidly worsening primary cutaneous CD30-positive, Epstein-Barr virus-negative anaplastic large cell lymphoma (ALCL) of T-cell origin, manifesting as an isolated nasal tip lesion in a 71-year-old man 4 years after orthotopic liver transplantation. Excisional biopsy with partial rhinectomy showed subepithelial diffuse infiltration of medium-to-large lymphoid cells having round-to-irregular nuclei, partially condensed chromatin and prominent nucleoli. Immunophenotypic studies revealed CD30-positive primary cutaneous ALCL. Positron emission tomography/CT imaging revealed a locally active disease, and radiation therapy was initiated with complete response. A high index of suspicion for PTLD when evaluating skin lesions in a post-transplant patient is paramount for its early recognition, prompt diagnosis and timely intervention while the window for curative therapy remains possible.



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Palm atheroma infection caused by Raoultella planticola

Description

A 74-year-old man presented to the emergency department with pain in the left hand. He had a history of lung carcinoma and was treated with chemotherapy for 2 years. On physical examination, his left hand was found to exhibit swelling and redness. There was an atheroma at the base of his middle finger, which was the most painful area (figure 1-A,B). He was prescribed cephalexin 2 g daily and ordered to see an orthopaedic surgeon the next day. However, the next day, his left hand became worse. There was increased swelling, redness, pain and pus (figure 1-C,D). The patient was treated with surgical drainage and intravenous cefazolin 2 g daily to control the infection (figure 2). A week later, bacterial isolation analysis revealed that the causative agent was Raoultella planticola. He was switched to ceftriaxone based on sensitivities and prior literature on the...



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Anti-LGI1 encephalitis causing faciobrachial dystonic seizures

Anti-leucine-richglioma inactivated protein 1 (LGI1) encephalitis has an autoimmune origin and can be reversed with immunotherapy. It is obvious that identifying and treating this condition early is of paramount importance. We present the case of a 69-year-old man who was admitted to hospital with faciobrachial dystonic seizures and was found to have antibodies to LGI1. His symptoms started approximately 3 months prior admission to the hospital. There had also been some subtle cognitive impairment. He was treated with two courses of intravenous immunoglobulin and commenced on prednisolone 50 mg daily and clonazepam 500 µg at night. Despite these treatments, his seizures were becoming progressively more frequent and severe. He then underwent treatment with a course of plasma exchange followed by an intravenous infusion of methylprednisolone and returned to his previous baseline function.



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Intestinal spirochaetosis mimicking acute appendicitis with review of the literature

Human intestinal spirochaetosis is a well-established micro-organism existing in the colon. It is less commonly seen in the appendix, and rarely presents as acute appendicitis. We present a case of a man presenting with symptoms consistent with acute appendicitis. The literature on spirochaetosis presenting as acute appendicitis is also reviewed.



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Global health challenges in treating an elderly institutionalised patient: an oral medicine perspective

A 64-year-old institutionalised woman presented to our clinic for the management of black hairy tongue. Despite the predictable outcome in treating this disease, this case presents multiple challenges such as the patients' cognitive impairment, her family dynamics, social factors and the health system as a whole, that makes it difficult to treat.



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Frequent neck massage leading to bilateral anterior cerebral artery infarction

Description

The anterior cerebral artery (ACA) is a major vessel responsible for the blood supply to the interhemispheric regions. Infarction of the ACA territory accounts for only 0.3% to 4.4% of cerebral infarctions reported.1 The usual causes are aneurysmal rupture of the anterior communicating artery or thrombosis of the precommunal anterior cerebral artery.2 We are describing here a patient with bilateral ACA infarction due to dual pathology and frequent neck massage being the cause of this young stroke.

A 45-year-old man was admitted with sudden onset aphasia and weakness of both lower limbs with bowel–bladder incontinence. There was no history of loss of consciousness, headache, nausea or vomiting and convulsions. He had no significant medical history and no vascular risk factors. There is history of frequent neck massages from a chiropractor for relaxation purposes with visits amounting to two to four per week. There...



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Giant calvarial haemangioma with classical radiological features

Description

A 12-year-old girl presented with a large painless hard swelling in the left parietal region, gradually increasing in size for 6 years. No complaint of headache or visual disturbance was present. Radiographs showed a large expansile lytic lesion with prominent bony trabeculae radiating centrifugally from the centre of the mass. On CT scan, the lytic area showed areas of rarefaction traversed by radiating bony spicules. On MRI, the lesion was isointense to hyperintense on T1-weighted images (T1WI), hyperintense on T2WI, indenting over underlying brain parenchyma, causing mass effect and midline shift. Avid enhancement was noted on postcontrast scans (figure 1). Based on typical clinical presentation and classical radiological findings, a diagnosis of giant calvarial haemangioma was made.

Figure 1

(A) Clinical photograph showing large left parietal swelling. (B and C) Skull radiograph in frontal and lateral projections showing lytic lesion with centrifugally radiating bony trabeculae...



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The effects of microduplication 1q21.1 and in-utero isotretinoin exposure

The impact of in-utero isotretinoin exposure has been widely reported, with many affected pregnancies failing to reach term.1 2 Due to the low numbers of in-utero isotretinoin exposed pregnancies, the interactions between this drug and rare genetic defects such as microduplication 1q21.1 are unclear, particularly how they might manifest phenotypically. We present this case of in-utero isotretinoin exposure occurring in a child with microduplication 1q21.1. The child was born with congenital abnormalities which did not fit into a single syndrome. Regrettably in-utero exposure to isotretinoin continues to occur. We hope this case will trigger further discussion on the dangers of dispensing Isotretinoin without ensuring stringent pregnancy testing and its potential interaction with genetic abnormalities, in particular with microduplication 1q21.1.



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Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways.

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Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways.

Biochim Biophys Acta. 2017 07;1861(7):1879-1894

Authors: Torres TEP, Russo LC, Santos A, Marques GR, Magalhaes YT, Tabassum S, Forti FL

Abstract
BACKGROUND: Radiotherapy causes the regression of many human tumors by increasing DNA damage, and the novel molecular mechanisms underlying the genomic instability leading to cancer progression and metastasis must be elucidated. Atypical dual-specificity phosphatase 3 (DUSP3) has been shown to down-regulate mitogen-activated protein kinases (MAPKs) to control the proliferation and apoptosis of human cancer cells. We have recently identified novel molecular targets of DUSP3 that function in DNA damage response and repair; however, whether DUSP3 affects these processes remains unknown.
METHODS: Tumor cell lines in which DUSP3 activity was suppressed by pharmacological inhibitors or a targeted siRNA were exposed to gamma radiation, and proliferation, survival, DNA strand breaks and recombination repair pathways were sequentially analyzed.
RESULTS: The combination of reduced DUSP3 activity and gamma irradiation resulted in decreased cellular proliferation and survival and increased cellular senescence compared with the effects of radiation exposure alone. Gamma radiation-induced DNA damage was increased by the loss of DUSP3 activity and correlated with increased levels of phospho-H2AX protein and numbers of ionizing radiation-induced γ-H2AX foci, which were reflected in diminished efficiencies of homologous recombination (HR) and non-homologous end-joining (NHEJ) repair. Similar results were obtained in ATM-deficient cells, in which reduced DUSP3 activity increased radiosensitivity, independent of increased MAPK phosphorylation.
CONCLUSION: The loss of DUSP3 activity markedly increases gamma radiation-induced DNA strand breaks, suggesting a potential novel role for DUSP3 in DNA repair.
GENERAL SIGNIFICANCE: The radioresistance of tumor cells is effectively reduced by a combination of approaches through the inhibition of DUSPs.

PMID: 28389334 [PubMed - indexed for MEDLINE]



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Cell Cycle Arrest as a Therapeutic Target of Acute Kidney Injury.

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Cell Cycle Arrest as a Therapeutic Target of Acute Kidney Injury.

Curr Protein Pept Sci. 2017;18(12):1224-1231

Authors: Wang WG, Sun WX, Gao BS, Lian X, Zhou HL

Abstract
The current lack of complete understanding of the pathogenesis of acute kidney injury (AKI) is a significant barrier to its early diagnosis and treatment. Cell cycle arrest plays an important role in the protection of renal tubular epithelial cells and maladaptive repair following AKI. G1 phase cell arrest serves as a protective mechanism following AKI, avoiding replication of damaged DNA. Insulinlike growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) are closely associated with G1 cell cycle arrest during the very early phase of cellular damage and can serve as an ideal biomarker to predict AKI. However, sustained cell cycle arrest after severe AKI may result in cell senescence and maladaptive repair, with typical characteristics of the development of cell cycle arrest in the gap 2 (G2) or mitotic (M) phase. Markers of cell cycle arrest signal and spread the "alarm" from the site of injury to adjacent cells in an autocrine or paracrine manner, giving rise to abnormal amplification and release of profibrogenic factors, activation of pericytes/perivascular fibroblasts, and eventually fibrosis. Therefore, cell cycle regulation has become a potentially new target for the prevention and treatment of AKI. In this review, we summarize the characteristics of the cell cycle following AKI and the markers of cell cycle arrest that enable the early detection of AKI. We also discuss how to prevent the progression of chronic kidney disease (CKD) by regulating cell cycle arrest.

PMID: 27634440 [PubMed - indexed for MEDLINE]



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Association between coagulation function and patients with primary angle closure glaucoma: a 5-year retrospective case-control study

Objective

To evaluate the association between coagulation function and patients with primary angle closure glaucoma (PACG).

Design

A retrospective, hospital-based, case–control study.

Setting

Shanghai, China.

Participants

A total of 1778 subjects were recruited from the Eye & ENT Hospital of Fudan University from January 2010 to December 2015, including patients with PACG (male=296; female=569) and control subjects (male=290; female=623).

Outcome measures

Sociodemographic data and clinical data were collected. The one-way analysis of variance test was used to compare the levels of laboratory parameters among the mild, moderate and severe PACG groups. Multivariate logistic regression analyses were performed to identify the independent risk factors for PACG. The nomogram was constructed based on the logistic regression model using the R project for statistical computing (R V.3.3.2).

Results

The activated partial thromboplastin time (APTT) of the PACG group was approximately 4% shorter (p<0.001) than that of the control group. The prothrombin time (PT) was approximately 2.40% shorter (p<0.001) in patients with PACG compared with the control group. The thrombin time was also approximately 2.14% shorter (p<0.001) in patients with PACG compared with the control group. The level of D-dimer was significantly higher (p=0.042) in patients with PACG. Moreover, the mean platelet volume (MPV) of the PACG group was significantly higher (p=0.013) than that of the control group. A similar trend was observed when coagulation parameters were compared between the PACG and control groups with respect to gender and/or age. Multiple logistic regression analyses revealed that APTT (OR=1.032, 95% CI 1.000 to 1.026), PT (OR=1.249, 95% CI 1.071 to 1.457) and MPV (OR=1.185, 95% CI 1.081 to 1.299) were independently associated with PACG.

Conclusion

Patients with PACG had a shorter coagulation time. Our results suggest that coagulation function is significantly associated with patients with PACG and may play an important role in the onset and development of PACG.



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Evidence of accessibility and utility of point-of-care diagnostics as an integral part of prevention of mother-to-child transmission services: systematic scoping review protocol

Introduction

Point-of-care (POC) testing has been shown to help improve healthcare access in resource-limited settings. However, there is paucity of evidence on accessibility of POC testing for prevention of mother-to-child transmission (PMTCT) in resource-limited settings. We propose to conduct a systematic scoping review to map the evidence on POC testing services for PMTCT.

Methods and analysis

A scoping review framework, proposed by Arksey and O'Malley, will guide the study. A comprehensive literature search will be performed in the following electronic databases: PubMed, Science Direct, Cochrane Central, Google Scholar and databases within EBSCOhost (Medline and CINAHL). The primary research articles published in peer-reviewed journals and grey articles addressing our question will be included. One reviewer will conduct title screening and the results will be exported to endnote library. Two independent reviewers will perform abstract, then full article screening in parallel. The same process shall be employed to extract data from eligible studies. Data analysis will involve a narrative summary of included studies and thematic content analysis aided by NVIVO software V.11. The mixed methods assessment tool will be used to assess the quality of studies that will be included.

Ethics and dissemination

Ethical approval is not applicable to this study. The study findings will be disseminated through publication in a peer-reviewed journal and presentations at conferences related to syphilis, HIV, PMTCT, bacterial infections and POC diagnostics.

Trial registration number

CRD42017056267.



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Excess burden of non-communicable disease years of life lost from heat in rural Burkina Faso: a time series analysis of the years 2000-2010

Objectives

Investigate the association of heat exposure on years of life lost (YLL) from non-communicable diseases (NCD) in Nouna, Burkina Faso, between 2000 and 2010.

Design

Daily time series regression analysis using distributed lag non-linear models, assuming a quasi-Poisson distribution of YLL.

Setting

Nouna Health and Demographic Surveillance System, Kossi Province, Rural Burkina Faso.

Participants

18 367 NCD-YLL corresponding to 790 NCD deaths recorded in the Nouna Health and Demographic Surveillance Site register over 11 years.

Main outcome measure

Excess mean daily NCD-YLL were generated from the relative risk of maximum daily temperature on NCD-YLL, including effects delayed up to 14 days.

Results

Daily average NCD-YLL were 4.6, 2.4 and 2.1 person-years for all ages, men and women, respectively. Moderate 4-day cumulative rise in maximum temperature from 36.4°C (50th percentile) to 41.4°C (90th percentile) resulted in 4.44 (95% CI 0.24 to 12.28) excess daily NCD-YLL for all ages, rising to 7.39 (95% CI 0.32 to 24.62) at extreme temperature (42.8°C; 99th percentile). The strongest health effects manifested on the day of heat exposure (lag 0), where 0.81 (95% CI 0.13 to 1.59) excess mean NCD-YLL occurred daily at 41.7°C compared with 36.4°C, diminishing in statistical significance after 4 days. At lag 0, daily excess mean NCD-YLL were higher for men, 0.58 (95% CI 0.11 to 1.15) compared with women, 0.15 (95% CI –0.25 to 9.63) at 41.7°C vs 36.4°C.

Conclusion

Premature death from NCD was elevated significantly with moderate and extreme heat exposure. These findings have important implications for developing adaptation and mitigation strategies to reduce ambient heat exposure and preventive measures for limiting NCD in Africa.



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Selecting pH cut-offs for the safe verification of nasogastric feeding tube placement: a decision analytical modelling approach

Objectives

The existing British National Patient Safety Agency (NPSA) safety guideline recommends testing the pH of nasogastric (NG) tube aspirates. Feeding is considered safe if a pH of 5.5 or lower has been observed; otherwise chest X-rays are recommended. Our previous research found that at 5.5, the pH test lacks sensitivity towards oesophageal placements, a major risk identified by feeding experts. The aim of this research is to use a decision analytic modelling approach to systematically assess the safety of the pH test under cut-offs 1–9.

Materials and methods

We mapped out the care pathway according to the existing safety guideline where the pH test is used as a first-line test, followed by chest x-rays. Decision outcomes were scored on a 0–100 scale in terms of safety. Sensitivities and specificities of the pH test at each cut-off were extracted from our previous research. Aggregating outcome scores and probabilities resulted in weighted scores which enabled an analysis of the relative safety of the checking procedure under various pH cut-offs.

Results

The pH test was the safest under cut-off 5 when there was ≥30% of NG tube misplacements. Under cut-off 5, respiratory feeding was excluded; oesophageal feeding was kept to a minimum to balance the need of chest X-rays for patients with a pH higher than 5. Routine chest X-rays were less safe than the pH test while to feed all without safety checks was the most risky.

Discussion

The safety of the current checking procedure is sensitive to the choice of pH cut-offs, the impact of feeding delays, the accuracy of the pH in the oesophagus, as well as the extent of tube misplacements.

Conclusions

The pH test with 5 as the cut-off was the safest overall. It is important to understand the local clinical environment so that appropriate choice of pH cut-offs can be made to maximise safety and to minimise the use of chest X-rays.

Trial registration number

ISRCTN11170249; Pre-results.



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The development of dendritic cell vaccine-based immunotherapies for glioblastoma.

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The development of dendritic cell vaccine-based immunotherapies for glioblastoma.

Semin Immunopathol. 2017 Feb;39(2):225-239

Authors: Reardon DA, Mitchell DA

Abstract
In this review, we focus on the biologic advantages of dendritic cell-based vaccinations as a therapeutic strategy for cancer as well as preclinical and emerging clinical data associated with such approaches for glioblastoma patients.

PMID: 28138787 [PubMed - indexed for MEDLINE]



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Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma

.


http://ift.tt/2iuTlx8

The Tension Biology of Wound Healing

Summary

Following skin wounding, the healing outcome can be; regeneration, repair with normal scar tissue, repair with hypertrophic scar tissue, or the formation of keloids. The role of chemical factors in wound healing has been extensively explored, and while there is evidence suggesting the role of mechanical forces, its influence is much less well defined. Here we provide a brief review on the recent progress of the role of mechanical force in skin wound healing by comparing laboratory mice, African spiny mice, fetal wound healing, and adult scar keloid formation. A comparison across different species may provide insight into key regulators. Interestingly, some findings suggest tension can induce an immune response, and this provides a new link between mechanical and chemical forces. Clinically, manipulating skin tension has been demonstrated to be effective for scar prevention and treatment, but not for tissue regeneration. Utilizing this knowledge, specialists may modulate regulatory factors and develop therapeutic strategies to reduce scar formation and promote regeneration.

This article is protected by copyright. All rights reserved.



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TNF stimulates IL-6, CXCL8 and VEGF secretion from human keratinocytes via activation of mTOR, inhibited by tetramethoxyluteolin

Abstract

Psoriasis is an autoimmune skin disease characterized by keratinocyte hyper-proliferation and chronic inflammation. The pathogenesis of psoriasis involves pro-inflammatory cytokines, such as tumor necrosis factor (TNF), but the mechanism of keratinocyte activation is not well understood. Here we show that TNF (10 or 50 ng/mL) stimulates significant (p<0.0001) gene expression and secretion of pro-inflammatory IL-6, CXCL8 and VEGF from both cultured human HaCaT and normal epidermal human keratinocytes (NHEKs). This effect occurs via activation of the mammalian target of rapamycin (mTOR) signaling complex as shown by Western Blot analysis and phospho-ELISAs. Pre-treatment with the novel natural flavonoid tetramethoxyluteolin (10-100 μM) significantly (p<0.0001) inhibits gene expression and secretion (p<0.0001) of all three mediators in a concentration-dependent manner. Moreover, tetramethoxyluteolin (50 μM) appears to be a potent inhibitor of the phosphorylated mTOR substrates (pmTORSer2448, pp70S6KThr389 and p4EBP1Thr37/46) as compared to known mTOR inhibitors in keratinocytes. The present findings indicate that TNF stimulates skin inflammation via mTOR signaling. Inhibition by tetramethoxyluteolin, may be used in the treatment of psoriasis.

This article is protected by copyright. All rights reserved.



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A somewhat unexpected result from the deconvolution of DSC-curves for human hair: There is no apparent relation between cortical cell fractions and hair curliness

Abstract

A deconvolution process has been developed for curves obtained by Differential Scanning Calorimetry in water for Merino wool and the main ethnic hair types. This enables estimation of the fractions of ortho- and para-type cell groups. The results also indicate that hair may contain a further, low-sulphur sub-group of ortho-type cells. The sizes of the major cell fractions are in line with expectations from microscopical investigations. The fractions are comparable for hair types and no consistent association between cell type fractions and hair curvature is observed.

This article is protected by copyright. All rights reserved.



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Comparing state-wide and single-center data to predict high-frequency emergency department utilization among patients with asthma exacerbation

Abstract

Background

Previous studies examining high-frequency ED utilization have primarily used single-center data, potentially leading to ascertainment bias if patients visit multiple centers. The goals of this study were (1) to create a predictive model to prospectively identify patients at risk of high-frequency ED utilization for asthma, and (2) to examine how that model differed using state-wide versus single-center data.

Methods

To track ED visits within a state, we analyzed 2011-2013 data from the New York State Healthcare Cost and Utilization Project (HCUP) State Emergency Department Databases (SEDD). The first year of data (2011) was used to determine prior utilization; 2012 was used to identify index ED visits for asthma and for demographics; and 2013 was used for outcome ascertainment. High-frequency utilization was defined as 4+ ED visits for asthma within one year after the index visit. We performed analyses separately for children (age <21 years) and adults, and constructed two models: one included all state-wide (multi-center) visits, and the other was restricted to index hospital (single-center) visits. Multivariable logistic regression models were developed from potential predictors selected a priori. The final model was chosen by evaluating model performance using AIC scores, 10-fold cross validation, and ROC curves.

Results

Among children, high-frequency ED utilization for asthma was observed in 2,417/94,258 (2.56%) using all state-wide visits, compared to 1,853/94,258 (1.97%) for index hospital visits only. Among adults, the corresponding results were 7,779/159,874 (4.87%) and 5,053/159,874 (3.16%), respectively. In the multi-center visit model, the area under the curve (AUC) from 10-fold cross validation for children was 0.70 (95% CI: 0.69-0.72), compared to 0.71 (95% CI: 0.69-0.72) in the single-center visit model. The corresponding AUC results for adults were 0.76 (95% CI: 0.76-0.77) and 0.76 (0.75-0.77), respectively.

Conclusion

Data available at the index ED visit can predict subsequent high-frequency utilization for asthma with AUC ranging from 0.70-0.76. Model accuracy was similar regardless of whether outcome ascertainment included all state-wide visits (multi-center) or was limited to the index hospital (single-center).

This article is protected by copyright. All rights reserved.



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Early Recurrence of First Unprovoked Seizures in Children

Abstract

Objectives

The risk of early seizure recurrences after first unprovoked seizures in children is largely unknown. We aimed to determine the rate of seizure recurrence within 14 days of first, unprovoked seizures in children and identify associated risk factors. Secondarily, we aimed to determine the risk of recurrence at 48 hours and 4 months.

Methods

We conducted a secondary analysis of a multicenter cohort study of children 29 days-18 years with first, unprovoked seizures. Emergency department (ED) clinicians completed standardized histories and physical examinations. The primary outcome, recurrent seizure at 14 days, and the secondary outcomes, recurrence at 48 hours and 4 months, were assessed by telephone follow-up and medical record review. For each recurrence time point, we excluded those patients for whom no seizure had recurred but chronic antiepileptic drugs (AEDs) had been initiated.

Results

475 patients were enrolled in the parent study. Of evaluable patients for this secondary analysis, 26/392 (6.6%, 95% CI: 4.4-9.6%) had recurrences within 48 hours of the incident seizures, 58/366 (15.8%; 12.3-20.0%) had recurrences within 14 days, and 107/340 (31.5%; 26.6-36.7%) had recurrences within 4 months. On logistic regression analysis, age younger than 3 years was independently associated with a higher risk of 14-day recurrence (adjusted OR 2.1, 95% CI 1.2, 3.7; p=0.01). Having had more than 1 seizure within the 24 hours prior to ED presentation was independently associated with a higher risk of seizure recurrence at 48 hours (adjusted OR 4.3, 95% CI 1.9, 9.8; p<0.001).

Conclusions

Risk of seizure recurrence 14 days after first unprovoked seizures in children is substantial, with younger children at higher risk. Prompt completion of an EEG and evaluation by a neurologist is appropriate for these children.

This article is protected by copyright. All rights reserved.



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CFTR Modulator Therapy for Cystic Fibrosis

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2zhc35g

Tezacaftor–Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2zuJ52F

Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2zjn1r9

CFTR Modulator Therapy for Cystic Fibrosis

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2zhc35g

Tezacaftor–Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2zuJ52F

Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del

New England Journal of Medicine, Ahead of Print.


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Cytomorphologic features of metastatic endometrioid carcinoma by fine needle aspiration

Abstract

Background

Although metastatic disease is commonly seen in high grade carcinomas of gynecologic origin, it also occurs in low to intermediate grade endometrioid carcinomas (LGEMCAs), and may even be the primary presentation of disease. Tissue confirmation is necessary to guide therapy, but performing biopsies might not always be feasible or practical. In such instances, fine needle aspiration (FNA) is a safe and efficient alternative. No comprehensive series describing the cytomorphologic features of metastatic LGEMCA on FNA samples has been published. This study describes clinical and cytomorphologic features of metastatic LGEMCA diagnosed by FNA.

Methods

The pathology archives at 2 academic institutions were searched for patients with endometrial or ovarian endometrioid carcinoma, with concurrent or subsequent sampling of metastatic sites by FNA.

Results

Twelve cases were identified; all slides were reviewed and cytomorphologic features recorded. Four cases were obtained from metastatic sites as primary presentation of disease, and 8 cases were obtained from metastatic sites in patients with known history of LGEMCA. Metastatic LGEMCAs generate cellular specimens composed of cohesive clusters of cells with areas of gland formation. Consistent cytomorphologic features included nuclear overlapping, low to intermediate nuclear to cytoplasmic ratios, round to elongated nuclear shape, finely vacuolated cytoplasm, mild to moderate nuclear membrane irregularities, squamous metaplasia, and inconspicuous nucleoli. Variability was seen with regards to the presence of necrosis (50% of cases) and mitosis (25% of cases).

Conclusion

The presence of these features on FNA samples should raise concern for an underlying gynecologic malignancy.



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Letter to the editor: A rare case of microfilaria in ascitic fluid



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Cell cycle-dependent translocation and regulatory mechanism of CacyBP/SIP in gastric cancer cells.

Our previous results showed that calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) inhibits the proliferation and tumorigenicity of gastric cancer; however, the exact mechanism remains unclear, especially from the aspect of cell cycle. The subcellular localization of CacyBP/SIP, Siah-1, and Skp1 in SGC7901 gastric cancer cells was assessed by immunofluorescence after cell cycle synchronization. Levels of CacyBP/SIP, Siah-1, Skp1, [beta]-catenin, and p-ERK1/2 were analyzed by western blotting. CacyBP/SIP phosphorylation (p-CacyBP/SIP) and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP in nucleoprotein were determined by immunoprecipitation. CacyBP/SIP, Siah-1, and Skp1 were mainly in the cytoplasm in the G1 phase, but translocated to the nucleus during G2. Their expression in total protein was not altered, but elevated in the G2 phase in nucleoprotein. The CacyBP/SIP nucleus translocation of cells transfected with mutant CacyBP/SIP that does not bind S100 (CacyBP-[DELTA]S100) was significantly increased compared with wild-type CacyBP/SIP. In the G2 phase, p-CacyBP/SIP expression and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP were all increased, whereas levels of [beta]-catenin and p-ERK1/2 reduced, compared with the G1 phase. CacyBP/SIP or CacyBP-[DELTA]S100 overexpression was correlated with constitutively low [beta]-catenin expression and affected its level through cell cycle. CacyBP/SIP overexpression led to retarded proliferation, G1 arrest, and [beta]-catenin reduction, which could be abolished by lithium chloride, [beta]-catenin activator, and further enhanced by the Wnt inhibitor XAV-939. In addition, CacyBP-[DELTA]S100 further suppressed cell proliferation and induced G1 arrest compared with CacyBP/SIP. In conclusion, CacyBP/SIP nuclear localization, dependent on S100 protein, suppresses gastric cancer tumorigenesis through [beta]-catenin degradation and the dephosphorylation of ERK1/2 during the G2 phase. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Autophagy and doxorubicin resistance in cancer.

Doxorubicin (DOX), also known as adriamycin, is a DNA topoisomerase II inhibitor and belongs to the family of anthracycline anticancer drugs. DOX is used for the treatment of a wide variety of cancer types. However, resistance among cancer cells has emerged as a major barrier to effective treatment using DOX. Currently, the role of autophagy in cancer resistance to DOX and the mechanisms involved have become one of the areas of intense investigation. More and more preclinical data are being obtained on reversing DOX resistance through modulation of autophagy as one of the promising therapeutic strategies. This review summarizes the recent advances in autophagy-targeting therapies that overcome DOX resistance from in-vitro studies to animal models for exploration of novel delivery systems. In-depth understanding of the mechanisms of autophagy regulation in relation to DOX resistance and development of molecularly targeted autophagy-modulating agents will provide a promising therapeutic strategy for overcoming DOX resistance in cancer treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors with a strong genetic background. The mainstay of treatment for PCC/PGLs is surgery. However, for unresectable lesions, no curative treatment is currently available. Temozolomide (TMZ) has been shown to determine radiological and biochemical response in malignant PCC/PGLs. We report two cases of PCC/PGLs treated with TMZ. Case 1 is a 51-year-old man with local and distant recurrence (liver and bone metastases) of right adrenal PCC. Case 2 is a 54-year-old woman with a PCC/PGL syndrome caused by a mutation in MAX gene (c.171+1G>A), operated on for bilateral adrenal PCC and presenting with a large unresectable abdominal PGL. Both patients presented hypertension due to catecholamine hypersecretion. TMZ determined radiological response according to RECIST criteria, reduction of urinary catecholamine levels, and controlled hypertension in both patients. Furthermore, the current study demonstrates, for the first time, that MAX-related PGLs are responsive to TMZ. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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On the 18 F–fluoride PET imaging quantification to predict 223 Ra-dichloride treatment response



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Parenchymal asbestosis due to primary asbestos exposure among ship-breaking workers: report of the first cases from Bangladesh

We report for the first time asbestosis among ship-breaking workers of Sitakunda in Bangladesh who were exposed to asbestos during ship-based and beach-based operations for at least 10 years. Asbestosis was present among 35% of workers. Years of work (>20) and forced vital capacity (<80% of predicted) were significantly associated with the disease. Currently, global ship-breaking operations are mainly concentrated in the Indian subcontinent, and Bangladesh has the majority share. Ninety per cent of domestic steel is produced in the ship-breaking operations in Bangladesh and is an important contributor to the economy. It also gives employment to more than 100 000 people. It is imperative to medically check up all the workers for benign and malignant diseases causally related to asbestos among these vulnerable population of workers.



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Postprandial angina: not always due to stenotic coronary artery disease

Description

A 68-year-old man presented with history of postprandial angina for 6 months. He was a diabetic and hypertensive for 10 years. He was also a reformed smoker with 20 pack-years history of smoking. He did not give any history of acute coronary syndrome or any cardiac catheterisation. Clinical examination was unremarkable. ECG and chest X-ray were normal. Echocardiography revealed normal left ventricular function with features of left ventricular hypertrophy.

Coronary angiography revealed abnormal spillage of contrast in the left ventricular apical region with each diastole from obtuse marginal (OM) branch of left circumflex coronary artery (LCx) and distal part of left anterior descending coronary artery (LAD) suggestive of coronary–cameral fistula (CCMF) (figure 1, figure 2, online ). Coronary angiography did not show any signs of atherosclerotic coronary artery disease. Absence of dilated communicative fistulous tracts between the coronary arteries and the drainage chamber was...



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Delayed ischemic stroke due to stent marker band occlusion after stent-assisted coiling

A middle-aged patient with an internal carotid-posterior communicating artery aneurysm and basilar artery tip aneurysm was treated by stent-assisted coiling. One ischemic infarction and two transient ischemic attacks occurred with the same symptoms (inability to walk unassisted and tendency to fall to the left) during the first 2 years post-treatment. The ischemic infarction was found in the right side of the pons, consistent with the vascular territory of the stent-containing vessel. The cause of the delayed ischemic stroke was investigated on DSA and cone beam CT, which revealed that the proximal end of the stent, one marker band, was just covering a small perforating artery of the basilar artery trunk. The present case suggests that marker band occlusion can induce delayed ischemic stroke. To prevent this complication, it is important to evaluate the perforating vessels preoperatively and carefully deploy a stent for the marker band to avoid occlusion of large perforating vessels. Post-treatment evaluation is also important because dual antiplatelet therapy will be required for a longer period if an artery is occluded by a marker band.



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Fatal delayed haemolytic transfusion reaction in a patient without previous transfusions but with an obstetric history of 13 pregnancies

Delayed haemolytic transfusion reaction is a rare, life-threatening complication of blood transfusion that has been typically described among patients with sickle cell disease (SCD) due to alloimmunisation induced by their exposure to red blood cell antigens through recurrent transfusions. We report the case of a patient who suffered from fatal delayed haemolytic transfusion reaction (DHTR) occurring 1 week after blood transfusion. Indirect antiglobulin testing confirmed the presence of anti-Kell antibodies that were absent in the pretransfusion sample. The patient did not receive blood transfusions in the past, but her obstetric history was remarkable for 13 pregnancies. Although DHTR occurs more commonly among patients with SCD, this type of reaction can occur in any patient who is able to mount an immune response. We would to like to draw the attention of physicians to this rare and potentially lethal complication of blood transfusion, especially in grand multiparous women.



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Hepatic epithelioid haemangioendothelioma (HEHE): a diagnostic dilemma between haemangioma and angiosarcoma

We present a case of a 77-year-old male patient with a liver tumour diagnosed as hepatic epithelioid haemangioendothelioma (HEHE), a potentially malignant tumour treated with liver resection. The patient is disease-free 3 years after resection. Imaging features using fludeoxyglucose F 18 positron emission tomography CT and MRI with gadoxic acid as well as histopathological findings are discussed.



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Urinary tract aspergillosis in a patient with chronic kidney disease

Invasive aspergillosis is a life-threatening fungal infection, especially in immunocompromised patients. Pulmonary aspergillosis is the most common type of the infection, while urinary tract infection is relatively rare. Here, we describe a case of a 46-year-old man with chronic renal disease presenting with intermittent abdominal pain. The diagnosis of aspergillosis was established by pathological findings of the fungal ball in the bladder. The patient underwent multiple antimicrobial treatments and surgical interventions and was finally cured by posaconazole.



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Cabergoline-induced fibrosis of prolactinomas: a neurosurgical perspective

Presently, the standard of care for prolactinomas, a type of pituitary adenoma, is dopaminergic agents such as bromocriptine and cabergoline. However, dopaminergic agents may induce fibrosis of cardiac valves leading to valvular insufficiency, necessitating surgical treatment of prolactinoma. Fibrosis of prolactinoma can be induced by prolonged medical treatment with bromocriptine, and this usually occurs after years of treatment. In comparison to bromocriptine, there have been no reports of cabergoline-induced fibrosis of prolactinoma. There is a potential for greater emphasis to be placed on assessing the tumour consistency from preoperative MRI scans, or even preoperative contrast-enhanced 3D Fast Imaging Employing Steady-state Acquisition imaging to allow better planning of the surgery. We report a rare case of fibrosis of prolactinoma after cabergoline treatment resulting in its subsequent difficult surgical removal. This patient had early MRI changes of fibrosis of prolactinoma after a short period of 6 months of cabergoline treatment.



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Inflammatory optic disc neovascularisation managed with oral steroids/immunosuppressants and intravitreal ranibizumab

Inflammatory optic disc neovascularisation (NVD) has been treated with periocular or systemic steroids, immunosuppressants, panretinal photocoagulation and bevacizumab. However, the role of intravitreal ranibizumab in inflammatory NVD has not been explored in the peer-reviewed indexed literature. In case 1, NVD and associated subhyaloid haemorrhage showed rapid and dramatic regression after intravitreal ranibizumab. Recurrence was noted 8 weeks after injection which was managed by oral steroids. In case 2, intravitreal ranibizumab led to partial resolution of NVD. The addition of steroids, azathioprine and panretinal photocoagulation led to further fibrosis of the neovascularisation. Ranibizumab may be an important adjunct to anti-inflammatory therapy in the management of inflammatory NVD.



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Delayed-onset heparin-induced skin necrosis: a rare complication of perioperative heparin therapy

An uncommon case of delayed-onset dalteparin-induced skin necrosis in an 83-year-old Caucasian female patient associated with heparin-induced thrombocytopaenia (HIT) presenting on day 30 following dalteparin therapy is reported. Investigations revealed mild thrombocytopaenia with normal protein C, protein S, coagulation screen and positive test for heparin–platelet factor-4 antibody. Clinical diagnosis of heparin-induced skin necrosis with HIT was made. Dalteparin injection was discontinued promptly and substituted with fondaparinux therapy. The patient achieved good recovery following cessation of dalteparin therapy and was subsequently discharged.



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Giant phaeochromocytoma presenting with an acute stroke: reappraising phaeochromocytoma surveillance for the neurofibromatosis type 1 phakomatosis

Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder associated with reduced lifespan attributed largely to malignancy and vascular causes. One of the tumours associated with NF1 is phaeochromocytoma. The phaeochromocytoma has earned the moniker, a 'great mimicker', due to its varied means of presentation. We present a patient with NF1 who was diagnosed with a giant 20 cm phaeochromocytoma after suffering from an ischaemic stroke. Current guidelines do not advocate surveillance of phaeochromocytoma in asymptomatic patients with NF1, unlike other genetic syndromes associated with phaeochromocytoma. However, there is increasing evidence that this approach may not help in the early detection and treatment of this potentially life-threatening disease. Our patient remained hypertensive after surgery despite achieving biochemical cure. The suggested chronicity of the underlying tumour in our patient is a reminder to practising clinicians to rethink our strategy in identifying phaeochromocytoma in adults with NF1.



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Spontaneous subdural haematoma in a paediatric patient on anticoagulant therapy

Description

A 5-year old girl with congenital mitral and subaortic stenosis on anticoagulant therapy since her mechanical mitral valve replacement, and a remote history of idiopathic intrahepatic cholestasis requiring liver transplantation presented with jaundice and pruritus. She was found to have elevated transaminases, and an echocardiogram revealed significantly increased right ventricular pressures concerning for pulmonary hypertension. Subsequently, the patient needed to be intubated for respiratory insufficiency and poor cardiac output. After several days in the intensive care unit (ICU), she was noted to be bradycardic and have a dilated right pupil. A stat CT of the head demonstrated a large mixed density right-sided subdural haematoma with mass effect, midline shift and early uncal and transtentorial herniation, as well as a small subdural haematoma on the left (figure 1). The mixed density of the haematoma on CT scan was likely a result of multiple haemorrhages over the...



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Missed opportunity to diagnose subungual melanoma: potential pitfalls!

Subungual melanoma, an uncommon form of acral melanoma that arises within the nail matrix, accounts for 1%–3% of all cutaneous melanoma in Caucasians. As subungual melanoma presents in a more disguised manner than cutaneous lesions, increased vigilance is required. It most commonly presents as a discolouration of the nail, nail splitting or nail-bed bleeding. Black pigmentation of the adjacent nail fold, termed Hutchinson's sign, may be a diagnostic clue. Treatment of subungual melanoma remains surgical with wide local excision and amputation primary modalities. We present the case of a 61-year-old man with an 18-month history of a left thumb nail-bed abnormality and a 6-week history of left axillary lymphadenopathy. One year earlier, he presented to the emergency department with a purulent discharge from his left thumb but declined nail-bed ablation. He was referred to the 'Hand and Plastic Injuries Clinic' by his general practitioner and diagnosed with a chronic traumatic-induced nail-bed injury. As his symptoms did not improve, he was referred to the 2-week wait Skin Cancer Clinic. The left thumb nail-bed was excised as a nail unit down to bone, and the diagnosis of melanoma was rendered. Left axillary lymphadenopathy was confirmed as metastatic melanoma. He underwent amputation of his left thumb at the interproximal phalangeal joint, and a left axillary node dissection was performed. No residual melanoma was identified in his thumb. Microscopically, his left axillary dissection confirmed 9 out of 36 positive nodes for metastatic melanoma with extracapsular spread. He was staged at IIIC disease. This case report demonstrates missed opportunities to diagnose subungual melanoma and acts as a cautionary tale in considering this pathology in the differential diagnosis of nail-bed lesions with prompt referral for further investigation.



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