Extracellular ATP signaling and clinical relevance

Publication date: Available online 20 December 2017
Source:Clinical Immunology
Author(s): Lei Dou, Yi-Fa Chen, Peter J. Cowan, Xiao-ping Chen
Since purinergic signaling was discovered in the early 1970s, it has been shown that extracellular nucleotides, and their derivative nucleosides, are released in a regulated or unregulated manner by cells in various challenging settings and then bind defined purinergic receptors to activate intricate signaling networks. Extracellular ATP plays a role based on different P2 receptor subtypes expressed on specific cell types. Sequential hydrolysis of extracellular ATP catalyzed by ectonucleotidases (e.g. CD39, CD73) is the main pathway for the generation of adenosine, which in turn activates P1 receptors. Many studies have demonstrated that extracellular ATP signaling functions as an important dynamic regulatory pathway to coordinate appropriate immune responses in various pathological processes, including intracellular infection, host-tumor interaction, pro-inflammation vascular injury, and transplant immunity. ATP receptors and CD39 also participate in related clinical settings. Here, we review the latest research in to the development of promising clinical treatment strategies.



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Impaired Th1 responses in patients with acute exacerbations of COPD are improved with PD-1 blockade

Publication date: Available online 20 December 2017
Source:Clinical Immunology
Author(s): Dino B.A. Tan, Teck-Hui Teo, Abdul M. Setiawan, Nathanael E. Ong, Maja Zimmermann, Alan Chen-Yu Hsu, Peter A.B. Wark, Yuben P. Moodley




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IL-21 dependent Granzyme B production of B-cells is decreased in patients with lupus nephritis

Publication date: Available online 21 December 2017
Source:Clinical Immunology
Author(s): Mariam Rabani, Benjamin Wilde, Katharina Hübbers, Shilei Xu, Andreas Kribben, Oliver Witzke, Sebastian Dolff
ObjectivesB-cells play a crucial role in the pathogenesis of lupus nephritis. Recently, a separate subset has been discovered characterized by expression of Granzyme B. The aim of this study is to investigate this subset in patients with systemic lupus erythematosus (SLE).MethodsIsolated PBMCs of SLE-patients (n=30) and healthy controls (n=21) were in vitro stimulated with CPG, IgG+IgM and IL-21. Patients were sub-grouped in patients with and without biopsy proven lupus nephritis. B-cells were analyzed for intracellular Granzyme B expression by flow cytometry.ResultsThe strongest stimulus for Granzyme B secretion of B-cells was IgG+IgM in presence of IL-21. SLE-patients had a significant decreased percentage of Granzyme B⁺ B-cells in particular SLE-patients with active disease and with lupus nephritis.ConclusionsThe frequency of GrB+ producing B-cells is reduced in SLE patients. This may contribute to an imbalanced B-cell regulation towards effector B-cells which might promote the development of lupus nephritis.



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Issue Information - Cover and Editorial Board

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Issue Information - TOC

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Case of warty dyskeratoma on the anterior chest: The relationship between its dermoscopic and histopathological findings

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Granulocyte and monocyte adsorption apheresis for palmoplantar pustulosis with extra-palmoplantar lesions and pustulotic arthro-osteitis

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Epidermal mast cells in the nail matrix of a patient with psoriasis confined to the nails

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Multiple cutaneous and uterine leiomyomata with features of benign metastasing leiomyomatosis: a novel mutation of the fumarate hydratase gene

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Unilesional CD30+ mycosis fungoides with large cell transformation and spontaneous regression, masquerading as verruca vulgaris

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Localized, ovoid urticarial plaques with fine, nonfollicular pustules

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Combination of low-dose total skin electron beam therapy and subsequent localized skin electron beam therapy as a therapeutic option for advanced-stage mycosis fungoides

Summary

Electron beam therapy (EBT) is an established treatment for mycosis fungoides (MF), but evidence for the use of EBT in advanced cutaneous conditions is limited, and optimal scheduling of the regimen for such conditions remains unclear. We report the case of a 44-year-old woman diagnosed with MF with widespread cutaneous lesions, including multiple huge tumours in the craniofacial area. Low-dose total skin (TS)EBT and subsequent localized skin (LS)EBT achieved striking improvements in eruptions. Oral etretinate was also administered during therapy. Our experience implies that combined TSEBT and LSEBT may be worth attempting when a patient presents with both widespread lesions and prominent tumours, even when the tumours are extremely large.

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In reference to should infants who fail their newborn hearing screen undergo cytomegalovirus testing?

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Extraocular sebaceous carcinoma accompanied by invasive squamous cell carcinoma: The first case report and consideration of histogenesis

Abstract

A 61-year-old man presented with a dome-shaped nodule, 1.2 cm in size, with a central crater covered by keratinous material near the left lateral malleolus. Histological findings demonstrated a basophilic circular cone in the center, surrounded and sharply demarcated by a broad eosinophilic area. The central conical mass was composed mainly of atypical basaloid cells intermingled with scattered atypical sebaceous cells with scalloped nuclei and microvesicular cytoplasms, suggesting sebaceous carcinoma. The peripheral area consisted of atypical keratinizing squamoid cells without sebaceous cells, suggesting invasive squamous cell carcinoma. Atypical sebaceous cells were positive for adipophilin. Atypical basaloid cells were positive for 34βE12 and CAM5.2. Peripheral squamoid cells were positive for 34βB4 and 34βE12 throughout, and were positive for LHP1 in the superficial layer. We herein describe the first case of extraocular sebaceous carcinoma accompanied by invasive squamous cell carcinoma, which might have arisen from biphasic differentiation of cancer stem cells.

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Endodontic management of taurodontism with a complex root canal anatomy in mandibular posterior teeth

One of the biggest challenges in endodontic treatment is to comprehensively understand the variation of tooth root canal anatomy. To a large degree, the anatomy and furcation distribution of teeth, which vary from nationality and ethnic groups, will influence the clinical diagnosis, treatment plan and even prognosis. Taurodontism, as one of anatomic variation in tooth structures, is relatively hard to be seen in dental clinics. Two special cases of taurodontism with varied root canal anatomies in mandibular second premolar and first molar are reported in this paper.

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Subacute combined degeneration of the spinal cord in vitamin B12 and copper deficiency

Description

A 67-year-old man with a medical history of pancreatoduodenectomy (Whipple procedure) in September 2015 due to a pancreatic cancer was admitted to our department of neurology 1 year later with a progressively disturbed gait. He reported weakness and numbness of both legs. Clinical examination revealed a spastic sensomotoric tetraparesis with ataxia and bladder dysfunction. MRI showed longitudinal myelopathy exactly limited to the posterior tracts (fasciculus gracilis and fasciculus cuneatus) indicating a metabolic origin (subacute combined degeneration of the spinal cord; figure 1A,B).

Figure 1

(A) Axial T2-weighted and (B) sagittal short T1 inversion recovery (STIR) MRI of the cervical spine showing longitudinal myelopathy exactly limited to the posterior tracts (fasciculus gracilis and fasciculus cuneatus, arrows). (C) Sagittal STIR MRI of the cervical spine 4 months later.

Consistently and according to the medical history of the Whipple procedure, a moderate vitamin B₁₂ deficiency...

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Interstitial lung disease secondary to Cetuximab in bladder cancer: an Oncologists perspective

A wide variety of cytotoxic medications cause interstitial lung disease (ILD). For the first time, we describe ILD in an 82-year-old woman with muscle invasive bladder cancer 10 days after receiving cetuximab as part of a novel trial. She had no significant medical history or drug allergies, had good exercise tolerance and a 5 pack-year smoking history. She received neoadjuvant chemotherapy (gemcitabine, cisplatin) with a good response on MRI. She was eligible for a phase 2 trial of cetuximab with chemotherapy and radiotherapy for muscle invasive bladder cancer (TUXEDO), in which the trial arm used cetuximab plus standard chemoradiotherapy to the bladder (64 grey in 32 fractions plus mitomycinandfluorouracil). Ten days after her third infusion of cetuximab, she was presented with type 1 respiratory failure. Thoracic CT scan demonstrated new widespread ground glass change in the lungs. She received high-dose steroids (prednisolone 1 mg/kg), broad spectrum antibacterial cover and non-invasive ventilation. She survived to be discharged with residual respiratory failure.

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Deliberate self-poisoning with long-acting anticoagulant rodenticides

Long-acting anticoagulant rodenticides, also called superwarfarins, are known for their greater potency, longer half-life and delayed onset of symptoms. Cases of superwarfarin poisoning can pose a diagnostic and clinical challenge due to a wide array of presentations and prolonged severe coagulopathy requiring months of high-dose oral vitamin K therapy. The most common presentation of long-acting anticoagulant rodenticide poisoning is mucocutaneous bleeding, with other common presentations including haematuria, gingival bleeding, epistaxis and gastrointestinal bleeding. We discuss a case of deliberate self-poisoning with long-acting anticoagulant rodenticides presenting with haematuria and coagulation values above measurable limits. This case is important as it required immediate and maintenance therapy in order to prevent profound bleeding, as well as the evaluation of the patient's psychosocial factors to ensure medical compliance and to prevent refractory complications or repeated self-harm.

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Stenotrophomonas maltophilia: an emerging multidrug-resistant opportunistic pathogen in the immunocompromised host

Stenotrophomonas maltophilia is a multidrug-resistant opportunistic pathogen with increasing prevalence and high morbidity and mortality. In addition to its classic association with pulmonary infections, S. maltophilia can cause skin and soft tissue infections with varying clinical presentations. We describe the case of a man in his 30s with B-cell acute lymphoblastic leukaemia who presented with a solitary patch of faint but tender purpura found to have rapidly progressive S. maltophilia infection diagnosed on skin biopsy. S. maltophilia infection should be considered in the cutaneous evaluation of the immunocompromised host.

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Colonic perforation by an intrathecal baclofen pump catheter causing delayed Escherichia coli meningitis

Intrathecal baclofen (ITB) delivery via an implanted pump is frequently used for the treatment of spasticity. This is an effective and safe neurosurgical and pharmacological intervention associated with an improvement in patient quality of life. There is, however, a risk of device-related infection. We present a patient with pump-site infection and Escherichia coli meningitis secondary to transcolonic perforation of an intrathecal baclofen pump catheter. While this is rare, we review the intraoperative precautions and best practices that should be taken to prevent and manage this unusual complication.

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A disclosed diagnosis for 24 years unknown illness

IgG4-related disease (IgG4-RD) is a newly described illness over the last several years. A 57-year-old man, who had been followed for chronic kidney disease (CKD), chronic pancreatitis and history of operated cholangitis, was admitted to our hospital for abdominal pain and worsening renal function. Serum levels of IgG and IgG4 were elevated. CT scan showed the characteristic findings of IgG4-related retroperitoneal fibrosis, pancreas and kidney disease. An endoscopic biopsy revealed the finding compatible with IgG4-RD. Steroid therapy led to the remission of his abdominal pain. Patients with CKD of unknown aetiology may have IgG4-RD.

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A surgeons nightmare: pyoderma gangrenosum with pathergy effect mimicking necrotising fasciitis

A 53-year-old woman was admitted for vulval swelling and fever. She was initially diagnosed with vulval cellulitis and given parenteral antibiotics. Within 1 week, she developed necrotic-looking skin lesions extending from her vulva to her buttock. Emergency surgical debridement with diversion colostomy was performed in view of suspected necrotising fasciitis. Shortly after the surgery, she developed necrotic-looking skin lesions at the peripheral venous cannula insertion site, central line insertion site, and around her surgical wounds and stoma. A second surgical debridement was performed and shortly afterwards, similar skin lesions appeared around her surgical wounds. Her clinical progression was suggestive of pyoderma gangrenosum with pathergy effect. Hence, she was started on topical steroid, systemic steroid and immunosuppressant. The skin lesions responded well to medical therapy. Further systemic workup for conditions associated with this disease revealed findings suspicious for myelodysplastic syndrome.

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Management of atypical femoral fracture in a patient with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a generalised connective tissue disorder associated with low bone mass, bone fragility and increased susceptibility to fractures. First-line treatment to improve bone mineral density (BMD) is usually with bisphosphonates but long-term usage has been associated with uncommon complications such as atypical femoral fractures (AFF). Treatment with teriparatide in this situation has been reported with positive outcomes. However, choice of treatment after 2 years of teriparatide has not been well studied or reported. We describe a patient with OI treated with bisphosphonates for 9 years, who then suffered a spontaneous AFF, was subsequently started on teriparatide for 2 years followed by 6 monthly Denosumab. 1 year post-treatment with Denosumab, there was significant improvement in BMD, good fracture healing and no new fractures. This case highlights the potential use of denosumab following 2 years of teriparatide treatment in patients with OI with AFF.

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Spinal cord abscess secondary to infected dorsal dermal sinus in an infant: uncommon presentation of a known entity

Infection along the congenital dermal sinus tract is well known. However, congenital dorsal dermal sinus presenting with intramedullary abscess is quite rare. The sinus tract usually presents in the midline and acts as a portal of entry for infection that may manifest as meningitis, extradural or subdural abscess and may further involve the cord. Surgical drainage of pus and complete excision of the sinus tract is the standard treatment. Here we describe an infant with an infected congenital dorsal dermal sinus with atypical presentation as large paracentral abscess in the upper back. We further highlight the importance of recognising and treating these skin dimples even when clinically silent to avoid catastrophic complications.

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Uvular necrosis following diagnostic gastroscopy

Uvular necrosis is an extremely rare complication of gastroscopy. We describe the fifth published case of uvular necrosis following an uncomplicated diagnostic gastroscopy in a young man. Presentation with severe sore throat and inability to swallow saliva occurred within 24 hours of gastroscopy and resolved with conservative treatment.

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Auditory agnosia caused by bilateral putamen haemorrhage

A 55-year-old right-handed man with a history of hypertension suddenly fell and developed right hemiparesis. Neurological examination revealed that he was alert, but did not appropriately respond to verbal questions and commands. Detailed examination revealed that he could correctly respond to written commands. His speech was almost fluent, showing no paraphasia and normal articulation. His written sentences were legible. Pure tone audiometry showed that his auditory acuity was relatively preserved. His brainstem auditory evoked potential components from I to V were recorded bilaterally with normal latency. Cerebral CT demonstrated fresh bleeding in the left putamen and an old haemorrhage on the opposite side. He was treated by antihypertensive therapy and rehabilitation. Although there remained mild sensory deficit on his right extremities and he felt a slight noise during conversation, he had little difficulty with verbal communication when he was transferred to another hospital on day 38.

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Successful embolisation of an intracranial meningioma via a right-sided aortic arch

Right aortic arch is an unusual arch variation. Supra-aortic neurointervention in such cases has been sparingly reported. This case highlights the unusual association of a left hemispheric convexity meningioma with a right aortic arch which was successfully navigated. Particle embolisation of the meningioma produced good results followed by complete surgical excision and gratifying overall final outcome in this challenging scenario.

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Primary apocrine carcinoma of an unusual site

Primary apocrine carcinoma is a rare malignancy most commonly occurring in apocrine dense areas like axilla. There are only about 200 cases reported to date. We report a case of primary apocrine carcinoma present at an unusual site, that is, the arm. A wide local excision of the mass was done and was diagnosed as apocrine carcinoma on histopathological examination and was confirmed by immunohistochemistry. Wide local excision is the treatment required.

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Mystery ring: a case of TIPS stent migration

Description

We present a 50-year-old man with history of end-stage liver disease secondary to hepatitis C, who frequently presents to the hospital with ascites. He recently underwent Trans jugular Intrahepatic Portosystemic Shunt (TIPS) stent placement after becoming resistant to diuresis and large volume therapeutic paracentesis. He presented to the emergency room with altered mental status due to hepatic encephalopathy. On physical exam, he was noted to have a systolic murmur; hence, a transthoracic echocardiogram was ordered. It showed an echo dense ring-like shadow in the right atrium close to intra-atrial septum (figure 1). Transoesophageal echocardiogram was obtained for better visualisation, and it showed a migrated TIPS stent entering the right atrium from the inferior vena cava with its cephalad end close to the intra-atrial septum (figure 2). There was no evidence of mechanical complication related to stent migration by echocardiography. The patient declined percutaneous retrieval....

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Ultrawide field imaging with navigable magnifier for diagnosis of diffuse unilateral subacute neuroretinitis

Description

A 52-year-old female presented with painless loss of vision in right eye since 3–4 years. Visual acuity was counting fingers close to face in right eye and 20/20 in left eye. Anterior segment examination and intraocular pressure were normal in both eyes. Right eye had multiple areas of pigment mottling and deep retinal scarring scattered throughout the fundus, along with optic disc atrophy (figure 1). Fundus examination of left eye was unremarkable. Window defects were detected on ultrawide field fluorescein angiography. Diffuse unilateral subacute neuroretinitis (DUSN) was suspected due to the ultrawide field imaging (UWFI) characteristics. The clinical UWFI was scanned with a navigable magnifier available in the software (Optos PLC, Dunfermline, UK). A slender, white-coloured, minimally curved structure was identified in the temporal pre-equatorial region with an adjoining scar (figure 2).

Figure 1

UWFI of the right eye depicting multiple...

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Recurrent lower gastrointestinal bleeding in an 87-year-old woman

Description

An 87-year-old woman presented to an outside hospital with a complaint of bright red blood per rectum (BRBPR), where her haemoglobin was found to be 4.6 g/dL. An extensive gastrointestinal (GI) work was performed, including oesophagogastroduodenoscopy, colonoscopy and a video capsule endoscopy, followed by a superior mesenteric artery (SMA) angiogram which showed no active extravasation. The patient continued to have BRBPR and was transferred to our hospital for further work-up. Her medical history was significant for hypertension, hyperlipidaemia and coronary artery disease. Her surgical history included knee arthroplasty, hernia repair, hysterectomy, cholecystectomy and appendectomy. Physical examination of the abdomen was soft, non-distended and non-tender. On transfer, a CT enterography was obtained and could not identify the source of bleeding but did note some stenosis of the superior mesenteric artery (SMA). A colonoscopy was then performed, which revealed old blood in her colon, but no active bleeding was found. A subsequent nuclear tagged...

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Giant ductal pseudoaneurysm in infancy: a lesson learnt the hard way

Description

A 7-month-old girl, ex-preterm (26-weeker), 4.5 kg, with 4 mm patent ductus arteriosus (PDA) underwent PDA device closure (Amplatzer duct occluder - ADO II 4x6 mm) elsewhere and was readmitted 4 days later with pericardial effusion. Needle pericardiocentesis drained 50 mL of haemorrhagic fluid. Septic screen was negative. Severe dyspnoea ensued 2 weeks later. Chest X-ray excluded lung pathology. Bedside echocardiogram showed PDA device in situ (online ), no residual ductus, vegetation or pericardial recollection, unobstructed flow in the pulmonary artery and descending aorta, normal pulmonary arterial pressures, and normal biventricular function. Curiously, a giant anechoic mass (22x25 mm) (online ) was visualised posteroinferior to the device with its neck communicating with lesser curvature of the thoracic aorta at the level of origin of the left subclavian artery (figure 1A,B). Intra-aneurysmal thrombus or aortic dissection was absent. We diagnosed giant ductal pseudoaneurysm with possible left bronchial compression.

Figure 1

(A) Parasternal short-axis transthoracic two-dimensional echocardiogram...

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Sensory neuronopathy associated with cholangiocarcinoma diagnosed 6 years after symptom onset

A pure sensory neuronopathy (also referred to as a sensory ganglionopathy) is one of a handful of classical neurological paraneoplastic syndromes. Current guidelines recommend that in cases of sensory neuronopathy, a search for an underlying malignancy be pursued for up to 4 years. We report the case of a 52-year-old woman with a sensory neuronopathy who was eventually diagnosed with a cholangiocarcinoma 6 years after the onset of her disease. A CT fluorodeoxyglucose positron emission tomography (FDG-PET) scan performed 18 and 24 months after disease onset failed to identify an underlying neoplasm. Immunomodulatory treatment with corticosteroids, intravenous immunoglobulins and plasma exchange were ineffective. Investigations for Sjogren's disease were negative. A third FDG-PET performed 6 years after symptom onset identified a cholangiocarcinoma, which was confirmed histologically following open resection. Since the tumour was removed, our patient's condition has not progressed, but there has been no improvement and she remains severely disabled.

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Nasal tip schwannoma mimicking rhinophyma

Description

Rhinophyma meaning 'nose growth' in Greek is a relatively common condition that describes thickening of the nasal skin with enlargement of the sebaceous glands. While not fully understood, it is believed to be a result of vascular instability causing leakage of fluid into the tissues. This subsequently triggers inflammation and scarring.1 Treatment is initially medical; systemic isotretinoin has been shown to reduce the bulk of rhinophyma. Many surgical techniques have also been described, all of which involve tissue removal. Previous literature has demonstrated other skin conditions mimicking this diagnosis including angiosarcoma, squamous cell carcinoma and sarcoidosis.2

A 52-year-old woman was referred to ear, nose and throat (ENT) from dermatology for surgical management of rhinophyma. She described a 3-year history of an increasing swelling on the tip of her nose (figure 1). During this time, she underwent extensive conservative treatment with...

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Intrapulmonary Pharmacokinetics of Levonadifloxacin Following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects [PublishAheadOfPrint]

Alalevonadifloxacin (WCK 2349) is a novel L-alanine ester prodrug of levonadifloxacin being developed as an oral fluoroquinolone antibiotic. The primary objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levonadifloxacin following oral administration of alalevonadifloxacin in healthy adult subjects. Levonadifloxacin concentrations in plasma, ELF, and AM of 30 healthy subjects were measured by LC-MS/MS following oral dosing of alalevonadifloxacin (1000 mg twice daily for 5 days). Six subjects were assigned to each bronchoalveolar lavage sampling time at 2, 4, 6, 8 or 12 hours after the ninth oral dose. Noncompartmental pharmacokinetic (PK) parameters were determined from serial total plasma concentrations collected over a 12-hour interval following the first and ninth oral doses. Penetration ratios were calculated from the AUC_0—12 for plasma, ELF, and AM using mean (and median) concentrations at each BAL sampling times. Unbound plasma concentrations (plasma protein binding ~85%) were used to determine site-to-plasma penetration ratios. Plasma PK parameter values for levonadifloxacin were similar after the first and ninth doses. The respective AUC_0-12 values based on mean ELF and AM concentrations were 172.6 and 35.3 mg·h/L, respectively. The penetration ratios for ELF and AM to unbound plasma levonadifloxacin concentrations were 7.66 and 1.58, respectively. Similar penetration ratios were observed with median concentrations. The observed plasma, ELF, and AM concentrations of levonadifloxacin support further studies of alalevonadifloxacin for treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

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Bayesian Estimation of Tobramycin Exposure in Patients with Cystic Fibrosis -- an update [PublishAheadOfPrint]

Recently, a comparison of estimated tobramycin exposure (AUC_0-24) using Bayesian forecasting (BF) versus true exposure demonstrated accuracy in patients with cystic fibrosis. Theoretically, when using BF methods the predictive performance towards estimating an individual's exposure should improve with additional observations; however, there is limited applicable evidence against true exposure. We demonstrate that with additional data from previous dosing intervals, predicted performance to estimate exposure improves.

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Reversal of azole resistance in Candida albicans by sulfa antibacterial drugs [PublishAheadOfPrint]

Invasive candidiasis presents an emerging global public health challenge due to the emergence of resistance to the frontline treatment options, such as fluconazole. Hence, the identification of other compounds capable of pairing with fluconazole and averting azole-resistance would potentially prolong the clinical utility of this important group. In an effort to repurpose drugs in the field of antifungal drug discovery, we explored sulfa antibacterial drugs for the purpose of reverting azole resistance in Candida. In this study, we assembled and investigated a library of 21 sulfa antibacterial drugs for their ability to restore fluconazole sensitivity in Candida albicans. Surprisingly, the majority of assayed sulfa drugs (15) were found to exhibit synergistic relationships with fluconazole by checkerboard assay with FIC values ranging from < 0.0312 to 0.25. Remarkably, five sulfa drugs, were able to revert azole resistance in a clinically achievable range. The structure-activity-relationships (SAR) of the amino benzene sulfonamide scaffold as antifungal agents were studied. We also identified the possible mechanism of the synergistic interaction of sulfa antibacterial drugs with azole antifungal drugs. Furthermore, the ability of sulfa antibacterial drugs to inhibit Candida biofilm by 40% in vitro was confirmed. In addition, effect of sulfa-fluconazole combination on Candida growth kinetics and efflux machinery was explored. Finally, using a Caenorhabditis elegans infection model, we demonstrated that the sulfa-fluconazole combination does possess potent antifungal activity in vivo reducing Candida in infected worms by ~50% compared to the control.

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Activity of Ceftolozane-Tazobactam Tested against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States During 2013 to 2015 [PublishAheadOfPrint]

The activity of ceftolozane-tazobactam and comparator agents was evaluated against organisms deemed to be the cause of pneumonia among patients hospitalized in the United States (US) during 2013 to 2015. Isolates included 1,576 Pseudomonas aeruginosa and 2,362 Enterobacteriaceae susceptibility tested using reference broth microdilution methods. Ceftolozane-tazobactam, cefepime, ceftazidime, meropenem, and piperacillin-tazobactam inhibited 96.3%, 84.8%, 83.5%, 80.0%, and 78.6%, respectively, of the P. aeruginosa isolates. Ceftolozane-tazobactam inhibited 77.5-85.1% of isolates nonsusceptible to antipseudomonal β-lactams and 86.6% and 71.0% of the 372 (23.6% overall) multidrug- and 155 (9.8%) extensively drug-resistant isolates tested. The activity of this combination was greater than other β-lactams evaluated against all P. aeruginosa groups across all US census divisions. Ceftolozane-tazobactam was active against 90.6% of the Enterobacteriaceae, being only less active than meropenem (95.6% susceptible) among the β-lactams evaluated. Against 145 Escherichia coli and Klebsiella pneumoniae isolates carrying extended-spectrum β-lactamase (ESBLs) encoding genes without carbapenemases, ceftolozane-tazobactam inhibited 82.8% of these isolates and was more active than cefepime and piperacillin-tazobactam (15.2% and 74.3% susceptible, respectively). ESBL genes included in this analysis were mainly bla_CTX-M-15-like (89 isolates) and bla_CTX-M-14-like (22), but also bla_SHV (31) and bla_TEM (3). Ceftolozane-tazobactam also displayed activity (84.6% susceptible) against 13 isolates harboring acquired AmpC genes. All β-lactams displayed limited activity against bla_KPC-carrying isolates. Ceftolozane-tazobactam was the most active β-lactam tested against P. aeruginosa isolates from isolates that were the probable cause of pneumonia and displayed in vitro activity against Enterobacteriaceae, including isolates resistant to cephalosporins that carry ESBL genes.

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Parasite-mediated degradation of synthetic ozonide antimalarials impacts in vitro antimalarial activity [PublishAheadOfPrint]

The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the ozonides. Similar to the artemisinins, heme-mediated degradation of the ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of in vitro drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439 and this is associated with a reduction in in vitro antimalarial activity. Under conditions of very high parasitemia (~90%), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite stage parasite cultures exposed to a 3 h drug pulse. This work highlights the impact of increasing parasite load on ozonide stability and in vitro antimalarial activity and should be considered when investigating the antimalarial mode of action of the ozonide antimalarials under conditions of high parasitemia.

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AmBisome(R) treatment of murine cutaneous leishmaniasis: relation between skin pharmacokinetics and efficacy [PublishAheadOfPrint]

AmBisome® (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Little is known about its tissue distribution and pharmacodynamics to inform clinical use in CL. Here, we compared the skin pharmacokinetics of LAmB with Fungizone® (DAmB), the deoxycholate form of AmB, in murine models of Leishmania major CL. Drug levels at the target site (the localized lesion) 48 hours after single intravenous (IV) dosing of the individual AmB formulations (1 mg/kg of body weight) were similar, but were 3-fold higher for LAmB than for DAmB on day 10 after multiple administrations (1 mg/kg on days 0, 2, 4, 6 and 8). After single and multiple dosing, intralesional concentrations were respectively 5- and 20-fold higher compared to those in the healthy control skin of the same infected mice. We then evaluated how drug levels in the lesion after LAmB treatment relate to therapeutic outcomes. After five administrations of the drug at 0, 6.25 or 12.5 mg/kg (IV), there was a clear correlation between dose level, intralesional AmB concentration and relative reduction in parasite load and lesion size (R² values > 0.9). This study confirms the improved efficacy of the liposomal over the deoxycholate AmB formulation in experimental CL, which is related to higher intralesional drug accumulation.

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Effect of genetic variation of NAT2 on isoniazid, SLCO1B1, and CES2 on rifampin pharmacokinetics in Ghanaian children with tuberculosis [PublishAheadOfPrint]

Isoniazid and rifampin are essential components of first-line antituberculosis (anti-TB) therapy. Understanding the relationship between genetic factors and the pharmacokinetics of these drugs could be useful in optimizing treatment outcomes, but this is understudied in children. We investigated the relationship between N-acetyltransferase type 2 (NAT2) genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by SLCO1B1) and carboxylesterase 2 (CES2) single nucleotide polymorphisms (SNPs) and rifampin pharmacokinetics in Ghanaian children. Blood samples were collected at times 0, 1, 2, 4, and 8 hours post-dose in children with tuberculosis (TB) on standard first-line therapy for at least 4 weeks. Isoniazid and rifampin concentrations were determined by validated LC/MS/MS method and pharmacokinetic parameters calculated using noncompartmental analysis. Genotyping of NAT2, SLCO1B1 and CES2 SNPs were performed using validated TaqMan® genotyping assays. Kruskal—Wallis test was used to compare pharmacokinetic parameters among the three genotypic groups followed by Wilcoxon Rank Sum test for pairwise group comparisons. Genotype status inferred by the NAT2 4-SNP and 7-SNP genotyping panel identified children with slow acetylator phenotype but not the rapid. For rifampin, only the rare SLCO1B1*1b homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that NAT2 and SCLCO1B1*1b genotyping may have minimal clinical utility in dosing decisions at the population level in Ghanaian children, but it could be useful at the individual level or in populations that have high frequency of implicated genotypes. Further studies in other populations are warranted.

http://ift.tt/2kRDdae

Pharmacokinetic/pharmacodynamic (PK/PD) Determinants of Vancomycin Efficacy in Enterococcal Bacteremia [PublishAheadOfPrint]

Background. While pharmacokinetic-pharmacodynamic targets for vancomycin therapy are recognized for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, scant data are available to guide therapy for other gram positive infections.

Methods. A retrospective single-centre cohort of patients with Enterococcus spp. bacteremia hospitalized between 1^st January 2009 and 31^st May 2015 were studied. Average vancomycin AUC_0-24hrs was computed using a Bayesian approach. MIC was determined by gradient diffusion (E-test, bioMerieux) and the average AUC_0-24hrs/MIC over the initial 72 hours of therapy was calculated. We assessed 30-day all-cause mortality as the primary outcome. Classification and regression tree analysis (CART) was used to identify vancomycin AUC_0-24hrs/MIC associated with 30-day mortality.

Results. Fifty-seven patients with enterococcal bacteremia (32 E. faecium, 21 E. faecalis, 4 other Enteroccocus spp.) were studied. The median vancomycin MIC was 0.75 mg/L (range 0.38-3 mg/L). All-cause 30-day mortality occurred in 10 out of 57 patients (17.5%). A CART-derived vancomycin AUC/MIC_Etest of ≥389 was associated with reduced mortality (P= 0.017); failure to achieve this independently predicted 30-day mortality [OR 5.65 (95% CI 1.18-27.03), P= 0.03].

Conclusion. We found that a vancomycin AUC/MIC_Etest (≥389), achieved within 72 hours, was associated with reduced mortality. Larger, prospective studies are warranted to verify the vancomycin pharmacodynamic targets associated with maximal clinical outcomes and acceptable safety.

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Dramatic increase of amoxicillin induced crystal nephropathy: a cohort study from the French pharmacovigilance [PublishAheadOfPrint]

An increase in amoxicillin induced crystal nephropathy (AICN) incidence has been recently suggested. The aims of this study were to investigate the trend of AICN incidence through Paris' regional centers of pharmacovigilance (Paris-RCPVs) and better describe this rare adverse drug reaction. Forty-five AICN cases were identified between 1985 and 2016. All cases, except one, were reported since 2010. Amoxicillin (AMX) was administered intravenously (65 [43;110] mg/kg/day) in all patients, either for treating infection (n=15) or as surgical prophylaxis (n=30). Delay between AMX administration and AICN onset was 1 [1; 3] day; 30, 4 and 11 patients developed KDIGO stage 1,2 and 3, acute kidney injury, respectively. Delay between AICN onset and kidney function recovery was 4 [2; 6] days. Precipitating factors were identified in only one third of cases. Twelve patients required ICU admission, and 8, renal replacement therapy. Neither chronic kidney disease nor death was observed. We confirmed the recent and dramatic increase of AICN to the Paris-RCPVs since 2010. The absence of precipitating factors in the majority of cases and the onset of AICN in apparent routine indications, such as surgical prophylaxis, are alarming and justify a high vigilance from all AMX prescribers.

http://ift.tt/2kTmkvL

Antimicrobial Activity of Dalbavancin Tested against Staphylococcus aureus with Decreased Susceptibility to Glycopeptides, Daptomycin, and/or Linezolid from United States Medical Centers [PublishAheadOfPrint]

Dalbavancin activity was assessed against a large collection of Staphylococcus aureus (n=59,903), including isolates with decreased susceptibility to vancomycin (MIC ≥2 mg/L; n=1,141), daptomycin (MIC ≥2 mg/L; n=48), telavancin (MIC ≥0.12 mg/L; n=52), teicoplanin (MIC ≥4 mg/L; n=143), and/or linezolid (MIC ≥8 mg/L; n=25). Dalbavancin displayed susceptibility rates ranging from 90.4% (isolates with telavancin MIC ≥0.12 mg/L) to 100.0% (linezolid-resistant isolates), and lower MIC values than the comparators against these resistant subsets.

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Pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis clinical isolates in Myanmar [PublishAheadOfPrint]

The emergence and spread of multidrug-resistant tuberculosis (MDR-TB) have been a serious threat to control TB....

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Aminoarabinosylation of lipid A is critical for the development of colistin resistance in Pseudomonas aeruginosa [PublishAheadOfPrint]

Lipid A aminoarabinosylation is invariably associated with colistin resistance in Pseudomonas aeruginosa; however, the existence of alternative, aminoarabinosylation-independent colistin resistance mechanisms in this bacterium remained elusive. By combining reverse genetics with experimental evolution assays we demonstrate that a functional lipid A aminoarabinosylation pathway is critical for acquisition of colistin resistance in reference and clinical P. aeruginosa isolates. This highlights lipid A aminoarabinosylation as a promising target for the design of colistin adjuvants against P. aeruginosa.

http://ift.tt/2ktTbrJ

Impact of Real-Time Therapeutic Drug Monitoring on the Prescription of Antibiotics in Burn Patients Requiring Admission to the Intensive Care Unit [PublishAheadOfPrint]

Background: As pharmacokinetics after burn trauma are difficult to predict, we conducted a 3-year prospective, monocentric, randomized controlled trial to determine the extent of under and overdosing of antibiotics and further evaluate the impact of systematic therapeutic drug monitoring (TDM) with same day real-time dose adaptation to reach and maintain antibiotic concentrations within therapeutic range.

Methods: Forty-five consecutive burn patients treated with antibiotics were prospectively screened. Forty fulfilled inclusion criteria; after one refusal and one withdraw consent, 19 were randomly assigned to an intervention group (real-time antibiotic concentration determination and subsequent adaptations), and 19 to a standard-of-care group (antibiotic administration at physician's discretion without real-time TDM).

Results: Seventy-three infectious episodes were analyzed. Before intervention, only 46/82 (56%) initial trough concentrations fell within the range. There was no difference between groups in initial trough concentrations (adjusted HR=1.39 [95%CI: 0.81-2.39], p=0.227) or time to reach the target. However, thanks to real-time dose adjustments, trough concentrations of the intervention group remained more within the predefined range (57/77 [74.0%] vs. 48/85 [56.5%], adjusted OR=2.34 [95%CI: 1.17-4.81], p=0.018); more days were spent within the target range (193 days/297 days on antibiotics [65.0%] vs. 171/311 [55.0%], adjusted OR=1.64 [95%CI: 1.16-2.32], p=0.005); and fewer results were below target trough concentrations (25/118 [21.2%] vs. 44/126 [34.9%], adjusted OR=0.47 [95%CI: 0.26-0.87], p=0.015). No difference in infection outcomes was observed between study groups.

Conclusions: Systematic TDM with same day real-time dose adaptation was effective in reaching and maintaining therapeutic antibiotic concentrations in infected burn patients, which prevented both over- and under-dosing. A larger multicentric study is needed to further evaluate the impact of this strategy on infection outcomes and the emergence of antibiotic resistance during long-term burn treatment.

This study was registered with the ClinicalTrials.gov platform on September 27^th 2013.

Trial Registration: NCT01965340.

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Effects of Renal Impairment and Hemodialysis on the Pharmacokinetics and Safety of the Glecaprevir and Pibrentasvir Combination in HCV-Negative Subjects [PublishAheadOfPrint]

Hepatitis C virus (HCV) infection is an independent risk factor for developing chronic renal impairment and end-stage renal disease. Limited treatment options are available for HCV genotypes 2, 3, 5, and 6 infection in patients with eGFR <30 mL/min. Glecaprevir and pibrentasvir are active against all six major HCV genotypes, primarily excreted in the bile, and have minimal renal elimination. Therefore, combined treatment with these direct-acting antivirals may be useful for patients with HCV infection and chronic kidney disease. A Phase 1, multicenter, open-label study evaluated the effects of renal impairment on the pharmacokinetics and safety of glecaprevir/pibrentasvir. In sub-study 1, 38 subjects with chronic kidney disease Stages 2 to 5 not on dialysis or with normal renal function received single doses of the glecaprevir 300 mg and pibrentasvir 120 mg combination. In sub-study 2, 8 subjects requiring hemodialysis received single doses of the glecaprevir 300 mg and pibrentasvir 120 mg combination under dialysis and non-dialysis conditions. Regression analyses demonstrated increased glecaprevir and pibrentasvir plasma exposure, as determined by area under the curve, with decreasing renal function up to 56% and 46%, respectively, in subjects with eGFR <15 mL/min/1.73 m². In dialysis-dependent subjects, glecaprevir and pibrentasvir exposures were similar (≤ 18% difference) when study drugs were administered before hemodialysis or on a non-dialysis day. Adverse events were mostly mild, the most common being self-limited fatigue (3 subjects). The study findings support clinical evaluation of glecaprevir/pibrentasvir without dose adjustment in HCV-infected subjects with renal impairment.

This study is registered at ClinicalTrials.gov: NCT 02442258.

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Depot subcutaneous injection with chalcone CH8-loaded PLGA microspheres aiming at a single-dose treatment of cutaneous leishmaniasis [PublishAheadOfPrint]

Conventional chemotherapy of cutaneous leishmaniasis (CL) is based on multiple parenteral or intralesional injections with systemically toxic drugs. Aiming at a single-dose localized therapy, biodegradable PLGA (poly-(lactide-co-glycolide) microparticles loaded with 7.8% of an antileishmanial nitrochalcone named CH8 (CH8/PLGA) were constructed to promote sustained subcutaneous release. In vitro, murine macrophages avidly phagocytosed CH8/PLGA smaller than 6μm without triggering oxidative mechanisms. Upon 48-hour incubation, both CH8 and CH8/PLGA were 40 times more toxic to intracellular Leishmania amazonensis than to macrophages. In vivo, BALB/c were given one or three subcutaneous injections in the infected ear with 1.2mg/kg of CH8 in free or CH8/PLGA forms, while controls received three CH8-equivalent doses of naked PLGA microparticles or Glucantime. While a single injection with CH8/PLGA reduced the parasite loads by 91%, triple injections with free CH8 or CH8/PLGA caused 80% and 97% reduction, respectively, in relation to saline controls. Glucantime treatment was the least effective (only 36% reduction) and the most toxic as seen by elevated alanine aminotransferase serum levels. Together, those findings show that CH8/PLGA microparticles can be effectively and safely used for single-dose treatment of CL.

http://ift.tt/2kRq8NY

Successive emergence of ceftazidime-avibactam resistance through distinct genomic adaptations in blaKPC-2-harboring Klebsiella pneumoniae ST307 [PublishAheadOfPrint]

Ceftazidime-avibactam (CAZ/AVI) is a promising novel treatment for carbapenem-resistant Enterobacteriaceae (CRE). Despite improved treatment outcomes compared to aminoglycoside- and colistin-based regimens, rapid evolution of CAZ/AVI resistance during treatment has previously been reported in Klebsiella pneumoniae ST258 bla_KPC-3 harboring isolates. Here, we report the step-wise evolution and isolation of two phenotypically distinct CAZ/AVI resistant Klebsiella pneumoniae phenotypes from a patient with pancreatitis. All susceptible (n=3) and resistant (n=5) isolates were of the ST307 clonal background, a rapidly emerging clone. Taking advantage of short-read Illumina and long-read Oxford Nanopore sequencing and full-length assembly of the core chromosome and plasmids, we demonstrate that CAZ/AVI resistance first occurred through a 532G->T bla_KPC-2 point mutation in bla_KPC-2 (D179Y protein substitution) following only 12 days of CAZ/AVI exposure. While subsequent isolates exhibited substantially decreased meropenem (MEM) MICs (≤ 2 μg/mL), later cultures demonstrated a second CAZ/AVI resistance phenotype with a lower CAZ/AVI MIC (12 μg/ml) but also MEM resistance (MIC > 128 μg/ml). These CAZ/AVI and MEM-resistant isolates showed evidence of multiple genomic adaptations, mainly through insertions and deletions. This included amplification and transposition of wild-type bla_KPC-2 into a novel plasmid, IS1 insertion upstream of ompK36 and disruption of the rfb gene locus in these isolates. Our findings illustrate the potential of CAZ/AVI resistance to emerge in non-K. pneumoniae ST258 clonal backgrounds and alternative bla_KPC variants. These results raise concerns about strong selective pressures incurred by novel carbapenemase inhibitors such as avibactam on isolates previously considered invulnerable to CAZ/AVI resistance. There is an urgent need to further characterize non-KPC mediated modes of carbapenem resistance and the intrinsic bacterial factors that facilitate rapid emergence of resistance during treatment.

Importance Few treatment options are available for carbapenem-resistant Enterobacteriaceae infections, leading to high morbidity and mortality. Novel beta-lactam/beta-lactamase inhibitor combinations such as ceftazidime/avibactam (CAZ/AVI) promise better clinical outcomes. In K. pneumoniae ST258 CAZ/AVI resistance due to bla_KPC-3 mutations following in vivo exposure has been reported. Our report demonstrates that diverse mechanisms of CAZ/AVI resistance can develop in K. pneumoniae ST307, an emerging multi-drug resistant clone. We studied sequential K. pneumoniae ST307 isolates that rapidly developed CAZ/AVI resistance during treatment. We initially noted a 532G->T point mutation in bla_KPC-2 leading to a D179Y protein substitution, associated with decreased carbapenem MIC. After cessation of CAZ/AVI a novel phenotype emerged, characterized by both CAZ/AVI and high-level meropenem resistance. Using short- and long-read sequencing, we detected a transposed copy of bla_KPC-2 and additional transposon insertions into the bacterial chromosome. Our findings highlight the vulnerability of novel carbapenemase inhibitors to resistance and demonstrate that numerous resistance mechanisms may evolve during antibiotic exposure.

http://ift.tt/2kvcjW5

Characterization of KPC-encoding plasmids from Enterobacteriaceae isolated in a Czech hospital [PublishAheadOfPrint]

Ten Enterobacteriaceae, collected in a Czech hospital, carried bla_KPC-positive plasmids of different sizes (~30, ~45, and ~80 kb). Sequencing revealed three types of plasmids (A to C) with Tn4401a. Type A plasmids comprised an IncR backbone and a KPC-2-encoding multidrug resistant (MDR) region. Type B were derivatives of type A plasmids carrying an IncN3-like segment, while type C were IncP6 plasmids sharing the same KPC-2-encoding MDR region with type A and B plasmids.

http://ift.tt/2kUW3xg

Prediction of fluoroquinolone susceptibility directly from whole genome sequence data using liquid chromatography-tandem mass spectrometry to identify mutant genotypes. [PublishAheadOfPrint]

Fluoroquinolone resistance in Gram-negative bacteria is multifactorial, involving target site mutations, reductions in fluoroquinolone entry due to reduced porin production, increased fluoroquinolone efflux, enzymes that modify fluoroquinolones, and Qnr, a DNA mimic that protects the drug target from fluoroquinolone binding. Here we report a comprehensive analysis using transformation and in vitro mutant selection, of the relative importance of each of these mechanisms in fluoroquinolone non-susceptibility, using Klebsiella pneumoniae as a model system. Our improved biological understanding was then used to generate 47 rules that can predict fluoroquinolone susceptibility in K. pneumoniae clinical isolates. Key to the success of this predictive process was the use of liquid chromatography tandem mass spectrometry to measure the abundance of proteins in extracts of cultured bacteria, identifying which sequence variants seen in the whole genome sequence data were functionally important in the context of fluoroquinolone susceptibility.

http://ift.tt/2kvcbG5

Nitric oxide-mediated induction of dispersal in Pseudomonas aeruginosa biofilms is inhibited by flavohemoglobin production and is enhanced by imidazole [PublishAheadOfPrint]

The biological signal molecule nitric oxide (NO) was found to induce biofilm dispersal across a range of bacterial species, which led to its consideration for therapeutic strategies to treat biofilms and biofilm-related infections. However, biofilms are often not completely dispersed after exposure to NO. To better understand this phenomenon, we investigated the response of Pseudomonas aeruginosa biofilm cells to successive NO treatments. When biofilms were first pre-treated with a low, non-effective dose of NO, a second dose of the signal molecule, at a concentration usually capable of inducing dispersal, did not have any effect. Amperometric analysis revealed that pre-treated P. aeruginosa cells had enhanced NO scavenging activity and this effect was associated with the production of the flavohemoglobin Fhp. Further, qRT-PCR analysis showed that fhp expression increased by over 100-fold in NO pre-treated biofilms compared to untreated biofilms. Biofilms of mutant strains harboring deletions in fhp or fhpR, encoding a NO-responsive regulator of fhp, were not affected in their dispersal response after the initial pre-treatment with NO. Overall, these results suggest that FhpR can sense NO to trigger production of the flavohemoglobin Fhp and inhibit subsequent dispersal responses to NO. Finally, the addition of imidazole, which can inhibit the NO dioxygenase activity of flavohemoglobin, attenuated the prevention of dispersal after NO pre-treatment, and improved the dispersal response in older, starved biofilms. This study clarifies the underlying mechanisms of impaired dispersal induced by repeated NO treatments and offers new perspective for improving the use of NO in biofilm control strategies.

http://ift.tt/2kRDaey

The impact of homologous resistance mutations from pathogenic yeast on Saccharomyces cerevisiae lanosterol 14{alpha}-demethylase [PublishAheadOfPrint]

Fungal infections frequently affect immune deficient individuals and are estimated to kill 1.35 million people per annum. Azole antifungals target the membrane bound cytochrome P450 monooxygenase lanosterol 14α-demethylase (CYP51, Erg11p). Mutations in CYP51 can render the widely-used triazole drugs less effective. The Candida albicans CYP51 mutation G464S, the double mutation Y132F G464S (Y140F and G464S Saccharomyces cerevisiae numbering), as well as the CYP51A G54E/R/W mutations of Aspergillus fumigatus (G73E/R/W S. cerevisiae numbering) have been reproduced in a recombinant C-terminal hexahistidine-tagged version of S. cerevisiae CYP51 (ScErg11p6xHis). Phenotypes and X-ray crystal structures were determined for the mutant enzymes. Liquid microdilution assays showed that the G464S mutation in ScErg11p6xHis conferred no difference in the susceptibility of yeast to triazole drugs but in combination with Y140F gave a 4-fold reduction in susceptibility to the short-tailed triazole fluconazole. ScErg11p6xHis Y140F G464S was unstable during purification and was not crystallized. The G73E/R/W ScErg11p6xHis mutations conferred increased susceptibly to all triazoles tested in liquid microdilution assays. High resolution X-ray crystal structures reveal two different conformations of the ligand itraconazole, including a previously unseen conformation, as well as interactions between the tail of this triazole and E/W73 residues. This study shows that S. cerevisiae CYP51 adequately represents some but not all mutations in CYP51s of pathogenic fungi. Insight into the molecular mechanisms of resistance mutations in CYP51 will assist the development of inhibitors that will overcome antifungal resistance.

http://ift.tt/2kvbJHT

The influence of developmental timing on B cell diversity

Trine A Kristiansen | Stijn Vanhee | Joan Yuan

http://ift.tt/2Bq3s2J

Is tracheotomy on the decline in otolaryngology? A single institutional analysis

A recent study reported decreasing trends in tracheotomy procedures by its otolaryngology service. We set out to determine whether the previously reported decrease in otolaryngology performed tracheotomies by one institution is a local or generalizable phenomenon.

http://ift.tt/2BULyEm

Safety and efficacy of intratympanic ciprofloxacin otic suspension post-tubes in a real-world pediatric population

Otorrhea frequently follows tympanostomy tube (TT) placement. We evaluated otorrhea following single 6mg OTO-201 (OTIPRIO®, ciprofloxacin otic suspension 6%) intraoperative injection into each middle ear in a variety of effusion types and concurrent procedures in children undergoing TT placement. Secondary objective: Efficacy based on Medicaid status and safety.

http://ift.tt/2Bcsxd9

A new method for removal of eyelid-margin-molluscum

http://ift.tt/2COIZ3t

Faster suction blister formation using two hair dryers

http://ift.tt/2BHXAyB

More Tumor Mutations Equals Higher Success Rate With Cancer Immunotherapy Drugs

The "mutational burden," or the number of mutations present in a tumor's DNA, is a good predictor of whether that cancer type will respond to a class of cancer immunotherapy drugs known as checkpoint inhibitors, a new study led by Johns Hopkins Kimmel Cancer Center researchers shows. The finding, published in the Dec. 21 New England Journal of Medicine, could be used to guide future clinical trials for these drugs.

http://ift.tt/2BpgXja

Age-related changes of CD4+ T cell migration and cytokine expression in germ-free and SPF mice periodontium

Publication date: March 2018
Source:Archives of Oral Biology, Volume 87
Author(s): Koichiro Irie, Takaaki Tomofuji, Daisuke Ekuni, Daiki Fukuhara, Yoko Uchida, Kota Kataoka, Shuichiro Kobayashi, Takeshi Kikuchi, Akio Mitani, Yoshihiro Shimazaki, Manabu Morita
ObjectiveIncreasing age is a potential risk factor for periodontal tissue breakdown, which may be affected by commensal flora. The aim of this study evaluated age-related changes in CD4⁺ T cells, C-C chemokine ligand 5 (CCL5), interleukin (IL)-17A, and receptor activator of nuclear factor-kappa B ligand (RANKL) expression using germ-free (GF) and conventionally reared (SPF) mice.DesignGF and SPF mice at 8 (n = 6/group) and 22 weeks old (n = 6/group) were used. Immunohistochemical analyses were performed to determine the effects of aging on protein expression in periodontal tissues. Age-related changes in alveolar bone were quantified using micro-CT analysis.ResultsSPF mice, but not GF mice, showed an age-related increase in alveolar bone loss (P < 0.01). SPF mice at 22 weeks of age increased expression of CD4⁺ T cells, CCL5, IL-17A, and RANKL compared to those at 8 weeks of age in connective tissue and alveolar bone surface (P < 0.01). Furthermore, there was increased CD4⁺ T cells, which were co-expressed with IL-17A and RANKL in SPF mice at 22 weeks of age. On the other hand, the GF mice did not show any significant differences in CD4⁺ T cells, CCL5, IL-17A and RANKL expression between the two age groups.ConclusionsSPF mice induced an age-related increase in CD4⁺ T cells co- expressed with IL-17A and RANKL, with occurring alveolar bone loss. In contrast, GF mice did not show age-related changes in CD4⁺ T cell migration and cytokine expression.



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Surgical management of inverted papilloma; a single-center analysis of 247 patients with long follow-up

Our aim was to review our management of inverted papilloma (IP), perform a recurrence analysis, and review the literature.

http://ift.tt/2oX9t0L

Reconstruction of a skull base defect after endoscopic endonasal resection of a pituitary adenoma: Sphenoid mucosal flaps

Publication date: Available online 20 December 2017
Source:American Journal of Otolaryngology
Author(s): Erden Goljo, Eliezer Kinberg, Katelyn Stepan, Jill K. Gregory, Alfred M. Iloreta, Satish Govindaraj, Hongyan Zou
This report describes a bilateral sphenoid sinus mucosal flap for the repair of a sellar floor defect and CSF leak following endoscopic endonasal skull base surgery. The key advantage of this technique is enabling the sphenoid mucosal flaps to remain vascularized, which reduces postoperative complications including CSF leakage, recurrent sinusitis, meningitis, encephalitis and pneumocephalus. The use of this technique is a viable and possibly favorable alternative to free grafts in the reconstruction of small to medium sized sellar defects with low flow or absent CSF leaks base surgery.



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An algorithm for the classification of mRNA patters in eosinophilic esophagitis: integration of machine learning

Publication date: Available online 19 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Benjamin F. Sallis, Lena Erkert, Sherezade Moñino-Romero, Utkucan Acar, Rina Wu, Liza Konnikova, Willem S. Lexmond, Matthew J. Hamilton, W. Augustine Dunn, Zsolt Szepfalusi, Jon A. Vanderhoof, Scott B. Snapper, Jerrold R. Turner, Jeffrey D. Goldsmith, Lisa A. Spencer, Samuel Nurko, Edda Fiebiger
BackgroundDiagnostic evaluation of eosinophilic esophagitis (EoE) remains difficult, particularly the assessment of the patient's allergic status.ObjectiveEstablish an automated medical algorithm to assist in the evaluation of EoE.MethodsMachine learning techniques were used to establish a diagnostic probability score for EoE (pEoE) based on esophageal mRNA transcript patterns from biopsies of patients with EoE, gastroesophageal reflux disease, and controls. Dimensionality reduction in the training set established weighted factors, which were confirmed by immunohistochemistry. Following weighted factor analysis, p(EoE) was determined by Random Forest classification. Accuracy was tested in an external test set and predictive power was assessed with equivocal patients. Esophageal IgE production was quantified with epsilon germ line (IGHE) transcripts and correlated with serum IgE and the Th2-type mRNA profile to establish an IGHE-score for tissue allergy.ResultsIn the primary analysis, a three-class statistical model generated a p(EoE) score based on common characteristics of the inflammatory EoE profile. A p(EoE) ≥25 successfully identified EoE with high accuracy (sensitivity 94.4%, specificity 92.9%, AUC 0.985) and improved diagnosis of equivocal cases by 84.6%. The p(EoE) changed in response to therapy. A secondary analysis loop in EoE patients defined an IGHE-score≥37.5 for a patient subpopulation with increased esophageal allergic inflammation.ConclusionThe development of intelligent data analysis from a machine learning perspective provides exciting opportunities to improve diagnostic precision and improve patient care in EoE. The p(EoE) and the IGHE-score are steps towards the development of decision trees to define EoE subpopulations and, consequently, will facilitate individualized therapy.

Graphical abstract

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Zika Virus: An Emerging Infectious Disease with Serious Perinatal and Neurologic Complications

Publication date: Available online 19 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Thomas B. Casale, Michael N. Teng, Jamie P. Morano, Thomas Unnasch, Charles J. Lockwood
Zika virus (ZIKV) is a flavivirus that is primarily transmitted by Aedes aegypti, the mosquito vector also important in the transmission of the flaviviruses responsible for dengue fever, yellow fever and chikungunya. Due to occurrence in the same geographic regions, serological cross-reactivity, and similar, albeit often less severe clinical manifestations as dengue and chikungunya infections, ZIKV infection likely went undetected and/or misdiagnosed for many years. ZIKV is somewhat unique among flaviviruses in its ability to also be transmitted via sexual contact, non-sexual body fluids and perinatally. The relatively recent detection of the link between ZIKV infection and Guillain-Barré syndrome and fetal neurological defects including microcephaly has prompted intense efforts aimed at the development of new and specific diagnostic tests. Infection with ZIKV has been postulated to lead to a more severe clinical course from other structurally related viruses, especially dengue, and vice versa, due to a phenomenon termed antibody-dependent enhancement. Inactivated whole virus, DNA, RNA and vectored vaccine approaches to prevent ZIKV infection are in development as are treatments for active disease that are safe in pregnant women. Here we summarize the important epidemiologic and clinical features of ZIKV infection as well as the progress and challenges in developing rapid point of care diagnostic tests and vaccines to prevent disease. We used electronic databases to identify relevant published data regarding ZIKV MeSH searches.



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What is Botox for hair and what does it do?

Botox for hair may refer to a topical cream or scalp injections, both with the aim of improving the look and health of hair. Learn more about them here.

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Comparative effectiveness of allergy testing method in driving immunotherapy outcomes

Background

Skin-prick testing (SPT), in vitro testing (IVT), and intradermal-dilutional testing (IDT) are methods to detect patient sensitivities to specific allergens and direct immunotherapy dosing. We used objective and subjective measures of improvement to compare outcomes based on test method.

Methods

Patients underwent 1 of 3 protocols: SPT, screening SPT followed by IDT, or IVT. We used institution billing data to do a cost analysis of these tests. The time to maintenance (TTM) therapy was analyzed and patients were stratified into high and low reactors. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was used to quantify symptoms pre-maintenance and post-maintenance.

Results

Of 177 patients (SPT, n = 40; IVT, n = 91; IDT, n = 46), 115 (SPT, n = 35; IVT, n = 39; IDT, n = 41) were high reactors. Out of 90 patients (SPT, n = 17; IVT, n = 37; IDT, n = 36) reaching maintenance, 58 were high reactors (SPT, n = 15; IVT, n = 12; IDT, n = 31). Overall, SPT, IVT, and IDT median TTM were 542, 329, and 578.5 days, respectively. IDT TTM was shorter compared to IVT overall and in high reactors (hazard ratio [HR] = 1.91, p = 0.02; HR = 2.12, p = 0.03), but was not significant compared to SPT high reactors (p = 0.33). The IDT cost was $62.66, translating to an incremental cost-effectiveness ratio of $0.23 per day of shortened TTM. Median RQLQ change for the SPT, IVT, and IDT groups was 6.5, 1, and 1.5, respectively, but was not significant (p = 0.60).

Conclusion

IDT reached maintenance immunotherapy quicker than IVT but there was no difference compared to SPT. TTM did not correlate with improvements in patient symptoms between testing methods. This study represents a novel comparison of outcomes based on initial allergy testing method.

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Medical and surgical rhinology—outcomes matter

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Perioperative management in endoscopic endonasal skull-base surgery: a survey of the North American Skull Base Society

Background

The objective of this work was to better understand variations in perioperative management in endoscopic endonasal skull-base surgery (EESBS) and to identify trends in management based upon the practice patterns of North American Skull Base Society (NASBS) members.

Methods

A 29-question survey evaluating perioperative EESBS management was sent to all NASBS members. Responses were analyzed with descriptive statistics. Subgroup analysis was performed based on participant demographics. A Bonferroni correction was performed and a p value <0.01 was considered statistically significant for subgroup analysis.

Results

Of 651 invitees, 116 responded (17.8%). Participants were primarily from the United States (81.0%), and practiced in academic centers (83.6%). The majority were neurosurgeons (55.2%) or rhinologists (27.6%). Most surgeons (83.6%) advocated use of preoperative intravenous antibiotics (96.6%) and image guidance in all cases (83.6%). Lumbar drains were not recommended for cases in which an intraoperative cerebrospinal fluid (CSF) leak was not anticipated (94.8%). Nasoseptal flaps (NSFs) were not recommended in cases without intraoperative CSF leak (84.5%), but were recommended in cases of high-flow intraoperative CSF leak (97.4%). While postoperative restrictions were highly variable, most providers recommended CSF leak precautions (89.7%), flying restrictions (94.0%), and driving restrictions (95.6%) regardless of intraoperative CSF leak status. Most experts also recommended that continuous positive airway pressure (CPAP) be avoided for at least 2 weeks when an intraoperative CSF leak is encountered (81.9%).

Conclusion

Despite variation in perioperative management of EESBS patients, important trends were identified by this study. Further investigation is needed to standardize perioperative practice patterns in EESBS.

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Herpes Zoster Rates in a Large Cohort of Patients With Systemically Treated Psoriasis

This cohort study examines estimated herpes zoster incidence rates among systemically treated patients with psoriasis in a community-based health care delivery setting.

http://ift.tt/2CKCS04

Digital Photographic Assessment of Acne Vulgaris Using NORA Technology

This pilot validation study determines whether acne scoring through digital self-photographs is accurate and reliable compared with in-person examination findings in patients with acne vulgaris.

http://ift.tt/2BE2IDD

Hypopigmented, Atrophic, and Folliculocentric Papules on the Trunk

A woman in her 60s presented with multiple hypopigmented, flat-topped papules on the back, waist, and inframammary area without genital involvement. What is your diagnosis?

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Newborn Treated With Drug That Triggered Maternal SJS During Pregnancy

This case report of a woman who developed Stevens-Johnson syndrome during pregnancy describes the treatment of her newborn with the culprit drug.

http://ift.tt/2BFHjtW

Tumor Classifications in 7th and 8th Editions of AJCC Cancer Staging Manual

This retrospective cohort study compares the tumor classifications for head and neck squamous cell carcinoma using the 7th vs 8th editions of the AJCC Cancer Staging Manual for head amd neck cutaneous csquamous cell carcinomas.

http://ift.tt/2CMkvrZ

Voice outcome indicators for unilateral vocal fold paralysis surgery: a review of the literature

Abstract

Introduction

There is no consensus on which voice outcome indicators (VOIs) should be used to compare the merits of the various surgical treatments for unilateral vocal fold paralysis (UVFP). Authors performed a literature review to identify which VOIs are most frequently used and most relevant, in terms of significant change in pre- and post-operative measurements, to assess UVFP surgical treatments.

Method

A Medline/Pubmed literature review was performed and the most frequently used VOIs were identified using a Pareto diagram. For these most frequently used VOI's, the number of studies that showed a statistically significant change in pre- and post-operative results were compared to the total number of studies found using that same VOI, this portion was expressed in percent. This percentage was defined as the "percentage of significance" and used to assess changes of each VOI.

Results

Eleven VOIs were identified using the Pareto analysis. These were, in decreasing order of frequency of citation: maximum phonation time (MPT), jitter, Shimmer, video-stroboscopic examination, noise to harmonic ratio (NHR/HNR), mean air flow (MeAF), fundamental frequency (F0), "Infrequent Perceptional Scales", GRBAS scale, mean subglottic pressure (MSGP). MPT, MeAF, factor G of GRBAS-I, Jitter, shimmer and VHI-30 had respective "percentage of significance" of 90, 86, 85, 74, 68 and 64%, respectively.

Conclusion

The results indicate that MPT, MeAF and GRBAS-I, represent the top-three most frequently used and the most relevant VOIs in terms of "percentage of significance". VHI-30 showed a relatively low rate of use and low "percentage of significance". The role of Jitter and Shimmer remains unclear. Finally, MSGP and the F0 appear to be less relevant VOIs for the evaluation of UFVP surgical treatments in terms of significant change in pre- and post-operative measurements.

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Einfluss externer und endogener Faktoren auf Halslymphknoten

Zusammenfassung

Hintergrund

Die sonographische Dignitätsbeurteilung zervikaler Lymphknoten ist essenziell für die weitere Diagnostik und Therapieplanung verschiedener Krankheitsbilder. Ziel dieser prospektiven, monozentrischen Arbeit war es, die Sonomorphologie und Größe benigner Lymphknotenveränderungen anhand gesunder und operierter Probanden zu eruieren und den Einfluss verschiedener Faktoren zu prüfen.

Material und Methoden

Daten von 205 Gesunden sowie von 15 Probanden mit einer Op. wurden prä- und postoperativ erhoben. Sonographisch repräsentative Lymphknoten wurden in ihren Durchmessern erfasst, das Volumen berechnet, die Begrenzung, die Erkennbarkeit eines Hilus und die Vaskularisation dokumentiert. Eine detaillierte Anamnese erfolgte mittels eines standardisierten Fragebogens.

Ergebnisse

Bei den 20- bis 39-Jährigen waren größere Lymphknotendurchmesser als bei 40- bis 59- und über 60-Jährigen zu erkennen, und 40- bis 59-Jährige zeigten größere Lymphknoten als über 60-jährige Probanden. Bei Personen mit einem Konsum von unter 10 und 10–20 Zigaretten pro Tag fanden sich im Vergleich zu Probanden mit einem Konsum von über 20 Zigaretten pro Tag größere zervikale Lymphknoten. Raucher, die gleichzeitig sportlich aktiv waren, wiesen größere Lymphknoten auf als Probanden, die die Fragen nach Rauchen und Sport beide verneinten. Zudem war zu beobachten, dass sowohl die Größe als auch die Anzahl der Halslymphknoten postoperativ im Vergleich zu präoperativ zunahm.

Schlussfolgerung

Die gemessenen Lymphknoten entsprechen den bekannten sonographischen Kriterien benigner Halslymphknoten. Der Studie zufolge haben Alter, Intensität des Nikotinkonsums, die Kombination von Rauchen mit sportlicher Aktivität und Operationen einen Einfluss auf die Größe sonographisch gemessener zervikaler Lymphknoten.

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Possible therapeutic effect of orally administered ribavirin for respiratory syncytial virus-induced acute respiratory distress syndrome in an immunocompetent patient: a case report

Human respiratory syncytial virus usually causes self-limiting upper respiratory infection and occasionally causes pneumonia in immunocompromised hosts. Respiratory syncytial virus-induced severe pneumonia or ...

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Sub-Populations of Dermal Skin Fibroblasts Secrete Distinct Extracellular Matrix: Implications for Using Skin Substitutes in the Clinic

Summary

Background

While several commercial dermo-epidermal scaffolds can promote wound healing of the skin, the achievement of complete skin regeneration still represents a major challenge.

Objective

We postulated that three dimensional structures derived through the physiological cell secretion of extracellular matrix (ECM) may be a bioinspired scaffold for skin tissue engineering. In the present study we performed a biological characterization of self-assembled ECMs from three different sub-populations of fibroblasts found in human skin; papillary fibroblasts (Pfi), reticular fibroblasts (Rfi), and dermal papilla fibroblasts (DPfi).

Methods

Fibroblast sub-populations were cultured with ascorbic acid to promote cell assembled matrix production for 10 days. Subsequently, cells were removed and the remaining matrices were characterized. Additionally, in another experiment, keratinocytes were seeded on the top of cell depleted ECMs to generate epidermal only skin constructs.

Results

We found that the ECM self-assembled by Pfi exhibited randomly oriented fibers associated with highest interfibrillar space, reflecting ECM characteristics which are physiologically present within the papillary dermis. Mass spectrometry followed by validation with immunofluorescence analysis showed that THROMBOSPONDIN 1 (THBS1) is preferentially expressed within the DPfi derived matrix. Moreover we observed that epidermal constructs grown on DPfi or Pfi matrices exhibited normal basement membrane formation, while Rfi matrices were unable to support membrane formation.

Conclusion

We argue that inspiration can be taken from these different ECMs, to improve the design of therapeutic biomaterials in skin engineering applications.

This article is protected by copyright. All rights reserved.

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OMT to Improve Feeding After Hypothermia

Conditions:   Neonatal Encephalopathy;   Feeding; Difficult, Newborn
Intervention:   Procedure: Osteopathic Manipulative Treatment (OMT)
Sponsor:   Maine Medical Center
Recruiting

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Surgical management of inverted papilloma; a single-center analysis of 247 patients with long follow-up

Abstract

Background

Our aim was to review our management of inverted papilloma (IP), perform a recurrence analysis, and review the literature.

Methods

A retrospective analysis of 247 patients treated for an IP. Patients were grouped according to surgical approach, tumor presentation (primary, residual and recurrence) and Krouse-stage.

Results

Recurrence was observed in 20.3%, 28.6% and 35.1% (p = 0.017) of the patients who underwent endoscopic, external and combined surgery, respectively. Recurrences occurred more often in residual than primary IP (36.9% vs. 22.3%, p = 0.021). Primary endoscopic surgery had a recurrence rate of 12.5%, which was comparable to the recent literature (11.2%, 161/1433).

Conclusions

The relatively high number of recurrences in this cohort is explained by the long follow-up and previous (incomplete) surgery in 61.5% of the cases. The inferior outcome of residual IP underscores the importance of having a low threshold for preoperative biopsy in unilateral and atypical sinonasal disease.

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Masthead

http://ift.tt/2CLdzLq

Table of contents

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Prevention of tracheal inflammation and fibrosis using nitinol stent coated with doxycycline

Objectives

This study was conducted to determine whether a nitinol stent coated with doxycycline prevents tracheal inflammation and fibrosis in a rabbit.

Methods

A nitinol stent coated with doxycycline was designed by us. Twelve rabbits were divided into three groups: normal, control (nondoxycycline-coated stent), and doxycycline-coated stent group. The stents were inserted into the tracheal lumen through the oral cavity. Tracheal granulation was evaluated and graded by laryngoscopy. Histological examinations evaluated the inflammatory response and fibrosis. Real-time polymerase chain reaction (PCR) and Western blot assessed the changes to the extracellular matrix (ECM).

Results

Endoscopic findings showed that the nitinol stent coated with doxycycline resulted in lesser granulation tissue in the trachea than the noncoated stent. Histologic examination further revealed that the doxycycline-coated stent was associated with decreased inflammatory cells and reduced fibrosis, compared to the noncoated stent. In PCR and Western blot, the doxycycline-coated stent showed lower expression of ECM components inducing fibrosis.

Conclusion

A nitinol stent coated with doxycycline showed favorable effects in reducing tracheal inflammation and fibrosis in a rabbit model. Further research is required to study the beneficial effects of local application of doxycycline for prevention of tracheal stenosis.

Level of Evidence

NA. Laryngoscope, 2017

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Factors affecting survival and locoregional control in head and neck cSCCA with nodal metastasis

Objectives

To determine factors affecting locoregional control (LRC) and disease-specific survival (DSS) in patients presenting with regionally metastatic cutaneous squamous cell carcinoma (cSCCA) of the head and neck.

Study Design

Retrospective review.

Methods

Upon review of institutional pathology database to identify patients with metastatic cSCCA, 62 subjects met the inclusion criteria between 2009 to 2012. Cox proportional hazard ratios for DSS and LRC were calculated for tumor, patient, lymph node, and treatment variables. These factors included primary site, primary tumor grade, primary tumor perineural invasion, extent of primary tumor invasion, age, immune status, parotid nodal status, invasion of facial nerve by parotid tumor, cervical nodal status, extracapsular spread, number of nodes involved, adjuvant radiation therapy, and chemotherapy. All variables were analyzed to determine impact on LRC and DSS. A disease-specific Kaplan-Meier curve was determined for the entire cohort.

Results

Five-year survival was 56% for all patients. The presence of extracapsular spread (ECS) and bone involvement of the primary tumor site resulted in statistically significant decreases in DSS (hazard ratio (HR) 41.3 and 270, respectively; P = 0.02 and P = 0.008, respectively) and LRC (HR 8.41 and 11.1, respectively; P = 0.005 and P = 0.04, respectively). The remaining factors had no statistically significant effect on DSS or LRC.

Conclusion

The presence of ECS in the metastatic lymph node and of bone invasion by the primary tumor appear to be important to the outcome of patients with metastatic cSCCA. These factors should be considered when developing multidisciplinary care plans and future investigations.

Level of Evidence

4. Laryngoscope, 2017

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Danish validation of sniffin' sticks olfactory test for threshold, discrimination, and identification

Objectives

The applicability of olfactory testing is dependent on cultural adaptation. The aim of this study was to validate the Sniffin' Sticks (Burghart Messtechnik, Wedel, Germany) threshold (T), discrimination (D), and identification (I) olfaction test. This data was subsequently used to investigate external validity of international normative values to separate hyposmia from normosmia.

Methods

The study included 388 participants. The first step was a questionnaire study in which 238 adults rated their familiarity with 125 odor descriptors. In the second step, we evaluated the original Sniffin' Sticks (Burghart Messtechnik) in 75 participants. In the third step, we modified our odor descriptors and tested 75 participants with the new version.

Results

In the I test, we found that 21 original odor descriptors were unfamiliar and that five odors had I rates < 75%. After modification, all odors had a successful I rate > 75%. By comparing the T, D, and I scores of previous validation studies, we found a significant variation in the scores between countries.

Conclusion

The original Sniffin' Sticks (Burghart Messtechnik) was not applicable in Denmark. The modification resulted in improvement of familiarity and rate of I, making the test valid for use in Denmark. Furthermore, the study found a large variation in T and D scores between different countries, which should be considered when using these scores to separate hyposmia and anosmia from normosmia.

Level of Evidence

2b. Laryngoscope, 2017

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Long-term mucocutaneous adverse effects of imatinib in Indian chronic myeloid leukemia patients

Abstract

Background

Short-term mucocutaneous adverse effects are well documented with imatinib. However, studies on long-term adverse effects and in the ethnic population are lacking.

Objective

To study the long-term mucocutaneous adverse effects of imatinib and factors predicting these adverse effects.

Methods

In this cross-sectional study, consenting adult chronic myeloid leukemia patients on imatinib for more than 250 days were recruited. The details of imatinib treatment were retrieved from hematology clinic records.

Results

Four hundred and thirty-eight patients who were on imatinib for a mean duration of 1820 days were recruited. A mean number of 1.42 ± 0.98 cutaneous adverse effects were seen per patient. Melasma-like pigmentation, periorbital edema, oral lichenoid reaction, cutaneous hypopigmentation, and vesicobullous eruptions were seen in 236 (53.9%), 81 (18.5%), 70 (16%), 42 (9.6%), and 12 (2.7%) patients, respectively. Drug-induced cutaneous eruptions (9.1%) and cutaneous hypopigmentation (9.6%) were seen less frequently. Cutaneous hyperpigmentation was more likely seen in younger patients (P = 0.001) and females (P < 0.001). On multivariate analysis, female gender was a significant risk factor for developing cutaneous hyperpigmentation and periorbital edema.

Conclusion

Cutaneous hyperpigmentation and periorbital edema are common long-term adverse effects of imatinib in Indian patients. Female gender is a significant risk factor for the development of both these adverse effects.

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Correction to: Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells

Abstract

The authors would like to make the following corrections to the published article.

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Splice variants of human natural cytotoxicity receptors: novel innate immune checkpoints

Abstract

The natural cytotoxicity receptors (NCRs; NKp30, NKp44, and NKp46) were first defined as activating receptors on human NK cells that are important in recognition of and response to tumors. A flurry of recent research, however, has revealed that differential splicing can occur during transcription of each of the NCR genes, resulting in some transcripts that encode receptor isoforms with inhibitory functions. These alternative transcripts can arise in certain tissue microenvironments and appear to be induced by cytokines. Evidence indicates that some of the inhibitory NCRs are triggered by specific ligands, such as the interaction of the inhibitory isoform of NKp44 with PCNA on the surface of tumor cells. Here, we review the different NCR splice variants, cytokines that modulate their expression, their functional impacts on innate immune cells, and their differential expression in the contexts of cancer, pregnancy, and infections. The recent discovery of these inhibitory NCR isoforms has revealed novel innate immune checkpoints, many of which still lack defined ligands and clear mechanisms driving their expression. These NCR checkpoint pathways offer exciting potential therapeutic targets to manipulate innate immune functions under defined pathological conditions, such as cancer, pregnancy disorders, and pathogen exposure.

http://ift.tt/2Dfm1Uv

Eczematous dermatitis in an infantile hemangioma with minimal or arrested growth

Abstract

Infantile hemangiomas (IHs) with minimal or arrested growth differ from standard IHs in that they have a reduced or absent growth phase. An association between IHs with minimal or arrested growth and superimposed eczematous dermatitis has not been described in the literature. We present a case detailing this association in which an IH with minimal or arrested growth responded well to treatment with propranolol and the superimposed eczema cleared completely with topical hydrocortisone.

http://ift.tt/2kssHXk

Pediatric dermatology procedures and pearls: Multimodal revision of earlobe keloids

Abstract

Keloid scars are benign proliferations of fibrous tissue and collagen that usually occur in response to cutaneous injury. Many treatment modalities have been described in the literature, with variable rates of recurrence and no clear consensus. Keloids remain a therapeutic challenge to patients and physicians alike. Herein we describe a novel technique for treating recurrent earlobe keloids in an outpatient setting with multimodal therapy including shave removal followed immediately by ablative fractional laser resurfacing (AFR) and laser-assisted delivery (LAD) of corticosteroids.

http://ift.tt/2kOMUGo

Fatal disseminated Trichosporon asahii fungemia in a child with acute lymphoblastic leukemia and a morbilliform eruption

Abstract

Trichosporonosis is a rare, life-threatening, opportunistic fungal infection that affects immunocompromised individuals with neutropenia, particularly those with underlying hematologic malignancies. We present the case of a 10-year-old boy with acute lymphoblastic leukemia who developed a diffuse, morbilliform eruption in the setting of fever and pancytopenia. He was found to have Trichosporon asahii fungemia with widespread visceral dissemination, and his condition rapidly deteriorated despite treatment. It is important to consider trichosporonosis in the evaluation of a critically ill individual with neutropena and a rash, because the initial cutaneous presentation may appear benign and delayed therapy results in death.

http://ift.tt/2kssFyG

Association between extremity kaposiform hemangioendothelioma and lymphedema

Abstract

Kaposiform hemangioendotheliomas are pediatric vascular tumors that do not metastasize. We present a patient with a thigh kaposiform hemangioendothelioma successfully treated using a systemic corticosteroid during infancy who was diagnosed with lymphedema in the extremity 9 years later. The observation that extremity kaposiform hemangioendothelioma could possibly be associated with lymphedema has implications for the care of patients with kaposiform hemangioendothelioma.

http://ift.tt/2B4sqjU

Unique presentation of transient zinc deficiency from low maternal breast milk zinc levels

Abstract

We report full-term siblings with a unique clinical presentation of polycyclic papulosquamous plaques secondary to transient zinc deficiency due to low maternal breast milk zinc levels. We present this case to highlight this unique presentation of zinc deficiency in breastfed infants.

http://ift.tt/2BOiX3H

Midline anterior neck inclusion cyst: A novel superficial congenital developmental anomaly of the neck

Abstract

Background/Objectives

A variety of congenital developmental anomalies arise on the neck because of the many fusion planes and complex embryologic structures in this region. We describe a series of seven patients with a novel type of superficial midline congenital anomaly.

Methods

Retrospective case series. Clinical and histopathologic features were compared and used to describe this entity.

Results

Seven patients with nearly identical clinical findings were identified. In all cases, a small superficial cyst resembling a giant milium was observed at birth. There were no significant changes during infancy and no evidence of underlying abnormalities. The histopathologic findings were identical to those of an infundibular follicular cyst.

Conclusion

We have termed this entity midline anterior neck inclusion cyst. We believe it is a superficial developmental anomaly, probably a forme fruste of a midline fusion developmental defect, which has not to our knowledge, previously been described.

http://ift.tt/2B4UJyl

Topical 1% propranolol ointment with occlusion in treatment of pyogenic granulomas: An open-label study in 22 children

Abstract

Background

Pyogenic granuloma (PG) is a common, acquired, benign vascular neoplasm of the skin and mucous membranes. It occurs most often in children and adolescents. First-line treatment options for PG are based on destructive approaches. Pain, permanent scarring, and pigmentation are potential complications of these therapies.

Methods

This single-arm, open-label, prospective study evaluated the efficacy of topical propranolol for treatment of PGs in children. All patients clinically diagnosed with cutaneous PG consecutively at the Dermatology Pediatric Outpatient Service of the University of Bologna from January 2010 to December 2010 received a compounded formulation of propranolol ointment 1%.

Results

We found propranolol ointment to be effective in consecutive patients; 59.0% completely regressed in a mean of 66 days, 18.2% remained stable, and 22.7% did not respond. No side effects (eg, skin irritation, allergy, bleeding) were observed.

Conclusion

Topical propranolol ointment 1% with occlusion appears to be an effective treatment for PGs in children. Early treatment was associated with a more favorable outcome.

http://ift.tt/2BCQqeR

Helicobacter Pylori infection of the gallbladder and the risk of chronic cholecystitis and cholelithiasis: A systematic review and meta-analysis

Abstract

Background

Helicobacter pylori is coexisted with various diseases, including chronic gastritis, ulcer, and gastric cancer. Besides, chronic cholecystitis and cholelithiasis are extremely widespread over the world, which are considered as high health-care cost burdens of digestive diseases. Epidemiologic evidence on Helicobacter pylori infection in gallbladder increasing the risk of biliary diseases has been contradictory.

Aim

Conduct a meta-analysis of overall studies and investigate an association between Helicobacter pylori infection of the gallbladder with chronic cholecystitis/cholelithiasis.

Methods

We used PubMed, EMBASE, and Cochrane library databases to identify all published studies before August 2017. Pooled odds ratios (OR) and corresponding 95% confidence intervals (CIs) were obtained using the random effects model. Heterogeneity, sensitivity, and stratified analyses were also performed.

Results

Eighteen studies involving 1544 participants and 1061 biliary cases with chronic cholecystitis/cholelithiasis were included. Helicobacter pylori infection of the gallbladder was significantly associated with an increased risk of chronic cholecystitis and cholecystitis (OR = 3.022; 95% CI, 1.897-4.815; I² = 20.1%). In addition, country-based subgroup analysis also showed a positive association between Helicobacter pylori positivity and chronic cholecystitis/cholelithiasis risk. The ORs (95% CIs) for Asian and non-Asian region studies were 3.75 (1.83-7.71) and 2.25 (1.29-3.89), respectively.

Conclusion

This meta-analysis suggests that infection of the gallbladder with Helicobacter pylori is closely related to an increased risk of chronic cholecystitis and cholelithiasis.

http://ift.tt/2kqGfTm

Turbinate reduction with complete preservation of mucosa and submucosa during rhinoplasty

Abstract

Background

Turbinate surgery is an important adjunct to functional and cosmetic rhinoplasty. Many studies have analyzed the effects of various mucosal-sparing techniques, such as radiofrequency, laser, shaver, and others. These techniques, however, result in the destruction of the submucosal tissue of the turbinate. The goal of this study was to determine whether excellent functional outcome could be achieved with techniques sparing both the mucosa and submucosa from destruction when addressing the turbinates in rhinoplasty surgery.

Materials and methods

A prospective single-surgeon clinical study analyzing submucous resection of turbinate bone without destruction of the submucosa or mucosa in patients undergoing functional–esthetic rhinoplasty was performed. In all, 122 patients (47 men, 75 women, average age: 32.1 years, range: 16–69 years) were eligible for the study. The functional outcome was measured prospectively using the Nasal Obstruction Symptom Evaluation (NOSE) score. Occurrence of complications was documented.

Results

Of over 1000 surgical patients, 307 candidates fulfilled multiple selection criteria and were entered in a rhinoplasty database. The surveys sufficient for the present study were completed by 122 of 307 patients (39.7%), of whom 91 patients reported improvement, 14 patients reported no subjective change, and 12 patients reported minimal worsening of nasal breathing. Overall, postoperative function was excellent (preoperative vs. postoperative NOSE score 47.5 vs. 20.1, p < 0.001). A large proportion of patients reporting worsening of symptoms (50%) were diagnosed with decongestant nasal spray abuse. Specific complications such as bleeding, foul drainage, dryness, and crusting were not reported.

Conclusion

All function-bearing structures of the inferior nasal turbinates, mucosa, and submucosa can be fully preserved without impairment of functional outcome during rhinoplasty. The technique of selective submucous bone resection is as an excellent alternative for patients undergoing rhinoplasty for concomitant treatment or prevention of nasal obstruction.

http://ift.tt/2koTmEI

All you need to know about varicose vein pain

A look at varicose vein pain, a condition where swollen veins become painful. Included is detail on prevention, potential causes, and when to see a doctor.

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