Immunotherapy Advances in Urothelial Carcinoma

Opinion statement

Checkpoint inhibitors have monumentally transformed the treatment of metastatic urothelial carcinoma. While the efficacy and safety of the different agents are similar in platinum-refractory metastatic urothelial carcinoma, pembrolizumab is the only agent that was superior to chemotherapy in a randomized phase III trial. Pembrolizumab and atezolizumab are also approved as first-line therapies in cisplatin-ineligible metastatic urothelial carcinoma. Several immunotherapy trials are ongoing in non-metastatic setting to maximize responses upfront. Despite the promising responses with immunotherapy, majority of patients do not respond to monotherapy and combination approaches would be the path moving forward to maximize responses. In addition, novel therapies are needed for patients who progress on checkpoint inhibitors. There is still a lot to be done to better understand predictive biomarkers, optimal combination, and sequences to improve clinical outcomes in urothelial carcinoma.

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Fucoxanthin prevents lipopolysaccharide-induced depressive-like behavior in mice via AMPK- NF-κB pathway

Abstract

Fucoxanthin (FX), a natural carotenoid abundant in edible brown seaweeds, has been shown the great anti-oxidant, anti-inflammatory and anti-diabetic effects in vivo and in vitro. The present study was designed to investigate the effects of FX on lipopolysaccharide (LPS)-induced behavioral defects in mice. In depressive behavior tests, the increased immobility time of forced swimming test and tail suspension test by LPS treatment in mice, which were significantly reversed by FX treatment (200 mg/kg, i.g.). In anxiety behavior tests, LPS injection was neither influence the anxiety-related parameters in marble burying test nor that in elevated plus maze test. Interestingly, anxiolytic effects were observed in single FX treated control and LPS-induced mice groups. FX treatment also reversed LPS-induced body weight loss and food intake decreases. Biochemical analysis indicated that FX inhibited LPS-induced overexpression of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), as well as iNOS and COX-2 in the hippocampus, frontal cortex and hypothalamus, via the modulation of AMPK-NF-κB signaling pathway.

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C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in pancreatic cancer

Abstract

Background

Chromatin modification at mitosis is closely related to transcriptional reactivation in the subsequent cell cycle. We reasoned this process is deregulated by oncogenic signals, which would contribute to mitotic stress resistance in pancreatic cancer. Here, we show DMAP1/Bub3 complex mediates mitotic stress-induced cellular apoptosis, while this effect is counteracted by c-Src in pancreatic cancer cells. Our study aims to uncover an unidentified mechanism underlying the distinct response to mitotic stress between normal cells and pancreatic cancer cells.

Methods

The interaction between Bub3 and DMAP1 upon mitotic stress signaling was determined through molecular and cell biological methods. The inhibitory effect of c-Src on DMAP1/Bub3-mediated DNA methylation and gene transcription profile was investigated. The association between c-Src-mediated DMAP1 phosphorylation and paclitaxel activity in vivo and clinicopathologic characteristics were analyzed.

Results

Mitotic arrest induced p38-dependent phosphorylation of Bub3 at Ser211, which promotes DMAP1/Bub3 interaction. DMAP1/Bub3 complex is recruited by TAp73 to the promoter of anti-apoptotic gene BCL2L1, thus mediates the DNA methylation and represses gene transcription linked to cell apoptosis. Meanwhile, DMAP1 was highly phosphorylated at Tyr 246 by c-Src in pancreatic cancer cells, which impedes DMAP1/Bub3 interaction and the relevant cellular activites. Blocking DMAP1 pTyr-246 potentiates paclitaxel-inhibited tumor growth. Clinically, DMAP1 Tyr 246 phosphorylation correlates with c-Src activity in human pancreatic cancer specimens and poor prognosis in pancreatic cancer patients.

Conclusions

Our findings reveal a regulatory role of Bub3 in DMAP1-mediated DNA methylation upon mitotic stress and provide the relevance of DMAP1 pTyr-246 to mitotic stress resistance during pancreatic cancer treatment.

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Playing Super Mario increases oculomotor inhibition and frontal eye field grey matter in older adults

Abstract

Aging is associated with cognitive decline and decreased capacity to inhibit distracting information. Video game training holds promise to increase inhibitory mechanisms in older adults. In the current study, we tested the impact of 3D-platform video game training on performance in an antisaccade task and on related changes in grey matter within the frontal eye fields (FEFs) of older adults. An experimental group (VID group) engaged in 3D-platform video game training over a period of 6 months, while an active control group was trained on piano lessons (MUS group), and a no-contact control group did not participate in any intervention (CON group). Increased performance in oculomotor inhibition, as measured by the antisaccade task, and increased grey matter in the right FEF was observed uniquely in the VID group. These results demonstrate that 3D-platform video game training can improve inhibitory control known to decline with age.

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Interaction of H. pylori with toll-like receptor 2-196 to -174 ins/del polymorphism is associated with gastric cancer susceptibility in southern China

Abstract

Background

Genetic polymorphisms of Toll-like receptors play important roles in gastric carcinogenesis. The aim of this study was to determine the role of TLR2-196 to -174 ins/del polymorphism in gastric cancer susceptibility and prognosis.

Methods

This study included 520 people from southern China. Samples were genotyped by the allele-specific polymerase chain reaction, among which 10% were randomly selected for sequencing. The serological method was used to determine Helicobacter pylori.

Results

The TLR2 genotype was not associated with the risk of H. pylori infection. The del/del genotype exhibited significantly higher gastric cancer risk (adjusted OR 2.59, 95% CI 1.33‒5.07) than that of the ins/ins genotype. Further stratification analyses demonstrated that the del/del genotype was associated with a risk of intestinal gastric cancer (adjusted OR 2.62, 95% CI 1.34–5.14). In addition, the presence of the del/del genotype and the H. pylori infection conferred a synergistic effect (OR 3.04, 95% CI 1.33‒6.98) for the development of gastric cancer. The del/del genotype was not associated with a poor prognosis in gastric cancer patients.

Conclusion

The del/del genotype is associated with an increased gastric cancer risk in the southern Chinese population. However, TLR2 polymorphism is neither associated with H. pylori infection, nor with a poor prognosis.

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Bidirectional ventricular tachycardia due to hypokalaemia

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Primary mural infective endocarditis with associated central line infection

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Late onset of dropped head syndrome following mantle radiation therapy for Hodgkin lymphoma

Dropped head syndrome (DHS) is a rare condition, characterised by weakness of the cervical paraspinal muscles with sagging of the head. It is usually seen in association with neurological disorders and rarely can follow radiotherapy. We report a case of a 54-year-old man survivor of Hodgkin lymphoma (HL), who developed DHS 28 years after radiotherapy. He was referred to our department due to progressive weakness and atrophy of cervical paraspinal and shoulder girdle musculature. Physical and neurophysiological examination, electromyography and MRI confirmed the diagnosis of DHS. In the following years, there was no progression of symptoms.

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Single right coronary artery with congenital absence of left coronary system

Single coronary artery (SCA) is a very rare coronary anomaly. The accurate diagnosis of the entity requires multimodality imaging of the coronary anatomy. SCA is often incidentally diagnosed when patients are investigated for symptoms of suspected coronary artery disease with invasive or non-invasive coronary angiography. There are no established diagnostic electrocardiographic or echocardiographic criteria to identify the presence of SCA, which makes the diagnosis a far-reaching fruit. We present a young male patient presenting with a non-ST elevation myocardial infarction. He was found to have SCA on invasive coronary angiography, which was subsequently confirmed by CT coronary angiography.

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MRI of radial cutaneous nerve abscess in recurrent neural leprosy

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Pericardial effusion as a complication of chronic graft versus host disease

A 24-year-old man with previous matched unrelated donor allogenic bone marrow transplant for aplastic anaemia and chronic graft versus host disease on steroid taper presented with progressively worsening anasarca. CT revealed large pericardial effusion, while echocardiogram was concerning for early tamponade physiology. He underwent emergent pericardiocentesis with pericardial drain placement. Extensive rheumatological and infectious work-up was unrevealing with patient's presentation attributed to pericardial graft versus host disease. This highlights the need of physicians to be aware of pericardial serositis as a complication of graft versus host disease due to its life-threatening complications, which require immediate intervention.

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Central serous retinopathy as presentation of an adrenal adenoma

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Catatonia due to alprazolam withdrawal

A 50-year-old man with multiple psychiatric comorbidities including major depressive disorder and general anxiety disorder presented to the emergency room (ER) with altered mental status, immobility and mutism. The patient was unresponsive to commands and unable to provide any history. In the ER he was given a provisional diagnosis of cerebrovascular accident (CVA). Vital signs on admission were stable. On physical examination, he exhibited grimacing, muscle rigidity and areflexia. Workup for CVA and infectious aetiology was unremarkable and the patient's urine toxicology screen was negative. History from the patient's family revealed that 4 days prior to presentation, the patient had discontinued his prescribed dose of alprazolam 1 mg four times per day. The patient was diagnosed with catatonia due to benzodiazepine withdrawal and had gradual return to baseline with administration of lorazepam 1 mg intravenous three times per day.

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Dexmedetomidine-assisted drug interviews: an observation in psychiatric setting

Drug-assisted interviews are an effective tool in the management of various psychiatric illnesses where psychopharmacological, as well as routine psychological interventions, do not prove beneficial. These have most commonly been done by using barbiturates and benzodiazepines that have given favourable results for a long time. However, they carry the risk of respiratory depression and difficulty in maintaining the plane of sedation where the patient is amenable to interviewing. In our experience of drug-assisted interviews with two patients we used intravenous dexmedetomidine, which is being used in anaesthesia practice for conscious sedation or sedation in the intensive care unit. We found dexmedetomidine to be superior to thiopentone in achieving a level of conscious sedation where the patients were amenable for an interview, with no significant adverse events and faster post-anaesthetic recovery.

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Anaphylaxis after treatment with recombinant factor VIII: investigation and therapeutic challenge

We report a 10-year-old patient with haemophilia A developing anaphylaxis to recombinant factor VIII (octocog alfa). Allergic reactions, and especially anaphylactic events, are rare in patients with haemophilia A. The nature of these reactions is not fully understood. Here, we demonstrate a type I hypersensitivity reaction using sodium dodecyl sulfate-polyacrylamide gel electrophoresis immunoblotting assay. This test revealed itself as an essential diagnostic tool, as it allowed us to choose an alternative treatment (moroctocog alfa). Its safety was later confirmed by an uneventful challenge test.

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Exogenous steroid-induced hypoadrenalism in a person living with HIV caused by a drug-drug interaction between cobicistat and intrabursal triamcinolone

We report a diagnosis of exogenous steroid-induced hypoadrenalism in a person living with HIV caused by a drug–drug interaction (DDI) between intrabursal triamcinolone and the pharmacokinetic booster cobicistat. A 53-year-old woman living with HIV, managed with dolutegravir and cobicistat-boosted darunavir, presented to the orthopaedic clinic with worsening hip pain. She was diagnosed with greater trochanteric pain syndrome (GTPS) of the hip and was treated with intrabursal injection of bupivacaine and triamcinolone. Seven days following this injection, she presented with Cushingoid features, an undetectable cortisol and was diagnosed with exogenous steroid-induced hypoadrenalism. Cobicistat is a cytochrome P450 3A inhibitor and in this case inhibited clearance of intrabursal triamcinolone, leading to exogenous glucocorticoid excess and adrenal suppression. This is the first report to describe this predictable DDI with cobicistat following intrabursal glucocorticoid injection. This case highlights the complexities in managing non-HIV-related chronic morbidities in people living with HIV.

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Perivascular tumour balls in primary vitreoretinal lymphoma

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Thyroid storm: a case of haemodynamic failure promptly reversed by aggressive medical therapy with antithyroid agents and steroid pulse

Hyperthyroidism is a common metabolic disorder, although its presentation as an endocrine emergency called thyroid storm is rare. Here we review a case of a thyroid storm as the initial presentation of thyrotoxicosis, with multiple organ failure and haemodynamic collapse due to low-output cardiac dysfunction. Quick intervention with aggressive antithyroid therapy, including steroid pulse, and supportive intensive care measures led to an outstanding improvement and full recovery. The present case clearly shows the beneficial impact of initial clinical suspicion resulting in an early diagnosis and intensive therapy. Moreover, it supports the additional role of steroids to aggressive antithyroid strategy in order to control associated deleterious systemic inflammatory reactions.

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Case of a missed airway stent migration

This case report describes a rare complication to stent management of airway compression. An 84- year-old man was admitted to the outpatient clinic with haemoptysis, cough and dyspnoea. A CT scan showed an intraluminal, non-occluding tumour close to the right side of the main carina. A stent was inserted in the right main bronchus. The patient was, 7 months later, admitted to the emergency room with severe cough and dyspnoea. The stent was produced during a coughing spell. Retrospective investigation of available imaging revealed that the stent had been dislodged to a nearly 'perfect' position in the left main bronchus several months earlier which, however, had not been noticed and thus not reported by the radiologist describing the CT. The possibility of a right-left confusion should always be kept in mind, especially if a patient presents with renewed symptoms that should have been managed successfully.

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Metastatic adenocarcinoma of mandible: in search of the primary

We present here a case of a 64-year-old female patient who reported with a complaint of pain in the chin region of 3-month duration. The radiographs revealed an irregular radiolucent lesion in the anterior part of the mandible. An incisional biopsy was carried out and the microscopy showed features of adenocarcinoma. Suspecting a metastatic lesion, the patient was then sent for whole body examination which showed a mass in the lungs. A whole body scan also showed metastasis to other organs such as kidney, gallbladder and vertebrae. This case is unusual in that the patient complained only of a vague jaw pain with no other systemic symptoms even in the presence of widespread disease.

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Giant juvenile papillomatosis of the breast in a Nigerian girl

Juvenile papillomatosis is a benign epithelial proliferative tumour of young women. It was recognised as a distinct clinicopathological entity with defining criteria by Rosen et al since 1980. However, giant juvenile papillomatosis is rare. We report a case of a 14-year-old girl who presented to our institution's breast clinic with a huge right breast mass measuring 20 cm x 15 cm. She had no personal history of previous breast disease and there was no family history of breast cancer. Our initial preoperative diagnosis was of a phylloides tumour. The patient had a total excision of her breast mass which revealed florid juvenile papillomatosis at histology. This presentation highlights the clinical presentation and imaging features of juvenile papillomatosis. The classical histopathological characteristics, unusual microscopic findings and management of a huge-sized tumour in an adolescent Nigerian patient are also presented.

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Unusual case of cellulitis due to primary cutaneous histoplasmosis

A 63-year-old white man with a history of rheumatoid arthritis on adalimumab was admitted to the hospital for left arm swelling and erythema. On physical examination, the patient was afebrile and non-toxic appearing and there was tense oedema of the left forearm. Initial laboratory work was unremarkable except for elevated inflammatory markers. MRI of the arm showed non-specific findings of inflammation. The patient was started on empiric antibiotics but did not improve. Given the patient's immunosuppression, early consideration was given to fungal or mycobacterial causes. Initial serum fungal studies were negative and the patient was taken for diagnostic local incision and biopsy of the left volar forearm. Grocott's methenamine silver and periodic acid–Schiff staining revealed fungal organisms resembling Histoplasma and intraoperative fungal cultures grew Histoplasma capsulatum confirming the diagnosis. The patient was treated with a 6-month course of itraconazole with improvement in his condition and eventual complete resolution.

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Haemostatic radiation therapy for a bleeding intraductal papillary neoplasm of the biliary tree

Haemostatic radiation was effectively used as a novel rescue therapy in a 60-year-old man who presented with recurrent melaena refractory to all conventional medical and surgical measures. He needed multiple transfusions and was diagnosed to be bleeding from an intraductal papillary biliary neoplasm which was not amenable to surgical resection in view of the background liver disease. He received conventional radiation therapy (RT) of a dose of 3 Gy per fraction for 3 consecutive days after which he stabilised. After cessation of the RT, he did not require transfusion for the next 2 months. His quality of life improved and it gave us time to evaluate for other definitive measures.

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Welcome to the 15th volume of Future Oncology

Future Oncology, Volume 15, Issue 1, Page 3215-3217, January 2019.


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Nilotinib in the treatment of chronic myeloid leukemia

Future Oncology, Ahead of Print.


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Cytohistological correlation, immunohistochemistry and Murine Double Minute Clone 2 amplification of pulmonary artery intimal sarcoma: A case report with review of literature

Pulmonary artery intimal sarcoma is a rare aggressive intraluminal tumor often misdiagnosed as acute or chronic pulmonary thromboembolism due to its clinical presentation and radiological findings. Thus early diagnosis is very crucial and may improve patient outcome. There is limited literature on diagnosis of pulmonary artery sarcoma by endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA). Herein, we report a case of mass‐like lesion in the PA diagnosed on cytological material obtained by EBUS‐TBNA with rapid on‐site evaluation (ROSE). The aspirate showed pleomorphic malignant spindled cells arranged in loosely cohesive clusters. The intraluminal origin of PAIS was supported by radiographic findings. Subsequently, the patient received preoperative chemotherapy and underwent tumor resection with reconstruction. This report describes the cytomorphologic features of this rare intravascular tumor and demonstrates how limited cytological sample obtained from EBUS‐TBNA with ROSE can be triaged efficiently for ancillary studies like immunohistochemistry and MDM2 amplification, thus expediting the management.

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Pleomorphic and atypical multinucleated giant cells in solid pseudopapillary neoplasm of pancreas: A diagnostic pitfall in cytology and a review of the literature

Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare low‐grade malignancy typically occurring in young women. Occasionally, these neoplasms present with pleomorphic to atypical multinucleated giant tumor cells which may mimic high‐grade malignancy. Our patient is a 25‐year‐old male who presented with one year of intermittent epigastric pain. Magnetic resonance imaging showed a 3.1 × 2.5 cm mass in the pancreas body. Endoscopic ultrasound‐guided fine needle aspiration of the mass showed large pleomorphic cells and atypical multinucleated giant cells in a background of singly scattered polygonal cells. Focally, these cells surrounded delicate hyalinized to fibrovascular cores forming pseudopapillae. Immunohistochemical stains show tumor cells are positive for beta‐catenin, CD10, vimentin, and CD56. Although rare surgical pathology publications have described the presence of pleomorphic to atypical multinucleated giant cells occurring in SPN, to our knowledge, this is the first case reported example focused on cytomorphologic illustration and description.

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Thyroid imaging reporting and data system (TI‐RADS) of the American College of Radiology (ACR) for predicting malignancy in thyroid nodules >1 cm with indeterminate cytology

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Mannose Inhibits Tumor Growth and Increases Tumor Chemosensitivity [Research Watch]

The monosaccharide mannose inhibits tumor glycolysis and enhances tumor response to chemotherapy.

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Transcription Factor Motif Density Can Confer Transcriptional Addiction [Research Watch]

ZFP64 binds to the MLL promoter and is essential for the growth of MLL-rearranged leukemia cells.

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The E3 Ligase FBXO38 Controls PD-1 Expression and Antitumor Immunity [Research Watch]

Regulation of PD-1 protein degradation by FBXO38 is necessary for T-cell antitumor activity.

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Truxima Gets High Marks from Physicians [News in Brief]

Doctors will likely prescribe first rituximab biosimilar, but say cost will be deciding factor.

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Early PT Linked to Less Opioid Use in Musculoskeletal Pain

FRIDAY, Dec. 14, 2018 -- For patients with musculoskeletal pain, early physical therapy is associated with reduced subsequent opioid use, according to a study published online Dec. 14 in JAMA Network Open. Eric Sun, M.D., Ph.D., from the Stanford...

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Phone-Based Intervention Aids Rheumatoid Arthritis Care

FRIDAY, Dec. 14, 2018 -- A nurse-based phone education intervention can promote shared decision making in patients with newly diagnosed rheumatoid arthritis (RA), according to a study published online Dec. 5 in Musculoskeletal Care. Siobhan Farley,...

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Apixaban Prevents VTE in Cancer Patients Initiating Chemotherapy

FRIDAY, Dec. 14, 2018 -- Among patients with cancer starting chemotherapy who are at intermediate-to-high risk, rates of venous thromboembolism are significantly lower for thromboprophylaxis with apixaban versus placebo, according to a study...

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Post-Inflammatory Polyps Not Linked to Colorectal Neoplasia

FRIDAY, Dec. 14, 2018 -- For patients with inflammatory bowel disease (IBD), post-inflammatory polyps (PIPs) are associated with greater severity and extent of colon inflammation and higher rates of colectomy, but not with development of colorectal...

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Emotional Stress of Holidays Can Trigger Heart Attacks

FRIDAY, Dec. 14, 2018 -- The highest risk for myocardial infarction occurs around 10 p.m. on Christmas Eve, according to a study published online Dec. 12 in The BMJ. Moman A. Mohammad, from Lund University in Sweden, and colleagues analyzed data...

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Single Subject Designs and Practice-Based Research in Palliative Care: A Letter to the Editor

Randomized controlled trials (RCTs) have advanced pain and symptom management in the context of chronic illnesses, and are regarded as the ideal designs to guard against threats to internal validity. These designs also enable researchers to obtain unbiased estimates of intervention effects compared to control conditions. However, overreliance on RCTs may stifle research progress if resources are limited, clinically meaningful differences are small, or participants differ from those who do not consent, are excluded, or leave the study prior to completion.

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Validation of Diagnostic and Performance Characteristics of the Wireless Motility Capsule in Patients With Suspected Gastroparesis

It is a challenge to make a diagnosis of gastroparesis. There is good agreement in results from wireless motility capsule (WMC) analysis and gastric emptying scintigraphy (GES), but the diagnostic yield of WMC is unclear and the accuracy of this method has not been validated. We compared the performance characteristics of WMC vs GES in assessing gastric emptying in patients with suspected gastroparesis.

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Jaccoud’s Arthropathy and Jaundice in a Young Female

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Prevalence of Germline Mutations in Polyposis and Colorectal Cancer-associated Genes in Patients With Multiple Colorectal Polyps

Guidelines recommend genetic testing of patients with 10 or more cumulative adenomatous polyps. However, little is known about the utility of these tests—especially for older patients. We aimed to determine the prevalence of pathogenic mutations in patients with multiple colorectal polyps, stratified by age.

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Measurement of Observed Eating Behaviors in Patients with Active and Inactive Eosinophilic Esophagitis

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Metal Biliary Stents in Benign Disease

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Pruritus is Common and Under-treated in Patients with Primary Biliary Cholangitis in the United Kingdom

Little is known about the prevalence or treatment of pruritus associated with primary biliary cholangitis (PBC). We analyzed data from patients with PBC recruited from all clinical centers in the United Kingdom (UK) to characterize the prevalence, severity, progression, and treatment of pruritus.

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Insurance Approval for Proton Beam Therapy and its Impact on Delays in Treatment

This study is the first to comprehensively assess the state of prior authorization (PA) for proton beam therapy (PBT). The majority of adults who require PA are initially denied and subsequently experience significant care delays. We found no clinical characteristics that predicted insurance approval for PBT. Insurers have not provided coverage for patients on randomized clinical trials to generate high-quality evidence for PBT and have not adopted clinical practice guidelines to guide their coverage decisions.

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Early toxicity of a phase II trial of combined salvage radiotherapy and hormone therapy in oligometastatic pelvic node relapses of prostate cancer (OLIGOPELVIS GETUG P07)

Limited pelvic nodal relapse of prostatic cancer is a paramount challenge for locoregional salvage treatments. Salvage whole pelvis radiotherapy as considered in the BLINDED trial, is an attractive option but with concerns about its toxicity. This article describes early toxicity with the technique.

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Mechanistic modelling of Radium-223 treatment of bone metastases

Despite the reported effectiveness of 223RaCl2 for treatment of bone metastases, many questions remain regarding its dosimetry and pharmacodynamics. This study models three different 223RaCl2 uptake scenarios, comparing their predictions of time to first symptomatic skeletal event to published clinical data. Our results suggest that approaches which assume a uniform biodistribution of 223Ra throughout metastatic sites do not accurately predict biological effects of α-radionuclide therapies, with exposure of small sub-populations providing superior agreement with clinical data.

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Deforestation impacts network co-occurrence patterns of microbial communities in Amazon soils

ABSTRACT

Co-occurrence networks allow for the identification of potential associations among species, which may be important for understanding community assembly and ecosystem functions. We employed this strategy to examine prokaryotic co-occurrence patterns in the Amazon soils and the response of these patterns to land use change to pasture, with the hypothesis that altered microbial composition due to deforestation will mirror the co-occurrence patterns across prokaryotic taxa. In this study, we calculated Spearman correlations between operational taxonomic units (OTUs) as determined by 16S rRNA gene sequencing, and only robust correlations were considered for network construction (−0.80 ≥ P ≥ 0.80, adjusted P < 0.01). The constructed network represents distinct forest and pasture components, with altered compositional and topological features. A comparative analysis between two representative modules of these contrasting ecosystems revealed novel information regarding changes to metabolic pathways related to nitrogen cycling. Our results showed that soil physicochemical properties such as temperature, C/N and H⁺+Al³⁺ had a significant impact on prokaryotic communities, with alterations to network topologies. Taken together, changes in co-occurrence patterns and physicochemical properties may contribute to ecosystem processes including nitrification and denitrification, two important biogeochemical processes occurring in tropical forest systems.

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Spruce and beech as local determinants of forest fungal community structure in litter, humus and mineral soil

ABSTRACT

Beech forests reaches its native distribution limit in SE Norway, but is expected to expand substantially northwards due to climate warming. This may potentially result in a fundamental transformation of contemporary Northern European forests, with tentative effects on the associated belowground fungi. Fungal communities mediate vital ecosystem processes such as ecosystem productivity and carbon sequestration in boreal forests. To investigate how soil fungi is affected by the vegetation transition from spruce to beech forest, we sampled litter, humus and mineral soil in a forest landscape dominated by beech, spruce or a mixture of these. The fungal communities in the soil samples were analyzed by DNA metabarcoding of the rDNA ITS2 region. Although soil layers were the most important structuring gradient, we found clear differences in fungal species composition between spruce and beech plots. The differences in fungal community composition were most evident in the litter and least in the mineral soil. Decomposers, most notably Mycena, dominated the litter layer while various mycorrhizal fungi dominated the humus and mineral layers. Some ectomycorrhizal taxa, such as Cenoccocum and Russula, were more abundant in spruce forests. Differences in fungal community composition between forest types can potentially have large impacts on carbon sequestration rates.

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Genomic insights into the metabolism of ‘Candidatus Defluviicoccus seviourii’, a member of Defluviicoccus cluster III abundant in industrial activated sludge

ABSTRACT

Filamentous cluster III Defluviicoccus (DF3) are known to proliferate and cause bulking issues in industrial wastewater treatment plants. Members of the genus Defluviicoccus are also known to exhibit the glycogen accumulating organism (GAO) phenotype, which is suggested to be detrimental to enhanced biological phosphorus removal (EBPR). Despite the reported negative impact members of the DF3 have on activated sludge wastewater treatment systems, limited research has focused on understanding the physiological traits that allow them to compete in these environments. In this study, a near complete genome of an abundant filamentous DF3 named 'Candidatus Defluviicoccus seviourii' was obtained from a full-scale sequencing batch reactor (SBR) treating winery wastewater. Annotation of the 'Ca. D. seviourii' genome revealed interesting metabolic features that help to understand the abundance of this microorganism in industrial wastewater treatment plants. Their potential for the storage of polyhydroxyalkanoates (PHA) is suggested to favour these organisms with the intermittent availability of carbon in these systems. An ability to fix nitrogen and take up urea may provide them with an additional advantage with the characteristically high carbon to nitrogen content of industrial waste. The genome and preliminary findings of this study provide a foundation for further research into these biotechnologically relevant organisms.

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Nitrogen availability facilitates phosphorus acquisition by bloom-forming cyanobacteria

ABSTRACT

Cyanobacterial blooms are threatening freshwater ecosystems. The physiological basis involved in the onset of cyanobacterial bloom is fundamental to advance in bloom predictions. Generally, cyanobacteria grow until the availability of nitrogen (N), phosphorus (P) or both nutrients becomes limited. Population survival may depend on physiological adjustments to nutrient deficiency as well as on the efficient use of episodic N and P inputs. This study investigated the effect of N inputs on phosphate uptake affinity and activity of N-deficient bloom-forming cyanobacteria. Lake samples dominated by filamentous cyanobacteria were preincubated with and without nitrate addition, and the uptake of [³²P] phosphate pulses was measured in the following days. Phosphate uptake kinetics were analyzed with a flow-force model that provides the threshold concentration, reflecting phosphate uptake affinity, and the membrane conductivity coefficient that corresponds to the activity of uptake systems. After 24 h of nitrate preincubation, phosphate uptake kinetics showed a progressive increase in affinity (nanomolar [P_e]_A) and activity (25-fold) concomitant with cyanobacterial growth. It was demonstrated that the alleviation of N-deficiency by N inputs boosts the activation of phosphate uptake systems of non-N₂-fixing cyanobacteria to sustain growth. Therefore, reduction of dissolved inorganic N levels in lakes is also mandatory to limit cyanobacterial phosphate uptake affinity and activity capabilities.

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Children less than 2 with Down syndrome and suffering from respiratory syncytial virus have a longer and more costly hospitalization

In regard to the article by Mitra et al, we would like to provide additional data.1 We used the 2016 Kids' Inpatient Database developed for the Healthcare Cost and Utilization Project by the Agency for Healthcare Research and Quality, which captures admission data from more than 2000 hospitals in the United States.2 We separated further all cases to limit the admission age to less than 2 years. The International Classification of Diseases, 10th Revision, Clinical Modification codes for respiratory syncytial virus and Down syndrome were also applied.

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Assessment of hemodynamic parameters in the assessment of a patent ductus arteriosus: It is still a puzzle

de Freitas et al showed in their retrospective study that a nonindexed ductal diameter demonstrated the best correlation with transductal shunt volume, whereas weaker associations were seen between a ductal diameter indexed to weight and indexed to left pulmonary artery diameter.1 Overall, 104 neonates born preterm with a gestational age of <30 weeks were examined with targeted echocardiography evaluation of a patent ductus arteriosus (PDA) performed between 7 and 30 days of life. The best correlation was found with markers of systemic hypoperfusion, such as diastolic flow reversal in the descending aorta and celiac artery, whereas markers of pulmonary overcirculation (left ventricular end-diastolic diameter and left ventricular output) showed only fair correlation with nonindexed ductal diameter.

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Lung Function in Infants with Sickle Cell Anemia

Lung volumes and forced expiratory flows were evaluated in 22 infants with sickle cell anemia and compared with a control group. Forced expiratory flows showed significantly lower values in the sickle cell group. The majority of infants had normal lung function, and obstruction was the most common pattern of abnormality.

https://ift.tt/2EsDVqs

Prevalence of Nonalcoholic Fatty Liver Disease in Children with Obesity

To determine the prevalence of nonalcoholic fatty liver disease (NAFLD) in children with obesity because current estimates range from 1.7% to 85%. A second objective was to evaluate the diagnostic accuracy of alanine aminotransferase (ALT) for NAFLD in children with obesity.

https://ift.tt/2EsDUTq

Casting New Light on Hand-Foot-and-Mouth Disease

A 3-year-old boy presented to the emergency department for evaluation of 4 days of rash associated with fever and cough. The rash began as a few pink bumps on the right forearm, at the site where a cast had been removed the day prior after 1 month of immobilization for a greenstick fracture, and progressed over the next few days to involve the perioral face, groin, buttocks, and bilateral arms, hands, and feet. He was seen by a dermatologist and referred to the emergency department out of concern for erythema multiforme.

https://ift.tt/2EiI6nQ

Reply

We appreciate the interest in our recent report and the critiques offered by Madenci et al, but we respectfully disagree with their assertions. Although "regression to the mean" is certainly a valid concept in population studies, it is not applicable in a study of a subset of 17 infants with extreme, life-threatening pulmonary hypertension. These infants represent the outliers in the cohort of 164 infants with congenital diaphragmatic hernia described in our study. The extraordinarily high mortality associated with severe, persistent pulmonary hypertension in infants with congenital diaphragmatic hernia1-3 indicates that this type of pulmonary hypertension does not regress, to the mean or otherwise.

https://ift.tt/2EvakwI

Time versus treatment: interpreting longitudinal data analysis of treprostinil

In a longitudinal analysis of observational data, Lawrence et al evaluated neonates with congenital diaphragmatic hernia (CDH) who received treprostinil for the treatment of pulmonary hypertension.1 Pulmonary hypertension drives CDH-related mortality,2 and careful study of therapeutic advancements is critical. However, this analysis may lead clinicians to adopt treprostinil before its risks and benefits have been delineated. We believe that several factors preclude the interpretation in the title that treprostinil improves persistent pulmonary hypertension associated with CDH.

https://ift.tt/2EnBZyT

Nutritional, Socioeconomic, and Delivery Characteristics Are Associated with Neurodevelopment in Tanzanian Children

To evaluate the hypothesis that various maternal, socioeconomic, delivery, and infant nutritional characteristics are associated with early childhood development in young Tanzanian children.

https://ift.tt/2EmbABi

Allostasis and the Clinical Manifestations of Mild to Moderate Chronic Hyponatremia: No Good Adaptation Goes Unpunished

When homeostatic regulatory systems are unable to maintain a normal serum sodium concentration, the organism must adapt to demands of a disordered internal environment, a process known as "allostasis." Human cells respond to osmotic stress created by an abnormal serum sodium level with the same adaptations used by invertebrate organisms that do not regulate body fluid osmolality. To avoid intolerable changes in their volume, cells export organic osmolytes when exposed to a low serum sodium concentration and accumulate these intracellular solutes when serum sodium concentration increases.

https://ift.tt/2QS5wr3

Drug Combination May Target the Unique Metabolism of Leukemia Stem Cells

Two new studies show how the drugs venetoclax (Venclexta) and azacitidine (Vidaza) team up to block the unique metabolism of leukemia stem cells and may explain why the drug combination is effective against acute myeloid leukemia.

https://ift.tt/2rC2Qzx

https://ift.tt/2Eu5T5j

Low dietary diversity and associated factors among lactating mothers in Angecha districts, Southern Ethiopia: community based cross-sectional study

The objective of the study was to assess prevalence low dietary diversity and associated factors among lactating mother in Angecha district, Southern Ethiopia.

https://ift.tt/2BhYGkD

Determinants of burnout syndrome among nurses in Cameroon

Burnout syndrome is common amongst medical personnel. The objective of this study was to identify determinants of burnout syndrome among nurses in the north west and south west regions of Cameroon.

https://ift.tt/2UKuyr5

A neural network analysis of Lifeways cross-generation imputed data

Neural networks are a powerful statistical tool that use nonlinear regression type models to obtain predictions. Their use in the Lifeways cross-generation study that examined body mass index (BMI) of children...

https://ift.tt/2BgQlO4

Preparation of lyophilized recombinant prion protein for TSE diagnosis by RT-QuIC

Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases, often referred as prion diseases. TSEs result from the misfolding of the cellular prion protein (PrPC) into a path...

https://ift.tt/2UNTGgu

The development of a survey instrument to measure the barriers to the conduct and application of research in complementary and alternative medicine: a Delphi study

As Complementary and Alternative medicine (CAM) grows in popularity, there is overt recognition for research evidence to inform clinical practice. While various strategies have been trialed to overcome the bar...

https://ift.tt/2rBKUFl

Exploring mental health practice among Traditional health practitioners: a qualitative study in rural Kenya

Involvement of traditional health practitioners (THPs) in the form of collaboration with the formal health care system is suggested to improve the pathways to mental health care in Kenya, yet understanding of ...

https://ift.tt/2GjewkS

Guidelines Developed for Opioid Use in Vaginal Birth

FRIDAY, Dec. 14, 2018 -- Guidelines have been developed for use of opioids for uncomplicated spontaneous vaginal birth; the draft consensus guidelines were published online Dec. 4 in Obstetrics & Gynecology. J. Rebecca Mills, Dr.P.H., from the...

https://ift.tt/2zYji1o

Medication Beliefs Affect Uptake of Preventive Tx for Breast Cancer

FRIDAY, Dec. 14, 2018 -- Beliefs about medication are associated with uptake of tamoxifen as a preventive therapy among women at increased risk for breast cancer, according to a study published online Dec. 2 in Clinical Breast Cancer. Rachael Jane...

https://ift.tt/2zVN7zF

BMI May Mediate Inverse Link Between Fiber Intake, Knee OA

FRIDAY, Dec. 14, 2018 -- The inverse association between fiber intake and the risk for incident symptomatic knee osteoarthritis may be partially mediated by body mass index, according to a study published in the December issue of The Journal of...

https://ift.tt/2PDv9XY

Persistent Discrimination ID'd Among Physician Mothers

FRIDAY, Dec. 14, 2018 -- Physician mothers experience discrimination in a range of ways, which can impact the medical profession, according to a study published online Dec. 12 in The BMJ. Meghan C. Halley, Ph.D., M.P.H., from the University of...

https://ift.tt/2A0kgdQ

T2DM Linked to Decline in Verbal Memory, Fluency in Older Adults

FRIDAY, Dec. 14, 2018 -- Type 2 diabetes is associated with declines in verbal memory and fluency among older community-dwelling adults, according to a study published online Dec. 13 in Diabetologia. Michele L. Callisaya, Ph.D., from the University...

https://ift.tt/2PDNhRl

Depressive Symptoms Up From Age 10 for Sexual-Minority Youth

FRIDAY, Dec. 14, 2018 -- Sexual-minority youth have higher depressive symptoms at age 10 and an increased likelihood of self-harm in adolescence and young adulthood, according to a study published online Dec. 11 in The Lancet Child & Adolescent...

https://ift.tt/2A1EROL

Racial Disparities Seen Among Teens Undergoing Flu Vaccination

FRIDAY, Dec. 14, 2018 -- Racial disparities exist among adolescents undergoing influenza vaccination, with lower odds of vaccination among black versus white adolescents, according to a study recently published in Public Health Reports. Noah S....

https://ift.tt/2PAz2g5

Certain Sites of Brain Lesions in MS Tied to Bowel Incontinence

FRIDAY, Dec. 14, 2018 -- Specific locations of cerebral multiple sclerosis lesions appear to be associated with bowel incontinence, according to a study published online Dec. 11 in the Journal of Neuroimaging. Kilian Frohlich, M.D., from the...

https://ift.tt/2PDU3qa

Subfertility Linked to Increased Asthma Risk in Offspring

FRIDAY, Dec. 14, 2018 -- Parental subfertility is associated with an increased asthma risk among offspring, according to a study published online Dec. 4 in Thorax. Maria Christine Magnus, Ph.D., from the Norwegian Institute of Public Health in Oslo,...

https://ift.tt/2zWMx52

EHR-Linked Reminder System for Glaucoma Meds Perceived Useful

FRIDAY, Dec. 14, 2018 -- Patients with glaucoma generally find an electronic health record (EHR)-linked reminder system for glaucoma medications useful, according to a study published online Dec. 13 in JAMA Ophthalmology. Varshini Varadaraj,...

https://ift.tt/2PDo2Pb

SIU-ICUD consultation on bladder cancer: basic science.

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SIU-ICUD consultation on bladder cancer: basic science.

World J Urol. 2018 Dec 13;:

Authors: McConkey DJ, Lerner SP

Abstract
PURPOSE: To provide a condensed summary of the Basic Science chapter that was included in the Third International Consultation on Bladder Cancer.
METHODS: World bladder cancer basic science experts used the published literature to create summaries of recent progress in their areas of expertise.
RESULTS: The completion of several large-scale genomics projects coupled with a strong collaborative culture within the research community and the exciting clinical activity of immune checkpoint blockade have combined to transform the bladder cancer research landscape. Bladder cancer molecular subtypes and the presence of specific DNA alterations provide important information about disease heterogeneity that has direct implications for clinical management, and some can be targeted by compounds that are already clinically available. Tests are being developed that can measure many of these alterations non-invasively in peripheral blood or urine, raising confidence that they could be used as biomarkers for surveillance and monitoring the effects of local and systemic therapies.
CONCLUSIONS: Although the bulk of the mechanistic work lies ahead, the genomics results have created a hypothesis-generating description of bladder cancer heterogeneity that has set the stage for deeper mechanistic studies, and they have already provided us with extremely attractive candidate biomarkers to guide clinical practice. Here, we will summarize the recent progress in basic bladder cancer research and highlight near-term opportunities for the future.

PMID: 30547196 [PubMed - as supplied by publisher]

https://ift.tt/2rEacSU

The concerted roles of FANCM and Rad52 in the protection of common fragile sites.

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The concerted roles of FANCM and Rad52 in the protection of common fragile sites.

Nat Commun. 2018 07 18;9(1):2791

Authors: Wang H, Li S, Oaks J, Ren J, Li L, Wu X

Abstract
Common fragile sites (CFSs) are prone to chromosomal breakage and are hotspots for chromosomal rearrangements in cancer cells. We uncovered a novel function of Fanconi anemia (FA) protein FANCM in the protection of CFSs that is independent of the FA core complex and the FANCI-FANCD2 complex. FANCM, along with its binding partners FAAP24 and MHF1/2, is recruited to CFS-derived structure-prone AT-rich sequences, where it suppresses DNA double-strand break (DSB) formation and mitotic recombination in a manner dependent on FANCM translocase activity. Interestingly, we also identified an indispensable function of Rad52 in the repair of DSBs at CFS-derived AT-rich sequences, despite its nonessential function in general homologous recombination (HR) in mammalian cells. Suppression of Rad52 expression in combination with FANCM knockout drastically reduces cell and tumor growth, suggesting a synthetic lethality interaction between these two genes, which offers a potential targeted treatment strategy for FANCM-deficient tumors with Rad52 inhibition.

PMID: 30022024 [PubMed - indexed for MEDLINE]

https://ift.tt/2NrDZaz

Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study

Abstract

Introduction

Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus^®) has not been compared with PR-Tac (Advagraf^®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations.

Methods

This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations.

Results

PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (t_max), lower maximum concentration (C_max) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar.

Conclusion

In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac.

Trial registration

Registered at ClinicalTrials.gov; study number NCT02500212.

Funding

Chiesi Farmaceutici S.p.A.

https://ift.tt/2rDqaNs

Basal ganglia hemorrhage in a case report following spinal surgery

Intracranial hemorrhage is a rare but potentially severe complication of spinal surgery. Most reported post-operative ICH cases consist of cerebellar hemorrhage. There are fewer reported cases of supratentoria...

https://ift.tt/2BiWoC3

Using automated electronic medical record data extraction to model ALS survival and progression

To assess the feasibility of using automated capture of Electronic Medical Record (EMR) data to build predictive models for amyotrophic lateral sclerosis (ALS) outcomes.

https://ift.tt/2UM1v6p

Family surprises dispatcher who saved dad’s life

Two years after Stephanie Cifuentes helped save a man by giving CPR instructions, the family surprised her by coming to say "thank you"

https://ift.tt/2GiZlrU

Therapeutic potentials of the Rho kinase inhibitor Fasudil in experimental autoimmune encephalomyelitis and the related mechanisms

Abstract

Multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and other neurodegenerative diseases of central nervous system (CNS) disorders are serious human health problems. Rho-kinase (ROCK) is emerging as a potentially important therapeutic target relevant to inflammatory neurodegeneration diseases. This is supported by studies showing the beneficial effects of fasudil, a ROCK inhibitor, in inflammatory neurodegeneration diseases. MS is an autoimmune disease resulting from inflammation and demyelination in the white matter of the CNS. It has been postulated that activation of Rho/ROCK causes neuropathological changes accompanied with related clinical symptoms, which are improved by treatment with ROCK inhibitors. Therefore, inhibition of abnormal activation of the Rho/ROCK signaling pathway appears to be a new mechanism for treating CNS diseases. In this review, we extensively discussed the role of ROCK inhibitors, summarized the efficacy of fasudil in the MS conventional animal model of experimental autoimmune encephalomyelitis (EAE), both in vivo and in vitro, and highlighted the mechanism involved. Overall, the findings collected in this review support the role of the ROCK signaling pathway in neurodegenerative diseases. Hence, ROCK inhibitors such as fasudil can be novel, and efficacious treatment for inflammatory neurodegenerative diseases.

https://ift.tt/2A1PFMK

Time-course study of high fat diet induced alterations in spatial memory, hippocampal JNK, P38, ERK and Akt activity

Abstract

Consumption of high fat diet (HFD) is a health concern in modern societies, which participate in wide range of diseases. One underlying mechanism in the HFD mediated pathologies is disruption of insulin signaling activity. It is believed that HFD activates several stress signaling molecules such as MAPKs signaling pathway and these molecules participate in harmful effects in different cell populations including hippocampal cells. However, the activity of MAPKs signaling molecules are time dependent, even causing some opposing effects. Given that, MAPKs activity fluctuate with time of stress, there is less cleared how different lengths of HFD consumption can affect hippocampal MAPK. To test how duration of HFD consumption affect hippocampal MAPKs and insulin signaling activity and animal's cognitive function, rats were fed with HFD for different lengths (up to 6 months) and after each point spatial memory performances of animals was tested, then the peripheral indices of insulin resistance and hippocampal MAPKs and insulin signaling activity was evaluated. Results showed that while different time courses of HFD, up to 6 months, did not bring about significant spatial memory impairment, meanwhile the peripheral insulin sensitivity as well as hippocampal insulin and MAPKs signaling showed significant fluctuations during the different time courses of high fat diet regime. These results showed that neuronal responses to HFD is not constant and differ in a time-dependent manner, it seems that in acute phase molecular responses aimed to compensate the HFD stress but in chronic states these responses failed and devastating effects of stress began.

https://ift.tt/2PDScSj

Trial watch: Peptide-based vaccines in anticancer therapy.

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Trial watch: Peptide-based vaccines in anticancer therapy.

Oncoimmunology. 2018;7(12):e1511506

Authors: Bezu L, Kepp O, Cerrato G, Pol J, Fucikova J, Spisek R, Zitvogel L, Kroemer G, Galluzzi L

Abstract
Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen.

PMID: 30524907 [PubMed]

https://ift.tt/2CfdEtv

Increased hepatitis C virus co-infection and injection drug use in HIV-infected fishermen in Myanmar

In Southeast Asia, though fishermen are known to be a key population at high risk of HIV, little is known about their co-infection rates with Hepatitis C virus (HCV), or how illness and risk behaviors vary by ...

https://ift.tt/2CeFFkU

Leptotrichia trevisanii bacteremia in a woman with systemic lupus erythematosus receiving high-dose chemotherapy

Leptotrichia species are aerotolerant, Gram-negative fusiform bacteria. Cases of bacteremia caused by Leptotrichia trevisanii in immunocompromised patients have been rarely reported.

https://ift.tt/2Ljeh86

Repeated doses of Praziquantel in Schistosomiasis Treatment (RePST) – single versus multiple praziquantel treatments in school-aged children in Côte d’Ivoire: a study protocol for an open-label, randomised controlled trial

Large scale administration of the anthelminthic drug praziquantel (PZQ) to at-risk populations is the cornerstone of schistosomiasis control, although persisting high prevalence of infections in some areas and...

https://ift.tt/2CemKqy

A retrospective study of factors associated with treatment decision for nontuberculous mycobacterial lung disease in adults without altered systemic immunity

Nontuberculous mycobacteria (NTM) lung diseases are increasingly recognized as chronic opportunistic infections, occurring in individuals with a wide variety of underlying conditions. In the absence of systemi...

https://ift.tt/2LjeacG

Improving detection of tuberculosis among household contacts of index tuberculosis patients by an integrated approach in Myanmar: a cross-sectional study

Contact tracing for tuberculosis (TB) is a recommended measure to improve the case detection rate; however, actual implementation in Myanmar is limited and low detection rates have been reported. Household con...

https://ift.tt/2Lje6ts

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells.

Related Articles

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells.

Oncoimmunology. 2019;8(1):e1523097

Authors: Krombach J, Hennel R, Brix N, Orth M, Schoetz U, Ernst A, Schuster J, Zuchtriegel G, Reichel CA, Bierschenk S, Sperandio M, Vogl T, Unkel S, Belka C, Lauber K

Abstract
The major goal of radiotherapy is the induction of tumor cell death. Additionally, radiotherapy can function as in situ cancer vaccination by exposing tumor antigens and providing adjuvants for anti-tumor immune priming. In this regard, the mode of tumor cell death and the repertoire of released damage-associated molecular patterns (DAMPs) are crucial. However, optimal dosing and fractionation of radiotherapy remain controversial. Here, we examined the initial steps of anti-tumor immune priming by different radiation regimens (20 Gy, 4 × 2 Gy, 2 Gy, 0 Gy) with cell lines of triple-negative breast cancer in vitro and in vivo. Previously, we have shown that especially high single doses (20 Gy) induce a delayed type of primary necrosis with characteristics of mitotic catastrophe and plasma membrane disintegration. Now, we provide evidence that protein DAMPs released by these dying cells stimulate sequential recruitment of neutrophils and monocytes in vivo. Key players in this regard appear to be endothelial cells revealing a distinct state of activation upon exposure to supernatants of irradiated tumor cells as characterized by high surface expression of adhesion molecules and production of a discrete cytokine/chemokine pattern. Furthermore, irradiated tumor cell-derived protein DAMPs enforced differentiation and maturation of dendritic cells as hallmarked by upregulation of co-stimulatory molecules and improved T cell-priming. Consistently, a recurring pattern was observed: The strongest effects were detected with 20 Gy-irradiated cells. Obviously, the initial steps of radiotherapy-induced anti-tumor immune priming are preferentially triggered by high single doses - at least in models of triple-negative breast cancer.

PMID: 30546963 [PubMed]

https://ift.tt/2UEv9dQ

Dendritic cell vaccine with Ag85A enhances anti-colorectal carcinoma immunity.

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Dendritic cell vaccine with Ag85A enhances anti-colorectal carcinoma immunity.

Exp Ther Med. 2018 Dec;16(6):5123-5129

Authors: Zhai J, Gao W, Zhao L, Gao Z, Jiang X, Lu C

Abstract
Dendritic cells (DCs) are able to trigger T-cell activation and thus have been considered important for vaccine production against cancers. Vaccines containing DCs have been reported to be effective for developing immunity against cancer cells. The interactions between DCs and auxiliary agents are critical in the development of second-generation vaccines. In the present study, it was evaluated whether Ag85A-mixed DCs could enhance anti-tumor immunity in laboratory mice with colorectal carcinoma. Functional and phenotypic analyses of the effects of Ag85A-mixed DCs were conducted via flow cytometry and measurement of T-cell proliferation. In addition, interferon (IFN)-γ production was assessed. The therapeutic efficacy of DC vaccination for colorectal carcinoma treatment in mice was investigated. It was identified that Ag85A-mixed DCs exhibited strong upregulation of CD80, CD86 and major histocompatibility complex class II. Cytotoxic T-lymphocytes with CT26-primed Ag85A-DCs were indicated to induce stronger responses against CT26 tumor cells and trigger IFN-γ production. Furthermore, the Ag85A-mixed DC vaccine exerted a considerable inhibitory effect on tumor progression in mice as compared with the control group. Therefore, DCs in combination with the Ag85A gene may reinforce anti-colorectal carcinoma immunity. The current study provides a novel potential strategy for cancer treatment by enhancing immunity via Ag85A-mixed DC vaccination.

PMID: 30542467 [PubMed]

https://ift.tt/2CeS2xz

Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication.

Related Articles

Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication.

J Immunother Cancer. 2018 Dec 12;6(1):146

Authors: Zom GG, Willems MMJHP, Khan S, van der Sluis TC, Kleinovink JW, Camps MGM, van der Marel GA, Filippov DV, Melief CJM, Ossendorp F

Abstract
BACKGROUND: Ligands for the Toll-like receptor (TLR) family can induce activation of cells of the innate immune system and are widely studied for their potential to enhance adaptive immunity. Conjugation of TLR2-ligand Pam3CSK4 to synthetic long peptides (SLPs) was shown to strongly enhance the induction of antitumor immunity. To further improve cancer vaccination, we have previously shown that the novel TLR2-L Amplivant (AV), a modified Pam3CSK4, potentiates the maturation effects on murine DCs. In the current study, we further assessed the immunological properties of AV.
METHODS: Naïve mice were vaccinated with a conjugate of either Pam3CSK4 or AV and an SLP to assess specific T cell priming efficiency in vivo. The potency of AV and Pam3CSK4, either as free compounds or conjugated to different SLPs, to mature murine DCs was compared by stimulating murine dendritic cells overnight followed by ELISA and flow cytometry analysis. Murine tumor experiments were carried out by vaccinating mice carrying established HPV16 E6 and E7-expressing tumors and subsequently analyzing myeloid and lymphoid cells infiltrating the tumor microenvironment. Furthermore, tumor outgrowth after vaccination was monitored to enable comparison of the efficiency to induce antitumor immunity by Pam3CSK-SLP and AV-SLP conjugates. To enhance therapeutic efficacy, AV-SLP conjugate vaccination was combined with ablative therapies to assess whether synergism between such therapies would occur.
RESULTS: SLPs conjugated to AV induce stronger DC maturation, in vivo T cell priming and antitumor immunity compared to conjugates with Pam3CSK4. Interestingly, AV-SLP conjugates modulate the macrophage populations in the tumor microenvironment, correlating with a therapeutic effect in an aggressive murine tumor model. The potency of AV-SLP conjugates in cancer vaccination operates optimally in combination with chemotherapy or photodynamic therapy.
CONCLUSION: These data allow further optimization of vaccination-based immunotherapy of cancer by use of the improved TLR2-ligand Amplivant.

PMID: 30541631 [PubMed - in process]

https://ift.tt/2LjdYKu

Dendritic cell-based vaccination: powerful resources of immature dendritic cells against pancreatic adenocarcinoma.

Related Articles

Dendritic cell-based vaccination: powerful resources of immature dendritic cells against pancreatic adenocarcinoma.

Oncoimmunology. 2018;7(12):e1504727

Authors: Collignon A, Silvy F, Robert S, Trad M, Germain S, Nigri J, André F, Rigot V, Tomasini R, Bonnotte B, Lombardo D, Mas E, Beraud E

Abstract
Pancreatic adenocarcinoma (PAC) has a poor prognosis. One treatment approach, investigated here, is to reinforce antitumor immunity. Dendritic cells (DCs) are essential for the development and regulation of adaptive host immune responses against tumors. A major role for DCs may be as innate tumoricidal effector cells. We explored the efficacy of vaccination with immature (i)DCs, after selecting optimal conditions for generating immunostimulatory iDCs. We used two models, C57BL/6Jrj mice with ectopic tumors induced by the PAC cell line, Panc02, and genetically engineered (KIC) mice developing PAC. Therapeutic iDC-vaccination resulted in a significant reduction in tumor growth in C57BL/6Jrj mice and prolonged survival in KIC mice. Prophylactic iDC-vaccination prevented subcutaneous tumor development. These protective effects were long-lasting in Panc02-induced tumor development, but not in melanoma. iDC-vaccination impacted the immune status of the hosts by greatly increasing the percentage of CD8+ T-cells, and natural killer (NK)1.1+ cells, that express granzyme B associated with Lamp-1 and IFN-γ. Efficacy of iDC-vaccination was CD8+ T-cell-dependent but NK1.1+ cell-independent. We demonstrated the ability of DCs to produce peroxynitrites and to kill tumor cells; this killing activity involved peroxynitrites. Altogether, these findings make killer DCs the pivotal actors in the beneficial clinical outcome that accompanies antitumor immune responses. We asked whether efficacy can be improved by combining DC-vaccination with the FOLFIRINOX regimen. Combined treatment significantly increased the lifespan of KIC mice with PAC. Prolonged treatment with FOLFIRINOX clearly augmented this beneficial effect. Combining iDC-vaccination with FOLFIRINOX may therefore represent a promising therapeutic option for patients with PAC.

PMID: 30524902 [PubMed]

https://ift.tt/2LfHErW

Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy.

Related Articles

Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy.

Oncoimmunology. 2018;7(12):e1474318

Authors: Noordam L, Kaijen MEH, Bezemer K, Cornelissen R, Maat LAPWM, Hoogsteden HC, Aerts JGJV, Hendriks RW, Hegmans JPJJ, Vroman H

Abstract
Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs. Objectives: The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients. Methods: Ten patients received mCTX and DC-based immunotherapy after chemotherapy (n = 5) or chemotherapy and debulking surgery (n = 5). Peripheral blood mononuclear cells before, during and after treatment were analyzed for various Treg and other lymphocyte subsets by flow cytometry. Results: After one week treatment with mCTX, both activated FoxP3hi and naïve CD45RA+ Tregs were effectively decreased in all patients. In addition, a shift from naïve and central memory towards effector memory and effector T cells was observed. Survival analysis showed that overall Treg levels before treatment were not correlated with survival, however, nTreg levels before treatment were positively correlated with survival. After completion of mCTX and DC-based immunotherapy treatment, all cell subsets returned to baseline levels, except for the proportions of proliferating EM CD8 T cells, which increased. Conclusions: mCTX treatment effectively reduced the proportions of circulating Tregs, both aTregs and nTregs, thereby favoring EM T cell subsets in mesothelioma patients. Interestingly, baseline levels of nTregs were positively correlated to overall survival upon complete treatment.

PMID: 30524884 [PubMed]

https://ift.tt/2CfdDpr

A Novel Cellular Pathway of Antigen Presentation and CD4 T Cell Activation in vivo.

Related Articles

A Novel Cellular Pathway of Antigen Presentation and CD4 T Cell Activation in vivo.

Front Immunol. 2018;9:2684

Authors: Scales HE, Meehan GR, Hayes AJ, Benson RA, Watson E, Walters A, Tomura M, Maraskovsky E, Garside P, Baz Morelli A, Brewer JM

Abstract
Dendritic cell activation of CD4 T cells in the lymph node draining a site of infection or vaccination is widely considered the central event in initiating adaptive immunity. The accepted dogma is that this occurs by stimulating local activation and antigen acquisition by dendritic cells, with subsequent lymph node migration, however the generalizability of this mechanism is unclear. Here we show that in some circumstances antigen can bypass the injection site inflammatory response, draining freely and rapidly to the lymph nodes where it interacts with subcapsular sinus (SCS) macrophages resulting in their death. Debris from these dying SCS macrophages is internalized by monocytes recruited from the circulation. This coordinated response leads to antigen presentation by monocytes and interactions with naïve CD4 T cells that can drive the initiation of T cell and B cell responses. These studies demonstrate an entirely novel pathway leading to initiation of adaptive immune responses in vivo.

PMID: 30524434 [PubMed - in process]

https://ift.tt/2LfVUBf

Imaging and Surgical Findings in Patients with Hemi-Laryngopharyngeal Spasm and the Potential Role of MRI in the Diagnostic Work-Up [HEAD & NECK]

BACKGROUND AND PURPOSE:

Hemi-laryngopharyngeal spasm is a recently discovered condition characterized by episodic coughing and unilateral throat contractions that may lead to severe stridor. These symptoms are caused by a vascular compression of the ipsilateral vagus nerve, typically the PICA. Microvascular decompression of the vagus nerve has been demonstrated to be a potential cure for this neurovascular compression syndrome. The main aim of this study was to clarify the role of MR imaging in the diagnostic work-up of this rare condition.

MATERIALS AND METHODS:

We describe the imaging and surgical findings of 3 patients from our prospective case series of patients with hemi-laryngopharyngeal spasm from 2015 to 2017. Second, the imaging data of 100 patients (control cohort) with symptoms unrelated to hemi-laryngopharyngeal spasm were reviewed to investigate the rate and degree of neurovascular conflict of the vagus nerve.

RESULTS:

All patients with hemi-laryngopharyngeal spasm reported to date have had vascular compression of the vagus nerve due to the PICA. In the control cohort, there was a good interrater agreement in scoring the "contact" and "compression" of the vagus nerve ( = 0.73. P = < .001). The frequency of contact or compression of the vagus nerve was approximately 50%. The PICA was the most frequent vessel involved in 74%.

CONCLUSIONS:

The presence of unilateral neurovascular contact or compression of the vagus nerve does not confirm the diagnosis of hemi-laryngopharyngeal spasm. The MR imaging finding of ipsilateral vascular compression of the vagus nerve is a necessary but not sufficient finding for the diagnosis of hemi-laryngopharyngeal spasm.

https://ift.tt/2S3am26

[other]

https://ift.tt/2QuwRA6

Reply: [LETTERS]

https://ift.tt/2QtME2d

Peeking into the Black Box of Coregistration in Clinical fMRI: Which Registration Methods Are Used and How Well Do They Perform? [FUNCTIONAL]

BACKGROUND AND PURPOSE:

Interpretation of fMRI depends on accurate functional-to-structural alignment. This study explores registration methods used by FDA-approved software for clinical fMRI and aims to answer the following question: What is the degree of misalignment when registration is not performed, and how well do current registration methods perform?

MATERIALS AND METHODS:

This retrospective study of presurgical fMRI for brain tumors compares nonregistered images and 5 registration cost functions: Hellinger, mutual information, normalized mutual information, correlation ratio, and local Pearson correlation. To adjudicate the accuracy of coregistration, we edge-enhanced echo-planar maps and rated them for alignment with structural anatomy. Lesion-to-activation distances were measured to evaluate the effects of different cost functions.

RESULTS:

Transformation parameters were congruent among Hellinger, mutual information, normalized mutual information, and the correlation ratio but divergent from the local Pearson correlation. Edge-enhanced images validated the local Pearson correlation as the most accurate. Hellinger worsened misalignment in 59% of cases, primarily exaggerating the inferior translation; no cases were worsened by the local Pearson correlation. Three hundred twenty lesion-to-activation distances from 25 patients were analyzed among nonregistered images, Hellinger, and the local Pearson correlation. ANOVA analysis revealed significant differences in the coronal (P < .001) and sagittal (P = .04) planes. If registration is not performed, 8% of cases may have a >3-mm discrepancy and up to a 5.6-mm lesion-to-activation distance difference. If a poor registration method is used, 23% of cases may have a >3-mm discrepancy and up to a 6.9-mm difference.

CONCLUSIONS:

The local Pearson correlation is a special-purpose cost function specifically designed for T2*–T1 coregistration and should be more widely incorporated into software tools as a better method for coregistration in clinical fMRI.

https://ift.tt/2RWlkGh

Perspectives on Neuroradiology Medical Expert Testimony: Fact and Fiction [research-article]

SUMMARY:

There are numerous misconceptions about serving as a medical malpractice expert witness. By maintaining an objective perspective based in the unbiased interpretation of the images provided (for both sides of the conflict), one can best serve society as a whole. Most cases for which a neuroradiology expert is recruited are the following: 1) not with the radiologist as a defendant, 2) resolved without court testimony, and 3) short-lived if frivolous. One can learn much about medicine, our nonradiology colleagues, and the litigation process by participating as an expert witness.

https://ift.tt/2QyPPFK

The Unwound Cochlea: A Specific Imaging Marker of Branchio-Oto-Renal Syndrome [HEAD & NECK]

BACKGROUND AND PURPOSE:

Branchio-oto-renal syndrome is an important syndromic cause of hearing loss. Our aim was to determine the test characteristics of the unwound cochlea on temporal bone CT for the diagnosis of branchio-oto-renal syndrome in a cohort of children with hearing loss.

MATERIALS AND METHODS:

Patients were identified retrospectively with a clinical diagnosis of branchio-oto-renal syndrome and CT imaging of the temporal bones. Age-matched controls were also identified with sensorineural hearing loss not related to a diagnosis of branchio-oto-renal syndrome and CT imaging of the temporal bones. All examinations were reviewed by 2 neuroradiologists blinded to the diagnosis of branchio-oto-renal syndrome versus controls for the absence/presence of an unwound cochlea defined as anteromedial rotation and displacement of the middle and apical turns away from the basal turn.

RESULTS:

The final study group comprised 9 patients with branchio-oto-renal syndrome (age range, 1–14 years; mean age, 8.0 ± 4.3 years) and 50 control patients (age range, 1–16 years; mean age, 7.9 ± 4.1 years). The cochlea was subjectively abnormal in all 9 patients. In 8 patients (89%), imaging demonstrated a typical unwound cochlear morphology. By contrast, none of the control subjects demonstrated an unwound cochlea on either side. Statistically, the unwound cochlea was significantly more frequent in the branchio-oto-renal group compared with controls (P < .001). The unwound cochlea was 89% sensitive and 100% specific for the diagnosis of branchio-oto-renal syndrome.

CONCLUSIONS:

The unwound cochlea is a specific imaging marker of branchio-oto-renal syndrome. These findings further support the diagnostic accuracy and therefore the utility of temporal bone imaging in the diagnosis of this disorder.

https://ift.tt/2RVFcJW

Contralateral Approach to Coil Embolization of Proximal A1 Aneurysms Using the Anterior Communicating Artery [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Aneurysms arising from the proximal A1 segment of the anterior cerebral artery are rare, and their distinctive configurations often pose technical challenges during endovascular embolization. Herein, we present 11 patients with proximal A1 aneurysms requiring a contralateral approach (via the anterior communicating artery) to coil embolization.

MATERIALS AND METHODS:

From a prospectively collected data repository, we retrieved records of 11 patients consecutively treated for proximal A1 aneurysms between January 2011 and March 2018. In each instance, coil embolization was performed by the contralateral route. Outcomes were analyzed in terms of morphologic features and clinical status.

RESULTS:

Aneurysms in all 11 patients were directed posteriorly and were small (<5 mm). A contralateral approach (via the anterior communicating artery) was used after ipsilateral attempts at aneurysm selection failed in each instance, despite using a variety of microcatheters. Single punctures and single guiding catheters sufficed in 9 patients, but 2 patients required dual punctures and 2 guiding catheters. All endovascular treatments ultimately yielded excellent outcomes. Although 1 symptomatic infarct was manifested in the course of ipsilateral treatment, no morbidity or mortality resulted from the contralateral access.

CONCLUSIONS:

Due to angio-anatomic constraints, a contralateral strategy for coil embolization of proximal A1 aneurysms is acceptable if ipsilateral access is technically prohibitive and the vessels (contralateral A1 and anterior communicating artery) are amenable to the passage of microdevices.

https://ift.tt/2S1O1Sz

Transdural Blood Supply in Cerebral Arteriovenous Malformations: A Systematic Evaluation of Angioarchitecture [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Arterial transdural blood supply is a rare angiographic phenomenon in cerebral AVMs. This study aimed to evaluate angiographic transdural blood supply characteristics and to describe the clinical peculiarities of these lesions.

MATERIALS AND METHODS:

A prospective AVM data base of 535 patients, enrolled from 1990 to 2016, was analyzed retrospectively. Clinical information was reviewed through patients' medical charts and radiologic studies. Patients with previous AVM treatment were excluded (n = 28).

RESULTS:

Patients with (n = 32, male/female ratio = 10:22; mean age, 46 ± 15 years; range, 13–75 years) and without transdural blood supply (n = 475, male/female ratio = 260:215; mean age, 40 ± 18 years; range, 2–87 years) did not show significant differences in clinical presentation (age, hemorrhage, seizures, chronic headache). The predominant nidus size in patients with transdural blood supply was ≥30 mm, with significantly more patients with large AVMs (>60 mm, P = .001). To describe the transdural blood supply, we used 3 grades based on the angiographic transdural blood supply proportion and intensity of AVM nidus perfusion (I–III). Fifty-seven percent of patients with chronic headache had a strong and substantial transdural nidus perfusion (III) and a high-flow transdural blood supply.

CONCLUSIONS:

Cerebral AVMs with transdural blood supply represent a rare and heterogeneous subgroup. Lesions can be graded by quantifying the transdural blood supply of the nidus and by capturing hemodynamic characteristics. The broad spread of angiographic features and comparable clinical patterns of patients with or without transdural blood supply raises questions about the relevance of the transdural blood supply to the natural history risk of an AVM and the intention for treatment.

https://ift.tt/2QyT00g

Brain MR Imaging Findings in Woodhouse-Sakati Syndrome [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Woodhouse-Sakati syndrome is a rare autosomal recessive disorder characterized by hypogonadism, alopecia, diabetes mellitus, and progressive extrapyramidal signs. The disease is caused by biallelic pathogenic variants in the DCAF17 gene. The purpose of this study was to describe the spectrum of brain MR imaging abnormalities in Woodhouse-Sakati syndrome.

MATERIALS AND METHODS:

We reviewed brain MR images of 26 patients with a clinical and genetic diagnosis of Woodhouse-Sakati syndrome (12 males, 14 females; age range, 16–45 years; mean age, 26.6 years). Follow-up studies were conducted for 6 patients.

RESULTS:

All patients had abnormal MR imaging findings. The most common abnormalities were a small pituitary gland (76.9%), pronounced basal ganglia iron deposition (73%), and white matter lesions in 69.2%. White matter lesions showed frontoparietal and periventricular predominance. All white matter lesions spared subcortical U-fibers and were nonenhanced. Prominent perivascular spaces (15.3%) and restricted diffusion in the splenium of the corpus callosum (7.6%) were less frequent findings. Follow-up studies showed expansion of white matter lesions with iron deposition further involving the red nucleus and substantia nigra. Older age was associated with a more severe degree of white matter lesions (P < .001).

CONCLUSIONS:

Small pituitary gland, accentuated iron deposition in the globus pallidus, and nonenhancing frontoparietal/periventricular white matter lesions were the most noted abnormalities seen in our cohort. The pattern and extent of these findings were observed to correlate with older age, reflecting a possible progressive myelin destruction and/or axonal loss. The presence of pituitary hypoplasia and white matter lesions can further distinguish Woodhouse-Sakati syndrome from other neurodegenerative diseases with brain iron accumulation subtypes.

https://ift.tt/2S1Z3Ha

Long-Term Ultrasound Follow-Up of Incidentally Detected Thyroglossal Duct Cysts in Adults [HEAD & NECK]

BACKGROUND AND PURPOSE:

There has been no previous study that used ultrasonography for longitudinal changes of thyroglossal duct cysts, to our knowledge. We assessed the prevalence and interval changes in incidentally detected thyroglossal duct cysts in adults.

MATERIALS AND METHODS:

From January 2010 to December 2016, we identified 796 ultrasonography radiologic reports from 513 subjects that contained the words "thyroglossal" or "TGDC" among 54,369 participants. Of 513 subjects, 172 (M/F = 103:69, mean age, 53 ± 11 years) who underwent ≥2 sonography studies were enrolled. Two reviewers determined ultrasonography features, including maximal diameter, location, internal echogenicity, wall thickness, and the presence of posterior enhancement, internal septa, and solid components.

RESULTS:

The mean follow-up time of total 172 lesions was 2.01 ± 1.13 years. Thyroglossal duct cysts ranged from 2 to 32 mm (mean, 8.77 ± 3.83 mm) on the initial ultrasonography examination. On follow-up ultrasonography studies, 14 lesions (8.2%) increased by >2 mm, while most thyroglossal duct cysts (133 lesions, 77.3%) remained stable in size. During the follow-up period, 31 lesions (18.0%) showed interval changes in ultrasonography features. There was no significant relationship between the presence of ultrasonography feature changes and size changes (P = .12).

CONCLUSIONS:

On ultrasonography, 0.9% of adults had incidental thyroglossal duct cysts. Most did not increase in size with time despite changes in various ultrasonography features. Therefore, we recommend performing an observation at long intervals of 2–3 years for asymptomatic thyroglossal duct cysts, and we suggest that fine-needle aspiration can be suspended unless suspicious findings of malignancy are detected.

https://ift.tt/2RZUZY8

Towards Reproducible Results: Validating CT Hemorrhage-Detection Algorithms on Standard Datasets [LETTERS]

https://ift.tt/2QtMFmN

Initial and Long-Term Outcomes of Complex Bifurcation Aneurysms Treated by Y-Stent-Assisted Coiling with Low-Profile Braided Stents [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Coiling complex intracranial bifurcation aneurysms often necessitates the implantation of double stents in various configurations, such as Y-stent placement. Low-profile braided stents have been introduced recently to facilitate the endovascular treatment of wide-neck aneurysms. We aimed to investigate the feasibility, safety, efficacy, and durability of Y-stent-assisted coiling with double low-profile braided stents for the treatment of complex bifurcation aneurysms.

MATERIALS AND METHODS:

A retrospective review was performed to identify patients who were treated using Y-stent-assisted coiling with low-profile braided stents. Technical success was assessed, as were initial and follow-up clinical and angiographic outcomes. Periprocedural and delayed complications were reviewed. Preprocedural and follow-up clinical statuses were assessed using the modified Rankin Scale.

RESULTS:

Forty patients with 40 intracranial aneurysms were included in the study. Y-stent placement was successfully performed in all cases. Immediate postprocedural digital subtraction angiography images revealed total aneurysm occlusion in 72.5% of cases. The mean angiographic follow-up time was 24.8 months. The last follow-up angiograms showed complete occlusion in 85% of patients. During follow-up, only 1 patient showed an increase in the filling status of the aneurysm and that patient did not require retreatment. There was no mortality in this study. The overall procedure-related complication rate, including asymptomatic complications, was 17.5%. A permanent morbidity developed in 1 patient (2.5%).

CONCLUSIONS:

The long-term angiographic and clinical outcomes of this retrospective study demonstrate that Y-stent-assisted coiling using low-profile braided stents is an effective, relatively safe, and durable endovascular treatment for wide-neck and complex bifurcation aneurysms.

https://ift.tt/2S1DXZB

Reply: [LETTERS]

https://ift.tt/2QAAMvd

Vessel Wall Enhancement in Treated Unruptured Aneurysms [LETTERS]

https://ift.tt/2QwAtBQ

Critical Assessment of Myelography Practices: A Call for Rational Guideline Revision [PATIENT SAFETY]

BACKGROUND AND PURPOSE:

Patient preparation for myelography and postprocedural monitoring varies widely between practices, despite published guidelines. Our aim was to examine the current practice variations in discontinuing reportedly seizure threshold–lowering medications before myelography and to assess the reported incidence of postmyelographic seizures.

MATERIALS AND METHODS:

An e-mail survey was sent to American Society of Neuroradiology members concerning the number of postmyelographic seizures experienced in the past 5 years, the presence of an institutional policy for discontinuing seizure threshold–lowering medications, and the type of myelographic contrast used. We compared the postmyelographic seizure frequency in the responses.

RESULTS:

Of 700 survey responses, 57% reported that they do not discontinue seizure threshold–lowering medications before myelography. Most (97%) indicated never having a patient experience a seizure following myelography. The number of postmyelographic seizures between those who discontinue seizure threshold–lowering medications and those who do not was not statistically significant (OR = 2.13; 95% CI, 0.91–4.98; P = .08). Most (95%) reported using nonionic hypo-osmolar agents.

CONCLUSIONS:

Survey results revealed widely variable practices for patient myelography preparation and postprocedural monitoring. We found no difference in reported seizures between those who discontinued seizure threshold–lowering medications and those who did not. In light of our findings, we propose that discontinuing reportedly seizure threshold–lowering medications is not warranted with the current nonionic water-soluble contrast agents and may be potentially harmful in some instances. This work supports revision of existing recommendations to withhold such medications before myelography.

https://ift.tt/2S1Okgb

Reply: [LETTERS]

https://ift.tt/2QBUK9a

Pipeline Diameter Significantly Impacts the Long-Term Fate of Jailed Side Branches during Treatment of Intracranial Aneurysms [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Although covered side branches typically remain patent acutely following Pipeline Embolization Device embolization of intracranial aneurysms, the long-term fate of these vessels remains uncertain. We therefore elected to investigate factors that may influence the long-term patency of these covered side branches.

MATERIALS AND METHODS:

We retrospectively evaluated the long-term patency of side branches covered by the Pipeline Embolization Device at our institution during treatment of intracranial aneurysms with at least 6 months of conventional angiography follow-up. Procedural and anatomic factors that might influence the fate of covered side branches were explored.

RESULTS:

One hundred forty-eight Pipeline Embolization Device treatments in 137 patients met the inclusion criteria. In 217 covered side branches, 29 (13.4%) were occluded on follow-up, and 40 (18.4%) were stenotic. All stenoses and occlusions were asymptomatic. In the entire cohort and in the largest subset of ophthalmic arteries, a smaller Pipeline Embolization Device diameter was associated with branch vessel occlusion (P = .001, P = .013). When we considered stenotic and occluded side branches together, smaller Pipeline Embolization Device size (P = .029) and administration of intraprocedural abciximab (P = .03) predicted side branch stenosis/occlusion, while anterior choroidal branch type (P = .003) was a predictor of gross side branch patency.

CONCLUSIONS:

A smaller Pipeline Embolization Device diameter is associated with delayed side branch stenosis/occlusion following Pipeline Embolization Device treatment, likely due to the higher metal density of smaller caliber devices. Although hemodynamic factors, including the potential for collateral flow, are still paramount in determining the fate of covered side branches, the amount of metal coverage at the side branch orifice also plays an important role.

https://ift.tt/2S2RDU3

Erratum [ERRATA]

https://ift.tt/2Qyvlgc

Functional MRI as an Objective Measure of Olfaction Deficit in Patients with Traumatic Anosmia [ADULT BRAIN]

BACKGROUND AND PURPOSE:

While posttraumatic anosmia is not uncommon, the olfactory function evaluation has strongly relied on subjective responses given by patients. We aimed to examine the utility of fMRI as an objective tool for diagnosing traumatic anosmia.

MATERIALS AND METHODS:

Sixteen patients (11 men and 5 women; mean age, 42.2 ± 10.4 years) with clinically diagnosed traumatic anosmia and 19 healthy control subjects (11 men and 8 women; mean age, 29.3 ± 8.5 years) underwent fMRI during olfactory stimulation with citral (a pleasant odor) or β-mercaptoethanol (an unpleasant odor). All patients were subjected to a clinical olfactory functional assessment and nasal endoscopic exploration. Two-sample t tests were conducted with age as a covariate to examine group differences in brain activation responses to olfactory stimulation (false discovery rate–corrected P < .05).

RESULTS:

Compared with healthy control subjects, patients with traumatic anosmia had reduced activation in the bilateral primary and secondary olfactory cortices and the limbic system in response to β-mercaptoethanol stimulation, whereas reduced activation was observed only in the left frontal subgyral region in response to citral stimulation.

CONCLUSIONS:

Brain activation was decreased in the bilateral primary and secondary olfactory cortices as well as the limbic system in response to olfactory stimulation in patients with traumatic anosmia compared with healthy control subjects. These preliminary results may shed light on the potential of fMRI for the diagnosis of traumatic anosmia.

https://ift.tt/2S6DPbu

Gadolinium and Multiple Sclerosis: Vessels, Barriers of the Brain, and Glymphatics [ADULT BRAIN]

SUMMARY:

The pathogenesis of multiple sclerosis is characterized by a cascade of pathobiologic events, ranging from focal lymphocytic infiltration and microglia activation to demyelination and axonal degeneration. MS has several of the hallmarks of an inflammatory autoimmune disorder, including breakdown of the BBB. Gadolinium-enhanced MR imaging is currently the reference standard to detect active inflammatory lesions in MS. Knowledge of the patterns and mechanisms of contrast enhancement is vital to limit the radiologic differential diagnosis in the staging and evaluation of MS lesion activity. The aim of this review was the following: 1) to outline the pathophysiology of the effect of lymphocyte-driven inflammation in MS, 2) to describe the effects of gadolinium on the BBB and glymphatic system, and 3) to describe gadolinium enhancement patterns and artifacts that can mimic lesions in MS.

https://ift.tt/2QAAHYr

Family counseling: Keeping bonds strong

First responder families face unique stressors, which can be overcome with the help of a professional family counselor

https://ift.tt/2Cf6qWp

Direct Lineage Reprogramming of Adult Mouse Fibroblast to Erythroid Progenitors

Here we present our protocol for producing induced erythroid progenitors (iEPs) from mouse adult fibroblasts using transcription factor-driven direct lineage reprogramming (DLR).

https://ift.tt/2EuVVRa

Back to the Box: Using Lung Volumes to Predict Susceptibility to Develop Chronic Obstructive Pulmonary Disease among Smokers

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S286-S287, December 2018.


https://ift.tt/2ULdgdm

Identifying Mesenchymal Pathways That Initiate Emphysema in Order to Develop Targeted Therapies

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S291-S292, December 2018.


https://ift.tt/2BiHaNq

The Role of IGSF3 in Cell Adhesion, Proliferation, and Cell Migration

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S291-S291, December 2018.


https://ift.tt/2BmCq9c

Bringing Light to Chronic Obstructive Pulmonary Disease Pathogenesis and Resilience

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S227-S233, December 2018.


https://ift.tt/2ULdam0

Inflammatory Phenotypes Associated with Chronic Obstructive Pulmonary Disease Increase Susceptibility to Exacerbation. Lessons from Single Cell Analysis of Lung Macrophages

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S289-S289, December 2018.


https://ift.tt/2ULQbHr

Common Mechanisms Linking Chronic Obstructive Pulmonary Disease and Lung Cancer

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S273-S277, December 2018.


https://ift.tt/2Bnwa0X

Chronic Obstructive Pulmonary Disease Phenotype Dictates Cancer-Promoting Stromal Gene Expression Programs

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S290-S291, December 2018.


https://ift.tt/2ULdm4I

Hybrid Three-Dimensional Lung Tissue Cultures to Improve Ex Vivo Models of Chronic Obstructive Pulmonary Disease

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S288-S288, December 2018.


https://ift.tt/2BhTZHD

Mitochondrial Dysfunction as a Pathogenic Mediator of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S266-S272, December 2018.


https://ift.tt/2BiK5Wi

Dysfunction of Airway Basal Progenitors Can Be Rescued by a Healthy Microenvironment. Implications in Regenerative Therapy

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S287-S288, December 2018.


https://ift.tt/2ULd3XC

Critical Challenges and Compelling Questions for Chronic Obstructive Pulmonary Disease. Moving the Field Forward: A National Heart, Lung, and Blood Institute Perspective

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S282-S284, December 2018.


https://ift.tt/2ULcWeE

Functional Studies of Single-Nucleotide Polymorphisms Suggest Heterogeneity in Chronic Obstructive Pulmonary Disease due to Susceptibility of Different Cell Types

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S285-S285, December 2018.


https://ift.tt/2ULrScQ

Peripheral Blood Natural Killer Cell Phenotypes Associated with Exacerbation Risk in Patients with Chronic Obstructive Pulmonary Disease

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S288-S289, December 2018.


https://ift.tt/2BhTYn3

Bioactive Sphingolipids in the Pathogenesis of Chronic Obstructive Pulmonary Disease

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S249-S252, December 2018.


https://ift.tt/2BikqNw

The Chronic Obstructive Pulmonary Disease Frequent Exacerbator Phenotype Is Associated with Decreased Upper Airway Microbiota α Diversity

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S286-S286, December 2018.


https://ift.tt/2ULrMlu

p73 Is Required for pIgR Expression in the Respiratory Epithelium

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S290-S290, December 2018.


https://ift.tt/2Bjo1L9

Improving Detection of Early Chronic Obstructive Pulmonary Disease

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S243-S248, December 2018.


https://ift.tt/2ULrFq4

Applying Functional Genomics to Chronic Obstructive Pulmonary Disease

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S239-S242, December 2018.


https://ift.tt/2BfYD94

Cell-based Therapy for Chronic Obstructive Pulmonary Disease. Rebuilding the Lung

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S253-S259, December 2018.


https://ift.tt/2ULrw60

Generation of Alpha-1 Antitrypsin Knockout and PI*ZZ Ferrets Using Crispr/Cas9. A Genetic Model of Emphysema

Annals of the American Thoracic Society, Volume 15, Issue Supplement_4, Page S292-S293, December 2018.


https://ift.tt/2BnEbmW

Cornification of nail keratinocytes requires autophagy for bulk degradation of intracellular proteins while sparing components of the cytoskeleton

Abstract

Epidermal keratinocytes undergo cornification to form the cellular building blocks of hard skin appendages such as nails and the protective layer on the surface of the skin. Cornification requires the cross-linking of structural proteins and the removal of other cellular components to form mechanically rigid and inert corneocytes. Autophagy has been proposed to contribute to this intracellular remodelling process, but its molecular targets in keratinocytes, if any, have remained elusive. Here, we deleted the essential autophagy factor Atg7 in K14-positive epithelia of mice and determined by proteomics the impact of this deletion on the abundance of individual proteins in cornified nails. The genetic suppression of autophagy in keratinocytes resulted in a significant increase in the number of proteins that survived cornification and in alterations of their abundance in the nail proteome. A broad range of enzymes and other non-structural proteins were elevated whereas the amounts of cytoskeletal proteins of the keratin and keratin-associated protein families, cytolinker proteins and desmosomal proteins were either unaltered or decreased in nails of mice lacking epithelial autophagy. Among the various types of non-cytoskeletal proteins, the subunits of the proteasome and of the TRiC/CCT chaperonin were most strongly elevated in mutant nails, indicating a particularly important role of autophagy in removing these large protein complexes during normal cornification. Taken together, the results of this study suggest that autophagy is active during nail keratinocyte cornification and its substrate specificity depends on the accessibility of proteins outside of the cytoskeleton and their presence in large complexes.

https://ift.tt/2Llmid2

Surgical outcomes associated with a sutureless drainage valve implantation procedure in patients with refractory glaucoma

https://ift.tt/2zY95C6

Effect of bilberry extract on slowing high-myopia progression in children: 2-year follow-up study

https://ift.tt/2PF2T7g