bluuebunny/crossref_metadata_2025 huggingface dataset:
DIFFUSE LARGE B-CELL LYMPHOMA-ASSOCIATED-RETINOPATHY CHARACTERIZED BY MINIMAL MORPHOLOGIC CHANGES AND SEVERE FUNCTIONAL IMPAIRMENT
Authors: Moyal Laura , Zambrowski Olivia , Thirkill Charles , Bottin Caroline , Blanco Rocio , Haioun Corinne , Souied Eric H.
Published: August 2016

Purpose:

To report the case of a patient whose retinal disease was found to be associated with a diffuse large B-cell lymphoma found 30 years after the apparent successful treatment of a classical Hodgkin lymphoma.

Methods:

Observational case report.

Results:

The authors describe the case of a 69-year-old man referred to their Department because of progressive, bilateral vision loss over the last few months. Deterioration in color vision and intense photophobia were also present. His best-corrected visual acuity was 20/400 in the right eye (RE) and 20/800 in the left eye (LE). Slit lamp and fundus examination failed to show any abnormalities. Spectral domain optical coherence tomography (SD-OCT) detected diffuse attenuation of the ellipsoid layers in addition to a focal subfoveal defect in both eyes. Both fluorescein and indocyanine angiographies (FA and ICGA) were normal. Full flash electroretinogram (ERG) revealed bilateral cone rod dysfunction with decreased amplitudes of both a and b waves.

Conclusion:

Because of the late onset of the disease, poor visual acuity compared with a small macular anatomical lesion and a history of Hodgkin lymphoma 30 years ago, a neoplastic etiology was investigated. Poor performance status and chest pain led to a thoracic CT scan, which identified a massive mediastinal tumor. Serum analysis found an abnormal amount of antibody activity within the 40 kD region of Western blot of retina. The diagnosis of diffuse large B-cell lymphoma was established. Systemic examinations found a Stage IV non-Hodgkin lymphoma.
POSTERIOR POLAR ANNULAR CHOROIDAL DYSTROPHY: A CASE SERIES
Authors: Lenis Tamara L. , Klufas Michael A. , Randhawa Sandeep , Sharma Mithlesh , Sarraf David
Published: August 2016

Purpose:

To describe the multimodal imaging findings of posterior polar annular choroidal dystrophy (PPACD).

Methods:

Retrospective case series of 2 patients diagnosed with PPACD. Spectral-domain optical coherence tomography, fundus autofluorescence, and fluorescein angiography findings of PPACD are described. Electroretinography results are also presented.

Results:

Both patients presented with bilateral peripapillary atrophy extending to involve the temporal arcades in an annular, foveal sparing pattern. Both cases demonstrated outer retinal atrophy with foveal sparing on spectral-domain optical coherence tomography, and fluorescein angiography illustrated corresponding window defects with late staining. Fundus autofluorescence showed hypoautofluorescence in the center of atrophic areas but hyperautofluorescence at the leading edge. Electroretinography findings included cone loss with rod preservation. Inflammatory and infectious workup was unremarkable in both cases.

Conclusion:

This report describes the multimodal imaging findings of a rare and poorly described chorioretinal disorder, PPACD, and will serve to guide clinicians regarding the evaluation and management of this elusive condition.
NEUROSARCOIDOSIS MASQUERADING AS A CENTRAL NERVOUS SYSTEM TUMOR
Authors: Elia Maxwell , Kombo Ninani , Huang John
Published: August 2016

Purpose:

To report a case of neurosarcoidosis with an isolated brain lesion mimicking a low-grade glioma.

Methods:

A 38-year-old woman presented with 2 weeks of blurry vision in the left eye. Ophthalmic examination, visual field testing, fluorescein angiography, laboratory testing, and MRI of the brain were performed.

Results:

Ophthalmic examination revealed left-sided optic nerve infiltration, and MRI of the brain demonstrated a solitary lesion in the brain. The visual symptoms and ophthalmic examination improved significantly with initiation of high-dose oral prednisone. Because the MRI appearance was concerning for malignancy, a brain biopsy was performed. Pathology demonstrated gliosis consistent with a low-grade central nervous system (CNS) glioma. One year later, after initial loss to ophthalmic follow-up, the right optic nerve became involved, and the patient was again treated successfully for presumed ocular sarcoidosis. At this time, serial neuroimaging demonstrated enlargement of the CNS lesion, prompting rebiopsy. Rebiopsy demonstrated a noncaseating granuloma, confirming the diagnosis of neurosarcoidosis. The patient was treated with 20 mg of methotrexate weekly and a prednisone taper with improvement in visual and neurologic symptoms.

Conclusion:

The authors present an unusual case of neurosarcoidosis masquerading as a CNS glioma. In cases of solitary CNS granulomas, radiographically differentiating neurosarcoidosis from a glioma can be challenging. In this case, serial ophthalmic examination identifying sequential involvement of both optic nerves helped to identify the underlying cause of the CNS disease as sarcoidosis.
GRAFT-VERSUS-HOST DISEASE PANUVEITIS AND BILATERAL SEROUS DETACHMENTS: MULTIMODAL IMAGING ANALYSIS
Authors: Jung Jesse J. , Chen Michael H. , Rofagha Soraya , Lee Scott S.
Published: August 2016

Purpose:

To report the multimodal imaging findings and follow-up of a case of graft-versus-host disease–induced bilateral panuveitis and serous retinal detachments after allogenic bone marrow transplant for acute myeloid leukemia.

Methods:

A 75-year-old black man presented with acute decreased vision in both eyes for 1 week. Clinical examination and multimodal imaging, including spectral domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, and swept-source optical coherence tomography angiography (Investigational Device; Carl Zeiss Meditec Inc) were performed.

Results:

Clinical examination of the patient revealed anterior and posterior inflammation and bilateral serous retinal detachments. Ultra-widefield fundus autofluorescence demonstrated hyperautofluorescence secondary to subretinal fluid; and fluorescein angiography revealed multiple areas of punctate hyperfluorescence, leakage, and staining of the optic discs. Spectral domain and enhanced depth imaging optical coherence tomography demonstrated subretinal fluid, a thickened, undulating retinal pigment epithelium layer, and a thickened choroid in both eyes. En-face swept-source optical coherence tomography angiography did not show any retinal vascular abnormalities but did demonstrate patchy areas of decreased choriocapillaris flow. An extensive systemic infectious and malignancy workup was negative and the patient was treated with high-dose oral prednisone immunosuppression. Subsequent 6-month follow-up demonstrated complete resolution of the inflammation and bilateral serous detachments after completion of the prednisone taper over a 3-month period.

Conclusion:

Graft-versus-host disease panuveitis and bilateral serous retinal detachments are rare complications of allogenic bone marrow transplant for acute myeloid leukemia and can be diagnosed with clinical and multimodal imaging analysis. This form of autoimmune inflammation may occur after the recovery of T-cell activity within the donor graft targeting the host. Infectious and recurrent malignancy must be ruled out before initiation of immunosuppression, which can affectively treat this form of graft-versus-host disease.
A NEW MACULAR DYSTROPHY SECONDARY TO A NOVEL MUTATION IN THE PROMININ 1 (PROM1) GENE
Authors: Randhawa Sandeep , Sharma Mithlesh
Published: August 2016

Purpose:

To report a case of a new macular dystrophy caused by a novel mutation in the PROM1 gene.

Methods:

History and clinical examination, fluorescein angiography, optical coherence tomography, autofluorescence, electrophysiology, and genetics.

Results:

We report a case of a 51-year-old man with progressive central visual loss in both his eyes. On fundus examination and imaging, there were asymmetric atrophic macular lesions in both his eyes. Electrophysiology revealed a bilateral macular atrophy; genetic testing revealed a novel PROM1 mutation as the probable cause.

Conclusion:

A novel PROM1 mutation as the cause of a new bilateral macular atrophy is revealed.
Complete Obliteration of the Left Atrial Appendage an Analysis of Epicardial Excision and Novel Pericardial Patch Exclusion
Authors: Malakouti-Nejad Bayan B. , Winkler Eliot J. , Johnson Marjorie I. , Catrip Jorge , Losenno Katie L. , Kiaii Bob B. , Chu Michael W. A.
Published: August 2016

Objective

Conventional epicardial excision is believed to be the most effective method of surgically obliterating the left atrial appendage (LAA), although incomplete resection and residual LAA volume may undermine its effectiveness. We sought to compare the impact of conventional epicardial excision with a novel LAA pericardial patch exclusion on residual LAA volume.

Methods

We performed LAA obliteration using pericardial patch exclusion, followed by conventional epicardial excision, in 27 cadaveric hearts. After each procedure, residual LAA volume was measured by two different techniques and compared with baseline volume. There was no difference in baseline LAA volume between each procedure.

Results

Procedural success was achieved in all hearts. Conventional epicardial excision left a residual LAA volume of 0.95 mL (24%), as compared with pericardial patch exclusion, which left a residual volume of 0.17 mL (4%, P = 0.0001). Further analysis of fixed and fresh hearts showed that reduction of LAA volume was more pronounced in the fresh hearts, suggesting effectiveness in live patients. Neither technique resulted in any significant change in the endocardial shape of the LAA orifice or injury to the circumflex artery.

Conclusions

Conventional epicardial excision of the LAA results in significantly more residual LAA volume, which may have important implications in persistent stroke risk. Pericardial patch exclusion seems to achieve near-total elimination of the LAA and may be a superior surgical option.
Prevalence of atlE, ica, mecA, and mupA Genes in Staphylococcus epidermidis Isolates
Authors: Mirzaei Rasoul , Sadeghi Javad , Talebi Malihe , Irajian Gholamreza
Published: August 2016

Background

Coagulase-negative staphylococcus (CoNS) bacteria, particularly Staphylococcus epidermidis, are one of the major causes of nosocomial infections. This study evaluated the prevalence of atlE, ica, mecA, and mupA genes in S. epidermidis isolates.

Methods

Two hundred thirty samples were collected from 2 hospitals (Ali Asghar and Hazrat Rasoul) in Tehran, Iran. One hundred twenty-three (53%) of isolates were identified as S. epidermidis. These isolates were tested for prevalence of atlE, ica, mecA, and mupA genes by using multiplex polymerase chain reaction.

Results

The prevalence of atlE, ica, mecA, and mupA were 94%, 78%, 76%, and 30% for clinical, 90%, 28%, 51%, and 13% for flora, and 94%, 29%, 51%, and 3% for environmental isolates, respectively.

Conclusions

Multiplex polymerase chain reaction revealed that occurrence of atlE, ica, mecA, and mupA in our isolates was relatively high. The growing problem of staphylococci especially S. epidermidis in Iran requires further cautious surveillance.
Mycobacterium bovis Aneurysm
Authors: Nandavaram Sravanthi , Al Twal Abdullah , Jacoby Helen , Lenox Robert
Published: August 2016

Bacillus Calmette-Guerin (BCG) is the attenuated strain of Mycobacterium bovis. Intravesicular live attenuated BCG is one of the well-known effective treatments for transitional cell carcinoma of the bladder. Severe disseminated mycobacterial infections in such patients are uncommon. Here, we present a case of M. bovis mycotic aneurysm of the left femoral artery, diagnosed 14 months after initiation of intravesical BCG immunotherapy for bladder cancer. Although rare, given the significant morbidity and mortality associated with mycotic aneurysms, physicians should be aware of this complication in appropriate clinical scenarios and should have high index of suspicion; appropriate treatment should be initiated promptly.
DRESS Syndrome Following Metformin Administration: A Case Report and Review of the Literature
Authors: Voore Prakruthi , Odigwe Chibuzo , Mirrakhimov Aibek E. , Rifai Dana , Iroegbu Nkemakolam A.
Published: August 2016

The drug rash with eosinophilia and systemic symptoms syndrome also known as DRESS syndrome refers to an idiosyncratic drug reaction commonly characterized by rashes, fever, lymphadenopathy, and internal organ involvement. We report a case of this syndrome in a 40-year-old man presenting with a rash, generalized pruritus, lymphadenopathy, and eosinophilia after metformin treatment. To the best of our knowledge, this is the first report linking metformin to the DRESS syndrome. The patient improved remarkably with drug withdrawal. A high index of clinical suspicion is emphasized to facilitate prompt diagnosis of medication related adverse effect and its discontinuation. In this article, we review the recent literature on DRESS syndrome.
Lactose Breath Test in Children: Relationship Between Symptoms During the Test and Test Results
Authors: Glatstein Miguel , Reif Shimon , Scolnik Dennis , Rom Liat , Yerushalmy-Feler Anat , Dali-Levy Margalit , Cohen Shlomi
Published: August 2016

Background:

Lactose malabsorption affects 70% of the world population. The hydrogen breath test (HBT) is used clinically to test for this condition. The aim of our study was to describe the relationship between symptoms experienced before and during the HBT and test results.

Methods:

We included children who underwent the HBT in the pediatric gastroenterology unit at Dana-Dwek Children's Hospital during a 6-month period. Previous symptoms and those experienced before and after the HBT were assessed using a questionnaire and a validated pain scale.

Results:

Ninety-five children were included in the study, and 66.3% had a positive HBT. Diarrhea and flatulence during the test were significantly more frequent in the group with a positive HBT compared to those with a negative test (31.7% vs. 9.4%, P = 0.016 and 69.8% vs. 40.6%, P = 0.006, respectively). The frequency of abdominal pain and bloating was similar.

Conclusions:

Diarrhea and flatulence during the HBT are the most specific symptoms of lactose intolerance. Abdominal pain should not be automatically attributed to lactose intolerance even in the presence of lactose malabsorption. Coupling the HBT with a real-time questionnaire facilitates interpretation of results and subsequent recommendations.
Pulmonary Hypertension and Atrial Septal Defect: Management Dilemma
Authors: El-Kersh Karim , Howsare Molly , Zaidi Ali , Flaherty Michael P. , Smith J. Shaun
Published: August 2016

The decision making in patients with an atrial septal defect (ASD) in setting of pulmonary hypertension is complex. In the era of pulmonary arterial vasodilator therapy, every patient should undergo evaluation by pulmonary hypertension experts especially if defect closure is being considered. Defect closure in the inappropriate group can lead to poor outcomes.
Limitations of Sacubitril/Valsartan in the Management of Heart Failure
Authors: Yandrapalli Srikanth , Aronow Wilbert S. , Mondal Pratik , Chabbott David R.
Published: August 2016

Background:

The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial was a double-blind trial that randomized 8442 patients with heart failure (HF) with reduced ejection fraction (HFrEF) to receive twice daily dosing of either 200 mg of LCZ696 or 10 mg of enalapril in addition to standard medical therapy for HF.

Areas of Uncertainty:

Limitations of this trial include (1) sacubitril has not been tested by itself in the treatment of HFrEF; (2) the maximum recommended dose of valsartan for the treatment of HFrEF was used in this trial, but the maximum recommended dose of enalapril for the treatment of HFrEF was not used; (3) a run-in phase was used in this trial to test the tolerability of LCZ696, and patients who had adverse effects in this period were excluded from randomization; (4) the percent of blacks enrolled in this trial was only 5%; (5) LCZ696 caused a 14% incidence of hypotension; (6) neprilysin inhibition might favor the development of Alzheimer dementia, which was not assessed in the PARADIGM-HF trial; (7) patients with severe symptomatic HF were underrepresented in this trial; (8) major exclusions from this trial included an acute coronary event in the last 3 months, severe pulmonary disease, hepatic impairment, and an estimated glomerular filtration rate <30 mL per minute per 1.73 m2.

Data Sources:

Review of the PARADIGM-HF trial.

Results:

At 27-month follow-up, the PARADIGM-HF trial showed that compared with enalapril, LCZ696 reduced the composite of cardiovascular death or hospitalization for HF 20% (absolute risk reduction 4.7%, P < 0.001).

Conclusions:

The numerous limitations discussed under the areas of uncertainty should be considered when prescribing LCZ696 for the treatment of HFrEF.
Diffusion-weighted Imaging Using Readout-segmented EPI Reveals Bony Metastases from Neuroblastoma
Authors: Hayes Laura L. , Alazraki Adina , Wasilewski-Masker Karen , Jones Richard A. , Porter David A. , Palasis Susan
Published: August 2016

Identifying neuroblastoma (NBL) metastases is crucial to treatment and prognosis. Metaiodobenzylguanidine and Tc99M bone scans are standard for identifying bony metastases but can underestimate disease. Diffusion-weighted imaging (DWI) of the spine has shown promise in evaluating bony metastases but has been limited by artifacts. Readout-segmented echo planar imaging is a technique for DWI that minimizes artifacts allowing for improved identification of spinal disease. This report illustrates the utility of DWI of the spine using readout-segmented echo planar imaging in the detection of bony NBL metastases in a child, lending support that DWI should be included in magnetic resonance imaging scans for NBL.
Neonatal Cyanosis Due to Hemoglobin Variant: Hb F-Sarajevo
Authors: Lozar-Krivec Jana , Stepic Maja , Hovnik Tinka , Krsnik Mladen , Paro-Panjan Darja
Published: August 2016

Neonatal cyanosis is rarely due to hemoglobin variants with low oxygen affinity. We describe the clinical course and results of molecular genetic analysis of a boy who presented after birth with severe cyanosis. Arterial blood-gas analysis demonstrated a pronounced shift of the oxygen-hemoglobin dissociation curve to the right and molecular genetic analysis revealed a Gγ-globin variant, Hb F-Sarajevo. The patient presented is the second reported case of neonatal cyanosis due to this mutation, which was first described in 2012 by Zimmermann-Baer and coauthors. With the introduction of universal screening for congenital heart disease, the finding of low oxygen saturation will uncover more neonates with hemoglobinopathies with low oxygen affinity.
A Dilated Cardiomyopathy Revealing a Neuroblastoma: Which Link?
Authors: Duhil de Bénazé Gwenaelle , Iserin Franck , Durand Philippe , Schleiermacher Gudrun , Orbach Daniel
Published: August 2016

Acute cardiac dysfunctions associated to neuroblastoma have rarely been reported. Cases already described are mainly related to high blood pressure, and rarely to an “acute catecholamine cardiomyopathy” more frequently found in adults with pheochromocytoma or secreting paraganglioma. We here report a case of an 8-month-old infant with severe acute cardiac failure with dilated cardiomyopathy and moderate ischemic myocardial signs, revealing a favorable histoprognosis neuroblastoma. After specific treatment, evolution was favorable, and cardiac function completely recovered. The association of reversible ischemic signs with high plasmatic level of catecholamines suggests the existence of a catecholamine-induced acute cardiac dysfunction which imitates a Tako-Tsubo syndrome in neuroblastoma.
Phenotypic Heterogeneity of Neutropenia and Gastrointestinal Illness Associated with G6PC3 Founder Mutation
Authors: Glasser Chana L. , Picoraro Joseph A. , Jain Preti , Kinberg Sivan , Rustia Evelyn , Gross Margolis Kara , Anyane-Yeboa Kwame , Iglesias Alejandro D. , Green Nancy S.
Published: August 2016

Severe congenital neutropenia type IV (SCN IV) is a syndrome of severe neutropenia, cardiac and urogenital defects, prominent superficial veins, facial dysmorphism, failure to thrive (FTT), and intermittent thrombocytopenia, caused by a glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene mutation. SCN IV has been linked to glycogen storage disease type 1b as both disorders involve disruption of the glucose-6-phosphatase/glucose-6-phosphate transporter complex, leading to arrested neutrophil maturation. Emerging evidence suggests that neutrophil function plays an important role in intestinal integrity, evidenced by inflammatory bowel disease in certain neutropenic patients. Here, we report 3 unrelated Hispanic males from the Dominican Republic with classic features of SCN IV found to share an identical inherited canonical splice-site mutation of the G6PC3 gene (c.218+1G>A). All 3 patients presented with severe FTT and gastrointestinal manifestations. Two of the patients had significant improvement in growth and resolution of gastrointestional symptoms with initiation of granulocyte colony-stimulating factor. We hypothesize that the gene variant described represents a founder mutation in the Dominican Republic, the first to be described in this geographical region. We discuss the potential associations between neutropenia and gastrointestinal disease with FTT and the role of granulocyte colony-stimulating factor in improving neutrophil count and intestinal integrity and growth.
Efficacy of a Solution Composed by Verbascoside, Polyvinylpyrrolidone (PVP) and Sodium Hyaluronate in the Treatment of Chemotherapy-induced Oral Mucositis in Children With Acute Lymphoblastic Leukemia
Authors: Bardellini Elena , Amadori Francesca , Schumacher Richard Fabian , D’Ippolito Carmelita , Porta Fulvio , Majorana Alessandra
Published: August 2016

The aim of this study was to assess the efficacy of a solution composed by verbascoside, polyvinylpyrrolidone, and sodium hyaluronate (Mucosyte) in the treatment of chemotherapy-induced oral mucositi (OM). Patients between 5 and 18 years receiving chemotherapy for acute lymphoblastic leukemia and with OM grade 1 or 2 were randomized in group A (treated with Mucosyte, 3 mouthwashes/d per 8 d) and group B (treated with placebo, ie, an inert water-based solution, 3 mouthwashes/d per 8 d). The OM scoring was performed at day 1 (diagnosis of OM-T0), after 3 days of treatment (T1), and at day 8 (T2). Pain was evaluated through the visual analog scale with the same timing of OM measurement. A total of 56 patients were included (28 patients per group). Group A experienced a statistically significant decline of OM at T2 (P=0.0038); a statistically significant difference in pain reduction between 2 groups both at T1 and at T2 (P<0.005) was observed. The use of Mucosyte mouthwashes in children with chemotherapy-induced OM may be recommended as supportive therapy.
Discontinuation of Folic Acid Supplementation in Young Patients With Sickle Cell Anemia
Authors: Nguyen Giang-Kim T. , Lewis Angela , Goldener Carol , Reed Brenda , Dulman Robin Yates , Yang Elizabeth
Published: August 2016

Folic acid (FA) is commonly prescribed for patients with sickle cell anemia, but evidence for the efficacy of this practice is lacking. We stopped FA supplementation and measured red blood cell folate levels after discontinuation of FA in 72 patients with clinically severe forms of sickle cell disease. We compared hemoglobin and reticulocyte counts before and after FA discontinuation in 51 of those patients, the majority of whom were on hydroxyurea. No patients had red blood cell folate levels below normal and no significant difference in hemoglobin levels (P=0.18) or reticulocyte counts (P=0.37) was found before and after FA discontinuation.
Association of Dyslipidemia and Glucose Abnormalities With Antiretroviral Treatment in a Cohort of HIV-Infected Latin American Children
Authors: Paganella Machline P. , Cohen Rachel A. , Harris Donald R. , de Souza Kuchenbecker Ricardo , Sperhacke Rosa D. , Kato Sergio K. , Oliveira da Silva Carmem L. , Sturzbecher Fernanda T. , Oliveira Ricardo H. S. , Pavía-Ruz Noris , Hazra Rohan ,   for the NISDI PLACES Protocol
Published: August 2016

Objective:

To estimate the incidence of lipid and glucose abnormalities and assess their association with exposure to antiretroviral (ARV) regimens among perinatally HIV-infected Latin American children.

Design:

Longitudinal cohort study.

Methods:

Data were analyzed from the Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative Pediatric Latin American Countries Epidemiologic Study. The incidence of dyslipidemia [total cholesterol >200 mg/dL, HDL < 35 mg/dL, LDL ≥ 130 mg/dL, triglycerides > 110 mg/dL (age < 10 years) or >150 mg/dL (≥10 years)] and fasting glucose abnormalities [homeostasis model assessment of insulin resistance >2.5 (Tanner stage 1) or >4.0 (Tanner stage > 1); impaired glucose: 110 to <126 mg/dL; diabetes: ≥126 mg/dL] was estimated. Proportional hazards regression was used to evaluate the risk of abnormalities associated with ARV regimen, adjusted for covariates.

Results:

There were 385 children eligible for analysis (mean age 6.6 years). Incident cholesterol abnormalities were reported in 18.1% of participants [95% confidence interval (CI): 14.1% to 22.8%], HDL and LDL cholesterol abnormalities in 19.6% (15.1%–24.7%) and 15.0% (11.3%–19.5%), respectively, and triglyceride abnormalities in 44.2% (37.7%–50.8%). In multivariable analysis, ARV regimen was only associated with triglyceride abnormalities; participants receiving a protease inhibitor (PI)-containing regimen were 3.6 times as likely to experience a triglyceride abnormality as those receiving no ARVs (95% CI: 1.3 to 10.5; P = 0.0167). The cumulative incidence of insulin resistance was 3.8% (1.8%–7.1%); there were no incident cases of diabetes and only 2 of impaired fasting glucose.

Conclusions:

Children receiving PI-containing regimens were at increased risk of developing triglyceride abnormalities. Continued monitoring of lipid levels in children receiving PI-containing regimens appears warranted.
Low Levels of Exhaled Surfactant Protein A Associated With BOS After Lung Transplantation
Authors: Ericson Petrea A. , Mirgorodskaya Ekaterina , Hammar Oscar S. , Viklund Emilia A. , Almstrand Ann-Charlotte R. , Larsson Per J-W. , Riise Gerdt C. , Olin Anna-Carin
Published: August 2016

Background

There is no clinically available marker for early detection or monitoring of chronic rejection in the form of bronchiolitis obliterans syndrome (BOS), the main long-term complication after lung transplantation. Sampling and analysis of particles in exhaled air is a valid, noninvasive method for monitoring surfactant protein A (SP-A) and albumin in the distal airways.

Methods

We asked whether differences in composition of exhaled particles can be detected when comparing stable lung transplant recipients (LTRs) (n = 26) with LTRs who develop BOS (n = 7). A comparison between LTRs and a matching group of healthy controls (n = 33) was also conducted. Using a system developed in-house, particles were collected from exhaled air by the principal of inertial impaction before chemical analysis by immunoassays.

Results

Surfactant protein A in exhaled particles and the SP-A/albumin ratio were lower (P = 0.002 and P = 0.0001 respectively) in the BOS group compared to the BOS-free group. LTRs exhaled higher amount of particles (P < 0.0001) and had lower albumin content (P < 0.0001) than healthy controls.

Conclusions

We conclude that low levels of SP-A in exhaled particles are associated with increased risk of BOS in LTRs. The possibility that this noninvasive method can be used to predict BOS onset deserves further study with prospective and longitudinal approaches.
Utility of Clinical Features for the Diagnosis of Seizures in the Intensive Care Unit
Authors: Schmitt Sarah E.
Published: August 2016

Purpose:

Seizures in the intensive care unit are often subtle, and may have little or no clinical correlate. This study attempts to determine what clinical features are most strongly associated with the presence of electrographic seizures on continuous EEG (cEEG) monitoring.

Methods:

A retrospective review for all patients who underwent cEEG monitoring between January 2003 and March 2009 for either characterization of clinical events or altered mental status was performed. Clinical events were categorized as (1) limb myoclonus/tremor, (2) extremity weakness, (3) eye movement abnormalities, (4) facial/periorbital twitching, and (5) other abnormal movements. The presence of associated dyscognitive event features was also recorded.

Results:

Records from 626 patients who underwent cEEG were reviewed—154 for event characterization and 472 for altered mental status. Seizures were captured in 48 patients (31.2%) undergoing cEEG monitoring for characterization of clinical events. This was not significantly different from the incidence of seizures in patients undergoing cEEG for altered mental status (N = 133, 28.2%). Patients undergoing cEEG monitoring for facial/periorbital twitching were significantly more likely to have electrographic seizures (78.9%, P < 0.005) than patients undergoing cEEG for altered mental status or characterization of other types of events.

Conclusions:

The incidence of seizures in patients in the intensive care unit with clinical events is generally not significantly higher than the incidence of seizures in patients in the intensive care unit with altered mental status. However, the presence of facial/periorbital twitching was associated a higher incidence of electrographic seizures.
Gender disparity in computational biology research publications
Authors: Bonham Kevin S. , Stefan Melanie I.
Published: August 2016

While women are generally underrepresented in STEM fields, there are noticeable differences between fields. For instance, the gender ratio in biology is more balanced than in computer science. We were interested in how this difference is reflected in the interdisciplinary field of computational/quantitative biology. To this end, we examined the proportion of female authors in publications from the PubMed and arXiv databases. There are fewer female authors on research papers in computational biology, as compared to biology in general. This is true across authorship position, year, and journal impact factor. A comparison with arXiv shows that quantitative biology papers have a higher ratio of female authors than computer science papers, placing computational biology in between its two parent fields in terms of gender representation. Both in biology and in computational biology, a female last author increases the probability of other authors on the paper being female, pointing to a potential role of female PIs in influencing the gender balance.
Metazoan ribotoxin genes acquired by Horizontal Gene Transfer
Authors: Lapadula Walter J. , Marcet Paula L. , Mascotti María L. , Puerta María V. Sánchez , Ayub Maximiliano Juri
Published: August 2016

Ribosome inactivating proteins (RIPs) are RNAN-glycosidases that depurinate a specific adenine residue in the conserved sarcin/ricin loop of 28S rRNA. These enzymes are widely distributed among plants and their presence has also been confirmed in several bacterial species. Recently, we reported for the first timein silicoevidence of RIP encoding genes in metazoans, in two closely related species of insects:Aedes aegyptiandCulex quinquefasciatus. Here, we have experimentally confirmed the presence of these genes in mosquitoes and attempted to unveil their evolutionary history. A detailed study was conducted, including evaluation of taxonomic distribution, phylogenetic inferences and microsynteny analyses, indicating that the culicine RIP genes derived from a single Horizontal Gene Transfer (HGT) event, probably from a Cyanobacterial donor species. Moreover, evolutionary analyses show that, after transference, these genes evolved under purifying selection, strongly suggesting that they play functional roles in these organisms. In this work we confirm the presence of RIP genes in Culicinae species, and show solid evidence supporting the hypothesis that these genes are derived from a single prokaryotic transferred gene through HGT. In addition, clear evidence of purifying selection pressure has been recorded, supporting the hypothesis that these genes are functional within this subfamily.
Fast Antibiotic Susceptibility Testing based on single cell growth rate measurements
Authors: Baltekin Özden , Boucharin Alexis , Tano Eva , Andersson Dan I. , Elf Johan
Published: August 2016

The emergence and spread of antibiotic resistant bacteria is a global threat to human health. The problem is aggravated by unnecessary and incorrect use of broad-spectrum antibiotics. One way to provide correct treatment and to slow down the development of antibiotic resistance is to assay the susceptibility profile of the infecting bacteria before treatment is initiated and let this information guide the choice of antibiotic. However, current methods for Antibiotics Susceptibility Testing (AST) are too slow for point of care application. Here we present a fast AST, fASTest, that rapidly captures individual bacterial cells in nanofluidics channels and monitors their response to different antibiotics based on direct imaging. By averaging the growth rate over many cells, we determined the susceptibility to several antibiotics in less than 25 min even at cell densities as low as 104 CFU/mL. The short time scale, high sensitivity and high specificity make the method practically useful for guiding antibiotic treatment in, for example, urinary tract infections.

One Sentence Summary

Individual bacterial cells can be captured and imaged in a microfluidic device to determine how their growth rate responds to antibiotic treatment in a few minutes.
Network analysis links genome-wide phenotypic and transcriptional stress responses in a bacterial pathogen with a large pan-genome
Authors: Jensen Paul A. , Zhu Zeyu , van Opijnen Tim
Published: August 2016

Background

Bacteria modulate subcellular processes to handle stressful environments. Genome-wide profiling of gene expression (RNA-Seq) and fitness (Tn-Seq) allows two views of the same genetic network underlying these responses. However, it remains unclear how they combine, enabling a bacterium to overcome a perturbation.

Results

Here we generate RNA-Seq and Tn-Seq profiles in three strains ofS. pneumoniaein response to stress defined by different levels of nutrient depletion. These profiles show that genes that change their expression and/or become phenotypically important come from a diverse set of functional categories, and genes that are phenotypically important tend to be highly expressed. Surprisingly, we find that expression and fitness changes rarely occur on the same gene, which we confirmed by over 140 validation experiments. To rationalize these unexpected results we built the first genome-scale metabolic model ofS. pneumoniaeshowing that differential expression and phenotypic importance actually correlate between nearest neighbors, although they are distinctly partitioned into small subnetworks. Moreover, a meta-analysis of 234S. pneumoniaegene expression studies reveals that essential genes and phenotypically important subnetworks rarely change expression, indicating that they are shielded from transcriptional fluctuations and that a clear distinction exists between transcriptional and phenotypic response networks.

Conclusions

We present a genome-wide computational/experimental approach that contextualizes changes that occur on transcriptomic and phenomic levels in response to stress. Importantly, this highlights the need to connect disparate response networks, for instance in antibiotic target identification, where preferred targets are phenotypically important genes that would be overlooked by transcriptomic analyses alone.
Influence of a mono-frequency sound on bacteria can be a function of the sound-level
Authors: Kothari Vijay , Joshi Chinmayi , Patel Pooja , Mehta Milan , Dubey Shashikant , Mishra Brijesh , Sarvaiya Niral
Published: August 2016

Chromobacterium violaceumwas subjected to sonic stimulation with 300 Hz sound, at five different levels of loudness in the range of 70 – 89.5 dB. Sonic stimulation was found to affect bacterial growth and quorum sensing regulated pigment (violacein) production significantly. Magnitude of this effect was found to be dependent on sound-level. The minimum critical difference required to cause any statistically significant change in bacterial response with respect to sound-level was found to be 13 dB. Growth ofC. violaceumwas affected more at lower sound intensity, whereas pigment production was affected more at higher sound intensity. Additional experiments withC. violaceumandSerratia marcescensindicated that even a silent speaker emitting no sound can alter bacterial growth and/or pigment production upto a minor extent. Size of the test tube in which bacteria are exposed to sonic stimulation, was not found to affect the results much.
Mycobacterium ulceranslow infectious dose and atypical mechanical transmission support insect bites and puncturing injuries in the spread of Buruli ulcer
Authors: Wallace John R. , Mangas Kirstie M. , Porter Jessica L. , Marcsisin Renee , Pidot Sacha J. , Howden Brian , Omansen Till F. , Zeng Weiguang , Axford Jason K. , Johnson Paul D. R. , Stinear Timothy P.
Published: August 2016

Addressing the transmission enigma of the neglected disease Buruli ulcer (BU) is a World Health Organization priority. In Australia, we have observed an association between mosquitoes harboring the causative agent,Mycobacterium ulcerans, and BU. Here we tested a contaminated skin model of BU transmission by dipping the tails from healthy mice in cultures of the causative agent,Mycobacterium ulcerans. Tails were exposed to mosquito (Aedes notoscriptusandAedes aegypti) blood feeding or punctured with sterile needles. Two of 11 of mice withM. ulceranscontaminated tails exposed to feedingA. notoscriptusmosquitoes developed BU. Eighteen of 20 mice subjected to contaminated tail needle puncture developed BU. Mouse tails coated only in bacteria did not develop disease. We observed a low infectious dose-50 of four colony-forming units and a median incubation time of 12 weeks, consistent with data from human infections. We have uncovered a highly efficient and biologically plausible atypical transmission mode of BU via natural or anthropogenic skin punctures.

Author summary

Buruli ulcer is a neglected tropical disease caused by infection withMycobacterium ulcerans. Unfortunately, how people contract this disease is not well understood. Here we show for the first time using experimental infections in mice that a very low dose ofM. ulceransdelivered beneath the skin by a minor injury caused by a blood-feeding insect (mosquito) or a needle puncture is sufficient to cause Buruli ulcer. This research provides important laboratory evidence to advance our understanding of Buruli ulcer disease transmission.
Hepatocyte nuclear factor 4-mediated lipotoxicity provokes mitochondrial damage in peroxisome-deficientpex19mutants
Authors: Bülow Margret H. , Sellin Julia , Wingen Christian , Senyilmaz Deniz , Gosejacob Dominic , Teleman Aurelio A. , Hoch Michael
Published: August 2016

Peroxisomes are important metabolic organelles involved in the catabolism of several lipid classes, e.g. very-long-chain fatty acids. Malfunction or absence of peroxisomes leads to accumulation of educts for peroxisomal β-oxidation and mitochondrial damage, resulting in fatal perturbation of metabolism. The impact of peroxisome deficiency on mitochondria is not elucidated yet. Here we present a model of Hepatocyte nuclear factor 4 (Hnf4)-induced lipotoxicity and accumulation of non-esterified fatty acids (NEFA) as the cause for mitochondrial damage in consequence of peroxisome loss in a Peroxin19 (pex19) mutant. Hyperactive Hnf4 signaling leads to upregulation oflipase 3and enzymes for mitochondrial β-oxidation. This results in enhanced lipolysis, elevated concentrations of NEFA, maximal β-oxidation and mitochondrial swelling. NEFA are ligands for Hnf4 and further enhance its activity. By genetic removal of Hnf4 inpex19mutants, lipotoxicity and mitochondrial swelling are reduced and their survival is rescued.

Author summary

Peroxisomes are cell organelles which play a major role in lipid metabolism. They interact with mitochondria, the organelles which are responsible for cellular energy production. Loss of peroxisomes, as it occurs in the rare, inheritable human disease class of Peroxisome Biogenesis Disorders, is lethal. Over the past couple of years, a number of studies showed that peroxisome loss leads to mitochondrial damage as a secondary consequence, but the underlying mechanism has not been understood yet. In our study, we use a mutant of the fruitflyDrosophila melanogasteras a model for Peroxisome Biogenesis Disorders and find that a protein called Hepatocyte nuclear factor 4 is hyperactive upon peroxisome loss, which provokes the mobilization of storage fat and, as a consequence, the accumulation of toxic free fatty acids. These enter the mitochondria, but cannot be used for energy gain. Free fatty acids are then trapped in the mitochondria and lead to their swelling and damage, which provides an explanation for mitochondrial defects in Peroxisomal Biogenesis Disorders. Genetic reduction of Hepatocyte nuclear factor 4 activity rescues the viability of the peroxisome mutant by reducing the accumulation of free fatty acids and the subsequent mitochondrial damage, which might provide a novel target for therapy development.
Individual level predictions ofStaphylococcus aureusbacteraemia-associated mortality
Authors: Recker Mario , Laabei Maisem , Toleman Michelle S. , Reuter Sandra , Blane Beth , Török Estee , Bayliss Sion , Peacock Sharon J. , Massey Ruth C.
Published: August 2016

The bacteriumStaphylococcus aureusis a major human pathogen, where the emergence of antibiotic resistance is a global public-health concern. Host factors such as age and the presence of co-morbidities have been implicated in a worse outcome for patient. However, this is complicated by the highly complex and multi-faceted nature of bacterial virulence, which has so far prevented a robust mapping between genotype, phenotype and infection outcome. To investigate the role of bacterial and host factors in contributing toS. aureusbacteraemia-associated mortality we sequenced a collection of clinical isolates (of the MLST clonal complex CC22) from patients with bloodstream infections and quantified specific virulence phenotypes. A genome-wide association scan identified several novel virulence-affecting loci, which we validated using a functional genomics approach. Analysing the data comprising bacterial genotype and phenotype as well as clinical meta-data within a machine-learning framework revealed that mortality associated with CC22 bacteraemia is not only influenced by the interactions between host and bacterial factors but can also be predicted at the individual patient-level to a high degree of accuracy. This study clearly demonstrates the potential of using a combined genomics and data analytic approach to enhance our understanding of bacterial pathogenesis. Considering both host and microbial factors, including whole genome sequence and phenotype data, within a predictive framework could thus pave the way towards personalised medicine and infectious disease management.
A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses
Authors: Bent Eric H. , Gilbert Luke A. , Hemann Michael T.
Published: August 2016

Cancer therapy targets malignant cells that are surrounded by a diverse complement of nonmalignant stromal cells. Therapy-induced damage of normal cells can alter the tumor microenvironment, causing cellular senescence and activating cancer-promoting inflammation. However, how these damage responses are regulated (both induced and resolved) to preserve tissue homeostasis and prevent chronic inflammation is poorly understood. Here, we detail an acute chemotherapy-induced secretory response that is self-limiting in vitro and in vivo despite the induction of cellular senescence. We used tissue-specific knockout mice to demonstrate that endothelial production of the proinflammatory cytokine IL-6 promotes chemoresistance and show that the chemotherapeutic doxorubicin induces acute IL-6 release through reactive oxygen species-mediated p38 activation in vitro. Doxorubicin causes endothelial senescence but, surprisingly, without a typical senescence secretory response. We found that endothelial cells repress senescence-associated inflammation through the down-regulation of PI3K/AKT/mTOR signaling and that reactivation of this pathway restores senescence-associated inflammation. Thus, we describe a mechanism by which damage-associated paracrine secretory responses are restrained to preserve tissue homeostasis and prevent chronic inflammation.
Direct interrogation of the role of H3K9 in metazoan heterochromatin function
Authors: Penke Taylor J.R. , McKay Daniel J. , Strahl Brian D. , Matera A. Gregory , Duronio Robert J.
Published: August 2016

A defining feature of heterochromatin is methylation of Lys9 of histone H3 (H3K9me), a binding site for heterochromatin protein 1 (HP1). Although H3K9 methyltransferases and HP1 are necessary for proper heterochromatin structure, the specific contribution of H3K9 to heterochromatin function and animal development is unknown. Using our recently developed platform to engineer histone genes in Drosophila, we generated H3K9R mutant flies, separating the functions of H3K9 and nonhistone substrates of H3K9 methyltransferases. Nucleosome occupancy and HP1a binding at pericentromeric heterochromatin are markedly decreased in H3K9R mutants. Despite these changes in chromosome architecture, a small percentage of H3K9R mutants complete development. Consistent with this result, expression of most protein-coding genes, including those within heterochromatin, is similar between H3K9R and controls. In contrast, H3K9R mutants exhibit increased open chromatin and transcription from piRNA clusters and transposons, resulting in transposon mobilization. Hence, transposon silencing is a major developmental function of H3K9.
The role of water molecules in the binding of class I and II peptides to the SH3 domain of the Fyn tyrosine kinase
Authors: Camara-Artigas Ana , Ortiz-Salmeron Emilia , Andujar-Sánchez Montserrrat , Bacarizo Julio , Martin-Garcia Jose Manuel
Published: August 2016

Interactions of proline-rich motifs with SH3 domains are present in signal transduction and other important cell processes. Analysis of structural and thermodynamic data suggest a relevant role of water molecules in these protein–protein interactions. To determine whether or not the SH3 domain of the Fyn tyrosine kinase shows the same behaviour, the crystal structures of its complexes with two high-affinity synthetic peptides, VSL12 and APP12, which are class I and II peptides, respectively, have been solved. In the class I complexes two water molecules were found at the binding interface that were not present in the class II complexes. The structures suggest a role of these water molecules in facilitating conformational changes in the SH3 domain to allow the binding of the class I or II peptides. In the third binding pocket these changes modify the cation–π and salt-bridge interactions that determine the affinity of the binding. Comparison of the water molecules involved in the binding of the peptides with previous reported hydration spots suggests a different pattern for the SH3 domains of the Src tyrosine kinase family.