bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enzyme catalysis by entropy without Circe effect
Authors: Kazemi Masoud , Himo Fahmi , Åqvist Johan 
Published: January 2016

Significance
One of the most influential hypotheses regarding enzyme catalysis is Jencks’s so-called Circe effect, in which the catalytic power is usually equated to proper alignment of substrates, bringing reacting groups into close proximity, and restriction of substrate motions. The entropic penalty associated with climbing the activation barrier could then be diminished because it has already been paid upon substrate binding. The enzyme cytidine deaminase appears to be the perfect example of this behavior. Here, we use extensive computer simulations to obtain thermodynamic activation parameters for this reaction. The very large activation entropy difference between the enzyme reaction and the uncatalyzed process is, however, found to be attributable to a change of reaction mechanism rather than the Circe effect.
Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure
Authors: Buczynski Matthew W. , Herman Melissa A. , Hsu Ku-Lung , Natividad Luis A. , Irimia Cristina , Polis Ilham Y. , Pugh Holly , Chang Jae Won , Niphakis Micah J. , Cravatt Benjamin F. , Roberto Marisa , Parsons Loren H. 
Published: January 2016

Significance
Many CNS disorders result from dysregulation of the mesocorticolimbic dopamine projections arising from the ventral tegmental area. A mechanistic understanding of these dysregulations is critical for developing treatments for these diseases. Nicotine addiction is a global health concern, and results in part from dysregulated mesocorticolimbic dopamine function. Here we present evidence that nicotine-induced 2-arachidonoylglycerol formation in the ventral tegmental area is sensitized following chronic nicotine exposure, and that this results in the loss of GABA-mediated constraint of mesocorticolimbic dopamine activity. Potent and selective diacylglycerol lipase inhibitors are characterized and used in ex vivo electrophysiology and in vivo behavioral analyses to demonstrate that this mechanism plays a prominent role in the dysregulation of ventral tegmental dopamine neurons following nicotine exposure.
Quantitative proteomics identify DAB2 as a cardiac developmental regulator that inhibits WNT/β-catenin signaling
Authors: Hofsteen Peter , Robitaille Aaron M. , Chapman Daniel Patrick , Moon Randall T. , Murry Charles E. 
Published: January 2016

Significance
The directed differentiation of human embryonic stem cells into cardiomyocytes provides a tool for understanding human heart development and disease. During the process of cardiomyocyte differentiation, tight regulation of the WNT/β-catenin signaling pathway is required. Thus, understanding which proteins are involved in promoting or repressing the WNT/β-catenin signaling pathway is crucial for identifying positive and negative regulators of cardiac development. Here we measured protein expression during a time course of cardiomyocyte differentiation. We identified a regulator of cardiac development, Disabled 2, and found that in zebrafish embryos, it negatively regulates WNT/β-catenin signaling to promote cardiomyocyte differentiation. Thus, our work reveals a highly conserved, previously unidentified process relevant for human heart development.
Amyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity
Authors: Müller-Schiffmann Andreas , Herring Arne , Abdel-Hafiz Laila , Chepkova Aisa N. , Schäble Sandra , Wedel Diana , Horn Anselm H. C. , Sticht Heinrich , de Souza Silva Maria A. , Gottmann Kurt , Sergeeva Olga A. , Huston Joseph P. , Keyvani Kathy , Korth Carsten 
Published: January 2016

AbstractDespite amyloid plaques, consisting of insoluble, aggregated amyloid-β peptides, being a defining feature of Alzheimer’s disease, their significance has been challenged due to controversial findings regarding the correlation of cognitive impairment in Alzheimer’s disease with plaque load. The amyloid cascade hypothesis defines soluble amyloid-β oligomers, consisting of multiple amyloid-β monomers, as precursors of insoluble amyloid-β plaques. Dissecting the biological effects of single amyloid-β oligomers, for example of amyloid-β dimers, an abundant amyloid-β oligomer associated with clinical progression of Alzheimer’s disease, has been difficult due to the inability to control the kinetics of amyloid-β multimerization. For investigating the biological effects of amyloid-β dimers, we stabilized amyloid-β dimers by an intermolecular disulphide bridge via a cysteine mutation in the amyloid-β peptide (Aβ-S8C) of the amyloid precursor protein. This construct was expressed as a recombinant protein in cells and in a novel transgenic mouse, termed tgDimer mouse. This mouse formed constant levels of highly synaptotoxic soluble amyloid-β dimers, but not monomers, amyloid-β plaques or insoluble amyloid-β during its lifespan. Accordingly, neither signs of neuroinflammation, tau hyperphosphorylation or cell death were observed. Nevertheless, these tgDimer mice did exhibit deficits in hippocampal long-term potentiation and age-related impairments in learning and memory, similar to what was observed in classical Alzheimer’s disease mouse models. Although the amyloid-β dimers were unable to initiate the formation of insoluble amyloid-β aggregates in tgDimer mice, after crossbreeding tgDimer mice with the CRND8 mouse, an amyloid-β plaque generating mouse model, Aβ-S8C dimers were sequestered into amyloid-β plaques, suggesting that amyloid-β plaques incorporate neurotoxic amyloid-β dimers that by themselves are unable to self-assemble. Our results suggest that within the fine interplay between different amyloid-β species, amyloid-β dimer neurotoxic signalling, in the absence of amyloid-β plaque pathology, may be involved in causing early deficits in synaptic plasticity, learning and memory that accompany Alzheimer’s disease.10.1093/brain/awv355_video_abstract awv355_video_abstract
Missed Opportunities to Diagnose Tuberculosis Are Common Among Hospitalized Patients and Patients Seen in Emergency Departments
Authors: Miller Aaron C. , Polgreen Linnea A. , Cavanaugh Joseph E. , Hornick Douglas B. , Polgreen Philip M. 
Published: January 2016

AbstractBackground.  Delayed diagnosis of tuberculosis (TB) may lead to worse outcomes and additional TB exposures.Methods.  To estimate the potential number of misdiagnosed TB cases, we linked all hospital and emergency department (ED) visits in California′s Healthcare Cost and Utilization Project (HCUP) databases (2005–2011). We defined a potential misdiagnosis as a visit with a new, primary diagnosis of TB preceded by a recent respiratory-related hospitalization or ED visit. Next, we calculated the prevalence of potential missed TB diagnoses for different time windows. We also computed odds ratios (OR) comparing the likelihood of a previous respiratory diagnosis in patients with and without a TB diagnosis, controlling for patient and hospital characteristics. Finally, we determined the correlation between a hospital′s TB volume and the prevalence of potential TB misdiagnoses.Results.  Within 30 days before an initial TB diagnosis, 15.9% of patients (25.7% for 90 days) had a respiratory-related hospitalization or ED visit. Also, within 30 days, prior respiratory-related visits were more common in patients with TB than other patients (OR = 3.83; P &lt; .01), controlling for patient and hospital characteristics. Respiratory diagnosis-related visits were increasingly common until approximately 90 days before the TB diagnosis. Finally, potential misdiagnoses were more common in hospitals with fewer TB cases (ρ = −0.845; P &lt; .01).Conclusions.  Missed opportunities to diagnose TB are common and correlate inversely with the number of TB cases diagnosed at a hospital. Thus, as TB becomes infrequent, delayed diagnoses may increase, initiating outbreaks in communities and hospitals.
Knowledge, Attitude, and Practices of Healthcare Personnel Regarding the Transmission of Pathogens via Fomites at a Tertiary Care Hospital in Karachi, Pakistan
Authors: Aftab Hassaan Bin , Zia Bushra , Zahid Mohammad Faizan , Raheem Ahmed , Beg Mohammad Asim 
Published: January 2016

AbstractBackground.  Fomites are objects that can become colonized and serve as vectors in the transmission of pathogenic microorganisms. Literature examining the knowledge of healthcare personnel about this method of spread of infection is lacking. We conducted a study to assess the knowledge, attitude, and practices of healthcare personnel across different areas of patient care regarding the spread of infections at a tertiary care hospital in Karachi, Pakistan.Methods.  A descriptive, cross-sectional study was conducted among healthcare personnel using a self-administered questionnaire. The questionnaire contained sections pertaining to demographic details and knowledge, attitude, and practices regarding fomites and their role in the transmission of pathogens.Results.  Three hundred and fifty-three participants completed the questionnaire: 168 were male and 185 were female. Laboratory coats, stethoscopes, and bedside curtains were most frequently identified as fomites by the participants. Medical students had significantly lower mean scores in the knowledge and attitude sections than consultant physicians, resident physicians, and nurses. Nurses scored higher than consultant physicians, resident physicians, and medical students regarding practices that minimize fomite-borne spread of infections. 95% of the participants scored above 50% on the knowledge component of the questionnaire, but only 32.3% scored above 50% in the practices section.Conclusions.  Our results show a large gap between the knowledge about fomites acting as vectors in the spread of pathogens and practices done to minimize this spread. Possessing adequate knowledge is ineffectual until and unless it is translated into the proper application of infection control practices. Incorporating awareness sessions and exercises into curricula are a reasonable way to raise awareness regarding this subject.
A Case of Long-Term Seronegative Human Immunodeficiency Virus (HIV) Infection: The Importance of the Humoral Response to HIV
Authors: Siemieniuk Reed A. C. , van der Meer Frank , van Marle Guido , Gill M. John 
Published: January 2016

Abstract
Background.  Seronegative human immunodeficiency virus (HIV) infections are exceedingly rare but might inform HIV-host physiology.
Methods.  We investigate the cause and consequences of a patient infected with HIV who did not mount a humoral response to HIV for 4 years.
Results.  The patient was confirmed HIV-uninfected by nucleic acid testing 4 months before rapidly progressing to acquired immune deficiency syndrome. The patient's humoral deficit was specific to HIV: he mounted robust humoral responses to all challenge vaccines including influenza A(H1N1)pdm09 and all T cell-dependent and -independent serotypes in the 23-valent pneumococcal polysaccharide vaccine. The virus had similar gp120 antigenicity to HIV-positive control serum as NL4-3 and YU2 prototype strains. Two human leukocyte antigen alleles associated with rapid progression were identified (B*08 and B*35), and a cytotoxic T-lymphocyte epitope site variant was noted: E277K. Viral decay (t1/2 ≈ 39 weeks) suggested that relatively long-lived cells were the source of ongoing viremia. Human immunodeficiency virus viremia was not suppressed until after the patient developed a humoral immune response, despite therapeutic antiretroviral levels. No resistance was detected by virtual phenotyping of virus obtained from serum or from gastrointestinal biopsies despite considerable antiretroviral selection pressure.
Conclusions.  Ineffective antibody production may be associated with a subgroup of extremely rapid HIV progressors. Although antiretroviral therapy may be sufficient to slow propagation of infection, it appears to be ineffective for HIV viral clearance in the absence of a humoral response.
Viral Escape in the Central Nervous System with Multidrug-Resistant Human Immunodeficiency Virus-1
Authors: Béguelin C. , Vázquez M. , Bertschi M. , Yerly S. , de Jong D. , Gutbrod K. , Rauch A. , Cusini A. 
Published: January 2016

Abstract
In this study, we report the case of a patient infected with human immunodeficiency virus (HIV)-1 who developed ataxia and neurocognitive impairment due to viral escape within the central nervous system (CNS) with a multidrug-resistant HIV-1 despite long-term viral suppression in plasma. Antiretroviral therapy optimization with drugs with high CNS penetration led to viral suppression in the CSF, regression of ataxia, and improvement of neurocognitive symptoms.
Management of Multiple Myeloma Complicated by Hepatitis C Virus Reactivation: The Role of New Antiviral Therapy
Authors: Mahale Parag , Thomas Sheeba K. , Kyvernitakis Andreas , Torres Harrys A. 
Published: January 2016

Abstract
Reactivation of chronic hepatitis C virus (HCV) infection has been reported in cancer patients receiving chemotherapy. In this study, we report the first case, to our knowledge, of thalidomide-induced acute exacerbation and reactivation of chronic HCV infection complicating management of multiple myeloma. Sofosbuvir-based antiviral therapy helped achieve viral clearance and normalization of liver enzymes, thus allowing access to future potentially life-saving chemotherapy agents.
Senior Center-Based Hepatitis C Screening in Baltimore
Authors: Falade-Nwulia Oluwaseun , Irvin Risha , McAdams-Mahmoud Ayesha , Mehta Shruti H. , Niculescu Alexander , Lasola Jackline , Baker Dorcas , Eppel Arnold , Chaulk Patrick , Page Kathleen R. , Sulkowski Mark , Thomas David 
Published: January 2016

Abstract
Despite significant advancements in hepatitis C virus (HCV) treatments, the majority of individuals infected with HCV remain undiagnosed. We report on senior citizen center-based HCV testing in Baltimore, which revealed a 9.4% prevalence of infection. Our data suggest that community-based HCV testing and linkage to care in appropriate settings is feasible and high yield.
Surgical Correction of Scoliosis in Patients With Duchenne Muscular Dystrophy: 30-Year Experience
Authors: Scannell Brian P. , Yaszay Burt , Bartley Carrie E. , Newton Peter O. , Mubarak Scott J. 
Published: January 2016

Background:
The natural history of scoliosis in Duchenne muscular dystrophy (DMD) is progressive and debilitating if neglected. The purpose of this study was to evaluate outcomes related to spinal deformity surgery in patients with DMD over a 30-year period.

Methods:
This was a single center retrospective study of all operatively treated scoliosis in DMD patients over 30 years. Minimum follow-up was 2 years. Owing to changes in instrumentation over time, patients were divided into 2 groups: Luque or pedicle screws (PS) constructs. Radiographic, perioperative variables, pulmonary function test (preoperatively and postoperatively), and complication data were evaluated.

Results:
There were 60 subjects (Luque: 47, PS: 13). The Luque group was on average 13 years old, 53 kg, and had 7 years of follow-up. Coronal Cobb was 31±12 degrees preoperatively, 16±11 degrees at first postoperatively, and 21±15 degrees at final follow-up (P≤0.001). Pelvic obliquity was 7±6 degrees preoperatively, 5±5 degrees at first postoperatively (P=0.43), and 5±4 degrees at final follow-up (P=0.77). The majority of this group was fused to L5 (45%) or the sacrum (49%). The PS group was on average 14 years old, 65 kg, and had 4 years of follow-up. Coronal Cobb was 43±19 degrees preoperatively, 12±9 degrees at first postoperatively (P≤0.001), and 12±8 degrees at final follow-up. Pelvic obliquity was 6±5 degrees preoperatively, 3±3 degrees at first postoperatively (P=0.06), and 2±2 degrees at final follow-up (P=0.053). The majority were fused to the pelvis (92%). Both groups’ pulmonary function declined with time. Both groups had high complication rates (Luque 68%; PS group 54%). The Luque group had more implant-related complications (26%); the PS group had a higher rate of early postoperative infections (23%).

Conclusions:
Over a 30-year period of operative treatment of scoliosis in DMD, both PS constructs and Luque instrumentation improved coronal Cobb. The PS group had improved and maintained pelvic obliquity. Both groups had high complication rates.

Level of Evidence:
Level IV—therapeutic.
Sacral Alar Iliac (SAI) Screws Fail 75% Less Frequently Than Iliac Screws in Neuromuscular Scoliosis
Authors: Shabtai Lior , Andras Lindsay M. , Portman Mark , Harris Liam R. , Choi Paul D. , Tolo Vernon T. , Skaggs David L. 
Published: January 2016

Background:
Despite recent popularity of sacral alar iliac (SAI) screws for fusion to the pelvis for neuromuscular scoliosis, there are little data regarding the failure rate of this technique compared with traditional modes of iliac fixation. Theoretical advantages of the SAI screws are obviating the need for a rod to iliac screw connector and a lower implant profile. The purpose of this study is to determine whether SAI screws have fewer failures than iliac screws in neuromuscular scoliosis.

Methods:
Review of neuromuscular patients treated with posterior spinal fusion with pelvic fixation from 2004 to 2012 with minimum 2-year follow-up was conducted. Medical records and imaging studies were reviewed. Patients were divided into 2 groups based on the type of pelvic fixation (SAI or iliac screws), and implant failures were compared between the groups.

Results:
A total of 101 patients were reviewed, including 55 patients with iliac screws and 46 patients with SAI screws. Implant failures included: disengagement of the rod to iliac screw connector (10%, 10/101), separation of screw head from screw shaft (4%, 4/101), and set screw disengagement (2%, 2/101). The SAI group had a lower implant failure rate (7%, 3/46) compared with the iliac screw group (24%, 13/55) (P=0.031). Rod to iliac screw connectors failed in 18% (10/55) of patients. There were significantly less surgical revisions in the SAI group (2%, 1/46) for pelvic screw prominence compared with the iliac screw group (11%, 6/55) (P=0.027).

Conclusions:
SAI screws had a lower rate of implant failure and revision surgery compared with iliac screws. If rod to screw connector failures are excluded, the failure rate of SAI screws of 6.5% (3/46) is similar to that of iliac screws 5.5% (3/55); therefore, the most important advantage of the SAI technique may be obviating the need for a screw to rod connector.

Level of Evidence:
Level III.
Primary Debulking Surgery Versus Neoadjuvant Chemotherapy in Advanced Epithelial Ovarian Cancer
Authors: Siesto Gabriele , Cavina Raffaele , Romano Fabrizio , Vitobello Domenico 
Published: January 2016

Aims:
To compare the surgical and survival outcomes of patients undergoing primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT) plus interval debulking surgery (IDS) for advanced epithelial ovarian cancer (EOC).

Materials and Methods:
Consecutive patients managed for advanced EOC since 2009 were matched through a propensity score analysis, defined as the probability of a woman having PDS or NACT plus IDS.

Results:
The study group consisted of 100 propensity-matched women receiving PDS or NACT plus IDS. Groups resulted homogeneous in terms of baseline characteristics and pathologic findings. Patients undergoing PDS had longer operative time (P=0.032) and more blood loss (P=0.011) than the counterpart receiving NACT. No differences were found in terms of residual disease (P=0.11), as well as in terms of hospitalization, intraoperative, and postoperative complications. The mean progression-free survival was 23.0 and 27.7 months (P=0.67), whereas the overall survival (OS) was 44.5 and 43.2 months (P=0.48) for the PDS and NACT plus IDS group, respectively. Residual disease (P<0.0001) was the only independent predictor of progression-free and OS at multivariate analysis.

Conclusions:
PDS and NACT plus IDS achieved comparable results in terms of progression-free and OS in patients with advanced EOC.
Albumin and Neutrophil-Lymphocyte Ratio (NLR) Predict Survival in Patients With Pancreatic Adenocarcinoma Treated With SBRT
Authors: Alagappan Muthuraman , Pollom Erqi L. , von Eyben Rie , Kozak Margaret M. , Aggarwal Sonya , Poultsides George A. , Koong Albert C. , Chang Daniel T. 
Published: January 2016

Purpose:
To determine if pretreatment nutritional status and inflammatory markers correlate with survival in patients with locally advanced pancreatic adenocarcinoma treated with stereotactic body radiotherapy (SBRT).

Materials and Methods:
We retrospectively reviewed 208 patients with newly diagnosed, locally advanced pancreatic adenocarcinoma treated with SBRT at our institution from 2002 to 2014. Laboratory values were collected before SBRT, including hemoglobin, platelets, albumin, red blood cell, white blood cell, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, and tumor markers CA 19-9 and CEA. Patients were followed every 3 months with computed tomography (CT) and/or positron emission tomography-CT imaging to monitor for local recurrence and overall survival (OS).

Results:
Median follow-up after SBRT was 7.5 months (interquartile range, 4.6 to 12.0 mo) for all patients. Median OS for patients with NLR>5 compared with NLR≤5 was 6.9 and 8.5 months, respectively (P=0.0057). On univariate analysis, receipt of chemotherapy (P=0.05, hazard ratio [HR]=0.69), increased albumin (P=0.002, HR=0.64), increased red blood cell (P=0.05, HR=0.75), increased lymphocyte count (P=0.002, HR=0.66), decreased CEA (P=0.01, HR=0.96), and NLR≤5 (P=0.01, HR=0.65) correlated with improved OS. On multivariate analysis, higher albumin (P=0.03, HR=0.70), receipt of chemotherapy (P=0.007, HR=0.56), and NLR≤5 (P=0.02, HR=0.66) correlated with better survival.

Conclusions:
Preradiotherapy low albumin levels and NLR>5 correlate with decreased survival in patients with locally advanced pancreatic adenocarcinoma treated with SBRT, indicating the prognostic value of systemic inflammatory markers (such as NLR) and a role of nutritional supplementation to improve outcomes in these patients. Further investigation is warranted.
INTRAARTERIAL CHEMOTHERAPY FOR RETINOBLASTOMA IN A 2-MONTH-OLD INFANT
Authors: Magan Tejal , Khoo Chloe T.L. , Jabbour Pascal M. , Shields Carol L. 
Published: January 2016

Purpose:
Intraarterial chemotherapy for retinoblastoma is usually reserved for infants aged 3 months or older because of the intricacy of the newborn vascular anatomy making the procedure technically challenging. The authors report a successful case of intraarterial chemotherapy performed in a 2-month-old infant using a minimal exposure approach.

Methods:
Case report.

Results:
A 2-month-old infant presented with leukocoria and was subsequently diagnosed with an exophytic Group D retinoblastoma in the right eye. The infant received melphalan 3 mg delivered into the ostium of the ophthalmic artery of the right eye under fluoroscopic guidance. Examination under anesthesia a month later showed complete tumor regression to a calcified Type I scar. After a second cycle of intraarterial chemotherapy, no further treatment was necessary. There were no complications.

Conclusion:
Intraarterial chemotherapy is generally used for retinoblastoma in infants aged 3 months or older. The patient was successfully catheterized and treated at 2 months of age, with complete tumor regression after a single chemotherapy dose. Thus, in expert hands, intraarterial chemotherapy can be considered in such young infants.