bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism and Function of Type IV Secretion During Infection of the Human Host
Authors: Gonzalez-Rivera Christian , Bhatty Minny , Christie Peter J. 
Published: May 2016

ABSTRACT
Bacterial pathogens employ type IV secretion systems (T4SSs) for various purposes to aid in survival and proliferation in eukaryotic hosts. One large T4SS subfamily, the conjugation systems, confers a selective advantage to the invading pathogen in clinical settings through dissemination of antibiotic resistance genes and virulence traits. Besides their intrinsic importance as principle contributors to the emergence of multiply drug-resistant “superbugs,” detailed studies of these highly tractable systems have generated important new insights into the mode of action and architectures of paradigmatic T4SSs as a foundation for future efforts aimed at suppressing T4SS machine function. Over the past decade, extensive work on the second large T4SS subfamily, the effector translocators, has identified a myriad of mechanisms employed by pathogens to subvert, subdue, or bypass cellular processes and signaling pathways of the host cell. An overarching theme in the evolution of many effectors is that of molecular mimicry. These effectors carry domains similar to those of eukaryotic proteins and exert their effects through stealthy interdigitation of cellular pathways, often with the outcome not of inducing irreversible cell damage but rather of reversibly modulating cellular functions. This article summarizes the major developments for the actively studied pathogens with an emphasis on the structural and functional diversity of the T4SSs and the emerging common themes surrounding effector function in the human host.
The Versatile Type VI Secretion System
Authors: Alteri Christopher J. , Mobley Harry L.T. 
Published: May 2016

ABSTRACT
Bacterial type VI secretion systems (T6SSs) function as contractile nanomachines to puncture target cells and deliver lethal effectors. In the 10 years since the discovery of the T6SS, much has been learned about the structure and function of this versatile protein secretion apparatus. Most of the conserved protein components that comprise the T6SS apparatus itself have been identified and ascribed specific functions. In addition, numerous effector proteins that are translocated by the T6SS have been identified and characterized. These protein effectors usually represent toxic cargoes that are delivered by the attacker cell to a target cell. Researchers in the field are beginning to better understand the lifestyle or physiology that dictates when bacteria normally express their T6SS. In this article, we consider what is known about the structure and regulation of the T6SS, the numerous classes of antibacterial effector T6SS substrates, and how the action of the T6SS relates to a given lifestyle or behavior in certain bacteria.
A qualitative analysis of Māori and Pacific smokers' views on informed choice and smoking
Authors: Gifford Heather , Tautolo El-Shadan , Erick Stephanie , Hoek Janet , Gray Rebecca , Edwards Richard 
Published: May 2016

ObjectivesTobacco companies frame smoking as an informed choice, a strategy that holds individuals responsible for harms they incur. Few studies have tested this argument, and even fewer have examined how informed indigenous smokers or those from minority ethnicities are when they start smoking. We explored how young adult Māori and Pacific smokers interpreted ‘informed choice’ in relation to smoking.ParticipantsUsing recruitment via advertising, existing networks and word of mouth, we recruited and undertook qualitative in-depth interviews with 20 Māori and Pacific young adults aged 18–26 years who smoked.AnalysesData were analysed using an informed-choice framework developed by Chapman and Liberman. We used a thematic analysis approach to identify themes that extended this framework.ResultsFew participants considered themselves well informed and none met more than the framework's initial two criteria. Most reflected on their unthinking uptake and subsequent addiction, and identified environmental factors that had facilitated uptake. Nonetheless, despite this context, most agreed that they had made an informed choice to smoke.ConclusionsThe discrepancy between participants' reported knowledge and understanding of smoking's risks, and their assessment of smoking as an informed choice, reflects their view of smoking as a symbol of adulthood. Policies that make tobacco more difficult to use in social settings could help change social norms around smoking and the ease with which initiation and addiction currently occur.
Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus
Authors: Venkatasubramanian Sowmya , Noh Radzi M , Daga Shruti , Langrish Jeremy P , Mills Nicholas L , Waterhouse Brian R , Hoffmann Ethan , Jacobson Eric W , Lang Ninian N , Frier Brian M , Newby David E 
Published: May 2016

ObjectiveArterial stiffness increases with age, and is associated with adverse cardiovascular outcome including increased mortality. The effect of the oral small molecule SIRT1 activator, SRT2104, on arterial stiffness was examined in otherwise healthy cigarette smokers and participants with type 2 diabetes mellitus.Methods24 otherwise healthy cigarette smokers and 15 people with stable type 2 diabetes were randomised in a double-blind placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Blood pressure was measured using non-invasive oscillatory sphygmomanometry. Pulse wave analysis and velocity were measured using applanation tonometry at baseline and the end of each treatment period. Owing to the small sample size and similar trends for both groups, data for the two groups were pooled (post hoc analysis).ResultsCompared to placebo, treatment with SRT2104 was associated with a significant reduction in augmentation pressure (p=0.0273) and a trend towards improvement in the augmentation index and corrected augmentation index (p>0.05 for both). However, no changes were observed in pulse wave velocity and time to wave reflection (p>0.05). Systolic and diastolic blood pressures remained unchanged throughout the study. Treatment by cohort interaction was not significant for any of the pulse wave parameters, suggesting that the response to SRT2104 in otherwise healthy smokers and people with diabetes was consistent.ConclusionsSRT2104 may improve measures of arterial stiffness in otherwise healthy cigarette smokers and in participants with type 2 diabetes. Definitive conclusions are not possible given the small sample size and exploratory nature of this analysis.Trial registration numberNCT01031108.
Use of Anti‐HIV Immunotoxins as Probes of the Biology of HIV‐Infected Cells
Authors: Pincus SETH H , McClure Jan , Fang Hua 
Published: May 2016

OBJECTIVE: Anti‐human immunodeficiency virus (HIV) immunotoxins are potential treatments for HIV infection. but they may also be used as probes to study the relationship between HIV and the cell it infects. Data from the present study indicate the complexity of this relationship.DESIGN: A panel of monoclonal antibodies directed against different epitopes on the HIV envelope protein(s) gp l20 and gp 41 was conjugated to ricin A chain. The activity of these immunotoxins on HIV‐infected cell lines was studied.RESULTS: The data demonstrate that HIV‐infected cell lines may be killed by some, but not all, of these
immunotoxins. The killing is not directly proportional to the binding of the antibody to the infected cell and is influenced by the viral strain. The immunotoxins were used to select persistently infected cell lines for immunotoxin‐resistant variants: these demonstrate several different viral or cellular defects. The incubation of infected cells with a soluble form of the viral receptor increases the sensitivity of the cells to anti‐gp41, but not anti‐gpl20, immunotoxins by altering both the levels of expression and internalization of the viral envelope. Drugs that inhibit lysosomal degradation (ammonium chloride, monensin. chloroquine) enhance the efficacy of these immunotoxins.CONCLUSIONS: Because immunotoxins must be internalized to function, they may be used to study the intracellular trafficking of the target antigens. In the present study, this was done using the HIV‐envelope protein as expressed in infected cells as the target antigen
Clinical Development of Biological Response Modifiers
Authors: Siegel Jay P 
Published: May 2016

OBJECTIVE: To present perspectives on selected issues that frequently arise during the clinical development of biological response modifier (BRM) therapies.DATA SOURCES: The perspectives and opinions presented herein were developed over several years of reviewing and consulting on the clinical development of BRM therapies at the United States Food and Drug Administration.CONCLUSIONS: BRM therapies encompass a broad spectrum of products used to treat a wide variety of diseases. Due to this diversity. most principles of clinical trial design and conduct applicable to the majority of BRMS are those that are applicable to all therapies. Nevertheless, the clinical development of BRM therapies often raises specific issues and problems in the areas of selecting animal models, defining the study population, adverse reactions, dosing and defining end‐points. Over 10 years’ experience in testing biotechnology derived BRMS in clinical trials has created a database from which we can draw valuable generalizations for guidance in future studies.
Early Changes in Hepatitis C Virus (HCV) RNA Levels Predict Response to Interferon Treatment in Non-Cirrhotic HCV Patients
Authors: Fallows Glen , Kaita Kelly , Minuk Gerald , Penner Faye , Smart Gerry , Dawood Magdy , Rosser Barry 
Published: May 2016

The role of hepatitis C virus (HCV) RNA quantification in determining ideal interferon (IFN) treatment of noncirrhotic HCV liver disease is uncertain. The specific aim of this study was to determine whether measurement of baseline HCV RNA or changes in HCV RNA levels ( HCV RNA) early during therapy predict response to IFN in noncirrhotic HCV patients.PATIENTS AND METHODS: Twenty-one noncirrhotic patients with chronic HCV were treated with 3 MU IFN -2a three times per week. HCVRNA levels were determined at baseline and after two, four, six, eight and 12 weeks of treatment. BaselineHCV RNA and HCV RNA during therapy were compared with treatment response results at six months. Data were expressed as mean SE, and differences were assessed using Student’s t test.RESULTS: Twenty-one patients initiated IFN therapy. Two patients were noncompliant and lost to follow-up. One patient discontinued IFN due to side effects. Apart from age, where responders tended to be younger than nonresponders, the baseline clinical characteristics and alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin and HCV RNA levels did not differ between IFN responders and nonresponders. Levels of HCVRNA were significantly lower after both two and four weeks of therapy in IFN responders compared with nonresponders (P<0.001). Changes in log HCV RNA levels after both two and four weeks of therapy were significantly greater in IFN responders compared with nonresponders (P<0.001). Changes in log HCV RNA of more than 1.0 after two weeks of IFN therapy identified all six-month responders, with a sensitivity of 100% and a specificity of 89%. Potential financial impact of these findings on patients’ management was also calculated. Decisions regarding discontinuation of therapy based on early changes in HCV RNA levels would result in a 40% to 50% reduction in IFN cost.CONCLUSIONS: In noncirrhotic HCV patients, the change in quantitative HCV RNA after the first two weeks of IFN therapy identifies responders. This finding would result in a 40% to 50% cost savings if decisions about continuing IFN were based on early changes in HCVRNA levels rather than ALT or HCVRNA assessment after the completion of three months of IFN treatment.
Molecular Drivers of the Non–T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer
Authors: Sweis Randy F. , Spranger Stefani , Bao Riyue , Paner Gladell P. , Stadler Walter M. , Steinberg Gary , Gajewski Thomas F. 
Published: May 2016

Abstract
Muscle-invasive urothelial bladder cancer is a common malignancy with poor outcomes for which immune checkpoint blockade is now showing promise. Despite clinical activity of PD-1/PD-L1–targeted therapy in this disease, most patients do not benefit and resistance mechanisms remain unknown. The non–T-cell-inflamed tumor microenvironment correlates with poor prognosis and resistance to immunotherapies. In this study, we determined tumor-oncogenic pathways correlating with T-cell exclusion. We first establish in this report that T-cell–inflamed bladder tumors can be identified by immune gene expression profiling with concordance with CD8+ T-cell infiltration. Upregulation of genes encoding immune checkpoint proteins PD-L1, IDO, FOXP3, TIM3, and LAG3 was associated with T-cell–inflamed tumors, suggesting potential for sensitivity to checkpoint blockade. β-Catenin, PPAR-γ, and FGFR3 pathways were activated in non–T-cell-inflamed tumors. No difference was seen in overall somatic mutational density between groups. The three pathways identified represent targetable potential pathways of tumor-intrinsic immunotherapy resistance. Cancer Immunol Res; 4(7); 563–8. ©2016 AACR.
Adding Injury to Insult
Authors: Hojjat Houmehr , Svider Peter F. , Lin Ho-Sheng , Folbe Adam J. , Shkoukani Mahdi A. , Eloy Jean Anderson , Zuliani Giancarlo 
Published: May 2016

Objectives/Hypothesis: To estimate the incidence of patients presenting to emergency departments (EDs) for facial trauma sustained from participation in combat sports and evaluate injury patterns and patient demographics. Methods: The National Electronic Injury Surveillance System (NEISS) was evaluated for facial injuries from wrestling, boxing, and martial arts leading to ED visits from 2008 to 2013. Relevant entries were examined for injury mechanism, location, type, as well as other patient characteristics. Results: There were 1143 entries extrapolating to an estimated 42 395 ED visits from 2008 to 2013. Injury rates for boxing, marital arts, and wrestling were, respectively, 44, 56, and 120 injuries per 100 000 participants. Males comprised the majority (93.7%). A plurality of injuries involved lacerations (46.0%), followed by fractures (26.2%) and contusions/abrasions (19.3%). The proportion of fractures was highest among boxers (36.9%). Overall, the most common mechanisms of injury were punching, kicking, and head butting. Conclusions: The significant number of ED visits resulted from combat sports facial trauma, reinforcing the importance of familiarity with injury patterns among practitioners managing facial trauma. As most injuries involve individuals younger than 19 despite guidelines suggesting children and adolescents avoid combat sports, these findings may be used for patient education and encouragement of the use of personal protective equipment. Furthermore, injury patterns reported in this analysis may serve as an adjunct for enhancing clinical history taking and physical examination.
Palliative lumboperitoneal shunt for leptomeningeal metastasis–related hydrocephalus: A case series
Authors: Yamashiro Shigeo , Hitoshi Yasuyuki , Tajiri Seiji , Uchikawa Hiroki , Ito Kiyotaka , Yoshida Akimasa , Kuratsu Jun-ichi 
Published: May 2016

Background: Leptomeningeal metastasis–related hydrocephalus causes distress to patients with end-stage cancer through headache and other symptoms by elevating intracranial pressure, thus reducing quality of life. Ventriculoperitoneal shunt has been used as a treatment option in palliative care. We review four cases of patients who underwent lumboperitoneal shunt for leptomeningeal metastasis–related hydrocephalus. Cases: All patients suffered from severe headache and nausea. The primary lesion was histologically diagnosed as lung adenocarcinoma in each case. The duration from diagnosis to onset of hydrocephalus symptoms ranged from 0 to 52 (mean 26) months. Cerebrospinal fluid pressure in every case was above the normal range due to high intracranial pressure. Case management: Conventional procedures for lumboperitoneal shunt were employed for all patients. Adjustable pressure valves were retrofitted into the shunt system. Case outcome: Three patients demonstrated significant improvement of clinical symptoms and quality of life after placement of lumboperitoneal shunts. In two cases, not only did performance status improve to independent daily activity but also comparatively long-term survival was achieved due to subsequent chemotherapies after surgery. No symptoms of peritoneal dissemination by floating cancer cells in cerebrospinal fluid were seen in any patients. Conclusion: Lumboperitoneal shunt appears to improve quality of life if the patient is suffering from symptoms of leptomeningeal metastasis–related hydrocephalus. Compared to ventriculoperitoneal shunt, lumboperitoneal shunt is less invasive and simpler, providing a suitable option for frail patients with end-stage cancer. Adjustable pressure shunt valves can cope with varying symptoms and ventricle sizes.
Nurse Knowledge, Work Environment, and Turnover in Highly Specialized Pediatric End-of-Life Care
Authors: Lindley Lisa C. , Cozad Melanie J. 
Published: May 2016

Objective:To examine the relationship between nurse knowledge, work environment, and registered nurse (RN) turnover in perinatal hospice and palliative care organizations.Methods:Using nurse intellectual capital theory, a multivariate analysis was conducted with 2007 National Home and Hospice Care Survey data.Results:Perinatal hospice and palliative care organizations experienced a 5% turnover rate. The professional experience of advanced practice nurses (APNs) was significantly related to turnover among RNs (β = −.032, P < .05). Compared to organizations with no APNs professional experience, clinical nurse specialists and nurse practitioners significantly reduced RN turnover by 3 percentage points. No other nurse knowledge or work environment variables were associated with RN turnover. Several of the control variables were also associated with RN turnover in the study; Organizations serving micropolitan (β = −.041, P < .05) and rural areas (β = −.037, P < .05) had lower RN turnover compared to urban areas. Organizations with a technology climate where nurses used electronic medical records had a higher turnover rate than those without (β = .036, P < .05).Conclusion:The findings revealed that advanced professional experience in the form of APNs was associated with reductions in RN turnover. This suggests that having a clinical nurse specialist or nurse practitioner on staff may provide knowledge and experience to other RNs, creating stability within the organization.
Transitions to End-of-Life Care for Patients With Chronic Critical Illness: A Meta-Synthesis
Authors: Leung Doris , Angus Jan E. , Sinuff Tasnim , Bavly Sherri , Rose Louise 
Published: May 2016

Background: Adults with chronic critical illness (CCI) frequently experience a terminal trajectory but receive varying degrees of palliation and end-of-life care (EOLC) in intensive care units (ICUs). Why palliation (over curative treatment) is not augmented earlier for patients with CCI in ICU is not well understood. Purpose: To identify the social structures that contribute to timely, context-dependent decisions for transition from acute care to EOLC for patients with CCI and their families. Methods: We conducted a meta-synthesis of qualitative and/or mixed-method studies that recruited adults with CCI, their families or close friends, and/or health-care providers (HCPs) in an ICU environment. Results: Five studies reported data from 83 patients, 109 family members, and 57 HCPs across 5 institutions in Canada and the United States. Overall, we found that morally ambiguous social expectations of treatment tended to lock in HCPs to focus on prescriptive work of preserving life, despite pathways that could “open” access to augmenting palliation and EOLC. This process limited space for families’ reflexivity and reappraisal of CCI as a phase liminal to active dying. Notably, EOLC mechanisms were informal and less visible. Conclusion: The management of dying is one of the central tenets of ICU care. Our findings suggest that patients and families need help in negotiating meanings of this situation and in using mechanisms that allow reappraisal and permit understanding of CCI as a phase liminal to dying. Moreover, these mechanisms may paradoxically reduce the ambiguity of patients’ future, allowing them to live more fully in the present.
Are Calcium-Channel Blockers Effective in the Treatment of Tardive Dyskinesia?
Authors: Cates Marshall , Lusk Kim , Wells Barbara G. 
Published: May 2016

Objective To review the data describing the use of calcium-channel blockers in the treatment of tardive dyskinesia (TD). Data Sources A MEDLINE search of the English-language literature and a bibliographic review of pertinent articles examining the use of calcium-channel blockers in the treatment of TD were performed. Medical Subject Headings (MESH) terms used were calcium-channel blockers, tardive dyskinesia, nifedipine, verapamil, and diltiazem. STUDY SELECTION AND DATA EXTRACTION Relevant case reports, open trials, and controlled studies reporting on the efficacy of calcium-channel blockers for treating TD are reviewed. Appropriate conclusions are drawn from the data and guidelines are suggested for the practitioner. Data Synthesis Studies addressing the efficacy of calcium-channel blockers in the palliative treatment of TD have yielded mixed results. Positive findings have been reported for nifedipine, verapamil, and diltiazem; nifedipine may be the most efficacious treatment and diltiazem the least. It appears that patients with TD who can tolerate higher doses of calcium-channel blockers may respond more favorably to treatment. Patient characteristics that may help determine a better response to treatment with calcium-channel blockers include advanced age and more-severe TD. Conclusions To determine the efficacy of calcium-channel blockers in the treatment of TD, additional data are needed from double-blind, placebo-controlled studies with larger sample sizes and longer durations of treatment. Until these data are available, calcium-channel blockers should be considered potentially useful therapy for the heretofore unresponsive TD.