Solid lipid nanoparticles improve octyl gallate antimetastatic activity and ameliorate its renal and hepatic toxic effects.

Metastasis is the main cause of cancer-related death and requires the development of effective treatments with reduced toxicity and effective anticancer activity. Gallic acid derivatives have shown significant biological properties including antitumoral activity as shown in a previous study with octyl gallate (G8) in vitro. Thus, the aim of this work was to evaluate the antimetastatic effect of free and solid lipid nanoparticle-loaded G8 in mice in a lung metastasis model. Animals inoculated with melanoma cells presented metastasis in lungs, which was significantly inhibited by treatment with G8 and solid lipid nanoparticle-loaded G8, named G8-NVM. However, G8-treated mice showed an increase in several toxicological parameters, which were almost completely circumvented by G8-NVM treatment. This study supports the need for pharmacological studies on new potential medicinal plants to treat cancer and can provide new perspectives on using nanotechnology to improve biological activities while decreasing the chemotherapy toxicological effects of anticancer drugs. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Communication in pediatric oncology: State of the field and research agenda

Abstract

From the time of diagnosis through either survivorship or end of life, communication between healthcare providers and patients or parents can serve several core functions, including fostering healing relationships, exchanging information, responding to emotions, managing uncertainty, making decisions, and enabling patient/family self-management. We systematically reviewed all studies that focused on communication between clinicians and patients or parents in pediatric oncology, categorizing studies based on which core functions of communication they addressed. After identifying gaps in the literature, we propose a research agenda to further the field.

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VIncristine, irinotecan, and temozolomide in children and adolescents with relapsed rhabdomyosarcoma

Abstract

Background

The combination of vincristine, irinotecan, and temozolomide (VIT) is often used to treat children and adolescents with relapsed rhabdomyosarcoma (RMS); however, the outcome of these patients has not been previously described.

Procedures

We sought to determine the response rate (RR) and progression-free survival (PFS) for patients with relapsed RMS treated with VIT by retrospective review of patients treated at five tertiary care hospitals. Prior treatment with irinotecan was permitted.

Results

Among 19 patients with a median age of 8 years (range 2–17 years), 12 (63%) were males and 12 (63%) had embryonal histology. Median time to relapse from initial diagnosis was 16 months (range 2.8-45 months). VIT was used as first, second, third, or fourth line of therapy in four (21%), seven (37%), six (32%), and two (10%) patients, respectively. Four patients received VIT as adjuvant therapy following radiation and/or surgery. Therefore, among 15 evaluable patients, the best response to VIT was 0 (complete response, CR), 0 (partial response, PR), 4 (stable disease, SD), and 11 (progressive disease, PD) for an overall clinical benefit rate (CR + PR + SD) of 26.7% (95% CI: 7.8–55.1%). After a median follow-up of 8 months, 2 (10%) patients were alive without disease, 3 (16%) were alive with disease, and 14 (74%) patients died of PD. PFS at 3 months was 23% (95% CI: 5.7–46.7%).

Conclusions

VIT therapy in combination with adequate local control is associated with some disease control in patients with first relapse RMS and may be another reasonable option to offer patients as salvage therapy.

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Outcomes of matched sibling donor bone marrow transplantation in children using single-agent calcineurin inhibitors as prophylaxis for graft versus host disease

Abstract

Background

Optimal graft versus host disease (GVHD) prophylaxis prevents severe manifestations without excess immunosuppression. Standard prophylaxis includes a calcineurin inhibitor (CNI) with low-dose methotrexate. However, single-agent CNI may be sufficient prophylaxis for a defined group of patients. Single-agent CNI has been used for GVHD prophylaxis for human leukocyte antigen (HLA)-matched sibling donor (MSD) bone marrow transplants (BMTs) in young patients at the Children's Hospital of Philadelphia for over 20 years. Here, we describe outcomes using this prophylactic strategy in a recent cohort.

Procedure

We performed a single-institution chart review and retrospective analysis of consecutive children undergoing MSD BMT who received single-agent CNI for GVHD prophylaxis between January 2002 and December 2014.

Results

Fifty-two children with a median age of 6.1 years (interquartile range [IQR] 2.5–8.3) and donor age of 6 years (IQR 3–10), with malignant and nonmalignant diseases (n = 35 and 17, respectively) were evaluated. Forty-three (82.6%) received oral prophylaxis with single-agent tacrolimus after initial intravenous therapy. Rates of GVHD were consistent with reported rates on dual prophylaxis: the overall incidence of grades 2–4 acute GVHD was 25.5%, grades 3–4 GVHD 9.8%, and chronic GVHD 10.4%. The cumulative incidence of relapse among children with malignancy was 20% at a median of 237 days (IQR 194–318) post-transplant. Two-year overall survival was 82.7% (95% confidence interval [CI]: 69.4–90.6%) and event-free survival was 78.9% (95% CI: 65.1–87.7%). No patient experienced graft failure.

Conclusions

Single-agent CNI is a safe, effective approach to GVHD prophylaxis in young patients undergoing HLA-identical sibling BMT. Additionally, single-agent oral tacrolimus is a reasonable alternative to cyclosporine in this population.

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Novel activating BRAF fusion identifies a recurrent alternative mechanism for ERK activation in pediatric Langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by constitutive activation of extracellular signal-regulated kinase (ERK). Genomic characterization has identified activating point mutations including mutually exclusive BRAFV600E and activating MAP2K1 mutations to be responsible for ERK activation in a majority of pediatric LCH patients. Here, we report the discovery of a novel BRAF kinase fusion, PACSIN2-BRAF, in a child with multisystem LCH. This is the second reported case of an activating BRAF kinase fusion and indicates a recurrent pathologic mechanism. Genomic evaluation for activating kinase fusions should be strongly considered in pediatric LCH patients lacking more common mutations.

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Management of chemotherapy-induced febrile neutropenia in pediatric oncology patients: A North American survey of pediatric hematology/oncology and pediatric infectious disease physicians

ABSTRACT

Background

Chemotherapy-induced febrile neutropenia (FN) is traditionally managed with hospital admission for parenteral antibiotics until neutropenia resolves. Recent studies have explored risk stratification and the safety of managing "low-risk" patients as outpatients. Few studies have directly assessed pediatric provider preferences for managing FN.

Procedure

We conducted a survey of practicing US and Canadian pediatric hematology/oncology (PHO) and pediatric infectious disease (PID) physicians to assess their FN management preferences using case scenarios with varying risk profiles.

Results

Twenty-one percent (n = 186) of PHO and 32% (n = 123) of PID physicians completed the survey. Overall, both groups of providers agreed regarding which patients with FN could be managed outpatient. For a child with acute lymphoblastic leukemia receiving maintenance chemotherapy with an absolute neutrophil count (ANC) of 400 cells/μl, 35% (n = 66) of PHO and 49% (n = 60) of PID physicians would consider outpatient management (P = 0.02). Of those physicians selecting inpatient management, 41% (n = 49) of PHO and 52% (n = 33) of PID physicians would be willing to discharge the patient without an increase in ANC, if afebrile with a negative blood culture (P = 0.16). For a similar patient with an ANC of 100 cells/μl, only 23% (n = 35) of PHO and 42% (n = 39) of PID physicians would consider discharge without an increase in ANC (P = 0.002).

Conclusions

Despite the lack of established guidelines for low-risk pediatric FN, a significant proportion of North American physicians report willingness to modify traditional management. This reinforces the need for evidence-based low-risk criteria and outpatient management guidelines to optimize consistency of care for these patients.

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Reliable assessment of the incidence of childhood autoimmune hemolytic anemia

Abstract

Background

Childhood autoimmune hemolytic anemia (AIHA) is a rare and severe disease characterized by hemolysis and positive direct antiglobulin test (DAT). Few epidemiologic indicators are available for the pediatric population. The objective of our study was to reliably estimate the number of AIHA cases in the French Aquitaine region and the incidence of AIHA in patients under 18 years old.

Procedure

In this retrospective study, the capture–recapture method and log-linear model were used for the period 2000–2008 in the Aquitaine region from the following three data sources for the diagnosis of AIHA: the OBS'CEREVANCE database cohort, positive DAT collected from the regional blood bank database, and the French medico-economic information system.

Results

A list of 281 different patients was obtained after cross-matching the three databases; 44 AIHA cases were identified in the period 2000–2008; and the total number of cases was estimated to be 48 (95% confidence interval [CI]: 45–55). The calculated incidence of the disease was 0.81/100,000 children under 18 years old per year (95% CI 0.76–0.92).

Conclusion

Accurate methods are required for estimating the incidence of AIHA in children. Capture–recapture analysis corrects underreporting and provides optimal completeness. This study highlights a possible under diagnosis of this potentially severe disease in various pediatric settings. AIHA incidence may now be compared with the incidences of other hematological diseases and used for clinical or research purposes.

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Rethinking reconsent when minors reach adult age in minimal risk studies

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Transverse myelitis as an unexpected complication following treatment with dinutuximab in pediatric patients with high-risk neuroblastoma: A case series

Abstract

Immunotherapy with the anti-GD2 monoclonal antibody ch14.18, or dinutuximab, represents an important therapeutic advance in the treatment of pediatric high-risk neuroblastoma and is now considered part of standard of care in this patient population. To date, transverse myelitis as a result of dinutuximab therapy has not been reported in clinical trials or in the published literature. We describe three patients with clinical symptoms of transverse myelitis, confirmed via magnetic resonance imaging, shortly following initiation of dinutuximab. All patients were discontinued from dinutuximab treatment and received urgent treatment, with rapid improvement in symptoms and resultant functional recovery.

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On Heat and Mass Transfer within Thermally Shocked Region of Enhanced Geothermal System

An Enhanced Geothermal System (EGS) is an artificially created geothermal reservoir formed by hydrofracturing hot dry rock. Thermal shock occurs when the cold water contacts the hot rock near the injection borehole, creating a network of small, disorganized, closely spaced micro cracks. As the cold-water injection continues, the hot rock cools down and the micro cracks coalesce, becoming a better-defined network of thermal fractures. Thermal fractures in an EGS reservoir are believed to improve reservoir performance by increasing the surface area for heat exchange and lowering flow impedance; however, it is difficult to precisely predict how they grow and affect the permeability of the reservoir. The goal of this paper is to provide an insight into the transport mechanisms within the thin, permeable, thermally shocked region of an EGS reservoir. COMSOL Multiphysics® is used to set up an indealized porous region with identical geometrical features at different domain scales to show the scale dependence of heat and mass transport in the initial microscale crack network and in the later coalesced thermal fractures. This research shows the importance of EGS maturity in determining how heat and mass are transferred and how to select appropriate analytical tools for different stages of development.

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BVH expansion allows for greater head, shoulders, ear, nose and throat care - The Courier

The Courier

BVH expansion allows for greater head, shoulders, ear, nose and throat care The Courier The cancer is treated differently, and is also diagnosed in different ways. McBeath said if cancer is related to smoking and drinking it is usually painful and very obvious. With HPV-related cancer, there are "microscopic" tumors in the tonsil or base ...

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Give boys vaccine to fight HPV pandemic, says expert | Ireland | The ... - The Times

The Times

Give boys vaccine to fight HPV pandemic, says expert | Ireland | The ... The Times The world is experiencing an HPV pandemic, an Irish doctor has claimed. The human papilloma virus (HPV) is linked to cervical cancer in women but is also ... and more »

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BVH expansion allows for greater head, shoulders, ear, nose and throat care - The Courier

The Courier

BVH expansion allows for greater head, shoulders, ear, nose and throat care The Courier Dr. Vincent McGinniss, left, and Dr. Evan McBeath are ear, nose and throat doctors at Blanchard Valley Health System's recently expanded ENT practice. These doctors, also known as otolaryngologists, specialize in everything from head and neck cancer to ...

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Diving into cancer recovery with hyperbaric | Queensland Times - The Queensland Times

The Queensland Times

Diving into cancer recovery with hyperbaric | Queensland Times The Queensland Times CANCER survivor Fran Levy made a major step on the road to recovery when she found the Wesley Hyperbaric Centre in Brisbane. and more »

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Push to raise head, neck cancer awareness - SBS

ABC Online

Push to raise head, neck cancer awareness SBS An estimated five thousand Australians will be diagnosed with head or neck cancer this year, prompting a push to raise a awareness of the signs and symptoms. Cancer Council Australia is also encouraging teens to get the human papilloma virus ... World Head and Neck Cancer dayABC Online all 10 news articles »

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Breast cancer family history leads to early breast cancer detection and optimal management

Abstract

Purpose

We investigated whether the relationship between family history (FH) of breast cancer and survival of women with breast cancer is related to the quality of care received, once adjusted for other prognostic variables using data from the Geneva population-based cancer registry and quality of care indicators defined by the European Society of breast cancer specialists (EUSOMA).

Methods

We included non-metastatic malignant breast tumor patients who had their surgery between 2001 and 2010. We assessed the association between FH and patient and tumor characteristics on one hand, and each quality of care indicator and an overall score of quality of care, on the other hand, through logistic regression. We assessed the impact of FH and the quality of care-score on 5-year survival with Cox regression adjusting for patient and tumor characteristics.

Results

2,672 patients were included in the study. Women with a positive FH were younger, more likely from Switzerland, screen detected, had positive estrogen and progesterone receptor status, and had smaller and ductal tumors. A positive FH was also associated with better management for several quality indicators. Women with a positive FH had a better crude survival (Hazard Ratio 0.61, p = 0.006). This association was not substantially affected when adjusting for quality of care. However, the effect of FH did not persist when also adjusting for patient and tumor characteristics.

Conclusions

A positive FH of breast cancer is associated with earlier breast cancer diagnosis, better tumor features, and higher quality of care. These factors explain the better survival observed among breast cancer women with a positive FH as compared to women without positive FH.

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Giant oesophageal gastrointestinal stromal tumour presenting with dyspnoea and clubbed fingers

Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms of the gastrointestinal tract originating from the interstitial cells of Cajal. Giant oesophageal GISTs are rare since the oesophagus is rarely the primary site of GISTs, and they are usually diagnosed early due to complaints such as dysphagia. We present the case of a giant oesophageal GIST presenting with prominent clubbing. The case underlined the diagnostic importance of clubbing and the careful consideration of chemotherapy. Although clubbed fingers associated with GISTs are rare, our experience demonstrates the importance of physicians' recognition of clubbing as a paraneoplastic phenomenon for early diagnosis of malignancies since patients seldom notice their own clubbing by themselves. Chemotherapy using imatinib, an Bcr-Abl kinase inhibitor, is the standard option for unresectable giant GISTs. However, careful consideration must be made of the risk of complications associated with rapid mass reduction due to imatinib such as bleeding, oesophageal perforation and mediastinitis.

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Type I talon cusp on mandibular incisor

Description

Talon cusp is a comparably rare developmental dental anomaly assumed to arise because of evagination on the surface of a tooth crown during tooth calcification stage. Talon cusp also called as Eagle's is a well-defined extra cusp like structure located on lingual or palatal surface of deciduous or permanent anterior teeth. Its occurrence may be either unilateral or bilateral, single or multiple teeth in males or females. Prevalence of talon's cusp is reported to be between 0.06% to 7.7%. Eagle's talon is most commonly seen in maxillary lateral incisor >maxillary central incisor> maxillary canine> mandibular incisor.1

Mandibular talon cusp is a rare entity to occur. Mandibular talon cusps are more prevalent in men than women. Occurrence in talon cusp is more common in permanent dentition. Most of the mandibular talon cusp shows unilateral presentation. Talon cusp associated with permanent central incisor and primary lateral incisor...

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Between fire and ice: refractory hypothermia and warmth-induced pain in inherited erythromelalgia

Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Na_v1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise. Pain is not adequately treated by existing pharmacological agents. Individuals with IEM classically cool their limbs for relief, in some cases resulting in tissue injury. We describe a patient from a family with IEM due to the L858F mutation of Na_v1.7 who presented with refractory hypothermia due to overcooling. This presentation of refractory hypothermia necessitating warming strategies, complicated by severe warmth-induced pain, posed a substantial therapeutic challenge. We report our experience in overcoming hypothermia lasting 3 weeks in a child with IEM, discuss possible pathophysiological mechanisms underlying this unusual complication and suggest potential therapeutic interventions.

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Through the Glass Brightly

Hospital-centered academic surgical pathologists are essential members of multidisciplinary head and neck tumor boards. A working, multidisciplinary head and neck tumor board is composed of many dedicated professionals who contribute their individual pieces of patient data. This weekly congregation of head and neck specialists results in a special, concerted, and dynamic process of data integration into a holistic matrix view of the patients. Despite all the technological advances in communication, the fundamentals of human interactions still apply: there is no better substitute for a regular, working, multidisciplinary head and neck tumor board.

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It Takes Two: One Resects, One Reconstructs

Care of patients with advanced head and neck cancer is a multidisciplinary effort through all phases of care. Head and neck cancer surgery involves balancing oncologic control, functional preservation, and aesthetics. Given the advances in free tissue reconstruction, the majority of defects can be reconstructed using free tissue transfer flaps. A 2-team approach allows for early, continual communication and meticulous operative planning. Operations can be combined into a single effort. This approach maximizes efficiency and enables multidisciplinary collaboration for comprehensive surgical treatment. We present our experience and an outline of how responsibilities between the ablative and reconstructive teams are shared.

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Contributors

SUJANA S. CHANDRASEKHAR, MD

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Systemic Treatment for Squamous Cell Carcinoma of the Head and Neck

In patients with locally advanced squamous cell cancer of the head and neck, a multimodality treatment approach is recommended. The addition of platinum-based systemic therapy concurrently with radiation has been shown to be superior to radiation alone and is considered standard therapy for locally advanced disease. No study has shown superiority of induction therapy followed by chemoradiotherapy versus chemoradiotherapy alone. In the adjuvant setting only patients with nodal extracapsular extension or positive margins seem to benefit from chemoradiotherapy versus radiotherapy alone. In the recurrent or metastatic setting, systemic treatment with chemotherapy is palliative. A subset of patients treated with PD-1 immunotherapy may achieve durable responses.

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Multidisciplinary Approach to Head and Neck Cancer

OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA

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Psychosocial Distress and Distress Screening in Multidisciplinary Head and Neck Cancer Treatment

Psychosocial distress screening (DS) for cancer and head and neck cancer (HNC) patients is rapidly becoming the standard of care. DS is of particular importance for patients with HNC, given their heightened incidence of distress, depression, anxiety, suicide, quality of life impacts, and negative medical outcomes. In the absence of DS, distress is frequently missed in oncology settings. However, when identified, distress is highly responsive to treatment, with cognitive behavioral and behavioral medicine interventions demonstrating evidence of efficacy. Multidisciplinary HNC teams are uniquely positioned to implement effective DS programs and treatment tailored to HNC patients' psychological and medical vulnerabilities.

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Immunotherapy

Recurrent and/or metastatic head and neck cancer portends a poor prognosis with traditional treatments, but current immunotherapy with immune checkpoint inhibitors has the potential to improve these clinical outcomes. This review focuses on the major breakthroughs that have led to the current understanding of immunotherapy in head and neck cancer as well as the future direction of the field. Ultimately, this understanding will guide clinicians on the selection of patients with head and neck cancer and practical considerations before starting immunotherapy.

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Veterans' Preferences for Remote Management of Chronic Conditions

Telemedicine and e-Health , Vol. 0, No. 0.


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Through the Glass Brightly

Hospital-centered academic surgical pathologists are essential members of multidisciplinary head and neck tumor boards. A working, multidisciplinary head and neck tumor board is composed of many dedicated professionals who contribute their individual pieces of patient data. This weekly congregation of head and neck specialists results in a special, concerted, and dynamic process of data integration into a holistic matrix view of the patients. Despite all the technological advances in communication, the fundamentals of human interactions still apply: there is no better substitute for a regular, working, multidisciplinary head and neck tumor board.

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It Takes Two: One Resects, One Reconstructs

Care of patients with advanced head and neck cancer is a multidisciplinary effort through all phases of care. Head and neck cancer surgery involves balancing oncologic control, functional preservation, and aesthetics. Given the advances in free tissue reconstruction, the majority of defects can be reconstructed using free tissue transfer flaps. A 2-team approach allows for early, continual communication and meticulous operative planning. Operations can be combined into a single effort. This approach maximizes efficiency and enables multidisciplinary collaboration for comprehensive surgical treatment. We present our experience and an outline of how responsibilities between the ablative and reconstructive teams are shared.

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Multidisciplinary Approach to Head and Neck Cancer

The complexity of cancer care in the twenty-first century mandates the input of a spectrum of health care providers to achieve the best possible outcome. Head and neck cancer in particular occurs in an anatomical region unmatched in the number of physiological functions potentially affected with disease and treatment, including respiration, physical appearance, vocalization, gustation, olfaction, and alimentation. Further complicating treatment is the wide range of tumor types and tumor locations in head and neck cancer, all of which taken separately are relatively rare cancers.

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Contributors

SUJANA S. CHANDRASEKHAR, MD

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Systemic Treatment for Squamous Cell Carcinoma of the Head and Neck

In patients with locally advanced squamous cell cancer of the head and neck, a multimodality treatment approach is recommended. The addition of platinum-based systemic therapy concurrently with radiation has been shown to be superior to radiation alone and is considered standard therapy for locally advanced disease. No study has shown superiority of induction therapy followed by chemoradiotherapy versus chemoradiotherapy alone. In the adjuvant setting only patients with nodal extracapsular extension or positive margins seem to benefit from chemoradiotherapy versus radiotherapy alone. In the recurrent or metastatic setting, systemic treatment with chemotherapy is palliative. A subset of patients treated with PD-1 immunotherapy may achieve durable responses.

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Psychosocial Distress and Distress Screening in Multidisciplinary Head and Neck Cancer Treatment

Psychosocial distress screening (DS) for cancer and head and neck cancer (HNC) patients is rapidly becoming the standard of care. DS is of particular importance for patients with HNC, given their heightened incidence of distress, depression, anxiety, suicide, quality of life impacts, and negative medical outcomes. In the absence of DS, distress is frequently missed in oncology settings. However, when identified, distress is highly responsive to treatment, with cognitive behavioral and behavioral medicine interventions demonstrating evidence of efficacy. Multidisciplinary HNC teams are uniquely positioned to implement effective DS programs and treatment tailored to HNC patients' psychological and medical vulnerabilities.

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Forthcoming Issues

Simulation in Otolaryngology

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CME Accreditation Page

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Immunotherapy

Recurrent and/or metastatic head and neck cancer portends a poor prognosis with traditional treatments, but current immunotherapy with immune checkpoint inhibitors has the potential to improve these clinical outcomes. This review focuses on the major breakthroughs that have led to the current understanding of immunotherapy in head and neck cancer as well as the future direction of the field. Ultimately, this understanding will guide clinicians on the selection of patients with head and neck cancer and practical considerations before starting immunotherapy.

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Copyright

Elsevier

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More than Just Mitoses: Complete Care of the Patient with Head and Neck Cancer

Dr Maie St John has put together a most comprehensive, readable "monograph" on care of the patient with head and neck cancer, in this issue of Otolaryngologic Clinics of North America.

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Contents

Sujana S. Chandrasekhar

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West Nile virus

West Nile virus: The mosquito-borne virus that causes West Nile fever. One of the flaviviruses, a family of viruses also responsible for dengue, yellow fever, and tick-borne encephalitis virus. Like the other flaviviruses, the West Nile virus is a positive-strand RNA virus containing three structural proteins and a host-derived lipid bilayer. The West Nile virus is an icosahedral structure of about 500 angstroms in diameter. The overall structure of the West Nile virus most closely resembles that of dengue fever virus but the surface proteins are slightly different, which may give West Nile virus some of its unique features.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Identification of differentially expressed splice variants by the proteogenomic pipeline Splicify [Technological Innovation and Resources]

Proteogenomics, i.e. comprehensive integration of genomics and proteomics data, is a powerful approach identifying novel protein biomarkers. This is especially the case for proteins that differ structurally between disease and control conditions. As tumor development is associated with aberrant splicing, we focus on this rich source of cancer specific biomarkers. To this end, we developed a proteogenomic pipeline, Splicify, which is able to detect differentially expressed protein isoforms. Splicify is based on integrating RNA massive parallel sequencing data and tandem mass spectrometry proteomics data to identify protein isoforms resulting from differential splicing between two conditions. Proof of concept was obtained by applying Splicify to RNA sequencing and mass spectrometry data obtained from colorectal cancer cell line SW480, before and after siRNA-mediated down-modulation of the splicing factors SF3B1 and SRSF1. These analyses revealed 2172 and 149 differentially expressed isoforms, respectively, with peptide confirmation upon knock-down of SF3B1 and SRSF1 compared to their controls. Splice variants identified included RAC1, OSBPL3, MKI67 and SYK. One additional sample was analyzed by PacBio Iso-Seq full-length transcript sequencing after SF3B1 down-modulation. This analysis verified the alternative splicing identified by Splicify and in addition identified novel splicing events that were not represented in the human reference genome annotation. Therefore, Splicify offers a validated proteogenomic data analysis pipeline for identification of disease specific protein biomarkers resulting from mRNA alternative splicing. Splicify is publicly available on GitHub (http://ift.tt/2vJm0Ez) and suitable to address basic research questions using pre-clinical model systems as well as translational research questions using patient-derived samples, e.g. allowing to identify clinically relevant biomarkers.

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Toowoomba smoker, drinker warns: 'they took my voicebox' - Toowoomba Chronicle

Toowoomba smoker, drinker warns: 'they took my voicebox' Toowoomba Chronicle "I got cancer in my throat, so they took my voice box, then two years later I had a spot on my lung, so they took half of my right lung as well," he said. "Since then I've had my eyes done and my teeth done, so I'm fully re-conditioned." Celebrating ...

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Guideline recommendations and antimicrobial resistance: the need for a change

Objectives

Antimicrobial resistance has become a global burden for which inappropriate antimicrobial use is an important contributing factor. Any decisions on the selection of antibiotics use should consider their effects on antimicrobial resistance. The objective of this study was to assess the extent to which antibiotic prescribing guidelines have considered resistance patterns when making recommendations for five highly prevalent infectious syndromes.

Design

We used Medline searches complemented with extensive use of Web engine to identify guidelines on empirical treatment of community-acquired pneumonia, urinary tract infections, acute otitis media, rhinosinusitis and pharyngitis. We collected data on microbiology and resistance patterns and identified discrete pattern categories. We assessed the extent to which recommendations considered resistance, in addition to efficacy and safety, when recommending antibiotics.

Results

We identified 135 guidelines, which reported a total of 251 recommendations. Most (103/135, 79%) were from developed countries. Community-acquired pneumonia was the syndrome mostly represented (51, 39%). In only 16 (6.4%) recommendations, selection of empirical antibiotic was discussed in relation to resistance and specific microbiological data. In a further 69 (27.5%) recommendations, references were made in relation to resistance, but the attempt was inconsistent. Across syndromes, 12 patterns of resistance with implications on recommendations were observed. 50% to 75% of recommendations did not attempt to set recommendation in the context of these patterns.

Conclusion

There is consistent evidence that guidelines on empirical antibiotic use did not routinely consider resistance in their recommendations. Decision-makers should analyse and report the extent of local resistance patterns to allow better decision-making.

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Associations of anthropometry since birth with sagittal posture at age 7 in a prospective birth cohort: the Generation XXI Study

Objectives

Adult sagittal posture is established during childhood and adolescence. A flattened or hypercurved spine is associated with poorer musculoskeletal health in adulthood. Although anthropometry from birth onwards is expected to be a key influence on sagittal posture design, this has never been assessed during childhood. Our aim was to estimate the association between body size throughout childhood with sagittal postural patterns at age 7.

Design

Prospective cohort study.

Setting and participants

A subsample of 1029 girls and 1101 boys taking part in the 7-year-old follow-up of the birth cohort Generation XXI (Porto, Portugal) was included. We assessed the associations between anthropometric measurements (weight, height and body mass index) at birth, 4 and 7 years of age and postural patterns at age 7. Postural patterns were defined using latent profile analysis, a probabilistic model-based technique which allows for simultaneously including anthropometrics as predictors of latent profiles by means of logistic regression.

Results

Postural patterns identified were sway, flat and "neutral to hyperlordotic"in girls, and "sway to neutral", flat and hyperlordotic in boys; with flat and hyperlordotic postures representing a straightened and a rounded spine, respectively. In both girls and boys, higher weight was associated with lower odds of a flat pattern compared with a sway/"sway to neutral"pattern, with stronger associations at older ages: for example, ORs were 0.68 (95% CI 0.53 to 0.88) per SD increase in birth weight and 0.36 (95% CI 0.19 to 0.68) per SD increase in weight at age 7 in girls, with similar findings in boys. Boys with higher ponderal index at birth were more frequently assigned to the hyperlordotic pattern (OR=1.44 per SD; p=0.043).

Conclusions

Our findings support a prospective sculpting role of body size and therefore of load on musculoskeletal spinopelvic structures, with stronger associations as children get older.

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Profiles of children's social-emotional health at school entry and associated income, gender and language inequalities: a cross-sectional population-based study in British Columbia, Canada

Objectives

Early identification of distinct patterns of child social–emotional strengths and vulnerabilities has the potential to improve our understanding of child mental health and well-being; however, few studies have explored natural groupings of indicators of child vulnerability and strengths at a population level. The purpose of this study was to examine heterogeneity in the patterns of young children's social and emotional health and investigate the extent to which sociodemographic characteristics were associated.

Design

Cross-sectional study based on a population-level cohort.

Setting

All kindergarten children attending public schools between 2004 and 2007 in British Columbia (BC), Canada.

Participants

35 818 kindergarten children (age of 5 years) with available linked data from the Early Development Instrument (EDI), BC Ministry of Health and BC Ministry of Education.

Outcome measure

We used latent profile analysis (LPA) to identify distinct profiles of social–emotional health according to children's mean scores across eight social–emotional subscales on the EDI, a teacher-rated measure of children's early development. Subscales measured children's overall social competence, responsibility and respect, approaches to learning, readiness to explore, prosocial behaviour, anxiety, aggression and hyperactivity.

Results

Six social–emotional profiles were identified: (1) overall high social–emotional functioning, (2) inhibited-adaptive (3) uninhibited-adaptive, (4) inhibited-disengaged, (5) uninhibited-aggressive/hyperactive and (6) overall low social–emotional functioning. Boys, children with English as a second language (ESL) status and children with lower household income had higher odds of membership to the lower social–emotional functioning groups; however, this association was less negative among boys with ESL status.

Conclusions

Over 40% of children exhibited some vulnerability in early social–emotional health, and profiles were associated with sociodemographic factors. Approximately 9% of children exhibited multiple co-occurring vulnerabilities. This study adds to our understanding of population-level distributions of children's early social–emotional health and identifies profiles of strengths and vulnerabilities that can inform future intervention efforts.

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Respiratory syncytial virus: a systematic scientometric analysis of the global publication output and the gender distribution of publishing authors

Objective

Worldwide, the respiratory syncytial virus (RSV) represents the predominant viral agent causing bronchiolitis and pneumonia in children. To conduct research and tackle existing healthcare disparities, RSV-related research activities around the globe need to be described. Hence, we assessed the associated scientific output (represented by research articles) by geographical, chronological and socioeconomic criteria and analysed the authors publishing in the field by gender. Also, the 15 most cited articles and the most prolific journals were identified for RSV research.

Design

Retrospective, descriptive study.

Setting

The NewQIS (New Quality and Quantity Indices in Science) platform was employed to identify RSV-related articles published in the Web of Science until 2013. We performed a numerical analysis of all articles, and examined citation-based aspects (eg, citation rates); results were visualised by density equalising mapping tools.

Results

We identified 4600 RSV-related articles. The USA led the field; US-American authors published 2139 articles (46.5%% of all identified articles), which have been cited 83 000 times. When output was related to socioeconomic benchmarks such as gross domestic product or Research and Development expenditures, Guinea-Bissau, The Gambia and Chile were ranked in leading positions. A total of 614 articles on RSV (13.34% of all articles) were attributed to scientific collaborations. These were primarily established between high-income countries. The gender analysis indicated that male scientists dominated in all countries except Brazil.

Conclusions

The majority of RSV-related research articles originated from high-income countries whereas developing nations showed only minimal publication productivity and were barely part of any collaborative networks. Hence, research capacity in these nations should be increased in order to assist in addressing inequities in resource allocation and the clinical burden of RSV in these countries.

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Medication incidents in primary care medicine: a prospective study in the Swiss Sentinel Surveillance Network (Sentinella)

Objectives

To describe the type, frequency, seasonal and regional distribution of medication incidents in primary care in Switzerland and to elucidate possible risk factors for medication incidents.

Design

Prospective surveillance study.

Setting

Swiss primary healthcare, Swiss Sentinel Surveillance Network.

Participants

Patients with drug treatment who experienced any erroneous event related to the medication process and interfering with normal treatment course, as judged by their physician. The 180 physicians in the study were general practitioners or paediatricians participating in the Swiss Federal Sentinel reporting system in 2015.

Outcomes

Primary: medication incidents; secondary: potential risk factors like age, gender, polymedication, morbidity, care-dependency, previous hospitalisation.

Results

The mean rates of detected medication incidents were 2.07 per general practitioner per year (46.5 per 1 00 000 contacts) and 0.15 per paediatrician per year (2.8 per 1 00 000 contacts), respectively. The following factors were associated with medication incidents (OR, 95% CI): higher age 1.004 per year (1.001; 1.006), care by community nurse 1.458 (1.025; 2.073) and care by an institution 1.802 (1.399; 2.323), chronic conditions 1.052 (1.029; 1.075) per condition, medications 1.052 (1.030; 1.074) per medication, as well as Thurgau Morbidity Index for stage 4: 1.292 (1.004; 1.662), stage 5: 1.420 (1.078; 1.868) and stage 6: 1.680 (1.178; 2.396), respectively. Most cases were linked to an incorrect dosage for a given patient, while prescription of an erroneous medication was the second most common error.

Conclusions

Medication incidents are common in adult primary care, whereas they rarely occur in paediatrics. Older and multimorbid patients are at a particularly high risk for medication incidents. Reasons for medication incidents are diverse but often seem to be linked to communication problems.

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Ability to join the workforce and work productivity among drug users under methadone maintenance treatment in a mountainous area of Northern Vietnam: a cross-sectional study

Objectives

A major measure of treatment success for drug users undergoing rehabilitation is the ability to enter the workforce and generate income. This study examines the absenteeism and productivity among people who inject drugs (PWID) enrolled in methadone maintenance treatment (MMT) in Northern Vietnam.

Setting

We conducted a cross-sectional study in two clinics in Tuyen Quang province.

Participants

A total of 241 patients enrolled in MMT.

Primary and secondary outcome measures

Patients' work productivity was measured using the WPAI-GH instrument (Work Productivity and Activity Impairment Questionnaire: General Health V2.0). We also collected additional characteristics about participants' employment history, such as proficient jobs, whether they actively found a new job and be accepted by employers.

Results

Most of the participants (>90%) were employed at the time of the study. Rates of absenteeism (missed work), presenteeism (impairment while working) and overall loss of productivity were 15.8%, 5.6% and 11.2%, respectively, as measured by the WPAI-GH questionnaire. The most proficient job was 'freelancer' (17.5%), followed by 'blue-collar worker' (10.6%) and 'farmer' (10.2%). Only 26.8% of patients reported that they actively sought jobs in the past. About half of them had been refused by employers because of their drug use history and/or HIV status. We found no statistically significant difference between patients enrolled in MMT for <1 year and those who had been enrolled >1 year. Factors associated with higher work productivity included not endorsing problems in mobility, self-care or pain; being HIV-negative and having greater MMT treatment adherence.

Conclusion

Our study highlights the high employment rate and work productivity among PWID in MMT programmes in remote areas of Northern Vietnam. The results can help to improve the quality and structure of MMT programmes across Vietnam and in other countries.

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Common attributes in retired professional cricketers that may enhance or hinder quality of life after retirement: a qualitative study

Objectives

Retired professional cricketers shared unique experiences and may possess specific psychological attributes with potential to influence quality of life (QOL). Additionally, pain and osteoarthritis can be common in retired athletes which may negatively impact QOL. However, QOL in retired athletes is poorly understood. This study explores the following questions from the personal perspective of retired cricketers: How do retired cricketers perceive and experience musculoskeletal pain and function in daily life? Are there any psychological attributes that might enhance or hinder retired cricketers' QOL?

Design

A qualitative study using semistructured interviews, which were subject to inductive, thematic analysis. A data-driven, iterative approach to data coding was employed.

Setting

All participants had lived and played professional cricket in the UK and were living in the UK or abroad at the time of interview.

Participants

Eighteen male participants, aged a mean 57±11 (range 34–77) years had played professional cricket for a mean 12±7 seasons and had been retired from professional cricket on average 23±9 years.

Results

Fifteen participants reported pain or joint difficulties and all but one was satisfied with their QOL. Most retired cricketers reflected on experiences during their cricket career that may be associated with the psychological attributes that these individuals shared, including resilience and a positive attitude. Additional attributes included a high sense of body awareness, an ability to self-manage pain and adapt lifestyle choices to accommodate physical limitations. Participants felt fortunate and proud to have played professional cricket, which may have further contributed to the high QOL in this group of retired cricketers.

Conclusions

Most retired cricketers in this study were living with pain or joint difficulties. Despite this, all but one was satisfied or very satisfied with their QOL. This may be partly explained by the positive psychological attributes that these retired cricketers shared.

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Recruitment and retention in a 10-month social network-based intervention promoting diabetes self-management in socioeconomically deprived patients: a qualitative process evaluation

Objectives

Socioeconomically deprived patients with type 2 diabetes often face challenges with self-management, resulting in more diabetes-related complications. However, these groups are often under-represented in self-management interventions. Evidence on effective recruitment and retention strategies is growing, but lacking for intensive self-management interventions. This study aims to explore recruitment, retention and effective intervention strategies in a 10-month group-based intervention among Dutch, Moroccan, Turkish and Surinamese patients from socioeconomically deprived neighbourhoods.

Methods

Participants were recruited through general practitioners (GPs) and participated in a 10-month social network-based intervention (10 groups, n=69): Powerful Together with Diabetes. This intervention also targeted the significant others of participants and aimed to increase social support for self-management and to decrease social influences hindering self-management. A qualitative process evaluation was conducted. Retention was measured using log books kept by group leaders. Further, we conducted 17 in-depth interviews with participants (multiethnic sample) and 18 with group leaders. Interviews were transcribed, coded and analysed using framework analyses.

Results

The GP's letter and reminder calls, an informational meeting and the intervention's informal nature facilitated recruitment. During the first months, positive group atmosphere, the intervention's perceived usefulness, opportunities to socialise and a reduction in practical barriers facilitated retention. After the first months, conflicting responsibilities and changes in the intervention's nature and planning hindered retention. Calls from group leaders and the prospect of a diploma helped participants overcome these barriers.

Conclusion

To promote retention in lengthy self-management interventions, it seems important that patients feel they are going on an outing to a social gathering that is enjoyable, recreational, useful and easy to attend. However, rewards and intensive personal recruitment and retention strategies remained necessary throughout the entire intervention period.

Trial registration number

Dutch Trial Register NTR1886; Results.

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“Analysis of the correlation between dental arch and articular eminence morphology: a cone beam CT study”

Publication date: Available online 26 July 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Francielle Silvestre Verner, Gina Delia Roque-Torres, Laura Ricardina Ramírez-Sotello, Karina Lopes Devito, Solange Maria Almeida
Objective.To assess the correlation between the morphology of the dental arches (DA) of patients with normal occlusion and the articular eminence (AE) through cone beam computed tomography (CBCT).Study Design.CBCT scans of 60 patients were evaluated in terms of height (AEh) and inclinations (angles α, β and δ) of the AE. DA were classified regarding shape (tapered, square, ovoid), and perimeters, widths, and depths were measured. One-way ANOVA, Pearson's correlation coefficients, simple and multivariate linear regression models were calculated.Results.Ovoid arch was the most predominant shape (n = 66/120). Inclination of the AE (angle β) had the greatest difference between DA shapes, with this angle usually being greater in the ovoid and smaller in the square arches (p<0.05). The AEh presented greater correlation with DA measurements, with tapered arches having the most significant correlations (p<0.05). DA depth had no influence on AE measurements (p>0.05). Perimeter and width of the DA had some influence (p<0.05).Conclusions.Correlations between DA and AE morphologies of were found. Although the results do not prove absolute association between the variables, the correlations should be taken into consideration. Whenever possible, morphological features of DA should be preserved to avoid possible changes in AE.



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Targeted next-generation sequencing of glandular odontogenic cyst: a preliminary study

Publication date: Available online 26 July 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Elisa Carvalho de Siqueira, Silvia Ferreira de Sousa, Josiane Alves França, Marina Gonçalves Diniz, Thaís dos Santos Fontes Pereira, Rennan Garcias Moreira, Pablo Agustin Vargas, Ricardo Santiago Gomez, Carolina Cavalieri Gomes
Background: Glandular odontogenic cyst (GOC) is an uncommon developmental cyst. Its molecular pathogenesis is unclear and deep sequencing technologies may identify causative low-frequency variants in tumors. Objective: We investigated in GOC mutations in 50 genes commonly altered in human cancers Methods: Targeted next-generation sequencing was used to interrogate a panel of approximately 2,800 mutations in GOC. Results: Six missense single nucleotide variations (SNVs) were reported. Three SNVs (TP53 rs1042522, KDR rs1870377 and KIT rs3822214) are listed as "common SNPs" at the UCSC Genome Browser. The other SNVs (PIK3CA p.Glu689Lys, PIK3CA p.Ala708Thr and TP53 p.Leu289Phe) are predicted to have deleterious or damaging effects on the proteins, but they showed very low frequency in our samples and could not be further validated by orthogonal methods. Conclusion: No pathogenic SNV was detected in this cohort of GOC. Further studies with larger gene panels or whole exome sequencing are needed in order to reveal the genetic basis of GOC.



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In Vitro Maturation of Human iPSC-Derived Neuroepithelial Cells Influences Transplant Survival in the Stroke-Injured Rat Brain

Tissue Engineering Part A , Vol. 0, No. 0.


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Effect of superheated-steam roasting on physicochemical properties of peanut ( Arachis hypogea ) oil

Abstract

Peanut (Arachis hypogaea) is an important source of protein and lipid globally. The effect of superheated-steam roasting on quality of peanut oil was evaluated based on physicochemical quality parameters. Three roasting temperatures (150, 200, and 250 °C) were used for different periods of roasting time and the obtained results were compared with those of conventional roasting. At 250 °C, superheated-steam roasted peanuts yielded more oil (26.84%) than conventionally roasted peanuts (24.85%). Compared with conventional roasting, superheated-steam roasting resulted in lower oil color, peroxide, p-anisidine, free fatty acid, conjugated diene and triene, and acid values and higher viscosity and iodine values in the roasted peanut oil. These values were significantly different from each other (p < 0.05). The fatty acids in roasted peanut oils were affected by roasting temperature and time for both the roasting modes. The superheated steam technique can be used to roast peanuts while maintaining their favorable characteristics.

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Simultaneous occurrence of fibroblastic osteosarcoma and hypertrophic osteopathy (Marie’s disease) in a German shepherd dog

Abstract

Osteosarcoma, as a progressive tumor, accounts for approximately 80% of malignant bone tumors in dogs. Since it is a highly metastatic tumor, it develops pulmonary metastasis in the majority of cases. The considerable site preference of the tumor in dogs and the possibility of hypertrophic osteopathy in a number of cases must be considered. Clinical examination of a 12-year female German shepherd dog with lameness, weakness, and cachexia revealed an abnormal thickening in the left forelimb and a severe swelling in the left proximal humerus. Radiographic examinations showed severe swelling in the arm's soft tissue, proximal humerus osteolysis, and irregular and palisade periosteal reaction in most bones of thoracic and pelvic limbs as well as soft-tissue masses in the thoracic cavity. In postmortem examination, a semi-hard destructive mass extended from the central cavity of humerus to the surrounding soft tissue, pulmonary and splenic metastases were observed. According to microscopic features, the tumoric bone lesion was diagnosed as fibroblastic osteosarcoma. Hypertrophic osteopathy (Marie's disease) was also diagnosed due to gross characteristics of the forearm and palm along with radiographic findings of the forearm and tibia. This is the first report of simultaneous occurrence of fibroblastic osteosarcoma and Marie's disease in Iranian dogs.

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Half the atoms inside your body came from across the universe

Intergalactic winds carry gas and dust from one galaxy to the next, bringing half of the matter in our galaxy from up to a million light years away

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Galectin-8 regulates targeting of Gp135/podocalyxin and lumen formation at the apical surface of renal epithelial cells [Research]

Establishment of apical–basal polarity, through correct targeting of polarity determinants to distinct domains of the plasma membrane, is a fundamental process for the development of functioning epithelial tubules. Here we report that galectin (Gal)-8 regulates apical-basal polarity of Madin-Darby canine kidney (MDCK) cells via apical targeting of 135-kDa glycoprotein (Gp135). Gal-8 interacts with newly synthesized Gp135 in a glycan-dependent manner. Gal-8 knockdown induces aberrant lumens at the lateral domain and mistargeting of Gp135 to this structure, thus disrupting the kidney epithelial polarity of MDCK cells, which organize lumens at the apical surface. The O-glycosylation deletion mutant of Gp135 phenocopies the effect of Gal-8 knockdown, which suggests that Gal-8 is the decoding machinery for the apical sorting signals of Gp135 residing at its O-glycosylation–rich region. Collectively, our results reveal a new role of Gal-8 in the development of luminal organs by regulating targeting of apical polarity protein Gp135.—Lim, H., Yu, C.-Y., Jou, T.-S. Galectin-8 regulates targeting of Gp135/podocalyxin and lumen formation at the apical surface of renal epithelial cells.

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Palmitoylation is a prerequisite for dimerization-dependent raftophilicity of rhodopsin [Membrane Biology]

The visual photopigment rhodopsin (Rh) is a prototypical G protein-coupled receptor (GPCR) responsible for initiation of the phototransduction cascade in rod photoreceptors. Similar to other GPCRs, Rh can form dimers or even higher oligomers, and tends to have a supramolecular organization that is likely important in the dim light response. Rh also exhibits high affinity for lipid rafts (raftophilicity) upon light-dependent binding with cognate G protein transducin (Gt), suggesting the presence of lipid raft-like domains in the retinal disk membrane and their importance in phototransduction. However, the relationship between Rh oligomerization and lipid rafts in the disk membrane remains to be explored. Given previous findings that Gt binds to dimeric Rh and Rh is post-translationally modified with two highly raftophilic palmitoyl moieties, we hypothesized that Rh becomes raftophilic upon dimerization. Here, we tested this hypothesis biochemically. First, we found that Rh*-Gt complexes in the detergent-resistant membrane (DRM) are partially resistant to cholesterol depletion by methyl-β-cyclodextrin (MCD), and the stoichiometry of Rh to Gt in this MCD-resistant complex is 2:1. We then found that IgG-crosslinking renders Rh highly raftophilic, supporting the premise that Rh becomes raftophilic upon dimerization. Depalmitoylation of Rh with the reduction of thioester linkages by dithiothreitol blocked the translocation of IgG-crosslinked Rh to the DRM, highlighting the importance of the two palmitoyl moieties in the dimerization-dependent raftophilicity of Rh. These results indicate that palmitoylated GPCRs, such as Rh, may acquire raftophilicity upon G protein-stabilized dimerization and thereby organize receptor-cluster rafts by recruiting raftophilic lipids.

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The Alzheimer's Disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool [Glycobiology and Extracellular Matrices]

The immunomodulatory receptor Siglec-3/CD33 influences risk for late-onset Alzheimers disease (LOAD), an apparently human-specific post-reproductive disease. CD33 generates two splice variants: a full-length CD33M transcript produced primarily by the LOAD-risk allele and a shorter CD33m isoform lacking the sialic acid-binding domain, produced primarily from the LOAD-protective allele. A SNP that modulates CD33 splicing to favor CD33m is associated with enhanced microglial activity. Individuals expressing more protective isoform accumulate less brain Beta-amyloid and have a lower LOAD risk. How the CD33m isoform increases Beta-amyloid; clearance remains unknown. We report that the protection by the CD33m isoform may not be conferred by what it does, but rather from what it cannot do. Analysis of blood neutrophils and monocytes and a microglial cell line revealed that unlike CD33M, the CD33m isoform does not localize to cell surfaces; instead, it accumulates in peroxisomes. Cell stimulation and activation did not mobilize CD33m to the surface. Thus, the CD33m isoform may neither interact directly with amyloid plaques nor engage in cell-surface signaling. Rather, production and localization of CD33m in peroxisomes is a way of diminishing the amount of CD33M and enhancing Beta-amyloid clearance. We confirmed intracellular localization by generating a CD33m-specific monoclonal antibody. Of note, CD33 is the only Siglec with a peroxisome-targeting sequence, and this motif emerged by convergent evolution in toothed whales, the only other mammals with a prolonged post-reproductive lifespan. The CD33 allele that protects post-reproductive individuals from LOAD may have evolved by adaptive loss-of-function, an example of the less-is-more hypothesis.

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Crystal structure of the human Polε B-subunit in complex with the C-terminal domain of the catalytic subunit [Protein Structure and Folding]

The eukaryotic B-family DNA polymerases include four members, Polα, Polδ, Polϵ, and Polζ, which share common architectural features, such as the exonuclease/polymerase and C-terminal domains (CTDs) of catalytic subunits bound to indispensable B-subunits, which serve as scaffolds that mediate interactions with other components of the replication machinery. Crystal structures for the B-subunits of Polα and Polδ/Polζ have been reported; the former within the primosome and separately with CTD, and the latter with the N-terminal domain (NTD) of the C-subunit. Here we present the crystal structure of the human Polϵ B-subunit (p59) in complex with CTD of the catalytic subunit (p261C). The structure revealed a well-defined electron density for p261C and the phosphodiesterase (PDE) and oligonucleotide/oligosaccharide-binding domains of p59. However, electron density was missing for the p59 NTD and for the linker connecting it to the PDE domain. Similar to Polα, p261C contains a three-helix bundle in the middle and zinc-binding modules (Zn1 and Zn2) on each side. Intersubunit interactions involving 11 hydrogen bonds and numerous hydrophobic contacts account for stable complex formation with a buried surface area of 3094 Å2. Comparative structural analysis of p59-p261C with the corresponding Polα complex revealed significant differences between the B-subunits and CTDs as well as their interaction interfaces. The B-subunit of Polδ/Polζ also substantially differs from B-subunits of either Polα or Polϵ. This work provides a structural basis to explain biochemical and genetic data on the importance of B-subunit integrity in replisome function in vivo.

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Search for DNA Damage by Human Alkyladenine DNA Glycosylase Involves Early Intercalation by an Aromatic Residue [Enzymology]

DNA repair enzymes recognize and remove damaged bases that are embedded in the duplex. To gain access, most enzymes use nucleotide flipping , whereby the target nucleotide is rotated 180 degree into the active site. In human alkyladenine DNA glycosylase (AAG), the enzyme that initiates base excision repair of alkylated bases, the flipped-out nucleotide is stabilized by intercalation of the side chain of tyrosine 162 that replaces the lesion nucleobase. Previous kinetic studies provided evidence for the formation of a transient complex that precedes the stable flipped-out complex, but it is not clear how this complex differs from nonspecific complexes. We used site-directed mutagenesis and transient-kinetic approaches to investigate the timing of Y162 intercalation for AAG. The tryptophan substitution (Y162W) appeared to be conservative, because the mutant protein retained a highly favorable equilibrium constant for flipping the 1,N6-ethenoadenine (εA) lesion and the rate of N-glycosidic bond cleavage was identical to that of the wild-type enzyme. We assigned the tryptophan fluorescence signal from Y162W by removing two native tryptophan residues (W270A/W284A). Stopped-flow experiments then demonstrated that the change in tryptophan fluorescence of the Y162W mutant is extremely rapid upon binding to either damaged or undamaged DNA, much faster than the lesion-recognition and nucleotide-flipping steps that were independently determined by monitoring the εA fluorescence. These observations suggest that intercalation by this aromatic residue is one of the earliest steps in the search for DNA damage, and that this interaction is important for the progression of AAG from nonspecific searching to specific-recognition complexes.

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Thrombospondin-1 (TSP-1), a new bone morphogenetic protein-2 and -4 (BMP-2/4) antagonist identified in pituitary cells [Protein Structure and Folding]

Bone morphogenetic proteins (BMPs) regulate diverse cellular responses during embryogenesis and in adulthood including cell differentiation, proliferation and death in various tissues. In the adult pituitary, BMPs participate in the control of hormone secretion and cell proliferation suggesting a potential endocrine/paracrine role for BMPs, but some of the mechanisms are unclear. Here, using a bioactivity test based on embryonic cells (C3H10T1/2) transfected with a BMP-responsive element, we sought to determine whether pituitary cells secrete BMPs or BMP antagonists. Interestingly, we found that pituitary-conditioned medium contains a factor that inhibits action of BMP-2 and -4. Combining surface plasmon resonance (SPR) and high-resolution mass spectrometry helped pinpoint this factor as thrombospondin-1 (TSP-1). SPR and co-immunoprecipitation confirmed that recombinant human TSP-1 can bind BMP-2 and -4 and antagonize their effects on C3H10T1/2 cells. Moreover, TSP-1 inhibited the action of serum BMPs. We also report that the von Willebrand type C (VWC) domain of TSP-1 is likely responsible for this BMP-2/4 binding activity, an assertion based on sequence similarity that TSP-1 shares with the VWC domain of Crossveinless 2 (CV-2), a BMP antagonist and member of the chordin family. In summary, we identified for the first time TSP-1 as a BMP-2/-4 antagonist and presented structural basis for the physical interaction between TSP-1 and BMP-4. We propose that TSP-1 could regulate bioavailability of BMPs, either produced locally or reaching the pituitary via the blood circulation. In conclusion, our findings provide new insights into the involvement of TSP-1 in the BMP-2/-4 mechanisms of action.

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Efficient Methylation of C2 in L-Tryptophan by the Cobalamin-dependent Radical S-Adenosylmethionine Methylase TsrM Requires an Unmodified N1 Amine [Metabolism]

TsrM catalyzes the methylation of C2 in Ltryptophan (Trp). This reaction is the first step in the biosynthesis of the quinaldic acid moiety of the thiopeptide antibiotic thiostrepton, which exhibits potent activity against Gram-positive pathogens. TsrM is a member of the radical S-adenosylmethionine (SAM) superfamily of enzymes, but does not catalyze formation of 5'-deoxyadenosin-5'-yl or any other SAM-derived radical. In addition to a [4Fe-4S] cluster, TsrM contains a cobalamin cofactor that serves as an intermediate methyl carrier in its reaction. However, how this cofactor donates a methyl moiety to the Trp substrate is unknown. Here, we show that an unmodified N1 position of Trp is important for turnover and that 1-thia-Trp and 1-oxa-Trp serve as competitive inhibitors. We also show that β-cyclopropyl-Trp undergoes C2 methylation in the absence of cyclopropyl ringopening, disfavoring mechanisms that involve unpaired electron density at C3 of the indole ring. Moreover, we show that all other indole-substituted analogs of Trp undergo methylation at varying but measurable rates, and that the analog 7-aza-Trp - which is expected to temper the nucleophilicity of C2 in Trp-is a very poor substrate. Lastly, no formation of cob(II)alamin or substrate radicals is observed during the reaction with Trp or any molecule within a tested panel of Trp analogs. In summary, our results are most consistent with a mechanism that involves two polar nucleophilic displacements, the second of which requires deprotonation of the indole nitrogen in Trp during its attack on methylcobalamin.

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Rise in e-cigarette use linked to increase in smoking cessation rates

Evidence for the effectiveness of e-cigarettes as smoking cessation aids for individual smokers, still limited to just two randomised controlled trials of now obsolete e-cigarettes, suggests they are...

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The antibiotic course has had its day

Antibiotics are vital to modern medicine and antibiotic resistance is a global, urgent threat to human health. The relation between antibiotic exposure and antibiotic resistance is unambiguous both...

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E-cigarette use and associated changes in population smoking cessation: evidence from US current population surveys

Objective To examine whether the increase in use of electronic cigarettes in the USA, which became noticeable around 2010 and increased dramatically by 2014, was associated with a change in overall...

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Push to raise head, neck cancer awareness - NEWS.com.au

Push to raise head, neck cancer awareness NEWS.com.au "HPV is what causes cervical cancer, but many Australians may not be aware that it can also cause head and neck cancers. This is another reason for teenage boys and girls to get vaccinated when they are offered it through our national immunisation ... and more »

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– Androgen deprivation therapy and cardiovascular risk: No meaningful difference between GnRH antagonist and agonists

We thank Professor Albertsen for his interest in our study.

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Mesenchymal stem/stromal cell extracellular vesicles: From active principle to next generation drug delivery system

Publication date: 28 September 2017
Source:Journal of Controlled Release, Volume 262
Author(s): Barbara Crivelli, Theodora Chlapanidas, Sara Perteghella, Enrico Lucarelli, Luisa Pascucci, Anna Teresa Brini, Ivana Ferrero, Mario Marazzi, Augusto Pessina, Maria Luisa Torre
It has been demonstrated that the biological effector of mesenchymal stem/stromal cells (MSCs) is their secretome, which is composed of a heterogeneous pool of bioactive molecules, partially enclosed in extracellular vesicles (EVs). Therefore, the MSC secretome (including EVs) has been recently proposed as possible alternative to MSC therapy. The secretome can be considered as a protein-based biotechnological product, it is probably safer compared with living/cycling cells, it presents virtually lower tumorigenic risk, and it can be handled, stored and sterilized as an Active Pharmaceutical/Principle Ingredient (API). EVs retain some structural and technological analogies with synthetic drug delivery systems (DDS), even if their potential clinical application is also limited by the absence of reproducible/scalable isolation methods and Good Manufacturing Practice (GMP)-compliant procedures. Notably, EVs secreted by MSCs preserve some of their parental cell features such as homing, immunomodulatory and regenerative potential. This review focuses on MSCs and their EVs as APIs, as well as DDS, considering their ability to reach inflamed and damaged tissues and to prolong the release of encapsulated drugs. Special attention is devoted to the illustration of innovative therapeutic approaches in which nanomedicine is successfully combined with stem cell therapy, thus creating a novel class of "next generation drug delivery systems."

Graphical abstract

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Facile assembly and loading of theranostic polymersomes via multi-impingement flash nanoprecipitation

Publication date: 28 September 2017
Source:Journal of Controlled Release, Volume 262
Author(s): Sean Allen, Omar Osorio, Yu-Gang Liu, Evan Scott
Flash nanoprecipitation (FNP) has proven to be a powerful tool for the rapid and scalable assembly of solid-core nanoparticles from block copolymers. The process can be performed using a simple confined impingement jets mixer and provides an efficient and reproducible method of loading micelles with hydrophobic drugs. To date, FNP has not been applied for the fabrication of complex or vesicular nanoarchitectures capable of encapsulating hydrophilic molecules or bioactive protein therapeutics. Here, we present FNP as a single customizable method for the assembly of bicontinuous nanospheres, filomicelles and vesicular, multilamellar and tubular polymersomes from poly(ethylene glycol)-bl-poly(propylene sulfide) block copolymers. Multiple impingements of polymersomes assembled via FNP were shown to decrease vesicle diameter and polydispersity, allowing gram-scale fabrication of monodisperse polymersomes within minutes. Furthermore, we demonstrate that FNP supports the simultaneous loading of both hydrophobic and hydrophilic molecules respectively into the polymersome membrane and aqueous lumen, and encapsulated enzymes were found to be released and remain active following vesicle lysis. As an example application, theranostic polymersomes were generated via FNP that were dual loaded with the immunosuppressant rapamycin and a fluorescent dye to link targeted immune cells with the elicited immunomodulation of T cells. By expanding the capabilities of FNP, we present a rapid, scalable and reproducible method of nanofabrication for a wide range of nanoarchitectures that are typically challenging to assemble and load with therapeutics for controlled delivery and theranostic strategies.

Graphical abstract

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Harmful Contaminants Found In Florida Drinking Water: Study - Patch.com

Patch.com

Harmful Contaminants Found In Florida Drinking Water: Study Patch.com Radium-228 (linked to cancer). Found above health guidelines at 359 utilities. Chlorate (linked to impaired thyroid function, which can be harmful during pregnancy and childhood). Found above health guidelines at 239 utilities. Arsenic (linked to cancer). Contaminants in Indy water raise some concern, new report showsIndianapolis Star Check online for contaminants in your city's drinking waterSun Sentinel all 56 news articles »

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Clinical Features of Psoriatic Arthritis: a Comprehensive Review of Unmet Clinical Needs

Abstract

Psoriatic arthritis (PsA) is a form of inflammatory arthritis (IA) affecting approximately 0.25% of the population. It is a heterogeneous disorder associated with joint damage, disability, disfiguring skin disease and in severe cases, premature mortality. Inherently irreversible and frequently progressive, the process of joint damage begins at, or before, the clinical onset of disease. Early recognition and intervention is thus crucial to patient outcome. At disease onset, however, PsA often resembles other forms of arthritis—especially rheumatoid arthritis (RA). Despite the similarities between PsA and RA, their distinctive pathologies require different treatments. For example, drugs that are effective in RA may not be effective in PsA and can even cause adverse effects. Since there is no currently validated test for PsA, the diagnosis is often missed or delayed and this has functional consequences for the patient. In the context of PsA and RA, making an accurate diagnosis is not the only challenge faced by rheumatologists. Choosing an effective and safe medication to manage the disease is another significant challenge and currently approximately 40% achieve meaningful responses such as minimal disease activity status. For the patient, several months may be lost as a result of trial and error testing—meanwhile, irreversible joint damage may occur. Clearly, more effective clinical tests are urgently needed to improve personalised patient care in PsA. Specifically, there is need to develop minimally invasive tests predictive of diagnosis, response to treatment and radiographic progression. In this review, we examined the biomarker development process, highlighted the importance of qualifying unmet clinical needs and emphasised the challenges that impede biomarker studies. We have compiled a comprehensive list of potentially clinically relevant biomarkers in PsA and provided a summary of proteomic technologies that might usefully support additional biomarker research in PsA.

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Ahead of print: Comparison of two cold compression therapy protocols after tibial plateau leveling...

Objective: To evaluate two different protocols of cold compression therapy (CCT) for pain management and functional recovery in dogs undergoing tibial plateau leveling osteotomy (TPLO). Material and methods: A total of 27 adult dogs (n = 30 stifles; staged bilateral procedures: n = 3) undergoing routine TPLO were randomly allocated to three groups (n = 10/group). Dogs of group I received CCT once before and immediately after surgery. In dogs of group II CCT was performed postoperatively four times at 6-hour intervals. Dogs of the control group did not receive CCT. Circumference of the stifle joint and the following pain-related parameters were measured by a single blinded observer before surgery and 1, 10 and 42 days after surgery: stifle joint range of motion (ROM), subjective degree of lameness, and score of a modified Glasgow Pain Scale (GPS). Results: Both CCT groups showed significantly greater ROM and lower GPS scores 24 hours after surgery compared to the control group. Ten days after surgery there was a significantly lower degree of lameness in both CCT groups compared to the control group. Fourty-two days after surgery a significantly greater ROM was observed in both CCT groups compared to the control group. Group II also showed a significant improvement in the degree of lameness and GPS. There were no significant differences in any of the parameters between the two CCT groups at any time point. Conclusion: CCT applied preoperatively and immediately postoperatively showed similar short- and long-term beneficial results compared to a previously established protocol of applying CCT four times postoperatively. This protocol may be more suitable for practical use. Clinical significance: The reported data can be used to establish the new protocol of CCT in a clinical surrounding and to support postoperative rehabilitation of the canine patient....

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BMJ: Euratom withdrawal will put patients at risk

New concerns have been voiced about the U.K.'s proposed withdrawal from the...

Read more on AuntMinnieEurope.com

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Concerns emerge about EU radiation safety directive

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Impact of the Korean Diagnosis-Related Groups payment system on the outcomes of adenotonsillectomy: A single center experience

Publication date: Available online 26 July 2017
Source:Auris Nasus Larynx
Author(s): Sang Hyun Kwak, Ji Hoon Kim, Da Hee Kim, Jung Min Kim, Hyung Kwon Byeon, Won Shik Kim, Yoon Woo Koh, Se-Heon Kim, Eun Chang Choi
ObjectivesTo report outcomes with regard to clinical aspects and medical costs of adenotonsillectomy and tonsillectomy at a single institution before and after implementation of the Diagnosis-Related Groups (DRG) payment system in Korea.MethodsWe retrospectively reviewed the records of patients treated with adenotonsillectomy or tonsillectomy between July 2012 and June 2014. The Korean DRG payment system was applied to seven groups of specific diseases and surgeries including adenotonsillectomy and tonsillectomy from July 2013 at all hospitals in Korea. We divided patients into four groups according whether the fee-for-service (FFS) or DRG payment system was implemented and operation type (FFS-adenotonsillectomy (AT), DRG-AT, FFS-tonsillectomy (T), and DRG-T).ResultsA total of 1402 patients were included (485 FFS-AT, 490 DRG-AT, 203 FFS-T, and 223 DRG-T). The total medical cost of the DRG-AT group was significantly lower than that of the FFS-AT group (1191±404 vs. 1110±279 USD, P<0.05). There were no significant differences in length of hospital stay or postoperative complications among groups.ConclusionThe Korean DRG system for adenotonsillectomy and tonsillectomy reduced medical costs and clinical outcomes were not significantly altered by the adoption of the DRG system.Level of evidence4.



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Unilateral Headache Status after Intra-Aortic Balloon Pump Placement

Introduction. Intra-aortic balloon pump (IABP) counterpulsation is a catheter-based treatment for coronary artery disease and decompensated heart failure to increase coronary blood flow and improve cardiac output. IABP is generally well tolerated, and complications are usually related to peripheral vasculature or red blood cell and platelet consumption. The usual insertion site via femoral artery renders the patient bedbound. Recently, axillary artery has been used in patients with atherosclerotic peripheral vascular disease and documented small arteries or in those awaiting transplant to ensure ambulation and prevent deconditioning. Case Report. We present a patient with ischemic cardiomyopathy and severe left ventricular dysfunction, awaiting Orthotropic Heart Transplant. His worsening intractable angina and dyspnea necessitated IABP placement via left axillary artery, significantly improving his condition. He subsequently experienced migraine-type persistent unilateral headache refractory to standard pain management. Multiple strategies were utilized to treat his pain, but the patient insisted that his pain commenced after IABP placement. Ultimately, the removal of the pump led to complete resolution with no recurrence. Conclusion. The authors hypothesize that the unilaterally directed blood flow and direct increase in cerebral perfusion from the intra-aortic balloon pump may have caused vasodilation of the extracranial arteries, leading to a persistent and debilitating headache in this susceptible patient.

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Electrochemical Evaluation of trans-Resveratrol Levels in Red Wine Based on the Interaction between Resveratrol and Graphene

trans-Resveratrol is often considered as one of the quality standards of red wine, and the development of a sensitive and reliable method for monitoring the trans-resveratrol levels in red wine is an urgent requirement for the quality control. Here, a novel voltammetric approach was described for probing trans-resveratrol using a graphene-modified glassy carbon (GC) electrode. The proposed electrode was prepared by one-step electrodeposition of reduced graphene oxide (ERGO) at a GC electrode. Compared with the bare GC electrode, the introduced graphene film on the electrode surface dramatically improved the sensitivity of the sensor response due to the π-π interaction between the graphene and trans-resveratrol. The developed sensor exhibited low detection limit of 0.2 μM with wide linear range of 0.8–32 μM and high stability. For the analysis of trans-resveratrol in red wine, the high anti-interference ability and the good recoveries indicated the great potential for practical applications.

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Hexavalent Chromium Removal from Model Water and Car Shock Absorber Factory Effluent by Nanofiltration and Reverse Osmosis Membrane

Nanofiltration and reverse osmosis are investigated as a possible alternative to the conventional methods of Cr(VI) removal from model water and industrial effluent. The influences of feed concentration, water recovery, pH, and the coexisting anions were studied. The results have shown that retention rates of hexavalent chromium can reach 99.7% using nanofiltration membrane (NF-HL) and vary from 85 to 99.9% using reverse osmosis membrane (RO-SG) depending upon the composition of the solution and operating conditions. This work was also extended to investigate the separation of Cr(VI) from car shock absorber factory effluent. The use of these membranes is very promising for Cr(VI) water treatment and desalting industry effluent. Spiegler-Kedem model was applied to experimental results in the aim to determine phenomenological parameters, the reflection coefficient of the membrane , and the solute permeability coefficient . The convective and diffusive parts of the mass transfer were quantified with predominance of the diffusive contribution.

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A Correlation between the Higgs Mass and Dark Matter

Depending on the value of the Higgs mass, the Standard Model acquires an unstable region at large Higgs field values due to RG running of couplings, which we evaluate at 2-loop order. For currently favored values of the Higgs mass, this renders the electroweak vacuum only metastable with a long lifetime. We argue on statistical grounds that the Higgs field would be highly unlikely to begin in the small field metastable region in the early universe, and thus some new physics should enter in the energy range of order of, or lower than, the instability scale to remove the large field unstable region. We assume that Peccei-Quinn (PQ) dynamics enters to solve the strong CP problem and, for a PQ-scale in this energy range, may also remove the unstable region. We allow the PQ-scale to scan and argue, again on statistical grounds, that its value in our universe should be of order of the instability scale, rather than (significantly) lower. Since the Higgs mass determines the instability scale, which is argued to set the PQ-scale, and since the PQ-scale determines the axion properties, including its dark matter abundance, we are led to a correlation between the Higgs mass and the abundance of dark matter. We find the correlation to be in good agreement with current data.

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