Subarachnoid Hemorrhage

Foreword. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations. Stage. A 17-year-old…

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Case 22-2017: A 21-Year-Old Woman with Fever, Headache, and Myalgias

Presentation of Case. Dr. Nkemdilim Mgbojikwe (Medicine): A 21-year-old woman was admitted to this hospital during the winter because of fever, headache, and myalgias. The patient had been well until 4 days before this admission, when fever, chills, fatigue, malaise, retro-orbital headache, and…

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Subarachnoid Hemorrhage

Foreword. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations. Stage. A 17-year-old…

http://ift.tt/2tJal6w

Bronchoscopic Removal of an Obstructing Broncholith

Figure 1.

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Severe Plantar Warts in an Immunocompromised Patient

Figure 1.

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Certain about Dying with Uncertainty

Mrs. C. a woman with whom we'd had a long-standing patient–physician relationship, one of us for over 25 years, died recently in the 87th year of her life. A woman who had always maintained her cheerful spirit even in the midst of quite trying medical setbacks, she was one of our favorite patients.…

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Merging Biological Metaphors. Creativity, Darwinism and Biosemiotics

Abstract

Evolutionary adaptation has been suggested as the hallmark of life that best accounts for life's creativity. However, current evolutionary approaches still fail to give an adequate account of it, even if they are able to explain both the origin of novelties and the proliferation of certain traits in a population. Although modern-synthesis Darwinism is today usually appraised as too narrow a position to cope with all the complexities of developmental and structural biology—not to say biosemiotic phenomena—, Darwinism need not be if we separate metaphor from reality in natural selection in order to show the axiological complexity of this concept. This can shed light on the relationship between biosemiotics and biological evolution.

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Fluid Biosemiotic Mechanisms Underlie Subconscious Habits

Abstract

Although research into the biosemiotic mechanisms underlying the purposeful behavior of brainless living systems is extensive, researchers have not adequately described biosemiosis among neurons. As the conscious use of signs is well-covered by the various fields of semiotics, we focus on subconscious sign action. Subconscious semiotic habits, both functional and dysfunctional, may be created and reinforced in the brain not necessarily in a logical manner and not necessarily through repeated reinforcement. We review literature that suggests hypnosis may be effective in changing subconscious dysfunctional habits, and we offer a biosemiotic framework for understanding these results. If it has been difficult to evaluate any psychological approach, including hypnosis, this may be because contemporary neuroscience lacks a theory of the sign. We argue that understanding the fluid nature of representation in biological organisms is prerequisite to understanding the nature of the subconscious and may lead to more effective of treatments for dysfunctional habits developed through personal experience or culture.

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Issue Information

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Issue Information

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Role of anesthesia in endovascular stroke therapy.

Purpose of review: Recent randomized clinical trials have demonstrated strong efficacy of endovascular therapy (EVT) for acute ischemic stroke (AIS) from large vessel occlusions; in the USA alone, tens of thousands of patients annually may benefit. The impact of the type of anesthesia used during mechanical thrombectomy on patient outcomes remains controversial. This review discusses the current literature on the effects of anesthesia type on patient outcome following endovascular stroke therapy. Recent findings: EVT is the standard of treatment for intracranial large vessel occlusions. Recent studies show that general anesthesia is associated with negative clinical outcome in AIS patients undergoing EVT. Two of the possible mechanisms of this finding are systolic hypotension and hypocapnia. However, the only published randomized controlled studies to date, sedation vs. intubation for endovascular stroke treatment and anesthesia during stroke showed no difference in short-term clinical outcome between EVT patients treated with general anesthesia and conscious sedation and improved longer-term outcome in the general anesthesia group. Summary: Retrospective reports, and the 2015 American Heart Association/American Stroke Association Guideline (focused update of the 2013 guidelines for the early management of patients with AIS regarding endovascular treatment) based on these reports, are in favor of sedation (conscious sedation) over general anesthesia for endovascular stroke thrombectomy. However, the two randomized controlled prospective studies published provide inconclusive evidence as to the best anesthetic practice for endovascular stroke therapy. More randomized clinical trials are needed to optimize anesthetic patient care in AIS. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Patient-Perceived Facilitators of and Barriers to Electronic Portal Use: A Systematic Review.

This systematic review describes characteristics of portal users and their perceptions of this emerging technology. Recent empirical evidence (2010-2016) was reviewed to answer three questions: (1) What are the characteristics of electronic patient portal users? (2) What are patient-perceived facilitators of electronic patient portal use? (3) What are patient-perceived barriers to electronic patient portal use? Characteristics of portal users are described according to three broad categories: demographic characteristics, patterns of use, and complexity and duration of disease. Three themes were found related to patient-perceived facilitators of use: provider encouragement, access/control over health information, and enhanced communication; two themes were found related to patient-perceived barriers to use: lack of awareness/training and privacy and security concerns. Understanding a patient's perception of technology is paramount in optimizing use. These insights will allow for development of better products and clinical processes that facilitate broad goals of improved use of information technology. Policy and practice implications are discussed, as well as suggestions for future research. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://pdfs.journals.lww.com/cinjournal/9000/00000/Patient_Perceived_Facilitators_of_and_Barriers_to.99543.pdf

Concordance of Motion Sensor and Clinician-Rated Fall Risk Scores in Older Adults.

As the older adult population in the United States continues to grow, developing reliable, valid, and practical methods for identifying fall risk is a high priority. Falls are prevalent in older adults and contribute significantly to morbidity and mortality rates and rising health costs. Identifying at-risk older adults and intervening in a timely manner can reduce falls. Conventional fall risk assessment tools require a health professional trained in the use of each tool for administration and interpretation. Motion sensor technology, which uses three-dimensional cameras to measure patient movements, is promising for assessing older adults' fall risk because it could eliminate or reduce the need for provider oversight. The purpose of this study was to assess the concordance of fall risk scores as measured by a motion sensor device, the OmniVR Virtual Rehabilitation System, with clinician-rated fall risk scores in older adult outpatients undergoing physical rehabilitation. Three standardized fall risk assessments were administered by the OmniVR and by a clinician. Validity of the OmniVR was assessed by measuring the concordance between the two assessment methods. Stability of the OmniVR fall risk ratings was assessed by measuring test-retest reliability. The OmniVR scores showed high concordance with the clinician-rated scores and high stability over time, demonstrating comparability with provider measurements. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://pdfs.journals.lww.com/cinjournal/9000/00000/Concordance_of_Motion_Sensor_and_Clinician_Rated.99544.pdf

Insufficiency avulsion fracture of the femoral attachment of the posterior cruciate ligament of the knee joint

Abstract

Multiple ligaments are involved in avulsion injuries of the knee joint, including both anterior and posterior cruciate ligaments; however, avulsion injury of the posterior cruciate ligament is less frequently encountered than the anterior counterpart. Furthermore, avulsion of the femoral side of the posterior cruciate ligament is far less common than the tibial one.

Femoral attachment avulsion fracture of the posterior cruciate ligaments has been reported in literature in adolescents, rarely in adulthood, and never before in elderly patients, showing an inverse relationship with advancement in patient age. The case presented here shows femoral attachment avulsion fracture of the posterior cruciate ligament in an elderly patient with secondary osteoporosis.

http://link.springer.com/10.1007/s00256-017-2660-3

Autosomal dominant brachyolmia: transient metaphyseal striations

Abstract

We report transient proximal and distal femoral metaphyseal striations that have not previously been described in autosomal dominant brachyolmia. The pelvis/hip radiograph of a 13-year-old boy demonstrated bilaterally symmetrical proximal femoral metaphyseal vertical striations. Additional vertical striations were also observed at the distal femur and proximal tibia metaphysis. Radiography of the thoracolumbar spine demonstrated platyspondyly with irregular endplates and overfaced pedicles. TRPV4 mutations were confirmed in this patient. Similar proximal femoral metaphyseal vertical striations were noted in the patient's sibling. Those streaks disappeared on the follow-up radiographs, and we considered it a unique radiologic finding transiently observed in autosomal dominant brachyolmia.

http://link.springer.com/10.1007/s00256-017-2684-8

Incidental finding in a young man

http://link.springer.com/10.1007/s00256-017-2679-5

Tuberous sclerosis and its rare association with macrodactyly and fibrous hamartomas

Abstract

Tuberous sclerosis complex is a genetic disease that results in abnormal cellular proliferation and hamartoma growths in multiple organ systems. However, macrodactyly and subcutaneous fibrous harmatomas are very uncommon associations with this disease. We see these rare manifestations in our case report of a 16-year-old female with tuberous sclerosis complex and discuss the imaging findings and pathogenetics of these manifestations. Through this, our report aims to expand the known clinical spectrum of features seen in tuberous sclerosis and aid in its diagnosis.

http://link.springer.com/10.1007/s00256-017-2683-9

Vascular calcifications on the preoperative radiograph: harbinger of tourniquet failure in patients undergoing total knee arthroplasty?

Abstract

Objective

Vascular calcifications on the preoperative radiograph of patients scheduled for total knee arthroplasty (TKA) often give rise to concern, as their clinical relevance remains uncertain. The aim of this study was to investigate whether these vascular calcifications—especially medial artery calcifications (MACs), which increase arterial stiffness—were associated with tourniquet failure and thus with increased intraoperative blood loss.

Materials and methods

A total of 765 patients who underwent primary TKA with a tourniquet (cuff pressure 350 mmHg) between 2009 and 2011 were screened for vascular calcifications on the preoperative radiograph. Vascular calcifications were classified into intimal and medial artery calcifications. Intraoperative blood loss of patients with and without MAC was compared, and a mixed linear regression model was used to adjust for the presence of several confounding factors (e.g., obesity, operating time).

Results

None of the 50 (6.5%) patients with MAC showed signs of tourniquet failure. Intraoperative blood loss of patients with MAC was not significantly elevated compared to the overall study group (p = 0.592) even when corrected for the presence of several confounding factors.

Conclusion

We found no evidence that vascular calcifications seen on the preoperative radiograph might be associated with tourniquet failure. However, surgeons should be aware of this possibility as tourniquet failure might become more common considering the ongoing trend toward minimizing cuff pressures.

http://link.springer.com/10.1007/s00256-017-2681-y

Valgus slipped capital femoral epiphysis with contralateral pre-slip

Abstract

Slipped capital femoral epiphysis (SCFE) is a common hip disorder in older children and adolescents, classically with medial and posterior slippage of the proximal femoral epiphysis. However, valgus SCFE is a very rare entity, where the proximal femoral epiphysis slips laterally and posteriorly. To our knowledge, valgus SCFE with magnetic resonance imaging (MRI) features of contralateral pre-slip has not yet been reported. We present a case of a 9 year old girl with symptomatic valgus SCFE on the left and asymptomatic contralateral pre-slip on the right with concurrent radiographic, sonographic, and MRI findings. Such findings include bilateral coxa valga, radiographic irregularity of the left proximal femoral physis, bilateral hip effusions, abnormal MRI signal and enhancement about both proximal femoral physes, and minimal posterolateral slippage of the left proximal femoral epiphysis. We highlight these pertinent imaging findings and review the importance of accurately diagnosing this rare entity for appropriate surgical management.

http://link.springer.com/10.1007/s00256-017-2654-1

Evaluation of bone viability in patients after girdlestone arthroplasty: comparison of bone SPECT/CT and MRI

Abstract

Purpose

To test the diagnostic performance of bone SPECT/CT and MRI for the evaluation of bone viability in patients after girdlestone-arthroplasty with histopathology used as gold standard.

Materials and methods

In this cross-sectional study, patients after girdlestone-arthroplasty were imaged with single-photon-emission-computed-tomography/computed-tomography (SPECT/CT) bone-scans using 99mTc-DPD. Additionally, 1.5 T MRI was performed with turbo-inversion-recovery-magnitude (TIRM), contrast-enhanced T1-fat sat (FS) and T1-mapping. All imaging was performed within 24 h prior to revision total-hip-arthroplasty in patients with a girdlestone-arthroplasty. In each patient, four standardized bone-tissue-biopsies (14 patients) were taken intraoperatively at the remaining acetabulum superior/inferior and trochanter major/minor. Histopathological evaluation of bone samples regarding bone viability was used as gold standard.

Results

A total of 56 bone-segments were analysed and classified as vital (n = 39) or nonvital (n = 17) by histopathology. Mineral/late-phase SPECT/CT showed a high sensitivity (90%) and specificity (94%) to distinguish viable and nonviable bone tissue. TIRM (sensitivity 87%, specificity 88%) and contrast-enhanced T1-FS (sensitivity 90%, specificity 88%) also achieved a high sensitivity and specificity. T1-mapping achieved the lowest values (sensitivity 82%, specificity 82%). False positive results in SPECT/CT and MRI resulted from small bone fragments close to metal artefacts.

Conclusions

Both bone SPECT/CT and MRI allow a reliable differentiation between viable and nonviable bone tissue in patients after girdlestone arthroplasty. The findings of this study could also be relevant for the evaluation of bone viability in the context of avascular bone necrosis.

http://link.springer.com/10.1007/s00256-017-2692-8

The rising root sign: the magnetic resonance appearances of post-operative spinal subdural extra-arachnoid collections

Abstract

We present a case series of symptomatic post-operative spinal subdural extra-arachnoid collections that displace the cauda equina roots anteriorly. This is described as the "rising root sign".

http://link.springer.com/10.1007/s00256-017-2682-x

Browser’s notes

http://link.springer.com/10.1007/s00256-017-2703-9

Bone adaptation of a biologically reconstructed femur after Ewing sarcoma: Long-term morphological and densitometric evolution

Abstract

Combining bone allografts and vascularized fibular autografts in intercalary reconstructions after resection of bone sarcomas is of particular interest in young patients as it facilitates bone healing and union and helps reduce fractures. However, adverse events related to bone adaptation still occur. Bone adaptation is driven by mechanical loading, but no quantitative biomechanical studies exist that would help surgical planning and rehabilitation. We analyzed the bone adaptation of a successful femoral reconstruction after Ewing sarcoma during 76-month follow-up using a novel methodology that allows CT-based quantification of morphology and density. The results indicated that the vital allograft promoted bone adaptation in the reconstruction. However, an overall negative balance of bone remodeling and a progressive mineral density decrease in the femoral neck might threaten long-term bone safety. These concerns seem related to both surgical technique and mechanical stimuli, where a stiff metal implant may determine load sharing, which negatively affects bone remodeling.

http://link.springer.com/10.1007/s00256-017-2661-2

The pubo-femoral distance decreases with Pavlik harness treatment for developmental dysplasia of the hip in newborns

Abstract

Objective

To evaluate the evolution of the ultrasonographic pubo-femoral distance (PFD) before and after Pavlik harness treatment for developmental dysplasia of the hip (DDH) in newborns.

Patients and methods

Twenty-five patients (16.7 ± 10.4 days; 19 females, six males) diagnosed with DDH and treated using the Pavlik harness were included. Eighteen patients had bilateral, and seven unilateral DDH, with a total of 43 dysplastic hips. The seven non-dysplastic hips in unilateral cases were used for comparison. The PFD was measured in the coronal and axial planes with the hip flexed to approximately 90°, before and after an average of 93 days of treatment. The femoral head coverage was assessed in the coronal plane, and correlated with PFD values.

Results

In dysplastic hips, the mean PFD decreased from 6.1 ± 1.8 mm to 3.0 ± 0.7 mm in the axial (adjusted difference, 2.9 mm; p < 0.01), and from 5.9 ± 2.0 to 3.0 ± 0.6 mm in the coronal plane (adjusted difference 2.7 mm; p < 0.01). The femoral head coverage increased from 30.8 to 62.1%, and the mean differences of femoral head coverage and PFD were significantly correlated (p < 0.001). There was no difference between treated dysplastic and non-dysplastic hips. There was high intra- and inter-observer agreement for PFD measurements.

Conclusion

The PFD decreased significantly after DDH treatment using the Pavlik harness in newborns, and showed significant correlation with the femoral head coverage improvement. PFD might be a reliable tool for monitoring DDH treatment in newborns treated using the Pavlik harness.

http://link.springer.com/10.1007/s00256-017-2668-8

Functional popliteal artery entrapment syndrome: use of ultrasound guided Botox injection as a non-surgical treatment option

Abstract

Objective

To determine whether ultrasound-guided injection of botulinum toxin type A (BTX-A) is a viable alternative to surgical intervention for the treatment of functional popliteal artery entrapment syndrome (PAES).

Materials and methods

Twenty-seven patients met diagnostic criteria confirming the presence of functional PAES and agreed to go ahead with ultrasound-guided BTX-A injection at the level of artery occlusion. Patients were assessed and treated at baseline and given the option for 'top-up' injections at 6 and 12 months. Patients provided subjective symptom reports at 6 and 12 months post intervention.

Results

No patients reported being worse off after the intervention; 59% of patients were categorized as having a good response (i.e., initial improvement that was maintained at 12 months), 22% a mixed response (i.e., an initial improvement that subsequently reduced over 12 months) and 19% a poor response (i.e., no difference) to treatment.

Conclusions

Ultrasound-guided BTX-A injection represents a viable alternative to surgery in the treatment of functional PAES. Further study will help determine the optimum dose and frequency of injection to prevent recurrence of symptoms.

http://link.springer.com/10.1007/s00256-017-2686-6

Imaging features of mammary-type myofibroblastoma of soft tissue: a case series with literature review

Abstract

Mammary-type myofibroblastoma (MTM) is a rare, benign neoplasm that is histologically identical to myofibroblastoma of the breast, but occurring in an extramammary site. The masses have been reported in superficial and deep soft tissue sites and visceral locations with the inguinal area and lower extremities are the most common. Most previous reports of MTMs have concentrated on clinical and pathological findings, with very limited information regarding imaging characteristics. Here, we describe three cases of MTM diagnosed at our institution, with a focus on imaging findings. We compare our findings with previously reported cases. Although MTM is rare, radiologists should be aware of this benign diagnosis as imaging characteristics can mimic those of liposarcomas and atypical lipomatous tumor/well-differentiated liposarcoma. Unlike those tumor types, MTM virtually never recurs post-resection, even when there are positive margins. Biopsy is necessary for proper diagnosis and recommended as an initial step to avoid overly aggressive treatment.

http://link.springer.com/10.1007/s00256-017-2678-6

Incidental finding in a young man

http://link.springer.com/10.1007/s00256-017-2680-z

F-18 FDG PET differentiation of benign from malignant chondroid neoplasms: a systematic review of the literature

Abstract

Introduction

Discriminating among benign chondroid tumors, low-grade chondrosarcomas, and grade 2/3 chondrosarcomas is frequently difficult with standard imaging modalities. We systematically reviewed the literature to determine the performance of PET-CT in making this distinction.

Methods

A systematic review was performed identifying 811 PubMed- and Embase-indexed articles containing combinations of "chondrosarcoma," "enchondroma," "chondroid," "cartilage" and "PET/CT," "PET," "positron." Eight articles including 166 lesions were included. Age, gender, tumor size, histologic grade, and SUVmax values were extracted for individual lesions when possible and otherwise recorded as aggregated data. Comparisons in SUVmax among benign, low-grade, and intermediate-/high-grade chondroid neoplasms were made.

Results

Individual SUVs were available for 101 lesions; 65 additional lesions were reported as aggregated data. There were 101 malignant and 65 benign tumors. Benign tumors were seen more frequently in females (p = 0.04, Fischer's exact test), but malignancy was not associated with age or lesion size. SUVmax was lower for benign (1.6 ± 0.7) than malignant tumors (4.4 ± 2.5) (p < 0.0001, t-test). SUVmax was lower for grade 0/1 (2.0 ± 0.7) than grade 2/3 (6.0 ± 3.2) (p < 0.0001, t-test). Increasing SUVmax correlated with higher grade chondroid tumors (Spearman's rank, ρ = 0.78). SUVmax ≥4.4 was 99% specific for grade 2/3 chondrosarcoma.

Conclusions

SUVmax correlates with histologic grade in intraosseous chondroid neoplasms; very low SUVmax supports a diagnosis of benign tumor, while elevated SUVmax is suggestive of higher grade chondrosarcoma.

http://link.springer.com/10.1007/s00256-017-2685-7

The magnetic resonance imaging appearance of the anterolateral ligament of the knee in association with anterior cruciate rupture

Abstract

Objective

The magnetic resonance imaging (MRI) appearance of the anterolateral ligament (ALL) has been described. However, the appearance of this structure and injury, in the presence of anterior cruciate ligament (ACL) injury, is less well defined. We studied the incidence of injury to the ALL and the pattern of this injury on MRI.

Materials and methods

Following Institutional Review Board approval, a retrospective study of 375 consecutive MRI studies was performed. Cases were identified from a prospective database of ACL reconstruction patients. Following exclusions, 280 MRIs (277 patients; 197 males: 80 females; mean age 30.2 years, range, 16–54) were evaluated. Injury was defined as full thickness, partial thickness, or an avulsion fracture. Each study was independently assessed by two consultant musculoskeletal radiologists.

Results

Injury to the ALL was identified (by at least one observer) in only 10.7% of cases (2.50% full thickness, 7.50% partial thickness, and 0.71% avulsion fracture). There was an almost perfect level of interobserver agreement for both the identification of an injury (κ = 0.854) and grading of injury (κ = 0.858). The MRI incidence of ALL injury was significantly greater within 6 weeks of the knee injury (18.5 vs. 8.37%; p < 0.05).

Conclusions

ALL injury was identified in only one-tenth of cases of ACL rupture. MRI changes can be reliably identified with strong agreement between observers. ALL injury is found more frequently on MRI within 6 weeks of the knee injury (compared to scans performed after this time period) suggesting that some injuries may resolve or become less visible.

http://link.springer.com/10.1007/s00256-017-2657-y

Comparative study of fat-suppression techniques for hip arthroplasty MR imaging

Abstract

Objectives

The goal of this study was to evaluate different fat-suppressed fluid-sensitive sequences in association with different metal artifacts reduction techniques (MARS) to determine which combination allows better fat suppression around metallic hip implants.

Methods

An experimental study using an MRI fat–water phantom quantitatively evaluated contrast shift induced by metallic hip implant for different fat-suppression techniques and MARS. Then a clinical study with patients addressed to MRI unit for painful hip prosthesis compared these techniques in terms of fat suppression quality and diagnosis confidence.

Results

Among sequences without MARS, both T2 Dixon and short tau inversion recuperation (STIR) had significantly lower contrast shift (p < 0.05), Dixon offering the best fat suppression. Adding MARS (view-angle tilting or slice-encoding for metal artifact correction (SEMAC)) to STIR gave better results than Dixon alone, and also better than SPAIR and fat saturation with MARS (p < 0.05). There were no statistically significant differences between STIR with view-angle tilting and STIR with SEMAC in terms of fat suppression quality.

Conclusions

STIR sequence is the preferred fluid-sensitive MR sequence in patients with metal implant. In combination with MARS (view-angle tilting or SEMAC), STIR appears to be the best option for high-quality fat suppression.

http://link.springer.com/10.1007/s00256-017-2670-1

Visualization of a cam-type femoroacetabular impingement while squatting using image-matching techniques: a case report

Abstract

The in vivo assessment of the three-dimensional (3D) kinematics of the hip in patients with femoroacetabular impingement (FAI) under weight-bearing conditions has not been previously reported. We evaluated the pre- and postoperative hip kinematics of a 34-year-old man, with a cam-type FAI while squatting, using image-matching techniques with measurement of the rim-neck distance. Post-osteochondroplasty, the α-angle improved from 51.0° to 35.5° and the head-neck offset ratio from 0.04 to 0.23. Coxalgia during squatting disappeared, and the Harris Hip Score improved from 79 to 92 at 1 year post-surgery. Postoperative hip kinematic values (3.8° of posterior pelvic tilt and 101.2° of femoral flexion at 96.8° of maximum hip flexion) were similar to the preoperative values (2.9° of posterior pelvic tilt and 102.7° of femoral flexion at 98.8° of maximum hip flexion). Meanwhile, osteochondroplasty improved the minimum rim-neck distance at maximum hip flexion from 2.0 to 10.4 mm. In vivo 3D visualization of the clearance between the femoral head-neck junction and the acetabulum could assist surgeons in adequately identifying the location of impingement and confirming sufficient resection post-operatively.

http://link.springer.com/10.1007/s00256-017-2677-7

ISS 2017 Annual Meeting New York, New York

http://link.springer.com/10.1007/s00256-017-2691-9

Functioning metastatic paraganglioma of the urinary bladder in a 10-year-old child

Paragangliomas of the urinary bladder are very rare tumours representing less than 1% of bladder tumours. Preoperative diagnosis is essential to avoid perioperative complications related to catecholamine release. A high index of suspicion should be maintained when the classical symptoms of voiding-related paroxysms of headache, palpitation and dizziness are present. We present a rare case of malignant paraganglioma of the urinary bladder in a 10-year-old boy. The patient had the classic presentation. We review the radiological diagnostic tools and findings of this rare entity.

http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-220533?rss=1

Abundant dystrophic calcifications mimicking aortic valve abscess in a patient undergoing elective aortic valve replacement

Dystrophic calcifications of the aortic valve may cause symptomatic aortic stenosis and account for a significant portion of patients who undergo elective valve replacement. Calcifications appearing grossly as a cloudy fluid surrounding the aortic valve leaflets are an uncommon finding. Normally, calcified aortic valves are characterised by large, nodular masses within the aortic cusps. We report a case of dystrophic calcifications on a stenotic aortic valve encountered intraoperatively, which was suggestive of infective endocarditis and abscess formation. Aortic valve leaflets and necrotic-appearing thymic lymph node tissue were submitted for histology and special stains. Cultures were negative and histology did not show evidence of infection. Tissue histology demonstrated extensive dystrophic calcifications, which were polarised to reveal abundant calcium oxalate crystals. The benign nature of this unique pathological finding ruled out any suspicion of infection, avoiding a prolonged course of intravenous antibiotics in this patient.

http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-220368?rss=1

Very early great saphenous vein graft aneurysm treated by percutaneous coronary intervention under ChromaFlo imaging guidance

A 73-year-old man, who had undergone coronary artery bypass grafting (CABG) 10 days prior, presented with a great saphenous vein graft aneurysm (SVGA). CT revealed the increasing size of the aneurysm. Since the SVGA occurred immediately after CABG and there were no other complications, the aneurysm was treated percutaneously. While intravascular ultrasonography (IVUS) and optical coherence tomography failed to detect the entry point, an IVUS catheter with the addition of ChromaFlo imaging clearly revealed the entry point, size and length of the SVGA. To prevent migration and edge restenosis associated with covered stents, the covered stent (3.0x19 mm) was superimposed on a drug-eluting stent (3.0x28 mm) that covered the entry site. A follow-up study demonstrated the absence of flow into the aneurysm.

http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-220443?rss=1

Arthroscopic excision of an intra-articular osteoid osteoma in the elbow joint

An osteoid osteoma is a rare, small, benign and painful tumour occurring in the extra-articular portion of long bones seen most commonly in the lower extremities. This is a case report of a 23-year-old female patient who underwent arthroscopic resection of an intra-articular osteoid osteoma. The nidus was completely removed by arthroscopic excision. The diagnosis was confirmed by postoperative histopathological analysis. In the case presented we have shown that intra-articular arthroscopy can be successful in the surgical management of benign bony lesions involving the elbow joint. We also present a review of the literature which reports on similar cases or intra-articular disease, preferred methods of surgical management and limitations in histopathological specimen acquisition for diagnosis.

http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-220868?rss=1

Long-term peritoneal port-catheter in a patient with cardiac ascites

A peritoneal port-catheter was inserted in a 70-year-old man because of repeated paracentesis due to cardiac ascites. Instead of frequent hospital admissions, the patient could drain his ascites at home, which dramatically improved his quality of life and enabled him to perform his daily activities.

http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-219258?rss=1

Simultaneous Knockout of CXCR4 and CCR5 Genes in CD4+ T Cells via CRISPR/Cas9 Confers Resistance to Both X4- and R5-Tropic Human Immunodeficiency Virus Type 1 Infection

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2ua3Lrg

Curcumin: the spicy modulator of breast carcinogenesis

Abstract

Worldwide breast cancer is the most common cancer in women. For many years clinicians and the researchers are examining and exploring various therapeutic modalities for breast cancer. Yet the disease has remained unconquered and the quest for cure is still going on. Present-day strategy of breast cancer therapy and prevention is either combination of a number of drugs or a drug that modulates multiple targets. In this regard natural products are now becoming significant options. Curcumin exemplifies a promising natural anticancer agent for this purpose. This review primarily underscores the modulatory effect of curcumin on the cancer hallmarks. The focus is its anticancer effect in the complex pathways of breast carcinogenesis. Curcumin modulates breast carcinogenesis through its effect on cell cycle and proliferation, apoptosis, senescence, cancer spread and angiogenesis. Largely the NFkB, PI3K/Akt/mTOR, MAPK and JAK/STAT are the key signaling pathways involved. The review also highlights the curcumin mediated modulation of tumor microenvironment, cancer immunity, breast cancer stem cells and cancer related miRNAs. Using curcumin as a therapeutic and preventive agent in breast cancer is perplexed by its diverse biological activity, much of which remains inexplicable. The information reviewed here should point toward potential scope of future curcumin research in breast cancer.

http://ift.tt/2thsd8U

“Validation of Whole-Slide Imaging in the Primary Diagnosis of Liver Biopsies in a University Hospital”

Experience in the use of whole slide imaging (WSI) for primary diagnosis is limited and there are no comprehensive reports evaluating this technology in liver biopsy specimens.

http://ift.tt/2u9WyaJ

Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients

PURPOSE: The prevalence of mutations in cancer susceptibility genes such as BRCA1 and BRCA2 and other cancer susceptibility genes and their clinical relevance are largely unknown among a large series of unselected breast cancer patients in Chinese population. <p> </p> <p>METHODS: A total of 8085 consecutive unselected Chinese breast cancer patients were enrolled. Germline mutations in 46 cancer susceptibility genes were detected using a 62-gene panel.</p> <p> </p> <p>RESULTS: Pathogenic mutations were identified in 9.2% of patients among the 8085 unselected breast cancer patients .Of these, 5.3% of patients carried a BRCA1 or BRCA2 mutation (1.8% in BRCA1 and 3.5% in BRCA2), 2.9% carried other breast cancer susceptibility genes (BOCG), and 1.0% carried another cancer susceptibility genes. Triple-negative breast cancers had the highest prevalence of BRCA1/2 mutations (11.2%) and other BOCG mutations (3.8%) among the four molecular subgroups, whereas ER-/PR-HER2+ breast cancers had the lowest mutations in BRCA1/2 (1.8%) and BOCG (1.6%). In addition, BRCA1 mutation carriers had a significant worse disease-free survival [unadjusted hazard ratio (HR) 1.60; 95% confidence interval (CI) 1.10-2.34; p=0.014) and disease-specific survival (unadjusted HR 1.96; 95% CI, 1.03-3.65; p=0.040) than did non-carriers; whereas no significant difference in survival was found between BRCA2 mutation carriers and non-carriers.</p> <p> </p> <p>CONCLUSIONS: 9.2% of breast cancer patients carry a pathogenic mutation in cancer susceptibility genes in this large unselected series. Triple-negative breast cancers have the highest prevalence of mutations in BRCA1 /2 and other breast cancer susceptibility genes among the four molecular subgroups, whereas ER-/PR-HER2+ breast cancers had the lowest mutations in these genes.

http://ift.tt/2ua4bOi

BRAF inhibitors amplify the pro-apoptotic activity of MEK inhibitors by inducing ER stress in NRAS-mutant melanoma

Purpose: <p>NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected.</p> <br /><br />Experimental Design and results: <p>BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2α and upregulation of the ER stress-related factors ATF4, CHOP and NUPR1 and the pro-apoptotic protein PUMA. MEKi such as binimetinib induced the expression of the pro-apoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process.</p> <br /><br />Conclusions: <p>The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma.

http://ift.tt/2trW8j5

The c.1085A>G genetic variant of CSF1R gene regulates tumor immunity by altering the proliferation, polarization, and function of macrophages

Purpose: <p>Targeting tumor-associated macrophages with CSF-1R inhibition reveals a strategy for cancer therapy. Here, we studied the impact of CSF1R germline genetic variant on CSF-1R signaling and the susceptibility to CSF-1R inhibitors.</p> <p>Experimental designs: </p> <p>CSF1R germline genetic variants were studied in 140 cancer patients. CSF-1R phosphorylation, endocytosis and macrophage polarization were measured as the response to CSF-1 stimulation. Tumor-associated macrophages in surgical specimens and sensitivity to CSF-1R inhibitors were used to determine macrophage function.</p> <p>Results:</p> <p>A CSF1R c.1085A>G genetic variant causing the change of histidine to arginine in the domain of receptor dimerization was identified as a high allele frequency in Eastern Asian population. Cancer patients with this variant allele had less M2-like tumor-associated macrophages accompanied by low VEGF expression in tumor tissues. Importantly, CSF1R genetic variant was significantly associated with disease-free survival in colorectal, endometrial and ovarian cancer. In terms of differentiation, macrophages with CSF1R c.1085A>G genetic variant displayed a refractory response to CSF-1 stimulation and macrophage survival was sensitive to CSF-1R inhibitors with IC₅₀ of 0.1-1 nM range. On contrast, CSF-1 induced a prominent phosphorylation and rapid endocytosis of CSF-1R leading to an M2-like dominant polarization in macrophages with CSF1R c.1085 genotype A_A, in which CSF-1R inhibitors of PLX3397, BLZ945, and GW2580 inhibited macrophage survival with IC₅₀ of 10-100 nM range.</p> <p>Conclusions: </p> <p>The CSF1R c.1085A>G genetic variant regulates tumor immunity by altering the polarization and function of macrophages. This genetic variant confers the sensitivity to CSF-1R inhibitors, implying as a biomarker in targeting CSF-1R signaling for cancer treatment.

http://ift.tt/2uaoQSE

PD-L1 expression and immune escape in melanoma resistance to MAPK inhibitors

Purpose: To examine the relationship between immune activity, PD-L1 expression and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors. <p>Experimental design: Thirty-eight tumors from 17 patients treated with BRAF inhibitor (n=12) or combination BRAF/MEK inhibitors (n=5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pre-treatment (PRE, n=17), early during treatment (EDT, n=8) and progression (PROG, n=13) biopsies. HLA-A/HLA-DPB1 expression was assessed by immunohistochemistry (IHC).</p> <p>Results: Gene set enrichment analysis (GSEA) of PRE, EDT and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-ß-catenin activity were negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition.</p> Conclusions: PD-L1 expression correlates with immune cells and immune activity signatures in melanoma, but is not sufficient for tumor response to MAPK inhibition, as many PRE and PROG melanomas displayed both PD-L1 positivity and immune activation signatures. This confirms that immune escape is common in MAPK inhibitor-treated tumors. This has important implications for the selection of second-line immunotherapy because analysis of mechanisms of immune escape will likely be required to identify patients likely to respond to such therapies.

http://ift.tt/2tsnXaT

Biochemical, Molecular, and Clinical Characterization of Succinate Dehydrogenase Subunit A Variants of Unknown Significance

Purpose: Patients who inherit a pathogenic loss-of-function genetic variant involving one of the four succinate dehydrogenase (SDH) subunit genes have up to an 86% chance of developing one or more cancers by the age of 50. If tumors are identified and removed early in these high-risk patients, they have a higher potential for cure.  Unfortunately, many alterations identified in these genes are variants of unknown significance (VUS), confounding the identification of high-risk patients. If we could identify misclassified SDH VUS as benign or pathogenic SDH mutations, we could better select patients for cancer screening procedures and remove tumors at earlier stages.<br /><br />Experimental Design: In this study, we combine data from clinical observations, a functional yeast model, and a computational model to determine the pathogenicity of 22 SDHA VUS. We gathered SDHA VUS from two primary sources: The OHSU Knight Diagnostics Laboratory and the literature. We used a yeast model to identify the functional effect of a VUS on mitochondrial function with a variety of biochemical assays. The computational model was used to visualize variants' effect on protein structure.<br /><br />Results: We were able to draw conclusions on functional effects of variants using our three-prong approach to understanding VUS. We determined that 16 (73%) of the alterations are actually pathogenic, causing loss of SDH function, and six (27%) have no effect upon SDH function.<br /><br />Conclusions:We thus report the reclassification of the majority of the VUS tested as pathogenic, and highlight the need for more thorough functional assessment of inherited SDH variants.

http://ift.tt/2ua5e0Z

Bradykinin does not acutely sensitize the reflex pressor response during hindlimb skeletal muscle stretch in decerebrate rats

Hindlimb skeletal muscle stretch (i.e., selective activation of the muscle mechanoreflex) in decerebrate rats evokes reflex increases in blood pressure and sympathetic nerve activity. Bradykinin has been found to sensitize mechano-gated channels through a bradykinin B2 receptor-dependent mechanism. Moreover, bradykinin B2 receptor expression on sensory neurons is increased following chronic femoral artery ligation in the rat (a model of simulated peripheral artery disease). We tested the hypothesis that, in decerebrate, unanesthetized rats, the injection of bradykinin into the arterial supply of a hindlimb would acutely augment (i.e., sensitize) the increase in blood pressure and renal sympathetic nerve activity (RSNA) during hindlimb muscle stretch to a greater extent in rats with a ligated femoral artery than in rats with freely perfused femoral arteries. The pressor response during static hindlimb muscle stretch was compared before and after the hindlimb arterial injection of 0.5 µg of bradykinin. The injection of bradykinin itself increased blood pressure to a greater extent in "ligated" rats (n=10) than in "freely perfused" rats (n=10). The increase in blood pressure during hindlimb muscle stretch, however, was not different before compared to after bradykinin injection in either freely perfused (control: 14±2, post-bradykinin: 15±2 mmHg, p=0.62) or ligated (control: 15±3, post-bradykinin: 14±2 mmHg, p=0.80) rats. Likewise, the increase in RSNA during stretch was not different before compared to after bradykinin injection in either group of rats. We conclude that bradykinin does not acutely sensitize the pressor response during hindlimb skeletal muscle stretch in either freely perfused or ligated decerebrate rats.

http://ift.tt/2tspWvH

Long-term effects of a renin inhibitor versus a thiazide diuretic on arterial stiffness and left ventricular diastolic function in elderly hypertensive patients

Arterial stiffness and cardiac function are important predictors of cardiovascular events in patients with hypertension even with adequate blood pressure (BP) control. We evaluated whether a direct renin inhibitor, aliskiren, reduces arterial stiffness and modulates left ventricular function compared with a diuretic, hydrochlorothiazide, in elderly hypertensives. Twenty one hypertensives [67±14 (SD) yrs] were randomly assigned to receive 6-month aliskiren (n=11) or hydrochlorothiazide (n=10) based therapy. We assessed β-stiffness of the local arteries, arterial elastance (Ea), and echocardiographic variables including early (E) and late (A) mitral inflow velocity, deceleration time of E, early (E') and late (A') diastolic mitral annular velocity, and left ventricular end-systolic elastance (Ees) before and after treatment. BP similarly decreased (P<0.001) after both therapies. β-stiffness of the carotid artery decreased after aliskiren, but increased after hydrochlorothiazide treatment (aliskiren: 6.42±2.34 pre vs. 5.07±1.29 post; hydrochlorothiazide: 5.05±1.78 vs. 7.25±2.68, P=0.001 for interaction). β-stiffness of the femoral and radial arteries were not different after either treatment. Different from aliskiren, E decreased (73±16 vs. 67±14 cm/s, P=0.026) and the deceleration time prolonged (218±40 vs. 236±35 ms, P=0.032) after hydrochlorothiazide therapy, while the E/A, and E' remained unchanged after both treatments. Ea and Ees decreased after aliskiren therapy (both P<0.05), while the Ea/Ees (ventricular-arterial coupling) was maintained after both treatments. Thus, aliskiren decreased the stiffness of carotid artery and left ventricular end-systolic elastance with maintenance of ventricular-arterial coupling without any effects on diastolic filling, while hydrochlorothiazide increased carotid arterial stiffness and slowed early diastolic filling in elderly hypertensives.

http://ift.tt/2u9XZWN

High-protein diet promotes sensitivity to cholecystokinin and shifts the cecal microbiome without altering brain inflammation in diet-induced obesity in rats

High protein diet (HPD) curtails obesity and/or fat mass but it is unknown whether it reverses neuroinflammation, altered glucose levels, cholecystokinin (CCK) sensitivity and gut microbiome in rats fed a Western diet (WD)-induced obesity (DIO). Male rats fed a WD (high fat and sugar) for 12 weeks were switched to a HPD for 6 weeks. Body composition, food intake, meal pattern, sensitivity to intraperitoneal CCK-8S, blood glucose, brain signaling, and cecal microbiota were assessed. Compared to normal diet, WD increased body weight (9.3%) and fat mass (73.4%). CCK-8S (1.8 or 5.2 nmol/kg) did not alter food intake and meal pattern in DIO rats. Switching to a HPD for six weeks reduced fat mass (15.7%) with a non-significantly reduced body weight gain, normalized blood glucose and decreased feeding after CCK-8S. DIO rats on the WD or switched to a HPD showed comparable microbial diversity. However, in HPD vs WD rats, there was enrichment of 114 operational taxonomic units (OTUs) and depletion of 188 OTUs. Of those, Akkermansia muciniphila (enriched on a HPD), an unclassified Clostridiales, a member of the RF39 order, and a Phascolarctobacterium were significantly associated with fat mass. The WD increased cytokine expression in the hypothalamus and dorsal medulla that was unchanged by switching to HPD. These data indicate that HPD reduces body fat and restores glucose homeostasis and CCK sensitivity while not modifying brain inflammation. In addition, expansion of cecal Akkermansia muciniphila correlated to fat mass loss may represent a potential peripheral mechanism of HPD beneficial effects.

http://ift.tt/2trJAYO

Patterns of Emergency Department Care for Newly Diagnosed Immune Thrombocytopenia in United States Children's Hospitals

We used the Pediatric Health Information Systems database to ascertain treatment patterns of immune thrombocytopenia across the US. Despite the recently published guidelines by the American Society of Hematology, most patients are still being hospitalized for immune thrombocytopenia, even in the absence of documented bleeding symptoms.

http://ift.tt/2vkCnar

Exercise Performance and 22q11.2 Deletion Status Affect Quality of Life in Tetralogy of Fallot

To identify mediators of health status and quality of life (QOL) in children and adolescents aged 8-18 years old following surgical repair for tetralogy of Fallot (TOF), including resource use, exercise performance, and 22q11.2 deletion status.

http://ift.tt/2uKIism

Cognitive Function in Children with Lupus Nephritis: A Cross-Sectional Comparison with Children with Other Glomerular Chronic Kidney Diseases

To identify factors contributing to cognitive impairment in children with lupus nephritis.

http://ift.tt/2vler6E

Identification of new tumor suppressor genes in triple-negative breast cancer

Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step Sleeping Beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines. Among CCG whose SB-mediated genetic mutation resulted in increased cellular proliferation in all cell lines tested, the genes ADNP, AP2B1, TOMM70A and ZNF326 showed tumor suppressor (TS) activity in tumor xenograft studies. Subsequent studies showed that ZNF326 regulated expression of multiple EMT and cancer stem cell (CSC) pathway genes. It also modulated expression of TS genes involved in the regulation of migration and cellular invasion and was a direct transcriptional activator of genes that regulate CSC self-renewal. ZNF326 expression associated with TNBC patient survival, with ZNF326 protein levels showing a marked reduction in TNBC. Our validation of several new tumor suppressor genes in TNBC demonstrate the utility of two-step forward genetic screens in mice, and offer an invaluable tool to identify novel candidate therapeutic pathways and targets.

http://ift.tt/2u9PQkX

Our panel of experts highlights the most important research articles across the spectrum of topics relevant to the field of CNS oncology

CNS Oncology, Ahead of Print.


http://ift.tt/2u9MK0v

CNS Anticancer Drug Discovery and Development: 2016 conference insights

CNS Oncology, Ahead of Print.


http://ift.tt/2trPYPV

The role of surgery in low-grade gliomas: do timing and extent of resection matter?

CNS Oncology, Ahead of Print.


http://ift.tt/2u9PH0W

Savolitinib Heads for Phase III Trial in PRCC [News in Brief]

MET inhibitor shows promise treating papillary renal cell carcinoma in patients with abnormalities in MET signaling pathway.

http://ift.tt/2tIsocY

Endoscopic full-thickness resection using suture loop needle-T-tag tissue anchors in the porcine stomach (with video)

Endoscopic full-thickness resection (EFTR) is still challenging and a reliable technique is desirable. The aim of this study was to evaluate the feasibility of controlled EFTR using a pseudopolyp made from suture loop needle-T-tag (SLNT) tissue anchors in ex vivo porcine stomachs.

http://ift.tt/2uB8JQs

Cardiac ischemia after epinephrine injection during EMR for a large rectal polyp

http://ift.tt/2tJ1dyp

Endoscopic Muscle Biopsy (EMB) of the Duodenum and Rectum: A Pilot Survival Study in a Porcine Model to Detect Myenteric Neurons

Small bowel and colorectal muscle biopsies require a surgical approach. Advancing our understanding of the pathophysiology of motility disorders, such as functional bowel disorders, intestinal pseudo-obstruction and slow transit constipation, is hindered by our inability to non-invasively obtain muscularis propria (MP) for evaluation of multiple cell types, including myenteric neurons. The aims of this study were to determine (1) technical feasibility, reproducibility and safety of performing duodenal endoscopic muscle biopsy (dEMB) and rectal endoscopic muscle biopsy (rEMB) using a clip-assist technique; and (2) presence of myenteric neurons in tissue samples.

http://ift.tt/2uBHbKO

Opioid prescribing among cancer and non-cancer patients: Time trend analysis in the elderly using administrative data

Overall prescribing rates for cancer patients aged ≥65 remain unchanged over time, in spite of the introduction of a provincial symptom screening program. Decreasing prescription rates in some drug sub-classes were observed. The potential impact of these changes on the quality of symptom control for cancer patients needs further investigation.

http://ift.tt/2tIwfqv

State of the Science of Spirituality and Palliative Care Research PART II: Screening, Assessment, and Interventions

As discussed in Part I of the State of the Science in Spirituality in Palliative Care (SOS- SPC), there are notable relationships between spiritual domains and palliative care outcomes among patients and family members. The recommendations outlined in the summary in Part I, Table 3, highlight the critical methodological challenges together with key gaps in outcomes research. By employing definitional and methodological rigor, the field of palliative care can address these gaps and further the understanding of how spirituality, in its multidimensional complexity, relates to palliative care outcomes.

http://ift.tt/2uAXKXb

Preclinical evaluation of NF-κB-triggered dendritic cells expressing the viral oncogenic driver of Merkel cell carcinoma for therapeutic vaccination.

Related Articles

Preclinical evaluation of NF-κB-triggered dendritic cells expressing the viral oncogenic driver of Merkel cell carcinoma for therapeutic vaccination.

Ther Adv Med Oncol. 2017 Jul;9(7):451-464

Authors: Gerer KF, Erdmann M, Hadrup SR, Lyngaa R, Martin LM, Voll RE, Schuler-Thurner B, Schuler G, Schaft N, Hoyer S, Dörrie J

Abstract
BACKGROUND: Merkel cell carcinoma (MCC) is a rare but very aggressive skin tumor that develops after integration of a truncated form of the large T-antigen (truncLT) of the Merkel cell polyomavirus (MCV) into the host's genome. Therapeutic vaccination with dendritic cells (DCs) loaded with tumor antigens is an active form of immunotherapy, which intends to direct the immune system towards tumors which express the respective vaccination antigens.
METHODS: Cytokine-matured monocyte-derived DCs of healthy donors and MCC patients were electroporated with mRNA encoding the truncLT. To permit major histocompatibility complex (MHC) class II next to class I presentation, we used an RNA construct in which the antigen was fused to a DCLamp sequence in addition to the unmodified antigen. To further improve their immunogenicity, the DCs were additionally activated by co-transfection with the constitutively active nuclear factor (NF)-κB activator caIKK. These DCs were used to stimulate autologous CD8(+) T-cells or a mixture of CD4(+) and CD8(+) T-cells. Then the percentage of T-cells, specific for the truncLT, was quantified by interferon (IFN)γ ELISpot assays.
RESULTS: Both the truncLT and its DCLamp-fusion were detected within the DCs by flow cytometry, albeit the latter required blocking of the proteasome. The transfection with caIKK upregulated maturation markers and induced cytokine production. After 2-3 rounds of stimulation, the T-cells from 11 out of 13 healthy donors recognized the antigen. DCs without caIKK appeared in comparison less potent in inducing such responses. When using cells derived from MCC patients, we could induce responses for 3 out of 5 patients; however, here the caIKK-transfected DCs did not display their superiority.
CONCLUSION: These results show that optimized DCs are able to induce MCV-antigen-specific T-cell responses. Therapeutic vaccination with such transfected DCs could direct the immune system against MCC.

PMID: 28717398 [PubMed]

http://ift.tt/2tsaEqN

Pretreatment antigen-specific immunity and regulation - association with subsequent immune response to anti-tumor DNA vaccination.

Related Articles

Pretreatment antigen-specific immunity and regulation - association with subsequent immune response to anti-tumor DNA vaccination.

J Immunother Cancer. 2017 Jul 18;5(1):56

Authors: Johnson LE, Olson BM, McNeel DG

Abstract
BACKGROUND: Immunotherapies have demonstrated clinical benefit for many types of cancers, however many patients do not respond, and treatment-related adverse effects can be severe. Hence many efforts are underway to identify treatment predictive biomarkers. We have reported the results of two phase I trials using a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with biochemically recurrent prostate cancer. In both trials, persistent PAP-specific Th1 immunity developed in some patients, and this was associated with favorable changes in serum PSA kinetics. In the current study, we sought to determine if measures of antigen-specific or antigen non-specific immunity were present prior to treatment, and associated with subsequent immune response, to identify possible predictive immune biomarkers.
METHODS: Patients who developed persistent PAP-specific, IFNγ-secreting immune responses were defined as immune "responders." The frequency of peripheral T cell and B cell lymphocytes, natural killer cells, monocytes, dendritic cells, myeloid derived suppressor cells, and regulatory T cells were assessed by flow cytometry and clinical laboratory values. PAP-specific immune responses were evaluated by cytokine secretion in vitro, and by antigen-specific suppression of delayed-type hypersensitivity to a recall antigen in an in vivo SCID mouse model.
RESULTS: The frequency of peripheral blood cell types did not differ between the immune responder and non-responder groups. Non-responder patients tended to have higher PAP-specific IL-10 production pre-vaccination (p = 0.09). Responder patients had greater preexisting PAP-specific bystander regulatory responses that suppressed DTH to a recall antigen (p = 0.016).
CONCLUSIONS: While our study population was small (n = 38), these results suggest that different measures of antigen-specific tolerance or regulation might help predict immunological outcome from DNA vaccination. These will be prospectively evaluated in an ongoing randomized, phase II trial.

PMID: 28716080 [PubMed - in process]

http://ift.tt/2gLT0bM

Intradermal Delivery of Antigens Enhances Specific IgG and Diminishes IgE Production: Potential Use for Vaccination and Allergy Immunotherapy.

Related Articles

Intradermal Delivery of Antigens Enhances Specific IgG and Diminishes IgE Production: Potential Use for Vaccination and Allergy Immunotherapy.

PLoS One. 2016;11(12):e0167952

Authors: Yasuda T, Ura T, Taniguchi M, Yoshida H

Abstract
Skin is protected by a tough but flexible multilayered barrier and is a front line for immune responses against invading particles. For many years now, skin has been a tissue where certain vaccines are injected for the prevention of infectious disease, however, the detailed mechanisms of the skin immune response are not yet well understood. Using thin and small injection needles, we carefully injected OVA into a restricted region of mouse skin, i.e., intradermal (ID), and examined the antibody response in comparison with subcutaneous (SC) injection or epicutaneous patch administration of OVA. Epicutaneous patches induced a high IgE response against OVA, but IgG production was low. High IgG production was induced by both ID and SC injection, moreover, ID injection induced higher IgG production without any adjutants. Furthermore, OVA-specific IgE production was diminished by ID injection. We found that ID injection could efficiently stimulate skin resident DCs, drive Th1-biased conditions and diminish IgE production. The ID injection response was regulated by Langerin+ dermal DCs, because OVA was taken up mainly by these cells and, after transiently deleting them, the IgE response was no longer diminished and IgG1 production was enhanced. We also tested whether ID injection might be an effective allergy treatment by attempting to inhibit ongoing IgE production in mice with experimentally induced high serum IgE levels. Multiple ID injections of OVA were shown to prevent elevation of serum OVA-specific IgE after repeated allergen challenge. In contrast, SC OVA injection could only transiently inhibit the OVA-specific IgE production. These findings indicated that ID injection results in higher induction of antigen-specific IgG, and thus may be useful for vaccine delivery with little or no adjuvant components. Moreover, the observed diminishment of IgE and induction of Th1-biased immune responses suggest that ID may be a useful injection route for allergy immunotherapy.

PMID: 27973543 [PubMed - indexed for MEDLINE]

http://ift.tt/2u9PhIb

Nanoparticulate Tubular Immunostimulating Complexes: Novel Formulation of Effective Adjuvants and Antigen Delivery Systems

New generation vaccines, based on isolated antigens, are safer than traditional ones, comprising the whole pathogen. However, major part of purified antigens has weak immunogenicity. Therefore, elaboration of new adjuvants, more effective and safe, is an urgent problem of vaccinology. Tubular immunostimulating complexes (TI-complexes) are a new type of nanoparticulate antigen delivery systems with adjuvant activity. TI-complexes consist of cholesterol and compounds isolated from marine hydrobionts: cucumarioside A2-2 (CDA) from Cucumaria japonica and monogalactosyldiacylglycerol (MGDG) from marine algae or seagrass. These components were selected due to immunomodulatory and other biological activities. Glycolipid MGDG from marine macrophytes comprises a high level of polyunsaturated fatty acids (PUFAs), which demonstrate immunomodulatory properties. CDA is a well-characterized individual compound capable of forming stable complex with cholesterol. Such complexes do not possess hemolytic activity. Ultralow doses of cucumariosides stimulate cell as well as humoral immunity. Therefore, TI-complexes comprising biologically active components turned out to be more effective than the strongest adjuvants: immunostimulating complexes (ISCOMs) and complete Freund's adjuvant. In the present review, we discuss results published in series of our articles on elaboration, qualitative and quantitative composition, ultrastructure, and immunostimulating activity of TI-complexes. The review allows immersion in the history of creating TI-complexes.

http://ift.tt/2tI83Vc

The Role of Intereukin-31 in Pathogenesis of Itch and Its Intensity in a Course of Bullous Pemphigoid and Dermatitis Herpetiformis

Itch which is one of the major, subjective symptoms in a course of bullous pemphigoid and dermatitis herpetiformis makes those two diseases totally different than other autoimmune blistering diseases. Its pathogenesis is still not fully known. The aim of this research was to assess the role of IL-31 in development of itch as well as to measure its intensity. Obtained results, as well as literature data, show that lower concentration of IL-31 in patients' serum may be correlated with its role in JAK/STAT signaling pathway which is involved in development of autoimmune blistering disease. Intensity of itch is surprisingly huge problem for the patients and the obtained results are comparable with results presented by atopic patients.

http://ift.tt/2tI82R8

Trends and Inequalities in Use of Maternal Health Care Services in Nepal: Strategy in the Search for Improvements

Background. Nepal has made significant progress against the Millennium Development Goals for maternal and child health over the past two decades. However, disparities in use of maternal health services persist along geographic, economic, and sociocultural lines. Methods. Trends and inequalities in the use of maternal health services in Nepal between 1994 and 2011 were examined using four Nepal Demographic and Health Surveys (NDHS), nationally representative cross-sectional surveys conducted by interviewing women who gave birth 3–5 years prior to the survey. Sociodemographic disparities in maternal health service utilization were measured. Rate difference, rate ratios, and concentration index were calculated to measure income inequalities. Findings. The percentage of mothers that received four antenatal care (ANC) consultations increased from 9% to 54%, the institutional delivery rate increased from 6% to 47%, and the cesarean section (C-section) rate increased from 1% in 1994 to 6% in 2011. The ratio of the richest and the poorest quintile mothers for use of four ANC, institutional delivery, and C-section delivery were 5.08 (95% CI: 3.82–6.76), 9.00 (95% CI: 6.55–12.37), and 9.37 (95% CI: 4.22–20.83), respectively. However, inequality is reducing over time; for the use of four ANC services, the concentration index fell from 0.60 (95% CI: 0.56–0.64) in 1994–1996 to 0.31 (95% CI: 0.29–0.33) in 2009–2011. For institutional delivery, the concentration index fell from 0.65 (95% CI: 0.62–0.70) to 0.40 (95% CI: 0.38–0.40) between 1994–1996 and 2009–2011. For C-section deliveries, an increase in concentration index was observed, 0.64 (95% CI: 0.51–0.77); 0.76 (95% CI: 0.64–0.88); 0.77 (95% CI: 0.71–0.84); and 0.66 (95% CI: 0.60–0.72) in the periods 1994–1996, 1999–2001, 2004–2006, and 2009–2011, respectively. All sociodemographic variables were significant predictors of use of maternal health services, out of which maternal education was the most powerful. Conclusion. To increase equitable use of maternal health services in Nepal there is a need to strengthen the health system to increase access to and utilization of services among poorer women, those with less education, and those living in remote areas. Beyond the health sector stronger efforts are needed to tackle the root causes of health inequality, reduce poverty, increase female education, eradicate caste/ethnicity based social discrimination, and invest in the development of remote areas.

http://ift.tt/2tIORq1

Multirapid Serial Visual Presentation Framework for EEG-Based Target Detection

Target image detection based on a rapid serial visual presentation (RSVP) paradigm is a typical brain-computer interface system with various applications, such as image retrieval. In an RSVP paradigm, a P300 component is detected to determine target images. This strategy requires high-precision single-trial P300 detection methods. However, the performance of single-trial detection methods is relatively lower than that of multitrial P300 detection methods. Image retrieval based on multitrial P300 is a new research direction. In this paper, we propose a triple-RSVP paradigm with three images being presented simultaneously and a target image appearing three times. Thus, multitrial P300 classification methods can be used to improve detection accuracy. In this study, these mechanisms were extended and validated, and the characteristics of the multi-RSVP framework were further explored. Two different P300 detection algorithms were also utilized in multi-RSVP to demonstrate that the scheme is universally applicable. Results revealed that the detection accuracy of the multi-RSVP paradigm was higher than that of the standard RSVP paradigm. The results validate the effectiveness of the proposed method, and this method can provide a whole new idea in the field of EEG-based target detection.

http://ift.tt/2tIyPN1

HOXB9 Expression Correlates with Histological Grade and Prognosis in LSCC

The purpose of this study was to investigate the HOX gene expression profile in laryngeal squamous cell carcinoma (LSCC) and assess whether some genes are associated with the clinicopathological features and prognosis in LSCC patients. The HOX gene levels were tested by microarray and validated by qRT-PCR in paired cancerous and adjacent noncancerous LSCC tissue samples. The microarray testing data of 39 HOX genes revealed 15 HOX genes that were at least 2-fold upregulated and 2 that were downregulated. After qRT-PCR evaluation, the three most upregulated genes (HOXB9, HOXB13, and HOXD13) were selected for tissue microarray (TMA) analysis. The correlations between the HOXB9, HOXB13, and HOXD13 expression levels and both clinicopathological features and prognosis were analyzed. Three HOX gene expression levels were markedly increased in LSCC tissues compared with adjacent noncancerous tissues (). HOXB9 was found to correlate with histological grade () and prognosis () in LSCC. In conclusion, this study revealed that HOXB9, HOXB13, and HOXD13 were upregulated and may play important roles in LSCC. Moreover, HOXB9 may serve as a novel marker of poor prognosis and a potential therapeutic target in LSCC patients.

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Targeting PI3K Signaling in Combination Cancer Therapy.

Related Articles

Targeting PI3K Signaling in Combination Cancer Therapy.

Trends Cancer. 2017 Jun;3(6):454-469

Authors: Pons-Tostivint E, Thibault B, Guillermet-Guibert J

Abstract
Targeting upstream phosphatidylinositol-3-kinases (PI3Ks) in the PI3K/Akt/mTOR pathway appears to be a promising therapy in solid cancers; however, first early clinical trials with PI3K inhibitors in monotherapy have been disappointing. A massive array of preclinical and clinical trials are currently evaluating combinations of PI3K inhibitors in targeted therapies. These combinations include co-treatments with drugs directed against other intra-/extracellular signaling molecules, nuclear hormone receptors, DNA damage repair enzymes, and immune modulators. We review the literature and pinpoint mechanisms of action in different genomic and organ contexts. Combinatorial approaches are potentially superior to monotherapies and should become alternative clinical strategies to treat cancer patients.

PMID: 28718419 [PubMed - in process]

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Integration-defective lentiviral vector mediates efficient gene editing through homology-directed repair in human embryonic stem cells.

Related Articles

Integration-defective lentiviral vector mediates efficient gene editing through homology-directed repair in human embryonic stem cells.

Nucleic Acids Res. 2017 Mar 17;45(5):e29

Authors: Wang Y, Wang Y, Chang T, Huang H, Yee JK

Abstract
Human embryonic stem cells (hESCs) are used as platforms for disease study, drug screening and cell-based therapy. To facilitate these applications, it is frequently necessary to genetically manipulate the hESC genome. Gene editing with engineered nucleases enables site-specific genetic modification of the human genome through homology-directed repair (HDR). However, the frequency of HDR remains low in hESCs. We combined efficient expression of engineered nucleases and integration-defective lentiviral vector (IDLV) transduction for donor template delivery to mediate HDR in hESC line WA09. This strategy led to highly efficient HDR with more than 80% of the selected WA09 clones harboring the transgene inserted at the targeted genomic locus. However, certain portions of the HDR clones contained the concatemeric IDLV genomic structure at the target site, probably resulted from recombination of the IDLV genomic input before HDR with the target. We found that the integrase protein of IDLV mediated the highly efficient HDR through the recruitment of a cellular protein, LEDGF/p75. This study demonstrates that IDLV-mediated HDR is a powerful and broadly applicable technology to carry out site-specific gene modification in hESCs.

PMID: 27899664 [PubMed - indexed for MEDLINE]

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Regenerative Potential of Spermatogonial Stem Cells, Endothelial Progenitor Cells, and Epithelial Progenitor Cells of C57Bl/6 Male Mice with Metabolic Disorders

The properties of spermatogonial stem cells, endothelial progenitor cells, and the epithelial progenitors of C57Bl/6 mice under conditions of metabolic disorders were studied using the model of busulfan-induced suppression of spermatogenesis and in vitro culture technique. Spermatogonial stem cells CD117—CD90⁺ and epithelial progenitors CD45—CD31—Sca-1⁺CD49f⁺ derived from the testes of mice with metabolic disturbances demonstrated 17- and 28-fold increase in the respective cell mass and generated cell colonies in vitro. In contrast, spermatogonial stem cells with immune phenotype CD51—CD24⁺CD52⁺ had reduced selfrenewal capacity. Spermatogonial stem cells CD117—CD90⁺ and CD117⁺CD90⁺ as well as endothelial progenitors CD45—CD31⁺ derived from the testes of donor mice with metabolic disorders demonstrated high transplantation capacity in C57Bl/6 mouse testes damaged by cytostatic busulfan.

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Virtual Experimental Validation of Dynamic Osteosynthesis in the Treatment of Fractures of the Proximal Femur

Volume model of transtrochanteric fracture of the femoral bone fixed by Targon PF dynamic fixator was studied by the finite element analysis. The following parameters were measured: magnitude and direction of displacement of system elements, pressure between fragments, and von Mises stress distribution in the fixator depending on support screw plunging into the sleeve. The results indicate that stability of the bone-nail system increases during fracture union and 10-mm shortening of the femoral neck axis, which is seen from a decrease in system deformation under load by 16.8%, stress in the implant by 20.2%, and pressure in the zone of fragments contact by 19.8%.

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Dipeptidyl Peptidase 4 Inhibitors Diprotin A and Sitagliptin Administered on Weeks 2-3 of Postnatal Development Modulate Monoamine Metabolism in the Striatum of Adult Rats

The levels of monoamines and their metabolites in brain structures of adult (3-month-old) rats with emotional and motivational disorders induced by inhibitors of dipeptidyl peptidase 4 (DPP-4; EC 3.4.14.5) diprotin A and sitagliptin on weeks 2-3 of postnatal development (postnatal days 5-18) were studied by HPLC with electrochemical detection. A significant decrease in the level of serotonin metabolite, 5-hydroxyindoleacetic acid, and a pronounced tendency towards reduced serotonin level were detected in the striatum of rats in both study groups. In adult rats treated with diprotin A during the neonatal period, a tendency towards activation of dopamine metabolism was observed (judging from DOPAC/DA ratio). The levels of monoamines and their metabolites in the frontal cortex, hypothalamus, and amygdala remained unchanged. The findings suggest that administration of DPP-4 inhibitors during the neonatal period induces long-term dysfunction of the serotonergic and dopaminergic systems of the brain.

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A Study of the Protective Properties of an Antibody-Based Antidote Metabolizing Organophosphorus Pesticide Paraoxon

A catalytic antibody A17 and its mutants highly efficiently interact with organophosphorus pesticide paraoxon. In this work, we studied the protective properties of antibody A17-K47 in paraoxon poisoning using a mouse model. The optimal paraoxon dose simulating the acute toxic effect of organophosphorus compounds was 550 μg/kg. The pharmacokinetic parameters of A17-K47 antibody were t_1/2distr =7.2±1.4 min, t_1/2el =330±20 min. The antibody did not cause toxic effects when administered at a ten-fold calculated therapeutic dose (610 mg/kg). The drug did not reduce mortality from acute paraoxon poisoning; however, the absence of drug toxicity opens up prospects for its use in symptomatic treatment of chronic paraoxon poisoning.

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Mechanisms of Sensitivity of Soft Tissue Sarcoma Cells to Temozolomide

We studied the mechanisms of sensitivity of soft tissue sarcoma cells to alkylating agent temozolomide. The mechanisms of tumor cell sensitivity to temozolomide are complex and are determined by not only the level of O6-methylguanine-DNA-methyltransferase (MGTM) expression, but also activity of oncosuppressor protein p53. A-673 Ewing's sarcoma cells were found to be the most sensitive to temozolomide, whereas temozolomide-treated SK-LMS-1 leiomyosarcoma cells exhibited signs of cell aging.

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Immunolocation of Heme Oxygenases in the Walls of Cerebral Arteries of Various Diameters in Rats

The distribution of two enzymes involved in the formation of carbon monoxide, heme oxygenases 1 and 2, in the pial branches of orders I-V of the middle cerebral artery basin and in intracerebral vessels was studied in adult Wistar rats. Immunohistochemical studies detected hemeoxygenase-2 in the endothelium of the small pial and intracerebral arterioles and in myocytes of pial branches I-III. Heme oxygenase 1, an inducible form of the enzyme, is normally not expressed in the cerebral vessels, but the enzyme is expressed in response to sodium metaarsenite. In this case, heme oxygenase markers are detected in myocytes of pial arteries I-II and in the endothelium of small pial and intracerebral vessels. Sodium meta-arsenite is inessential for immunolocation and quantitative distribution of heme oxygenase 2 in the vessels.

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Cysteine-Containing Peptides Stimulate Monocyte Migration through NADPH-Oxidase Activation

We analyzed migration of monocytes under the effect of apocinin (NADPH inhibitor) and PD98059 (blocker of extracellular MEK/ERK kinase involved in Nox4 oxidase-mediated migration of monocytes). Migration of monocytes stimulated by cysteine-containing peptides (fragments of chemokines with free thiol group MCP-1 and fractalkine) was completely inhibited by apocinin and MEK/ERK blocker. It is assumed that the stimulating effect of cysteine-containing peptides on monocyte migration is mediated by the NADPH-oxidase system, in particular, Nox4.

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Experimental Assessment of the Effect of Kagocel on Reproductive Function in Pubertal Male Rats

We studied possible toxic effects of antiviral drug Kagocel on reproductive function in pubertal male rats. The drug was administered in therapeutic and 10-fold higher doses throughout the spermatogenesis cycle (48 days). Kagocel did not reduce mating and fertilizing capacities, did not suppress spermatogenesis, and had no toxic effects on the offspring. The results characterize Kagocel as a drug with a broad reproductive safety profile and demonstrate that the age limits for using Kagocel in pediatric practice can be extended.

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Delayed Results of Experimental Afobazole Therapy in Rats after Acute Myocardial Infarction

Delayed cardioprotective effects of anxiolytic Afobazole (15 mg/kg, intraperitoneally for 14 days) were evaluated using dynamic echocardiographic recordings on days 2, 15, 56, and 98 after experimental myocardial infarction modeling (rat model of acute myocardial ischemia). The cardiotropic activity of Afobazole is assumed to be related to its agonistic effects on σ₁ receptor of cardiomyocytes. It was found that animals treated with Afobazole had no signs of heart failure by the end of observation, as evidenced by left ventricular ejection fraction.

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Genetic Engineering of Native Chain Combinations of B-Cell Repertoires on the Surface of Methylotrophic Yeasts Pichia pastoris

We designed genetic constructs for exposing Fab-fragment library of natively paired single cell B-cell receptors on the surface of Pichia pastoris yeast cells. We have previously obtained the A17 antibody in our laboratory [6]. In this study we showed that the newly designed genetic constructs provide a compatible level of A17 antibody Fab fragment on the surface of yeast cells as well as in the case of vectors containing DNA fragments corresponding to each chain of the antibody. The data suggest that the developed approach for constructing immunoglobulin gene libraries is adequate and fully convenient for studying properties of the real human B-lymphocyte repertoire.

http://ift.tt/2vDFxW4

Intranasal Insulin Restores Metabolic Parameters and Insulin Sensitivity in Rats with Metabolic Syndrome

We studied the effect of 10-week treatment with intranasal insulin (0.5 IU/day) on glucose tolerance, glucose utilization, lipid metabolism, functions of pancreatic β cells, and insulin system in the liver of rats with cafeteria diet-induced metabolic syndrome. The therapy reduced body weight and blood levels of insulin, triglycerides, and atherogenic cholesterol that are typically increased in metabolic syndrome, normalized glucose tolerance and its utilization, and increased activity of insulin signaling system in the liver, thus reducing insulin resistance. The therapy did not affect the number of pancreatic islets and β cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome.

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Sodium Dodecyl Sulfate Cytotoxicity towards HaCaT Keratinocytes: Comparative Analysis of Methods for Evaluation of Cell Viability

Viability of keratinocytes of HaCaT immortalized line incubated with sodium dodecyl sulfate for 3 min, 1 and 48 h, was studied by light microscopy, MTT test, and neutral red absorption test. The IC₅₀ values were determined for each of the studied lengths of exposure. HaCaT cells exhibited a dose-dependent decrease of viability under the effect of sodium dodecyl sulfate, proportional to the length of exposure. The values measured by different methods (MTT test and neutral red absorption test) varied, the differences were determined by the duration of exposure to sodium dodecyl sulfate. The dispersion of values for 1 and 48 h exposure, obtained by MTT method, was greater than of the values obtained by neutral red absorption test.

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Association of Level of Proprotein Convertase Subtilisin/Kexin Type 9 with Intima-Media Thickness in Patients with Familial Hypercholesterolemia

We studied association of PCSK9 protein with the carotid artery intima-media thickness in patients with familial hypercholesterolemia (N=53; age 49.9±6.9 years) treated with statins. Blood level of PCSK9 protein was measured by ELISA; ultrasonography of the carotid arteries with measurement of the thickness of the intima-media complex of the common carotid arteries in the distal segment for 10 mm from the bifurcation on the far wall of the vessel was performed in on-line mode. The mean values were calculated for both sides, the maximum mean value was included in the analysis. It was shown that PCSK9 levels positively correlate with carotid artery intima-media thickness in patients with familial hypercholesterolemia.

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Approaches to Controlled Co-Amplification of Genes for Production of Biopharmaceuticals: Study of the Insertion and Amplification Dynamics of Genetic Cassettes in the Genome of Chinese Hamster Ovary Cells during Co-Expression of Compatible Pair of Plasmids

Plasmid vector family p1.1 based on non-coding regions of Chinese hamster housekeeping gene EEF1A and concatemer of Epstein—Barr virus terminal repeat increases the frequency of genome integration and provides rapid amplification of the target genes in the genome. For a pair of fluorescent proteins eGFP and mCherry it was shown that p1.1 vectors bearing dihydrofolate reductase and glutamine synthetase selection markers upon co-transfection into CHO DG44 cell line allow obtaining a polyclonal cell population in which ~70% of cells express both genes. The subsequent one-step gene amplification of the genome-integrated genetic cassettes under the selective pressure of increased concentrations of methotrexate can increase the expression of both integrated genes up to 8.2% eGFP and 9.9% mCherry of total protein. This approach can be used for the development of cell lines for the production of functional heterodimeric proteins, e.g. polypeptide hormones and therapeutic antibodies.

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Effect of Phenibut and Glufimet, a Novel Glutamic Acid Derivative, on Respiration of Heart and Brain Mitochondria from Animals Exposed to Stress against the Background of Inducible NO-Synthase Blockade

Increased oxygen consumption by heart and brain mitochondria in the absence of ADP and reduced mitochondrial respiration in the presence of ADP were observed in rats exposed to stress simulated by suspension by the dorsal neck skin fold for 24 h, which attests to uncoupling of substrate oxidation and ATP synthesis and can cause electron drain from the respiratory chain, formation of ROS, and oxidative damage to cell structures. Blockade of inducible NO synthase with aminoguanidine (single intraperitoneal dose of 50 mg/kg before stress exposure) increased coupling of respiration and oxidative phosphorylation in heart and brain mitochondria of rats exposed to immobilization-painful stress, which was especially pronounced in cardiomyocytes. The test compounds glufimet (single intraperitoneal dose of 29 mg/kg before stress exposure) and phenibut (single intraperitoneal dose of 50 mg/kg before stress exposure) limited stress-induced mitochondrial damage against the background of inducible NO synthase blockade and without it, which was seen from increased respiratory control ratio in comparison with that in untreated rats exposed to stress (control).

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A Simple Neuronal Mechanical Injury Methodology to Study Drosophila Motor Neuron Degeneration

Here we describe a simple and widely accessible method to injure segmental nerves in Drosophila larvae to visualize and quantify neurodegeneration of motor neurons at the neuromuscular junction (NMJ) of third instar larvae.

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Instructions to authors and Information for readers

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Hepatology Highlights – August 2017

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Table of contents

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Notices

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Quiz: Capnography for kids: Unique considerations

Test your knowledge on the challenges of assessing and treating children with capnography

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Utilization of Capsules for Negative Staining of Viral Samples within Biocontainment

This protocol provides instruction for negative staining virus samples which can easily be used in BSL-2, -3, or -4 laboratories. It includes the use of an innovative processing capsule, which protects the transmission electron microscopy grid and provides the user easier handling in the more turbulent environments within biocontainment.

http://ift.tt/2tr0J50

Reducing State Anxiety Using Working Memory Maintenance

This protocol demonstrates how to measure anxiety-potentiated startle during the Sternberg Working Memory paradigm.

http://ift.tt/2tr4g3m

Protective effects of chebulic acid on alveolar epithelial damage induced by urban particulate matter

Chebulic acid (CA) isolated from T. chebula, which has been reported for treating asthma, as a potent anti-oxidant resources. Exposure to ambient urban particulate matter (UPM) considered as a risk for cardiopulm...

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The lncRNA CASC15 regulates SOX4 expression in RUNX1-rearranged acute leukemia

Abstract

Background

Long non-coding RNAs (lncRNAs) play a variety of cellular roles, including regulation of transcription and translation, leading to alterations in gene expression. Some lncRNAs modulate the expression of chromosomally adjacent genes. Here, we assess the roles of the lncRNA CASC15 in regulation of a chromosomally nearby gene, SOX4, and its function in RUNX1/AML translocated leukemia.

Results

CASC15 is a conserved lncRNA that was upregulated in pediatric B-acute lymphoblastic leukemia (B-ALL) with t (12; 21) as well as pediatric acute myeloid leukemia (AML) with t (8; 21), both of which are associated with relatively better prognosis. Enforced expression of CASC15 led to a myeloid bias in development, and overall, decreased engraftment and colony formation. At the cellular level, CASC15 regulated cellular survival, proliferation, and the expression of its chromosomally adjacent gene, SOX4. Differentially regulated genes following CASC15 knockdown were enriched for predicted transcriptional targets of the Yin and Yang-1 (YY1) transcription factor. Interestingly, we found that CASC15 enhances YY1-mediated regulation of the SOX4 promoter.

Conclusions

Our findings represent the first characterization of this CASC15 in RUNX1-translocated leukemia, and point towards a mechanistic basis for its action.

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The burden of HIV on Tuberculosis patients in the Volta region of Ghana from 2012 to 2015: implication for Tuberculosis control

The impact of HIV on TB, and the implications for TB control, has been acknowledged as a public health challenge. It is imperative therefore to assess the burden of HIV on TB patients as an indicator for monit...

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Apple patents discreet 911 dialing technology

When alerted with the technology, responders would receive the phone's location as well as livestream video or audio

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Attention and Simulated Motivated Response to Male Advertisement Call Activates Forebrain Dopaminergic and Social Decision-Making Network Nuclei in Female Midshipman Fish

Abstract

Little is known regarding the coordination of audition with decision-making and subsequent motor responses that initiate social behavior including mate localization during courtship. Using the midshipman fish model, we tested the hypothesis that the time spent by females attending and responding to the advertisement call is correlated with the activation of a specific subset of catecholaminergic (CA) and social decision-making network (SDM) nuclei underlying auditory- driven sexual motivation. In addition, we quantified the relationship of neural activation between CA and SDM nuclei in all responders with the goal of providing a map of functional connectivity of the circuitry underlying a motivated state responsive to acoustic cues during mate localization. In order to make a baseline qualitative comparison of this functional brain map to unmotivated females, we made a similar correlative comparison of brain activation in females who were unresponsive to the advertisement call playback. Our results support an important role for dopaminergic neurons in the periventricular posterior tuberculum and ventral thalamus, putative A11 and A13 tetrapod homologues, respectively, as well as the posterior parvocellular preoptic area and dorsomedial telencephalon, (laterobasal amygdala homologue) in auditory attention and appetitive sexual behavior in fishes. These findings may also offer insights into the function of these highly conserved nuclei in the context of auditory-driven reproductive social behavior across vertebrates.

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Stags, Hawks, and Doves: Social Evolution Theory and Individual Variation in Cooperation

Synopsis

One of the triumphs of evolutionary biology is the discovery of robust mechanisms that promote the evolution of cooperative behaviors even when cooperation reduces the fertility or survival of cooperators. These mechanisms include, kin selection, reciprocity, and direct benefits to cooperation that are often nonlinear. Though they have been extensively studied separately, investigating the joint action of these mechanisms has been more difficult. Moreover, how these mechanisms shape variation in cooperation is not well known. Such variation is crucial for understanding the evolution of behavioral syndromes and animal personality. Here, I use the tools of kin selection and evolutionary game theory to build a framework that integrates these mechanisms for pairwise social interactions. Using relatedness as a measure of the strength of kin selection, responsiveness as a measure of reciprocity, and synergy as a measure of payoff nonlinearity, I show how different combinations of these three parameters produce directional selection for or against cooperation or variation in levels of cooperation via stabilizing or diversifying selection. Moreover, each of these outcomes maps uniquely to one of four classic games from evolutionary game theory, which means that modulating relatedness, responsiveness, and synergy effectively transforms the payoff matrix from one the evolutionary game to another. Assuming that cooperation exacts a fertility cost on cooperators and provides a fertility benefit to social partners, a prisoner's dilemma game and directional selection against cooperation occur when relatedness and responsiveness are low and synergy is not too positive. Enough positive synergy in these conditions generates a stag-hunt game and diversifying selection. High levels of relatedness or responsiveness turn cooperation from a fitness cost into a fitness benefit, which produces a mutualism game and directional selection for cooperation when synergy is not too negative. Sufficiently negative synergy in this case creates a hawk-dove game and stabilizing selection for cooperation. I extend the results with relatedness and synergy to social groups and show that how group size changes the effect of relatedness and synergy on selection for cooperation depends on how the per capita benefit of cooperation changes with group size. Together, these results provide a general framework with which to generate comparative predictions that can be tested using quantitative genetic techniques and experimental techniques that manipulate investment in cooperation. These predictions will help us understand both interspecific variation in cooperation as well as within-population and within-group variation in cooperation related to behavioral syndromes.

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Identity Signaling and Patterns of Cooperative Behavior

Synopsis

Recognition systems play a central role in mediating cooperative behavior among individuals in a population. Despite the importance of discriminating among potential recipients of cooperation, the evolutionary forces that maintain diversity in traits used for kin recognition are poorly understood. Greenbeard-based models of kin recognition in which alleles for cooperative behavior also control recognition of those alleles in potential cooperators suggest that discrimination based on a greenbeard locus leads to positive frequency dependence, eroding diversity at the very genes responsible for recognition. As a result, the phenotypic diversity used for kin recognition has been widely assumed to be cues rather than signals of genetic identity. Diversity in identity cues is maintained by selection on other traits for reasons unrelated to recognition. A major problem with greenbeard-based models is that greenbeard recognition systems are uncommon among animals, which tend to learn kin phenotypes. We develop a simple model showing that learning a kin recognition template is sufficient to increase and maintain diversity in genetic traits used for kin recognition. Thus, our results suggest that phenotypes used for recognition may be true signals of genetic identity. As such, phenotypes are expected to evolve to facilitate recognition. Increased diversity in genetically-based recognition signals is also predicted to initiate a positive feedback loop between recognition efficiency and levels of cooperation. Finally, we discuss how the genetic architecture of recognition traits may influence kin discrimination abilities.

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Fuel Use in Mammals: Conserved Patterns and Evolved Strategies for Aerobic Locomotion and Thermogenesis

Synopsis

Effective aerobic locomotion depends on adequate delivery of oxygen and an appropriate allocation of metabolic substrates. The use of metabolic substrates during exercise follows a predictive pattern of lipid and carbohydrate oxidation that is similar in lowland native cursorial mammals. We have found that in two highland lineages of mice (Phyllotis and Peromyscus) the fuel use pattern is shifted to a greater reliance on carbohydrates compared to their lowland conspecifics and congenerics. However, there is variation between lineages in the importance of phenotypic plasticity in the expression of this metabolic phenotype. Moreover, this metabolic phenotype is independent of running aerobic capacity and can also be independent of thermogenic capacity. For example, wild-caught mice from a highland population of deer mice (Peromyscus maniculatus) housed in warm normoxic laboratory conditions maintain higher maximum cold-induced oxygen consumption in acute hypoxia than lowland congenerics, but shivering and non-shivering thermogenesis is supported by high rates of lipid oxidation. This is reflected in the consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius of highland deer mice compared to lowlanders, which are resistant to hypoxia acclimation. While a fixed trait in muscle aerobic capacity may reflect the pervasive and unremitting low PO₂ at high altitudes, muscle capacities for substrate oxidation may be more flexible to match appropriate substrate use with changing energetic demands. How shivering thermogenesis and locomotion potentially interact in the matching of muscle metabolic capacities to appropriate substrate use is unclear. Perhaps it is possible that shivering serves as "training" to ensure muscles have the capacity to support locomotion or visa-versa.

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Effects of Ventral Striatum Lesions on Stimulus-Based versus Action-Based Reinforcement Learning

Learning the values of actions versus stimuli may depend on separable neural circuits. In the current study, we evaluated the performance of rhesus macaques with ventral striatum (VS) lesions on a two-arm bandit task that had randomly interleaved blocks of stimulus-based and action-based reinforcement learning (RL). Compared with controls, monkeys with VS lesions had deficits in learning to select rewarding images but not rewarding actions. We used a RL model to quantify learning and choice consistency and found that, in stimulus-based RL, the VS lesion monkeys were more influenced by negative feedback and had lower choice consistency than controls. Using a Bayesian model to parse the groups' learning strategies, we also found that VS lesion monkeys defaulted to an action-based choice strategy. Therefore, the VS is involved specifically in learning the value of stimuli, not actions.

SIGNIFICANCE STATEMENT Reinforcement learning models of the ventral striatum (VS) often assume that it maintains an estimate of state value. This suggests that it plays a general role in learning whether rewards are assigned based on a chosen action or stimulus. In the present experiment, we examined the effects of VS lesions on monkeys' ability to learn that choosing a particular action or stimulus was more likely to lead to reward. We found that VS lesions caused a specific deficit in the monkeys' ability to discriminate between images with different values, whereas their ability to discriminate between actions with different values remained intact. Our results therefore suggest that the VS plays a specific role in learning to select rewarded stimuli.

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Representations of Time-Varying Cochlear Implant Stimulation in Auditory Cortex of Awake Marmosets (Callithrix jacchus)

Electrical stimulation of the auditory periphery organ by cochlear implant (CI) generates highly synchronized inputs to the auditory system. It has long been thought such inputs would lead to highly synchronized neural firing along the ascending auditory pathway. However, neurophysiological studies with hearing animals have shown that the central auditory system progressively converts temporal representations of time-varying sounds to firing rate-based representations. It is not clear whether this coding principle also applies to highly synchronized CI inputs. Higher-frequency modulations in CI stimulation have been found to evoke largely transient responses with little sustained firing in previous studies of the primary auditory cortex (A1) in anesthetized animals. Here, we show that, in addition to neurons displaying synchronized firing to CI stimuli, a large population of A1 neurons in awake marmosets (Callithrix jacchus) responded to rapid time-varying CI stimulation with discharges that were not synchronized to CI stimuli, yet reflected changing repetition frequency by increased firing rate. Marmosets of both sexes were included in this study. By comparing directly each neuron's responses to time-varying acoustic and CI signals, we found that individual A1 neurons encode both modalities with similar firing patterns (stimulus-synchronized or nonsynchronized). These findings suggest that A1 neurons use the same basic coding schemes to represent time-varying acoustic or CI stimulation and provide new insights into mechanisms underlying how the brain processes natural sounds via a CI device.

SIGNIFICANCE STATEMENT In modern cochlear implant (CI) processors, the temporal information in speech or environmental sounds is delivered through modulated electric pulse trains. How the auditory cortex represents temporally modulated CI stimulation across multiple time scales has remained largely unclear. In this study, we compared directly neuronal responses in primary auditory cortex (A1) to time-varying acoustic and CI signals in awake marmoset monkeys (Callithrix jacchus). We found that A1 neurons encode both modalities using similar coding schemes, but some important differences were identified. Our results provide insights into mechanisms underlying how the brain processes sounds via a CI device and suggest a candidate neural code underlying rate–pitch perception limitations often observed in CI users.

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