The resuscitative endovascular balloon occlusion of the aorta, because of its efficacy and feasibility, has been widely used in treating patients with severe torso trauma. However, complications developing aro...
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Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τετάρτη 13 Δεκεμβρίου 2017
Resuscitative endovascular balloon occlusion of the aorta may increase the bleeding of minor thoracic injury in severe multiple trauma patients: a case report
The forgotten organ
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): L.M. Roussel, C. Escalard, M. Hitier
http://ift.tt/2o1VJ4y
Early cutaneous eruptions after oral hydroxychloroquine in a lupus erythematosus patient: A case report and review of the published work
Abstract
Hydroxychloroquine (HCQ) is an effective treatment of lupus erythematosus. Although adverse effects, mainly gastrointestinal and cutaneous manifestations, are rare, they may result in the cessation of medication in some patients with severe reactions. Therefore, the evaluation of a patient's condition is important for a dermatologist to decide whether to cease or continue HCQ. We herein report a case of a 36-year-old Japanese woman with systemic lupus erythematosus and cutaneous eruptions caused by the p.o. administration of HCQ. Because she wanted to continue the medication and had only mild cutaneous eruptions without any adverse effects in other organs, we continued HCQ with careful monitoring. All cutaneous eruptions disappeared within 1 week. We also reviewed published case reports on skin lesions that developed after HCQ treatments, and propose strategies for early cutaneous eruptions after HCQ treatments. When the cutaneous reactions are mild without any reactions in other organs, withdrawal of the drug is not required. However, when cutaneous eruptions are accompanied by some common reactions, HCQ needs to be stopped for a period of time and may subsequently be carefully re-administrated.
http://ift.tt/2C4ZyYN
MRI screening of the internal auditory canal: Is gadolinium necessary to detect intralabyrinthine schwannomas?
Source:American Journal of Otolaryngology
Author(s): Johnathan C. Valesano, Carrie M. Carr, Laurence J. Eckel, Matthew L. Carlson, John I. Lane
ObjectiveNon-contrast MRI of the internal auditory canal (IAC) using high-resolution T2WI (T2 weighted image) has been proposed as the primary screening study in patients with sudden or asymmetric sensorineural hearing loss (ASNHL). However, there are concerns that non-contrast MRI may not detect labyrinthine pathology, specifically intralabyrinthine schwannomas (ILSs). The purpose of this study was to determine if non-contrast high-resolution T2WI alone are adequate to exclude these uncommon intralabyrinthine tumors.Methods31 patients with ILSs and 36 patients without inner ear pathology that had dedicated MRI of the IAC performed with both non-contrast T2WI and post-contrast T1WI (T1 weighted image) were identified. Three board-certified neuroradiologists reviewed only the T2WI from these 67 cases. When an ILS was identified, its location and size were recorded. Sensitivity, specificity, and accuracy were calculated using the post-contrast T1WI as the "gold standard." A consensus review of cases with discordant results was conducted.ResultsThe sensitivity, specificity, and accuracy were 1.0, 1.0, and 1.0 for Observer 1; 0.84, 1.0, and 0.96 for Observer 2; 0.90, 1.0, and 0.98 for Observer 3. The 5 ILSs with discordant results were correctly identified upon consensus review. The median size of the ILSs was 4.4mm (±2.9mm) and most (18/31) were intracochlear in location.ConclusionNon-contrast high-resolution T2WI alone can detect ILSs with 84–100% sensitivity, suggesting that gadolinium may be unnecessary to exclude ILSs on screening MRI. These findings have implications for reducing cost, time, and adverse events associated with gadolinium administration in patients presenting with sudden or ASNHL.Level of evidence4
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Combined use of a nanocarbon suspension and 99mTc-MIBI for the intra-operative localization of the parathyroid glands
Publication date: Available online 13 December 2017
Source:American Journal of Otolaryngology
Author(s): Jun Chen, Qinyi Zhou, Jialin Feng, Jiadong Wang
ObjectiveTo investigate the combined use of a nanocarbon (NC) suspension and low-dose 99mTc-MIBI for parathyroid localization during surgery in patients with secondary hyperparathyroidism (sHPT).MethodsBetween March 2010 and September 2015, 40 patients with sHPT were enrolled in this study and were randomized to receive either low-dose 99mTc-MIBI+NC (group I) or low-dose 99mTc-MIBI (group II). Pre- and post-operative serum levels of intact PTH (iPTH), calcium and phosphorus between groups were compared and the intra-operative radioactive counts of the parathyroid glands were measured.ResultsThe post-operative iPTH level was significantly lower in patients of group I (24.2±31ng/L) than in those of group II (106±155ng/L) (P=0.03) while there were no significant differences in intra-operative parathyroid gland radioactive counts between the groups. The duration of the surgical procedure was shorter for patients of group I than patients of group II. There were no serious intra-operative or post-operative complications.ConclusionThe combined use of an NC suspension and 99mTc-MIBI for patients with sHPT is strongly recommended for the localization of parathyroid glands during surgery and is likely to improve clinical outcomes for patients.
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Nanoparticle delivery of RNA-based therapeutics to alter the vocal fold tissue response to injury
Objectives/Hypothesis
Our laboratory and others hypothesized that Smad3 is a principle mediator of the fibrotic phenotype in the vocal folds (VFs), and we further posited that alteration of Smad3 expression through short interfering (si)RNA holds therapeutic promise, yet delivery remains challenging. To address this issue, we employed a novel synthetic oligomer, lipitoid, complexed with siRNA to improve stability and cellular uptake with the goal of increased efficiency of RNA-based therapeutics.
Study Design
In vitro study and in vivo animal model.
Methods
In vitro, lipitoid cytotoxicity was quantified via colorimetric and LIVE/DEAD assays in immortalized human VF fibroblasts and primary rabbit VF fibroblasts. In addition, optimal incubation interval and solution for binding siRNA to lipitoid for intracellular delivery were determined. In vivo, a rabbit model of VF injury was employed to evaluate Smad3 knockdown following locally injected lipitoid-complexed siRNA.
Results
In vitro, lipitoid did not confer additional toxicity compared to commercially available reagents. In addition, 20-minute incubation in 1× phosphate-buffered saline resulted in maximal Smad3 knockdown. In vivo, Smad3 expression increased following VF injury. This response was significantly reduced in injured VFs at 4 and 24 hours following injection (P = .035 and .034, respectively).
Conclusions
The current study is the first to demonstrate targeted gene manipulation in the VFs as well as the potential utility of lipitoid for localized delivery of genetic material in vivo. Ideally, these data will serve as a platform for future investigation regarding the functional implications of therapeutic gene manipulation in the VFs.
Level of Evidence
NA Laryngoscope, 2017
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An innovative solution for T-tube obstruction: The tracheostomy–customized stent combination
The Montgomery T-tube (MTT) is a useful tool for post-tracheostomy tracheal stenosis. However, MTTs can get blocked. We present a case series of life-threatening MTT blockage, wherein a split-function option was implemented, which was a customized silicone Dumon stent above the tracheostomy to maintain both airway and phonation. This tracheostomy–customized stent combination serves the same function as an MTT, with a greater margin of safety due to the easy suctioning capacity of the tracheostomy. With a fenestrated tracheostomy and stent above, speech is effectively preserved. We recommend this strategy in severe MTT blockage as a superior option to regular tracheostomy. Laryngoscope, 2017
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Clinical implications of magnetic resonance imaging in temporomandibular disorders patients presenting ear fullness
Objectives/Hypothesis
The aim of this study was to investigate whether findings detected by temporomandibular joint magnetic resonance imaging (TMJ-MRI) can provide pathognomonic evidence of temporomandibular disorders (TMD) in patients with nonspecific ear fullness (EF). The association of nonspecific EF with clinical characteristics of TMD based on TMJ-MRI findings was examined.
Study Design
Retrospective analysis.
Methods
Thirty-four subjects (42 ears) who had no detectable otologic problems as a cause of EF were enrolled in this study. Each subject underwent TMJ-MRI to identify pathology of the TMJ as a possible cause of nonspecific EF. All subjects participated in the re-evaluation process following TMD treatment.
Results
Anatomical abnormalities in TMJ-MRI, irrespective of TMD signs, were observed in 34 of the 42 ears (80.9%), such as degenerative change of the TMJ (16 ears), articular disc displacement (11 ears), and joint effusion (seven ears). Specific abnormalities of the TMJ were associated with nonspecific EF, and this symptom showed improvement following individualized TMD treatment in those with internal derangement and/or effusion of the TMJ. However, abnormal TMJ-MRI findings were also observed in seven of nine ears with no TMD signs, and there was no significant association between the presence of TMD signs and abnormal TMJ-MRI findings (χ2 = 0.075, P = .784).
Conclusions
Patients presenting with nonspecific EF may have TMD, which can be effectively diagnosed using TMJ-MRI. The present study revealed the causal relationship between nonspecific EF and abnormal TMJ findings based on MRI. Individualized TMD treatments based on TMJ-MRI led to improved treatment outcomes with special regard to nonspecific EF
Level of Evidence
4 Laryngoscope, 2017
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Brain volume changes in hyposmic patients before and after olfactory training
Objectives/Hypothesis
Olfactory dysfunction is thought to be associated with reduced gray matter (GM) volume in olfactory-related brain areas. The aim of this study was to determine GM structural changes within olfactory-related regions of the brain in patients with smell loss due to upper respiratory tract infection (URTI) before and after olfactory rehabilitation.
Study Design
Prospective intervention case-control study.
Methods
Magnetic resonance imaging structural brain images were collected from 30 patients with smell loss due to URTI and 31 controls. Patients exposed themselves to odors (olfactory training [OT]) over 12 weeks and then were rescanned. Olfactory testing was performed using the validated Sniffin' Sticks test. GM was investigated with voxel-based morphometry.
Results
GM volumes were found to be reduced in the limbic system and thalamus among pretraining patients compared to controls; in patients, OT was associated with a significant increase of GM volume in these two regions. The GM volume within other olfactory-related regions was not different between patients and controls. In addition, no relevant difference between the GM volume pre- and post-OT was observed in primary olfactory-related regions.
Conclusions
OT was associated with an increase in GM volume of the hippocampus and the thalamus, possibly pointing toward a strategy for more effective exploitation of olfactory signals based on a higher degree of attention toward odors and association of memories with olfactory input.
Level of Evidence
3b Laryngoscope, 2017
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Use of autologous adipose-derived mesenchymal stem cells for creation of laryngeal cartilage
Objectives/Hypothesis
Adipose-derived mesenchymal stem cells (ASCs) are an exciting potential cell source for tissue engineering because cells can be derived from the simple excision of autologous fat. This study introduces a novel approach for tissue-engineering cartilage from ASCs and a customized collagen oligomer solution, and demonstrates that the resultant cartilage can be used for laryngeal cartilage reconstruction in an animal model.
Study Design
Basic science experimental design.
Methods
ASCs were isolated from F344 rats, seeded in a customized collagen matrix, and cultured in chondrogenic differentiation medium for 1, 2, and 4 weeks until demonstrating cartilage-like characteristics in vitro. Large laryngeal cartilage defects were created in the F344 rat model, with the engineered cartilage used to replace the cartilage defects, and the rats followed for 1 to 3 months. Staining examined cellular morphology and cartilage-specific features.
Results
In vitro histological staining revealed rounded chondrocyte-appearing cells evenly residing throughout the customized collagen scaffold, with positive staining for cartilage-specific markers. The cartilage was used to successfully repair large cartilaginous defects in the rat model, with excellent functional results.
Conclusions
This study is the first study to demonstrate, in an animal model, that ASCs cultured in a unique form of collagen oligomer can create functional cartilage-like grafts that can be successfully used for partial laryngeal cartilage replacement.
Level of Evidence
NA Laryngoscope, 2017
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Effect of rural and urban geography on larynx cancer incidence and survival
Objectives/Hypothesis
Investigate the impact of rural geography on larynx cancer incidence and survival.
Study Design
Surveillance, Epidemiology, and End Results (SEER) database study.
Methods
Incidence and survival rates by Rural–Urban Continuum codes for larynx squamous cell carcinoma patients diagnosed from 2004 to 2012 were evaluated using SEER statistical software and Cox proportional hazards survival analysis.
Results
The lowest age-adjusted incidence rates for larynx cancer were seen in densely populated urban regions, with mean rates of 2.8 per 100,000 person years (95% confidence interval [CI]: 2.7-2.8); the highest were in the most rural areas, with mean rates of 5.3 per 100,000 person years (95% CI: 4.7-5.9). Nevertheless, of 23,659 larynx cancer patients diagnosed over this period, 19,556 (82.7%) arose in urban residents, compared with 1,428 or 6% from rural areas. Urban larynx cancer patients more likely lived in counties with an American College of Surgeons–approved cancer center and/or a fourfold greater otolaryngology physician supply. Nevertheless, frequency of advanced stage at initial presentation was similar. Cause-specific and overall survival were no different, both on univariable and multivariable analyses.
Conclusions
Compared with urban populations, Rural populations are at greater risk of developing larynx cancer, but initial stage and survival after diagnosis are comparable. Priority should be given to prevention strategies to decrease incidence rates.
Level of Evidence
4 Laryngoscope, 2017
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Relationship between serum anti-varicella zoster virus antibody titer and time from onset of herpes zoster
Abstract
Herpes zoster is an internal reactivation of varicella zoster virus, and its onset depends on immunity against this virus. We have previously reported that antiviral antibody titers are inversely correlated with patient numbers. In this study, we hypothesized that patients with higher titers may be late visitors to the clinic, whose antibodies were already boosted at presentation because of the time lapse between onset of zoster and measurement of antibodies. We analyzed antibody titers of patients with acute herpes zoster who visited Fukuoka University Hospital from January 2009 to May 2016 (n = 141, 62 males and 79 females). Varicella zoster virus-specific immunoglobulin G, M and complement fixation tests were positive in 93.9%, 12.0% and 64.2% of the patients, respectively. Immunoglobulin G and complement fixation titers were strongly correlated (Spearman's r = 0.8634, P < 0.0001). Patients with high immunoglobulin G and complement fixation titers were immunoglobulin M-negative. Unexpectedly, immunoglobulin G and complement fixation titers showed large inter-subject variation, and were only weakly correlated with onset–measurement time lapse. Patients with consecutive tests tended to show increasing immunoglobulin G and complement fixation titers. Our data suggest that herpes zoster preferentially occurs in patients with low immunoglobulin G and complement fixation titers, and subsequently causes antibody elevation. However, the timing of elevation varies and can be as late as 10 days after zoster. The large variation in antibody titer over the time from onset to testing suggests that some mechanism exists that resists the local breakthrough of virus in the skin, and so delays the onset of blisters.
http://ift.tt/2o350JB
Postmenopausal craniofacial hyperhidrosis
Summary
Hyperhidrosis is a condition marked by excessive sweating, which can either be localized or generalized. Primary focal hyperhidrosis (PFH) can arise from the palms, plantar feet, axillae and also from the face and scalp. PFH primarily affects a younger population of children and young adults, with the majority presenting before the age of 25 years. We report a distinct subtype of craniofacial hyperhidrosis in 20 postmenopausal women; this subtype is often under-recognized.
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IL-25 is involved in CTCL progression by establishing Th2-dominant microenvironment
Summary
Background
Interleukin (IL)-25 is a member of the IL-17 family which can promote and augment T-helper type (Th) 2 responses. The expression of IL-25 and its cognate receptor, IL-25 receptor (IL-25R), is upregulated and correlated with disease activity in Th2-associated diseases.
Objective
To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL).
Methods
Expression and localization of IL-25 in lesional skin was investigated using immunohistochemistry. The effect of various cytokines on IL-25 production from normal human epidermal keratinocytes was assessed by quantitative reverse-transcription real-time polymerase chain reaction. Serum IL-25 levels were measured by enzyme-linked immunosorbent assay. The direct effect of IL-25 on tumor cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in Sézary syndrome patients.
Results
IL-25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL-4 and IL-13, and periostin induced IL-25 expression by normal human epidermal keratinocytes. Serum IL-25 levels were increased in patients with advanced CTCL (stage IIB-IV) and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL-25R and its expression was augmented by stimulation with IL-25. IL-25 enhanced IL-13 production from MyLa cells via phosphorylation of STAT6. Peripheral blood mononuclear cells from one patient with Sézary syndrome expressed IL-25R and showed increase of IL-13 production by IL-25.
Conclusions
Th2 cytokines highly expressed in CTCL lesional skin induce IL-25 production by epidermal keratinocytes, which may in turn lead to formation of Th2-dominant microenvironment through the direct induction of IL-13 by tumor cells.
This article is protected by copyright. All rights reserved.
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Regulation of MAVS activation through post-translational modifications
Bingyu Liu | Chengjiang Gao
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Methotrexate and azathioprine in severe atopic dermatitis: a 5-year follow up study of a randomised controlled trial
Summary
Background
Systemic treatment is indicated for moderate-to-severe atopic dermatitis (AD), refractory to topical treatment. Long-term evidence, up to 5 years, of off-label prescribed methotrexate (MTX) and azathioprine (AZA) is lacking.
Objectives
To investigate long-term effectiveness, safety and drug survival of MTX and AZA.
Methods
In an open-label follow up phase of a clinical trial patients were seen every 3 months for 5 years. MTX and AZA doses could be in- or decreased concurrent with daily clinical practice. Primary effectiveness outcomes were mean absolute and relative reduction in SCORing Atopic Dermatitis (SCORAD) index and Investigator Global Assessment (IGA) after 5 years compared to baseline. For safety type, frequency, severity and relatedness to treatment of adverse events were investigated. Drug survival was analysed by Kaplan-Meier curves.
Results
Thirty-five of 43 originally included patients participated, of which 27 completed follow up. At year 5 mean relative reduction in SCORAD index was similar in MTX and AZA group: 52.8% and 53.8% by descriptive analysis. Eleven serious adverse events occurred in 5 years; for three there was a possible causal relationship. Drug survival demonstrated a longer survival for MTX, but survival in both groups was low after 5 years (MTX n=5, AZA n=1).
Conclusion
Based on this relatively small pragmatic study, MTX and AZA seem to be effective and safe as maintenance treatments in moderate-to-severe AD up to 5 years. Few patients in both groups survive on their originally allocated drug although some discontinued due to controlled AD.
This article is protected by copyright. All rights reserved.
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Combined use of a nanocarbon suspension and 99mTc-MIBI for the intra-operative localization of the parathyroid glands
To investigate the combined use of a nanocarbon (NC) suspension and low-dose 99mTc-MIBI for parathyroid localization during surgery in patients with secondary hyperparathyroidism (sHPT).
http://ift.tt/2ynXsRE
MRI screening of the internal auditory canal: Is gadolinium necessary to detect intralabyrinthine schwannomas?
Non-contrast MRI of the internal auditory canal (IAC) using high-resolution T2WI (T2 weighted image) has been proposed as the primary screening study in patients with sudden or asymmetric sensorineural hearing loss (ASNHL). However, there are concerns that non-contrast MRI may not detect labyrinthine pathology, specifically intralabyrinthine schwannomas (ILSs). The purpose of this study was to determine if non-contrast high-resolution T2WI alone are adequate to exclude these uncommon intralabyrinthine tumors.
http://ift.tt/2AATjQ5
Steroidpsychose als Folge einer regulären Hörsturztherapie in der HNO-Heilkunde
Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-123654
Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Full text
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When to Stop Immunotherapy: First Response? Max Response? Toxicity?
There is an ongoing debate within the oncology community about when to stop immunotherapies, with treatment response, toxicity, and cost all playing important roles.
Medscape Oncology
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Distinctive cutaneous and systemic features associated with specific anti-myositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patients
Abstract
Background
Identification of myositis-specific autoantibodies (MSA) for dermatomyositis (DM) could allow the characterization of an antibody-associated clinical phenotype.
Objective
We sought to define the clinical phenotype of DM and the risk of cancer, interstitial lung disease (ILD) and calcinosis based on MSA.
Methods
A 3.5-year multicenter prospective study of adult DM patients was conducted to determine the clinical phenotype associated with MSA and the presence of cancer, ILD and calcinosis.
Results
MSA were detected in 47.1% of 117 included patients. Patients with anti-melanoma differentiation-associated protein 5 antibodies (13.7%) had significantly more palmar violaceous macules/papules (odds ratio (OR) 9.9), mechanic's hands (OR 8), cutaneous necrosis (OR 3.2), and articular involvement (OR 15.2), and a higher risk of ILD (OR 25.3). Patients with anti-transcriptional intermediary factor-1 antibodies (11.1%), anti-nuclear matrix protein-2 antibodies (6.8%) and anti-aminoacyl-transfer RNA synthetase (5.1%) had, respectively, significantly more poikiloderma (OR 5.9), calcinosis (OR 9.8), and articular involvement (OR 15.2). Cutaneous necrosis was the only clinical manifestation significantly associated with cancer (OR 3.1).
Conclusion
Recognition of the adult DM phenotype associated with MSA would allow more accurate appraisal of the risk of cancer, ILD and calcinosis.
This article is protected by copyright. All rights reserved.
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Perianal tuberculosis in an immunocompetent patient
Abstract
Tuberculosis (TB) is a major public health problem worldwide, considered to be the main cause of death from infectious diseases, ranking alongside HIV infection. Skin involvement occurs in 1.5% of the cases, and perianal involvement is extremely rare and tends to occur among immunocompromised patients. Due to its heterogeneous clinical presentation, the diagnosis of cutaneous TB is challenging, requiring a high level of suspicion.
This article is protected by copyright. All rights reserved.
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Epidermodysplasia verruciformis in an adult patient with a germline ITK mutation and lymphoma: the case of inherited versus acquired
Abstract
Epidermodysplasia verruciformis (EV) is characterized by a clinically distinctive pattern of beta-HPV induced flat warts that may evolve into epithelial skin cancers. The current understanding is that EV encompasses two etiological situations: Classic, inherited type EV (IEV), beginning in childhood or adolescence, due to Trans Membrane Channel (TMC) - 6 and 7 (EVER-1 and 2) gene mutations 75% of patients, or to alterations resulting in T-Cell immune deficiencies (IDs) on Ras Homolog Family Member H (RHOH), Coronin 1A (CORO 1A), Macrophage Stimulating factor 1 (MST-1), or interleukin 7 (IL7) genes.
This article is protected by copyright. All rights reserved.
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Dermoscopy for discriminating between Trichophyton and Microsporum infections in tinea capitis
Abstract
Tinea capitis (TC) is an infection of the scalp, most often observed in pre-school or early school ages. Diagnosis of TC is based on clinical signs and laboratory examinations (direct microscopy and culture). Dermoscopy is a non-invasive diagnostic technique with an already established role in the evaluation of skin tumors, and with a gradually expanding application also in the field of inflammatory and infectious skin diseases.
This article is protected by copyright. All rights reserved.
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Four cases of anti-Mi-2 antibody-positive dermatomyositis: relationship between anti-Mi-2 antibody titer and disease severity and activity
Abstract
Anti-Mi-2 antibody was found to be a specific marker for dermatomyositis (DM) [1, 2]. Patients with anti-Mi-2 antibody generally have a more favorable prognosis, such as milder muscle involvement and a lower risk of interstitial lung disease (ILD) and malignancy [3, 4]. However, it currently remains unclear whether the anti-Mi-2 antibody titer correlates with disease severity and activity, or if repeated testing for disease monitoring is beneficial.
This article is protected by copyright. All rights reserved.
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The Economics of Colon Cancer
Publication date: Available online 13 December 2017
Source:Surgical Oncology Clinics of North America
Author(s): Guy R. Orangio
Teaser
The economic burden of cancer on the national health expenditure is billions of dollars. The economic cost is measured on direct and indirect medical costs, which vary depending on stage at diagnosis, patient age, type of medical services, and site of service. Costs vary by region, physician behavior, and patient preferences. When analyzing the economic burden of survivors of colon cancer, we cannot forget the societal burden. Post-acute care and readmissions are major economic burdens. People with colon cancer have to be followed for their lifetime. Economic models are being studied to give cost-effective solutions to this problem.from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/2ACUbnq
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The Expanding Toolkit of Translating Ribosome Affinity Purification
Translating ribosome affinity purification is a method initially developed for profiling mRNA from genetically defined cell types in complex tissues. It has been applied both to identify target molecules in cell types that are important for controlling a variety of behaviors in the brain, and to understand the molecular consequences on those cells due to experimental manipulations, ranging from drugs of abuse to disease-causing mutations. Since its inception, a variety of methodological advances are opening new avenues of investigation. These advances include a variety of new methods for targeting cells for translating ribosome affinity purification by features such as their projections or activity, additional tags and mouse reagents increasing the flexibility of the system, and new modifications of the method specifically focused on studying the regulation of translation. The latter includes methods to assess cell type-specific regulation of translation in specific subcellular compartments. Here, I provide a summary of these recent advances and resources, highlighting both new experimental opportunities and areas for future technical development.
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Graded Elevation of c-Jun in Schwann Cells In Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination
Schwann cell c-Jun is implicated in adaptive and maladaptive functions in peripheral nerves. In injured nerves, this transcription factor promotes the repair Schwann cell phenotype and regeneration and promotes Schwann-cell-mediated neurotrophic support in models of peripheral neuropathies. However, c-Jun is associated with tumor formation in some systems, potentially suppresses myelin genes, and has been implicated in demyelinating neuropathies. To clarify these issues and to determine how c-Jun levels determine its function, we have generated c-Jun OE/+ and c-Jun OE/OE mice with graded expression of c-Jun in Schwann cells and examined these lines during development, in adulthood, and after injury using RNA sequencing analysis, quantitative electron microscopic morphometry, Western blotting, and functional tests. Schwann cells are remarkably tolerant of elevated c-Jun because the nerves of c-Jun OE/+ mice, in which c-Jun is elevated ~6-fold, are normal with the exception of modestly reduced myelin thickness. The stronger elevation of c-Jun in c-Jun OE/OE mice is, however, sufficient to induce significant hypomyelination pathology, implicating c-Jun as a potential player in demyelinating neuropathies. The tumor suppressor P19ARF is strongly activated in the nerves of these mice and, even in aged c-Jun OE/OE mice, there is no evidence of tumors. This is consistent with the fact that tumors do not form in injured nerves, although they contain proliferating Schwann cells with strikingly elevated c-Jun. Furthermore, in crushed nerves of c-Jun OE/+ mice, where c-Jun levels are overexpressed sufficiently to accelerate axonal regeneration, myelination and function are restored after injury.
SIGNIFICANCE STATEMENT In injured and diseased nerves, the transcription factor c-Jun in Schwann cells is elevated and variously implicated in controlling beneficial or adverse functions, including trophic Schwann cell support for neurons, promotion of regeneration, tumorigenesis, and suppression of myelination. To analyze the functions of c-Jun, we have used transgenic mice with graded elevation of Schwann cell c-Jun. We show that high c-Jun elevation is a potential pathogenic mechanism because it inhibits myelination. Conversely, we did not find a link between c-Jun elevation and tumorigenesis. Modest c-Jun elevation, which is beneficial for regeneration, is well tolerated during Schwann cell development and in the adult and is compatible with restoration of myelination and nerve function after injury.
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FGF-FGFR Mediates the Activity-Dependent Dendritogenesis of Layer IV Neurons during Barrel Formation
Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known for their potent effects on cell proliferation/differentiation and cortical patterning in the developing brain. However, little is known regarding the roles of FGFs/FGFRs in cortical circuit formation. Here we show that Fgfr1/2/3 and Fgf7/9/10/22 mRNAs are expressed in the developing primary somatosensory (S1) barrel cortex. Barrel cortex layer IV spiny stellate cells (bSCs) are the primary recipients of ascending sensory information via thalamocortical axons (TCAs). Detail quantification revealed distinctive phases for bSC dendritogenesis: orienting dendrites toward TCAs, adding de novo dendritic segments, and elongating dendritic length, while maintaining dendritic patterns. Deleting Fgfr1/2/3 in bSCs had minimal impact on dendritic polarity but transiently increased the number of dendritic segments. However, 6 d later, FGFR1/2/3 loss of function reduced dendritic branch numbers. These data suggest that FGFs/FGFRs have a role in stabilizing dendritic patterning. Depolarization of cultured mouse cortical neurons upregulated the levels of several Fgf/Fgfr mRNAs within 2 h. In vivo, within 6 h of systemic kainic acid administration at postnatal day 6, mRNA levels of Fgf9, Fgf10, Fgfr2c, and Fgfr3b in S1 cortices were enhanced, and this was accompanied by exuberant dendritogenesis of bSCs by 24 h. Deleting Fgfr1/2/3 abolished kainic acid-induced bSC dendritic overgrowth. Finally, FGF9/10 gain of function also resulted in extensive dendritogenesis. Together, our data suggest that FGFs/FGFRs can be regulated by glutamate transmission to modulate/stabilize bSC dendritic complexity. Both male and female mice were used for our study.
SIGNIFICANCE STATEMENT Glutamatergic transmission plays critical roles in cortical circuit formation. Its dysregulation has been proposed as a core factor in the etiology of many neurological diseases. We found that excessive glutamate transmission upregulated mRNA expression of Fgfrs and their ligands Fgfs. Deleting Fgfr1/2/3 not only impaired bSC dendritogenesis but also abolished glutamate transmission-induced dendritic overgrowth. Overexpressing FGF9 or FGF10 in cortical glutamatergic neurons results in excessive dendritic outgrowth within 24 h, resembling the changes induced by excessive glutamate transmission. Our findings provide strong evidence for the physiological role of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) in establishing and maintaining cortical circuits. Perturbing the expression levels of FGFs/FGFRs by excessive glutamatergic neurotransmission could lead to abnormal neuronal circuits, which may contribute to neurological and psychiatric disease.
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Activation of {gamma}-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1
-Secretase is an intramembrane cleaving protease that is responsible for the generation of amyloid-β peptides, which are linked to the pathogenesis of Alzheimer disease. Recently, -secretase modulators (GSMs) have been shown to specifically decrease production of the aggregation-prone and toxic longer Aβ species, and concomitantly increase the levels of shorter Aβ. We previously found that phenylimidazole-type GSMs bind to presenilin 1 (PS1), the catalytic subunit of the -secretase, and allosterically modulate -secretase activity. However, the precise conformational alterations in PS1 remained unclear. Here we mapped the amino acid residues in PS1 that is crucial for the binding and pharmacological actions of E2012, a phenylimidazole-type GSM, using photoaffinity labeling and the substituted cysteine accessibility method. We also demonstrated that a piston-like vertical motion of transmembrane domain (TMD) 1 occurs during modulation of Aβ production. Taking these results together, we propose a model for the molecular mechanism of phenylimidazole-type GSMs, in which the trimming activity of -secretase is modulated by the position of the TMD1 of PS1 in the lipid bilayer.
SIGNIFICANCE STATEMENT Reduction of the toxic longer amyloid-β peptide is one of the therapeutic approaches for Alzheimer disease. A subset of small compounds called -secretase modulators specifically decreases the longer amyloid-β production, although its mechanistic action remains unclear. Here we found that the modulator compound E2012 targets to the hydrophilic loop 1 of presenilin 1, which is a catalytic subunit of the -secretase. Moreover, E2012 triggers the piston movement of the transmembrane domain 1 of presenilin 1, which impacts on the -secretase activity. These results illuminate how -secretase modulators allosterically affect the proteolytic activity, and highlight the importance of the structural dynamics of presenilin 1 in the complexed process of the intramembrane cleavage.
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Detailed Dendritic Excitatory/Inhibitory Balance through Heterosynaptic Spike-Timing-Dependent Plasticity
The balance between excitatory and inhibitory inputs is a key feature of cortical dynamics. Such a balance is arguably preserved in dendritic branches, yet its underlying mechanism and functional roles remain unknown. In this study, we developed computational models of heterosynaptic spike-timing-dependent plasticity (STDP) to show that the excitatory/inhibitory balance in dendritic branches is robustly achieved through heterosynaptic interactions between excitatory and inhibitory synapses. The model reproduces key features of experimental heterosynaptic STDP well, and provides analytical insights. Furthermore, heterosynaptic STDP explains how the maturation of inhibitory neurons modulates the selectivity of excitatory neurons for binocular matching in the critical period plasticity. The model also provides an alternative explanation for the potential mechanism underlying the somatic detailed balance that is commonly associated with inhibitory STDP. Our results propose heterosynaptic STDP as a critical factor in synaptic organization and the resultant dendritic computation.
SIGNIFICANCE STATEMENT Recent experimental studies reveal that relative differences in spike timings experienced among neighboring glutamatergic and GABAergic synapses on a dendritic branch significantly influences changes in the efficiency of these synapses. This heterosynaptic form of spike-timing-dependent plasticity (STDP) is potentially important for shaping the synaptic organization and computation of neurons, but its functional role remains elusive. Through computational modeling at the parameter regime where previous experimental results are well reproduced, we show that heterosynaptic plasticity serves to finely balance excitatory and inhibitory inputs on the dendrite. Our results suggest a principle of GABA-driven neural circuit formation.
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The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1
Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Rac1 pathway might be a promising target to attenuate cerebral I/R injury.
SIGNIFICANCE STATEMENT Stroke is one of the most severe and devastating neurological diseases globally. The complicated pathophysiological processes restrict the translation of potential therapeutic targets into medicine. Further elucidating the molecular mechanisms underlying cerebral ischemia/reperfusion injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study revealed that ischemia-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) upregulation binds and ubiquitinates Rac1 directly, which promotes neuron death through neuroinflammation and neuro-oxidative signals. Therefore, precisely targeting the TRAF6-Rac1 axis may provide a novel therapeutic strategy for stroke recovery.
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Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis
Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.
SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system.
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Interlayer Repulsion of Retinal Ganglion Cell Mosaics Regulates Spatial Organization of Functional Maps in the Visual Cortex
In higher mammals, orientation tuning of neurons is organized into a quasi-periodic pattern in the primary visual cortex. Our previous model studies suggested that the topography of cortical orientation maps may originate from moiré interference of ON and OFF retinal ganglion cell (RGC) mosaics, but did not account for how the consistent spatial period of maps could be achieved. Here we address this issue with two crucial findings on the development of RGC mosaics: first, homotypic local repulsion between RGCs can develop a long-range hexagonal periodicity. Second, heterotypic interaction restrains the alignment of ON and OFF mosaics, and generates a periodic interference pattern map with consistent spatial frequency. To validate our model, we quantitatively analyzed the RGC mosaics in cat data, and confirmed that the observed retinal mosaics showed evidence of heterotypic interactions, contrary to the previous view that ON and OFF mosaics are developed independently.
SIGNIFICANCE STATEMENT Orientation map is one of the most studied functional maps in the brain, but it has remained unanswered how the consistent spatial periodicity of maps could be developed. In the current study, we address this issue with our developmental model for the retinal origin of orientation map. We showed that local repulsive interactions between retinal ganglion cells (RGCs) can develop a hexagonal periodicity in the RGC mosaics and restrict the alignment between ON and OFF mosaics, so that they generate a periodic pattern with consistent spatial frequency for both the RGC mosaics and the cortical orientation maps. Our results demonstrate that the organization of functional maps in visual cortex, including its structural consistency, may be constrained by a retinal blueprint.
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Sleep in Humans Stabilizes Pattern Separation Performance
Replay of hippocampal neural representations during sleep is thought to promote systems consolidation of declarative memory. How this reprocessing of memory during sleep affects the hippocampal representation itself, is unclear. Here we tested hippocampal stimulus processing (i.e., pattern separation) before and after periods of sleep and wakefulness in humans (female and male participants). Pattern separation deteriorated across the wake period but remained stable across sleep (p = 0.013) with this sleep–wake difference being most pronounced for stimuli with low similarity to targets (p = 0.006). Stimuli with the highest similarity showed a reversed pattern with reduced pattern separation performance after sleep (p = 0.038). Pattern separation performance was positively correlated with sleep spindle density, slow oscillation density, and theta power phase-locked to slow oscillations. Sleep, presumably by neural memory replay, shapes hippocampal representations and enhances computations of pattern separation to subsequent presentation of similar stimuli.
SIGNIFICANCE STATEMENT The consolidation of hippocampus-dependent memories is causally related to reactivation during sleep of previously encoded representations. Here, we show that reactivation-based consolidation processes during sleep shape the hippocampal representation itself. We studied the effect of sleep and wakefulness on pattern separation (i.e., orthogonalization of similar representations) and completion performance (i.e., recall of a memory in light of noisy input) that are essential cognitive elements of encoding and retrieval of information by the hippocampus. Our results demonstrate that pattern separation was stabilized after sleep but diminished after wakefulness. We further showed that pattern separation was related to EEG oscillatory parameters of non-REM sleep serving as markers of sleep-dependent memory consolidation and hippocampal reactivation.
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Morphological Constraints on Cerebellar Granule Cell Combinatorial Diversity
Combinatorial expansion by the cerebellar granule cell layer (GCL) is fundamental to theories of cerebellar contributions to motor control and learning. Granule cells (GrCs) sample approximately four mossy fiber inputs and are thought to form a combinatorial code useful for pattern separation and learning. We constructed a spatially realistic model of the cerebellar GCL and examined how GCL architecture contributes to GrC combinatorial diversity. We found that GrC combinatorial diversity saturates quickly as mossy fiber input diversity increases, and that this saturation is in part a consequence of short dendrites, which limit access to diverse inputs and favor dense sampling of local inputs. This local sampling also produced GrCs that were combinatorially redundant, even when input diversity was extremely high. In addition, we found that mossy fiber clustering, which is a common anatomical pattern, also led to increased redundancy of GrC input combinations. We related this redundancy to hypothesized roles of temporal expansion of GrC information encoding in service of learned timing, and we show that GCL architecture produces GrC populations that support both temporal and combinatorial expansion. Finally, we used novel anatomical measurements from mice of either sex to inform modeling of sparse and filopodia-bearing mossy fibers, finding that these circuit features uniquely contribute to enhancing GrC diversification and redundancy. Our results complement information theoretic studies of granule layer structure and provide insight into the contributions of granule layer anatomical features to afferent mixing.
SIGNIFICANCE STATEMENT Cerebellar granule cells are among the simplest neurons, with tiny somata and, on average, just four dendrites. These characteristics, along with their dense organization, inspired influential theoretical work on the granule cell layer as a combinatorial expander, where each granule cell represents a unique combination of inputs. Despite the centrality of these theories to cerebellar physiology, the degree of expansion supported by anatomically realistic patterns of inputs is unknown. Using modeling and anatomy, we show that realistic input patterns constrain combinatorial diversity by producing redundant combinations, which nevertheless could support temporal diversification of like combinations, suitable for learned timing. Our study suggests a neural substrate for producing high levels of both combinatorial and temporal diversity in the granule cell layer.
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Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities
Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9–11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16–19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages.
SIGNIFICANCE STATEMENT The present study proposes a "back translation" of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses.
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Working Memory and Decision-Making in a Frontoparietal Circuit Model
Working memory (WM) and decision-making (DM) are fundamental cognitive functions involving a distributed interacting network of brain areas, with the posterior parietal cortex (PPC) and prefrontal cortex (PFC) at the core. However, the shared and distinct roles of these areas and the nature of their coordination in cognitive function remain poorly understood. Biophysically based computational models of cortical circuits have provided insights into the mechanisms supporting these functions, yet they have primarily focused on the local microcircuit level, raising questions about the principles for distributed cognitive computation in multiregional networks. To examine these issues, we developed a distributed circuit model of two reciprocally interacting modules representing PPC and PFC circuits. The circuit architecture includes hierarchical differences in local recurrent structure and implements reciprocal long-range projections. This parsimonious model captures a range of behavioral and neuronal features of frontoparietal circuits across multiple WM and DM paradigms. In the context of WM, both areas exhibit persistent activity, but, in response to intervening distractors, PPC transiently encodes distractors while PFC filters distractors and supports WM robustness. With regard to DM, the PPC module generates graded representations of accumulated evidence supporting target selection, while the PFC module generates more categorical responses related to action or choice. These findings suggest computational principles for distributed, hierarchical processing in cortex during cognitive function and provide a framework for extension to multiregional models.
SIGNIFICANCE STATEMENT Working memory and decision-making are fundamental "building blocks" of cognition, and deficits in these functions are associated with neuropsychiatric disorders such as schizophrenia. These cognitive functions engage distributed networks with prefrontal cortex (PFC) and posterior parietal cortex (PPC) at the core. It is not clear, however, what the contributions of PPC and PFC are in light of the computations that subserve working memory and decision-making. We constructed a biophysical model of a reciprocally connected frontoparietal circuit that revealed shared and distinct functions for the PFC and PPC across working memory and decision-making tasks. Our parsimonious model connects circuit-level properties to cognitive functions and suggests novel design principles beyond those of local circuits for cognitive processing in multiregional brain networks.
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Neural Representations of Hierarchical Rule Sets: The Human Control System Represents Rules Irrespective of the Hierarchical Level to Which They Belong
Humans use rules to organize their actions to achieve specific goals. Although simple rules that link a sensory stimulus to one response may suffice in some situations, often, the application of multiple, hierarchically organized rules is required. Recent theories suggest that progressively higher level rules are encoded along an anterior-to-posterior gradient within PFC. Although some evidence supports the existence of such a functional gradient, other studies argue for a lesser degree of specialization within PFC. We used fMRI to investigate whether rules at different hierarchical levels are represented at distinct locations in the brain or encoded by a single system. Thirty-seven male and female participants represented and applied hierarchical rule sets containing one lower-level stimulus–response rule and one higher-level selection rule. We used multivariate pattern analysis to investigate directly the representation of rules at each hierarchical level in absence of information about rules from other levels or other task-related information, thus providing a clear identification of low- and high-level rule representations. We could decode low- and high-level rules from local patterns of brain activity within a wide frontoparietal network. However, no significant difference existed between regions encoding representations of rules from both levels except for precentral gyrus, which represented only low-level rule information. Our findings show that the brain represents conditional rules regardless of their level in the explored hierarchy, so the human control system did not organize task representation according to this dimension. Our paradigm represents a promising approach to identifying critical principles that shape this control system.
SIGNIFICANCE STATEMENT Several recent studies investigating the organization of the human control system propose that rules at different control levels are organized along an anterior-to-posterior gradient within PFC. In this study, we used multivariate pattern analysis to explore independently the representation of formally identical conditional rules belonging to different levels of a cognitive hierarchy and provide for the first time a clear identification of low- and high-level rule representations. We found no major spatial differences between regions encoding rules from different hierarchical levels. This suggests that the human brain does not use levels in the investigated hierarchy as a topographical organization principle to represent rules controlling our behavior. Our paradigm represents a promising approach to identifying which principles are critical.
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Firefighter Skin Cancer and Sun Protection Practices
This survey study examines skin cancer history, skin cancer screening, and sun protection habits among active Florida firefighters.
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Clinical Findings and Gene Expression in Balloon Cell Melanoma
This case series describes 2 patients with balloon cell melanoma to evaluate the association of clinical and histopathologic characteristics with findings of gene expression profiling tests.
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Tender Nodules on the Lower Legs
A man in his 20s with panhypopituitarism, septo-optic dysplasia, developmental delay, duodenal stricture, and a history of pancreatitis presented with a painful eruption on both lower legs. What is your diagnosis?
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Noninvasive Gene Expression Testing in Amelanotic Melanoma
This case report describes noninvasive gene expression testing in a patient with amelanotic melanoma.
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Hypercoagulable Conditions and Calciphylaxis in Renal Disease
This case-control study compares the hypercoagulability status of patients with calciphylaxis and renal disease with controls to identify conditions that are risk factors for developing calciphylaxis while controlling for chronic kidney disease.
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15,000 Cases Reports Published
By Nathan Douthit
BMJ Case reports published its 15,000th case earlier this year. This milestone represents innumerable hours of patient interaction, research, writing, and editing. These cases have given a forum for health professionals and students to discuss difficult and interesting cases of high educational value and to use their patient experiences as a means to teach others.
Of particular importance is the 70+ global health cases published by BMJ Case Reports. While a small number in volume, these cases have helped bring to light issues faced by practitioners around the globe in a variety of settings, and established a formidable base of literature in their texts and references regarding the true causes of disease—the social determinants of health. As an author privileged to publish two of these cases with the journal, I can attest that they have been a formative part of my education in global health. As I encountered patients with avoidable negative outcomes, I reviewed the relevant literature on global health and social determinants in order to understand why these patients had been ill, had delayed presentation to care, and had so much pain wrought in their lives and the lives of their families. This helped me to suggest alternatives and solutions to the current state of affairs in these areas, and to learn innovative ways of dealing with difficult patient populations in low-resource settings.
As a global health associate editor I have reviewed all of these global health cases and am continually learning. Whether this includes the plight of Syrian refugees and their fear of losing their belongings, rare presentations of tuberculosis, the ill effects of complementary and alternative medicine in the USA and in Africa, or the common desire to die a death in accordance with local customs regardless of culture and medical history, there is something to be gleaned from every case. Paul Farmer, American Anthropologist and Physician wrote: "Human rights can and should be declared universal, but the risk of having one's rights violated is not universal."[1] Sadly, many of these situations are avoidable, and these case reports motivate all who read them to advocate for their patients in local, national and global settings. It is our hope that these cases will be used to educate practitioners and students about global health, so they can contribute to the solution to these complicated problems as they advance in their own careers.
The first 15,000 cases is truly something to be celebrated. Hopefully the next 15,000 will continue the work begun here by BMJ Case Reports. This literature base will be of great use to future clinicians as they attempt to change the world, one patient case at a time.
[1] Farmer P. Pathologies of power: Health, human rights, and the new war on the poor. Univ of California Press; 2004 Nov
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Industry Influence in Dermatology Clinical Practice Guideline Development
In his farewell address to the nation, in 1961, President Dwight D. Eisenhower warned about the rising influence of the military establishment and the arms industry. "The potential for the disastrous rise of misplaced power exists," the President said, referring to the military-industrial complex, "and will persist."
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The Most Beautiful People
This study used People magazine to compare standards of beauty in 1990 with present-day standards.
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Chronic Urticaria in Children
Six years ago, we reviewed what was then known about chronic urticaria (CU) in children. We came to the conclusion that many important and interesting questions were unanswered. These included, but were not limited to, how common chronic spontaneous urticaria (CSU) and inducible urticaria are in children, the clinical presentation, underlying causes, impact on everyday life of CU in children, and the natural course of pediatric CU. We also suggested strategies to address and answer these questions and encouraged further studies to do so.
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The Epidemic of Guns
The shooting in Las Vegas, Nevada, that left 59 people dead, 10 times that number wounded, and thousands of people with the psychological distress from being present at the scene during and after the massacre has once again raised the issue of what we as a nation can and should do about guns. The solution lies in not just focusing on Las Vegas and the hundreds of other mass shootings that have occurred in the United States in the last 14 months, but rather to underscore that on average almost 100 people die each day in the United States from gun violence. The 36 252 deaths from firearms in the United States in 2015 exceeded the number of deaths from motor vehicle traffic crashes that year (36 161). That same year, the US Centers for Disease Control and Prevention reported that 5 people died from terrorism. Since 1968, more individuals in the United States have died from gun violence than in battle during all the wars the country has fought since its inception.
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A Transgender Woman With Anogenital Lichen Sclerosus
This case report describes a transgender woman with anogenital lichen sclerosus.
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Industry Payments Among Dermatology Clinical Practice Guidelines Authors
This study uses data extraction from the Open Payments database to evaluate the monetary values and types of payments received by physician authors of dermatology guidelines and the accuracy of conflict of interest disclosure statements.
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Factors Associated With Chronic Urticaria in Children
This cohort study examined the resolution rate of chronic urticaria in children and whether there are biomarkers that can predict resolution.
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Treatment of Psychiatric Disorders and Skin-Restricted Lupus Remission
This observational cohort study investigates the association between treatment of psychiatric disorders and skin-restricted lupus remission in a patient cohort over 2.5 years.
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Sclerotherapy for Reticular Veins in the Lower Limbs
This randomized clinical trial compares sclerotherapy of reticular veins of the lower limb with 2% polidocanol diluted in 70% hypertonic glucose vs hypertonic glucose alone.
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Prescription-Strength Topical Steroids Sold Without Prescription
This case report describes the use of a prescription-strength topical steroids obtained without prescription.
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Alcohol-Related Mortality in Patients With Psoriasis
This cohort study investigates whether patients with psoriasis have an elevated risk of alcohol-related mortality.
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Industry Influence in Dermatology Clinical Practice Guideline Development
In his farewell address to the nation, in 1961, President Dwight D. Eisenhower warned about the rising influence of the military establishment and the arms industry. "The potential for the disastrous rise of misplaced power exists," the President said, referring to the military-industrial complex, "and will persist."
http://ift.tt/2gT3Daa
http://ift.tt/2gT3Daa
The Most Beautiful People
This study used People magazine to compare standards of beauty in 1990 with present-day standards.
http://ift.tt/2hAVVRR
http://ift.tt/2hAVVRR
Chronic Urticaria in Children
Six years ago, we reviewed what was then known about chronic urticaria (CU) in children. We came to the conclusion that many important and interesting questions were unanswered. These included, but were not limited to, how common chronic spontaneous urticaria (CSU) and inducible urticaria are in children, the clinical presentation, underlying causes, impact on everyday life of CU in children, and the natural course of pediatric CU. We also suggested strategies to address and answer these questions and encouraged further studies to do so.
http://ift.tt/2xEm0Gd
http://ift.tt/2xEm0Gd
Prescription-Strength Topical Steroids Sold Without Prescription
This case report describes the use of a prescription-strength topical steroids obtained without prescription.
http://ift.tt/2iQbIjV
http://ift.tt/2iQbIjV
The Epidemic of Guns
The shooting in Las Vegas, Nevada, that left 59 people dead, 10 times that number wounded, and thousands of people with the psychological distress from being present at the scene during and after the massacre has once again raised the issue of what we as a nation can and should do about guns. The solution lies in not just focusing on Las Vegas and the hundreds of other mass shootings that have occurred in the United States in the last 14 months, but rather to underscore that on average almost 100 people die each day in the United States from gun violence. The 36 252 deaths from firearms in the United States in 2015 exceeded the number of deaths from motor vehicle traffic crashes that year (36 161). That same year, the US Centers for Disease Control and Prevention reported that 5 people died from terrorism. Since 1968, more individuals in the United States have died from gun violence than in battle during all the wars the country has fought since its inception.
http://ift.tt/2xQZppf
http://ift.tt/2xQZppf
A Transgender Woman With Anogenital Lichen Sclerosus
This case report describes a transgender woman with anogenital lichen sclerosus.
http://ift.tt/2ABEYCU
http://ift.tt/2ABEYCU
Industry Payments Among Dermatology Clinical Practice Guidelines Authors
This study uses data extraction from the Open Payments database to evaluate the monetary values and types of payments received by physician authors of dermatology guidelines and the accuracy of conflict of interest disclosure statements.
http://ift.tt/2yxBI9c
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Dermatology in Epic Poetry—From Beowulf to The Odyssey
Epic poems have captured the imaginations of readers, listeners, and artists alike for millennia. Michelangelo painted part of the Sistine Chapel after being inspired by Dante's Divine Comedy. Shakespeare's 1602 play, Troilus and Cressida, is based on The Iliad, an ancient Greek epic poem attributed to Homer. All told, epic poems are captivating tales full of wonder and adventure. Particularly, they have often integrated dermatology in their unique plots. Beowulf is an Old English poem (written circa ad 700-1000) that tells of the powerful Geat hero Beowulf, who visits the mead hall, Heorot, to kill the evil monster Grendel. Grendel, bothered by the sounds of joy, has gruesomely slaughtered Heorot's inhabitants for years. Owing to his magical gifts, no one has been able to slay him. Grendel not only possesses incredible strength, but his skin is also impenetrable to any blade: "Every nail, claw-scale, of that heathen brute…was like barbed steel. To pierced him through, no time proofed blade could cut his brutal, blood-caked claw." Beowulf notably does not use a sword, but rather kills Grendel by directly ripping his arm off, causing him to bleed to death. In the 13th century German epic poem Das Nibelungenlied (The Song of the Nibelungs), the skin of a main character is a weakness rather than a strength. In the beginning of the story, the knight Siegfried is said to have slaughtered a dragon and bathed in his blood—rendering him invulnerable to weaponry. However, a leaf from a linden tree fell between his shoulders during this bath, leaving that area untouched with blood. His wife, Kriemhild, mentions, "There one might stab him, and thence is my care and dole," indicating that this is his only weakness (similar to Achilles' heel). Unfortunately, Siegfried is later murdered by Hagen, who spears the unsuspecting knight while he is drinking from a brook. His death inspires Kriemhild's revenge, which is the focus of the second half of Das Nibelungenlied. The Odyssey, a Greek epic poem by Homer, details the legendary return of Odysseus to his home of Ithaca after the Trojan war. Arriving after 20 years, he discovers that multiple suitors are courting his wife, Penelope, presuming he is dead. Odysseus is then transformed by Athena (the goddess of war) into an old man as a disguise. However, his housekeeper, Eurycleia, identifies him because of a hunting scar on his leg: "She immediately recognized the scar; which once a boar inflicted upon him." This discovery demonstrates Eurycleia's loyalty and allows the Odysseus and Penelope to reunite. Together, they plot to kill the suitors and eventually restore peace to Odysseus' kingdom. Ultimately, epic poems are full of fantastic details and magical characters. Many tales involve the skin, demonstrating dermatology's unique significance in literature. Hopefully, epic poetry will continue inspiring many more for ages to come.
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Factors Associated With Chronic Urticaria in Children
This cohort study examined the resolution rate of chronic urticaria in children and whether there are biomarkers that can predict resolution.
http://ift.tt/2A3pfsm
http://ift.tt/2A3pfsm
Barber Recognition of Pseudofolliculitis Barbae and Acne Keloidalis Nuchae
This cross-sectional study analysis assesses barber knowledge and recommendations regarding various dermatologic conditions common among clients who use predominantly African American barbershops.
http://ift.tt/2yAq8dr
http://ift.tt/2yAq8dr
Diagnostic Accuracy of Pediatric Teledermatology Using Parent-Submitted Photographs
This randomized clinical trial assesses whether smartphone photographs of pediatric skin conditions taken by parents are of sufficient quality to permit accurate diagnosis.
http://ift.tt/2AOAaXz
http://ift.tt/2AOAaXz
Sclerotherapy for Reticular Veins in the Lower Limbs
This randomized clinical trial compares sclerotherapy of reticular veins of the lower limb with 2% polidocanol diluted in 70% hypertonic glucose vs hypertonic glucose alone.
http://ift.tt/2xHRBHf
http://ift.tt/2xHRBHf
Alcohol-Related Mortality in Patients With Psoriasis
This cohort study investigates whether patients with psoriasis have an elevated risk of alcohol-related mortality.
http://ift.tt/2ynl8oY
http://ift.tt/2ynl8oY
Joseph Goldberger—Public Health Champion and Investigator of Pellagra
Joseph Goldberger, MD (1874-1929), was an American physician whose commitment to public health led him to risk his own health and to confront the medical and political establishments of his day. In 1899, not long after graduating from Bellevue Hospital Medical College, Goldberger joined the US Marine Hospital Service (later the Public Health Service). Initially, his duties included inspecting immigrants in the Port of New York, but he soon became fascinated by epidemiology and infectious diseases. As a quarantine officer, Goldberger traveled extensively to study outbreaks of yellow fever, dengue fever, and typhus, and managed to contract each of these on his visits.
http://ift.tt/2ABFS2x
http://ift.tt/2ABFS2x
Resilience and Depression in Patients With Hidradenitis Suppurativa
This survey study uses clinical data from a set of self-administered, self-graded questionnaires to examine the correlation among resilience, depression, and health-related quality of life for patients with hidradenitis suppurativa.
http://ift.tt/2yIyWzq
http://ift.tt/2yIyWzq
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
This Patient Page provides information on Stevens-Johnson syndrome and toxic epidermal necrolysis and advises patients on care and treatment as well as ways to avoid recurrences.
http://ift.tt/2Bj1YGh
http://ift.tt/2Bj1YGh
Long-term Change in the Risk of Skin Cancer After Organ Transplantation
This population-based nationwide cohort study evaluates the long-term change in the risk of skin cancer after organ transplantation in Norway.
http://ift.tt/2ipFAUc
http://ift.tt/2ipFAUc
Hypophysenadenome – nicht immer benigner Natur
Zusammenfassung
Hintergrund
Mit einer Prävalenz von 80–100 Fällen pro 100.000 Einwohner sind Hypophysenadenome häufiger als allgemein angenommen. Meist werden sie jedoch erst Jahre nach Entwicklung der ersten Symptome diagnostiziert. Besonders die seltenen aggressiven Verlaufsformen stellen eine besondere Herausforderung dar.
Ziel
Die aktuellen diagnostischen und therapeutischen Möglichkeiten von Hypophysenadenomen werden dargestellt.
Material und Methode
Review der Literatur.
Ergebnisse
Hormoninaktive Hypophysentumoren werden in der Regel erst bei Entwicklung von Lokalsymptomen, Nachweis eines relevanten Tumorwachstums oder bei der Entwicklung einer Hypophyseninsuffizienz operiert. Prolaktinome werden typischerweise medikamentös behandelt; abhängig von Tumorgröße und Präferenz des Patienten kann aber auch eine primäre Operation angeboten werden. Eine Akromegalie wird unverändert erst sehr spät nach Erstentwicklung von Symptomen diagnostiziert − und dann mit einem Makroadenom. Die Behandlung beinhaltet häufig eine Kombination von Operation und medikamentösen Therapieverfahren. Der M. Cushing bedarf einer sorgfältigen diagnostischen Klärung und wird operiert. In den letzten Jahren wurden verschiedene medikamentöse Therapieansätze zugelassen, um die Behandlung von residuellen Tumoranteilen oder Rezidiven zu verbessern. Die Prognose von aggressiven Hypophysentumoren hat sich aufgrund von Studien verbessert, die die Effektivität einer Chemotherapie mit Temozolomid nachgewiesen haben.
Schlussfolgerungen
Die Behandlung von Hypophysenadenomen stellt aufgrund der heterogenen klinischen Präsentation unverändert eine Herausforderung dar. Die Patienten sollten von einem Team, mindestens bestehend aus einem Endokrinologen, Neurochirurgen, Strahlentherapeuten und Pathologen, behandelt werden.
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Pepsin in saliva as a diagnostic biomarker in laryngopharyngeal reflux: a meta-analysis
Abstract
Objective
Pepsin in saliva has been proposed as a biomarker for the diagnosis of laryngopharyngeal reflux (LPR), but the results remain controversial. We assessed the diagnostic value of pepsin in saliva for LPR.
Methods
PubMed, Embase, and Web of Science were searched for studies in English that evaluated the utility of pepsin in saliva in the diagnosis of LPR, published up to 15 March 2017. We used Stata 12.0 to summarize the diagnostic indexes for the meta-analysis.
Results
Eleven eligible studies met the inclusion criteria. After the meta-analysis of included studies, the pooled sensitivity and specificity were 64% [95% confidence interval (CI) 43–80%] and 68% (95% CI 55–78%), respectively; the positive (PLR) and negative (NLR) likelihood ratios were 2.0 (95% CI 1.4–2.9) and 0.54 (95% CI 0.33–0.87), respectively; the diagnostic odds ratio (DOR) was 4 (95% CI 2–8); and the area under the curve (AUC) was 0.71 (95% CI 0.67–0.75).
Conclusion
Pepsin in saliva has moderate value in the diagnosis of LPR. The cutoff value used could affect the diagnostic value. Therefore, further investigations are required to find the optimal method to detect salivary pepsin in diagnosing LPR.
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In vivo imaging the motility of monocyte/macrophage during inflammation in diabetic mice
Abstract
Diabetes, as a chronic metabolic disease, can impair the immune function of monocytes/macrophages (MMs). However, it is unclear how MMs immune response to inflammation with the development of diabetes, and whether immune response around the inflammatory foci depends on the depth in tissue. Footpad provides a classical physiological site for monitoring cellular behavior during inflammation, but limited to the superficial dermis due to the strong scattering of footpad. Herein, we used confocal microscopy to monitor the motility of MMs in deeper tissue around inflammatory foci with the development of type 1 diabetic (T1D) mice through a swithable footpad skin optical clearing window. Delayed-type hypersensitivity (DTH) model was elicited on the footpad of T1D. Results demonstrated that progressive T1D led to the gradually potentiated MMs recruitment and increased expression of monocyte chemoattractant protein-1 during DTH, but MMs migration displacement, motion velocity and motility coefficient were significantly attenuated. Besides, MMs from the deeper dermis had a much larger migration displacement than those from superficial dermis at early stages of DTH but an opposite tendency at late stages for non-T1D, while progressive T1D obscured this difference gradually. This study will be helpful for investigating the influences of progressive metabolic diseases on immune response. MMs motion trajectory at depth of superficial dermis and the deeper dermis at AOVA-4h and AOVA-72h on Non-T1D (A) and T1D-4w (B). Mean motility coefficient (C) at the two depths. Data were pooled from 6 mice per group. * (p < 0.05) and ** (p < 0.01) compared among different T1D disease durations. # (p < 0.05) compared between different depths.
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Cerebral blood flow changes after radiation therapy identifies pseudo-progression in diffuse intrinsic pontine gliomas
Abstract
Background
The interval between progression and death in diffuse intrinsic pontine glioma (DIPG) is usually < 6 months. However, reports of longer patient survival following radiotherapy, in the presence of radiological signs of progression, suggest that these cases may be comparable to pseudo-progression observed in adult glioblastoma. Our aim was to identify such cases and compare their multimodal MRI features with those of patients that did not present the same evolution. Methods
Multimodal MRI of 43 children treated for DIPG were retrospectively selected at four time points: baseline, after-radiotherapy, during true-progression, and at the last-visit. The patients were divided into two groups depending on whether they presented conventional MRI changes that mimicked progression. The apparent diffusion coefficient, arterial spin labelling blood flow (ASL-CBF) and dynamic susceptibility perfusion relative blood volume (DSCrCBV) and flow (DSCrCBF) values were recorded for each tumor voxel, avoiding necrotic areas. Results
After radiotherapy, 19 patients (44%) showed radiological signs that mimicked progression: 16 survived > 6 months following so-called pseudo-progression, with a median of 8.9 months and a maximum of 35.6 months. All 43 patients exhibited increased blood volume and flow after-radiotherapy, but the 90 th percentile of those with signs of pseudo-progression had a greater increase of ASL-CBF (p < 0.001). Survival between the two groups did not differ significantly. During true progression, DSCrCBF and DSCrCBV values increased only in patients that had not experienced pseudo-progression. Conclusions
Pseudo-progression is a frequent phenomenon in DIPG patients. This condition needs to be recognized before considering treatment discontinuation. In this study, the larger increase of the ASL-CBF ratio after radiotherapy accurately distinguished pseudo-progression from true-progression.from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/2Bi7hWv
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Isolated and repeated stroke-like episodes in a middle-aged man with a mitochondrial ND3 T10158C mutation: a case report
Abstract
Background
Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, is the most common phenotype of mitochondrial disease. It often develops in childhood or adolescence, usually before the age of 40, in a maternally-inherited manner. Mutations in mitochondrial DNA (mtDNA) are frequently responsible for MELAS.
Case presentation
A 55-year-old man, who had no family or past history of mitochondrial disorders, suddenly developed bilateral visual field constriction and repeated stroke-like episodes. He ultimately presented with cortical blindness, recurrent epilepsy and severe cognitive impairment approximately 6 months after the first episode. Genetic analysis of biopsied biceps brachii muscle, but not of peripheral white blood cells, revealed a T10158C mutation in the mtDNA-encoded gene of NADH dehydrogenase subunit 3 (ND3), which has previously been thought to be associated with severe or fatal mitochondrial disorders that develop during the neonatal period or in infancy.
Conclusion
A T10158C mutation in the ND3 gene can cause atypical adult-onset stroke-like episodes in a sporadic manner.
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Predictors of post-stroke body temperature elevation
Abstract
Background
Growing evidence indicates that elevated body temperature after stroke is associated with unfavorable outcome. The aim of the current study was to investigate which factors predict temperature elevation within 48 h of stroke onset. Specifically, we hypothesized that temperature elevation would be associated with stroke symptom severity and that hemorrhagic stroke would cause a more pronounced temperature increase compared to ischemic stroke.
Methods
The medical records of 400 stroke patients were retrospectively reviewed. Multiple linear regression analysis was used to determine which factors were associated with elevated body temperature.
Results
Several factors were significantly associated with peak body temperature (the highest recorded body temperature) within 48 h of stroke onset: stroke severity measured by the National Institutes of Health Stroke Scale (NIHSS) (regression coefficient; (RC) 0.022), female gender (RC 0.157), tympanic/non-rectal temperature reading (RC −0.265), swallowing difficulties (RC 0.335), intubation (RC 0.470), antipyretic treatment (RC 0.563), and C-reactive protein > 50 or signs of infection at admission (RC 0.298). Contrary to our expectations, patients with intracerebral hemorrhage did not have higher peak body temperatures than patients with ischemic stroke.
Conclusions
In conclusion, temperature elevation within the first 48 h of stroke onset is common, can be partially predicted using information at admission and is strongly associated with stroke severity. The strong association with stroke severity may, at least partly, explain the previously described association between post-stroke temperature elevation and unfavorable outcome.
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PEG Hydrogel Containing Calcium-Releasing Particles and Mesenchymal Stromal Cells Promote Vessel Maturation
Publication date: Available online 13 December 2017
Source:Acta Biomaterialia
Author(s): Claudia Navarro-Requena, Jessica D. Weaver, Amy Y. Clark, Douglas A. Clift, Soledad Pérez-Amodio, Óscar Castaño, Dennis W. Zhou, Andrés J. García, Elisabeth Engel
The use of human mesenchymal stromal cells (hMSC) for treating diseased tissues with poor vascularization has received significant attention, but low cell survival has hampered its translation to the clinic. Bioglasses and glass-ceramics have also been suggested as therapeutic agents for stimulating angiogenesis in soft tissues, but these effects need further evaluation in vivo. In this study, calcium-releasing particles and hMSC were combined within a hydrogel to examine their vasculogenic potential in vitro and in vivo. The particles provided sustained calcium release and showed proangiogenic stimulation in a chorioallantoic membrane (CAM) assay. The number of hMSC encapsulated in a degradable RGD-functionalized PEG hydrogel containing particles remained constant over time and IGF-1 release was increased. When implanted in the epidydimal fat pad of immunocompromised mice, this composite material improved cell survival and stimulated vessel formation and maturation. Thus, the combination of hMSC and calcium-releasing glass-ceramics represents a new strategy to achieve vessel stabilization, a key factor in the revascularization of ischemic tissues.SignificanceIncreasing blood vessel formation in diseased tissues with poor vascularization is a current clinical challenge. Cell therapy using human mesenchymal stem cells has received considerable interest, but low cell survival has hampered its translation to the clinic. Bioglasses and glass-ceramics have been explored as therapeutic agents for stimulating angiogenesis in soft tissues, but these effects need further evaluation in vivo. By incorporating both human mesenchymal stem cells and glass-ceramic particles in an implantable hydrogel, this study provides insights into the vasculogenic potential in soft tissues of the combined strategies. Enhancement of vessel formation and maturation supports further investigation of this strategy.
Graphical abstract
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Clinically Advancing and Promising Polymer-based Therapeutics
Publication date: Available online 13 December 2017
Source:Acta Biomaterialia
Author(s): Whitney Souery, Corey J. Bishop
In this review article, we will examine the history of polymers and their evolution from provisional World War II materials to medical therapeutics. To provide a comprehensive look at the current state of polymer-based therapeutics, we will classify technologies according to targeted areas of interest, including central nervous system-based and intraocular-, gastrointestinal-, cardiovascular-, dermal-, reproductive- , skeletal-, and neoplastic-based systems. Within each of these areas, we will consider several examples of novel, clinically available polymerbased therapeutics; in addition, this review will also include a discussion of developing therapies, ranging from the in vivo to clinical trial stage, for each targeted area of treatment. Finally, we will emphasize areas of patient care in need of more effective, accessible, and targeted treatment approaches where polymer-based therapeutics may offer potential solutions.
Graphical abstract
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Work Outcomes in Patients Who Stay at Work Despite Musculoskeletal Pain
Abstract
Purpose To assess self-reported work impacts and associations between psychosocial risk factors and work impairment amongst workers seeking care for musculoskeletal pain while continuing to work. Methods Patients were recruited from Musculoskeletal Assessment Clinics at 5 hospitals across Ireland. Participants completed questionnaires including assessments of work impairment (Work Productivity and Activity Impairment Questionnaire), work ability (single item from the Work Ability Index) and work performance (Work Role Functioning Questionnaire; WRFQ). Logistic and hierarchical regressions were conducted to analyse the relation between psychosocial variables and work outcomes. Results 155 participants (53.5% female; mean age = 46.50 years) who were working at the time of assessment completed the questionnaires. Absenteeism was low, yet 62.6% were classified as functioning poorly according to the WRFQ; 52.3% reported having poor work ability. Logistic regression analyses indicated that higher work role functioning was associated with higher pain self-efficacy (OR 1.51); better work ability was associated with older age (OR 1.063) and lower functional restriction (OR 0.93); greater absenteeism was associated with lower pain self-efficacy (OR 0.65) and poorer work expectancy (OR 1.18). Multiple regression analysis indicated that greater presenteeism was associated with higher pain intensity (β = 0.259) and lower pain self-efficacy (β = − 0.385). Conclusions While individuals continue to work with musculoskeletal pain, their work performance can be adversely affected. Interventions that target mutable factors, such as pain self-efficacy, may help reduce the likelihood of work impairment.
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Rational evaluation of the therapeutic effect and dosimetry of auger electrons for radionuclide therapy in a cell culture model
Abstract
Objective
Radionuclide therapy with low-energy auger electron emitters may provide high antitumor efficacy while keeping the toxicity to normal organs low. Here we evaluated the usefulness of an auger electron emitter and compared it with that of a beta emitter for tumor treatment in in vitro models and conducted a dosimetry simulation using radioiodine-labeled metaiodobenzylguanidine (MIBG) as a model compound.
Methods
We evaluated the cellular uptake of 125I-MIBG and the therapeutic effects of 125I- and 131I-MIBG in 2D and 3D PC-12 cell culture models. We used a Monte Carlo simulation code (PHITS) to calculate the absorbed radiation dose of 125I or 131I in computer simulation models for 2D and 3D cell cultures. In the dosimetry calculation for the 3D model, several distribution patterns of radionuclide were applied.
Results
A higher cumulative dose was observed in the 3D model due to the prolonged retention of MIBG compared to the 2D model. However, 125I-MIBG showed a greater therapeutic effect in the 2D model compared to the 3D model (respective EC50 values in the 2D and 3D models: 86.9 and 303.9 MBq/cell), whereas 131I-MIBG showed the opposite result (respective EC50 values in the 2D and 3D models: 49.4 and 30.2 MBq/cell). The therapeutic effect of 125I-MIBG was lower than that of 131I-MIBG in both models, but the radionuclide-derived difference was smaller in the 2D model. The dosimetry simulation with PHITS revealed the influence of the radiation quality, the crossfire effect, radionuclide distribution, and tumor shape on the absorbed dose. Application of the heterogeneous distribution series dramatically changed the radiation dose distribution of 125I-MIBG, and mitigated the difference between the estimated and measured therapeutic effects of 125I-MIBG.
Conclusions
The therapeutic effect of 125I-MIBG was comparable to that of 131I-MIBG in the 2D model, but the efficacy was inferior to that of 131I-MIBG in the 3D model, since the crossfire effect is negligible and the homogeneous distribution of radionuclides was insufficient. Thus, auger electrons would be suitable for treating small-sized tumors. The design of radiopharmaceuticals with auger electron emitters requires particularly careful consideration of achieving a homogeneous distribution of the compound in the tumor.
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REAL TIME PCR TO EVALUATE HSV-2 SHEDDING FROM ANAL AND GENITAL SAMPLES AMONG MEN WHO HAVE SEX WITH MEN, LIVING WITH HIV
Abstract
This study shows the relative quantification of HSV-2 by qPCR, using the MIQE Guidelines. The reaction efficiency was evaluated, and the relative quantification used the R=2−ΔCq method. The relative quantification of HSV-2 was conducted with anal and genital samples from men who have sex with men (MSM), living with HIV. The presence of a single amplification product was validated with a dissociation curves profile and the determination of the melting temperature. The limit of detection for β-globin was determined as 3.3 × 10−6ng/μl, and for HSV-2 at 6.0 × 10−6 ng/μl. The efficiency for β-globin was 100.2% and for HSV-2 was 106.8%. From 336 MSM, 2.1% and 3.9% individuals presented anal or genital HSV-2 shedding, respectively. The HSV-2 viral load was 9.2 RU, individuals with fewer CD4+ presented higher HSV-2 viral load. The qPCR method is reproducible and has optimal reaction efficiency. This article is protected by copyright. All rights reserved
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Recovery of Hepatitis C Specific T-cell Responses after Rituximab Therapy in Hepatitis C Mixed Cryoglobulinemic Vasculitis
Abstract
Background & Aims: Mixed cryoglobulinemic vasculitis is associated with monoclonal B cell expansion in patients with chronic hepatitis C (HCV) infection. B cell depletion therapy using rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from symptomatic disease. This study investigated whether B cell depletion therapy has an impact on activation of HCV-specific T cell phenotype and function.
Methods: Nineteen patients with Hepatitis C mixed cryoglobulinemic vasculitis were treated with 4 cycles of rituximab (375mg/m2) and variables were measured 6 months after therapy. Using flow cytometry and Enzyme-Linked Immunospot assay, the number of activated and tissue-like B cells and number of T cells expressing Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and multiple cytokines were measured before and after rituximab therapy.
Results: B cell depletion therapy is associated with a significant (P<0.0001) decline in peripheral T cells with exhaustive phenotype, from pre-therapy to post-therapy-of rituximab (mean±standard error): CD4+ (16.9±0.9% to 8.9±1.0%) and CD8+ (6.8±0.6% to 3.0±0.5%) T cells expressing PD-1 and CD4+ (11.0±1.0% to 6.1±0.8%) and CD8+ (12.7±0.7% to 6.4±0.4%) T cells expressing TIM-3. In addition, there was a significantly higher percentage of peripheral CD8+ T cells responding to HCV peptide stimulation in vitro secreting IFN-γ (4.55±0.3 to 9.6±1.0 IFN-γ/106 PBMCs, P<0.0001), and more than one cytokine (1.3±0.1% to 3.8±0.2%, P<0.0001) after therapy compared to pre-therapy.
Conclusion: B cell depletion therapy results in recovery of T cell exhaustion and function in patients with HCV cryoglobulinemic vasculitis. This article is protected by copyright. All rights reserved
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