Is insufficient pulmonary air support the cause of dysphonia in chronic obstructive pulmonary disease?

Publication date: Available online 8 January 2018
Source:Auris Nasus Larynx
Author(s): Megahed M. Hassan, Mona T. Hussein, Ahmed Mamdouh Emam, Usama M. Rashad, Ibrahim Rezk, Al Hussein Awad
ObjectiveOptimal pulmonary air support is essential pre-requisite for efficient phonation. The objective is to correlate pulmonary and vocal functions in chronic obstructive pulmonary disease (COPD) to find out whether the reduced pulmonary function per se could induce dysphonia.MethodsIn this prospective case-control study, sixty subjects with stable COPD underwent evaluation of pulmonary and vocal functions. The pulmonary functions measured include {Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, peak expiratory flow (PEF), maximum mid-expiratory flow (MMEF)}. The vocal functions were {jitter, shimmer, noise-to-harmonic ratio, pitch perturbation quotient, amplitude perturbation quotient, maximum phonation time (MPT), sound pressure level, phonatory efficiency, resistance and power. A control group (n=35) underwent the same measurements. These functions were compared between subjects and controls. Also, correlation of the vocal and pulmonary functions was conducted.ResultsThirty five (58.3%) of COPD subjects have dysphonia. The pulmonary functions were lower in all COPD group than in the control group (P<0.001 for all parameters). Also, the FVC, FEV1, PEF and MMEF % of predicted values were significantly lower in subjects with dysphonia (n=35) than those without dysphonia (n=25) with P values 0.0018, <0.001, 0.0011 and 0.0026 respectively. In addition, the MPT in all subjects showed positive correlations to the 5 pulmonary functions (P=0.004 for FEV1/FVC ratio and P<0.001 for the rest). Also, the phonatory efficiency showed significant positive correlations with the pulmonary functions FVC, FEV1, PEF and MMEF (P=0.001, 0.001, 0.002 and 0.001 respectively). Unlike efficiency, the phonatory resistance revealed significant negative correlations with these pulmonary functions in the same order (P=0.001, 0.003, 0.002, 0.001 respectively).ConclusionDysphonia is a common comorbidity with COPD which attributed to multifactorial etiologies. The lower the pulmonary function in COPD patients is the more likely to have dysphonia. Decreased pulmonary function was associated with reduced MPT and phonatory efficiency but with increased phonatory resistance. The reduced pulmonary functions in COPD can be the underlying cause of the altered vocal function and dysphonia. Great part of this dysphonia is functional, and hence, can be corrected by voice therapy in compensated subjects. Further researches are needed to evaluate the efficacy of voice therapy in these patients.



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Exogenous Cushing syndrome due to misuse of potent topical steroid

Abstract

We report an infant with exogenous Cushing syndrome after being treated for 2 months with a potent topical corticosteroid via the mother's application of topical clobetasol for diaper rash without a prescription. We emphasize that potent topical steroids should be used with great caution, especially when used under occlusion (e.g., diaper area) and that parents should be warned about potential side effects of these medications, particularly when used in infants.

http://ift.tt/2DbVFTH

Doing the math: A simple approach to topical timolol dosing for infantile hemangiomas

Abstract

Topical timolol maleate has recently gained popularity as a treatment for superficial infantile hemangiomas, but calculating a safe dose of timolol can be time consuming, which may limit the medication's use in fast-paced clinical environments. This report offers a simplified calculation of the maximum daily safe dosage as 1 drop of medication per kilogram of body weight.

http://ift.tt/2D9ZLvj

Mood changes with methotrexate therapy for dermatologic disease

Abstract

Neurotoxicity and cognitive effects of low-dose methotrexate for rheumatologic disease have often been described, but the neuropsychiatric effects of low-dose methotrexate for cutaneous disease have been underreported in the dermatology literature. We describe two children who experienced mood changes with methotrexate treatment for lichen sclerosus with morphea overlap and psoriasis, with rapid resolution of these symptoms after methotrexate cessation. We also detail possible mechanisms underlying psychiatric changes with methotrexate therapy.

http://ift.tt/2mfkXJ4

Pityriasis lichenoides: Long-term follow-up study

Abstract

Background/Objectives

Pityriasis lichenoides is an uncommon papulosquamous disorder of unknown etiology. The objective of this study was to review the clinical features and treatment responses of individuals with pityriasis lichenoides seen at a tertiary referral center.

Methods

Seventy-five patients diagnosed with pityriasis lichenoides between 1997 and 2013 were reviewed, and 46 had long-term follow-up via telephone interviews.

Results

Fifty (67%) patients were diagnosed with pityriasis lichenoides chronica, 22 (29%) with pityriasis lichenoides et varioliformis acuta, and 3 (4%) with mixed pityriasis lichenoides chronica and pityriasis lichenoides et varioliformis acuta features. Mean ± standard deviation age at onset was 12 ± 13 years (median 8 years). Disease duration was significantly shorter for patients with pityriasis lichenoides et varioliformis acuta (35 ± 35 months) than for those with pityriasis lichenoides chronica (at least 78 ± 48 months). At long-term follow-up, 23 of 28 (82%) patients with pityriasis lichenoides chronica and 3 of 16 (19%) with pityriasis lichenoides et varioliformis acuta had active disease. None progressed to lymphomatoid papulosis or cutaneous T-cell lymphoma. Ten of 23 active pityriasis lichenoides chronica cases had residual pigmentary change independent of race and lasted at least 35 ± 20 months. The most effective treatments were phototherapy (47% response rate), heliotherapy (33%), topical corticosteroids (27%), and antibiotics (25%).

Conclusion

Pityriasis lichenoides is a predominantly pediatric disorder. The time course of pityriasis lichenoides chronica is significantly longer than that of pityriasis lichenoides et varioliformis acuta. Pityriasis lichenoides chronica may persist with pigmentary alterations in the absence of other signs of active inflammation. Treatment response is often limited, particularly for patients with pityriasis lichenoides chronica.

http://ift.tt/2mfa6iB

Incidence, outcomes, and resource use in children with Stevens-Johnson syndrome and toxic epidermal necrolysis

Abstract

Background/Objectives

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions, typically to drugs or infection. The incidence and outcomes of these conditions in children are unknown. The objective of this study was to report the overall burden of Stevens-Johnson syndrome and toxic epidermal necrolysis in children in the United States.

Methods

We performed a retrospective cohort analysis of children and adolescents younger than 18 years of age using the 2009 and 2012 Kids' Inpatient Database.

Results

We identified 1486 children and adolescents hospitalized with a diagnosis of Stevens-Johnson syndrome or toxic epidermal necrolysis. The national incidence per 100 000 was 6.3 for Stevens-Johnson syndrome, 0.7 for Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome, and 0.5 for toxic epidermal necrolysis. The highest incidence in children was in those aged 11-15 years (38.4 per 100 000). Toxic epidermal necrolysis and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome were associated with longer stay, greater mortality, and higher hospital charges than those with Stevens-Johnson syndrome. Hospital mortality was highest in children with toxic epidermal necrolysis and in children aged 0-5 years.

Conclusions

The incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis in children is higher than reported in adults, and there are significant age-based variations in incidence and outcomes across the pediatric population. Further study is needed to determine the most effective treatment strategies to reduce costs and improve outcomes in children hospitalized with severe cutaneous reactions.

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Towards an international language for Incontinence-Associated Dermatitis (IAD): design and evaluation of psychometric properties of the Ghent Global IAD Categorisation Tool (GLOBIAD) in 30 countries

Summary

Background

Incontinence-associated dermatitis (IAD) is a specific type of irritant contact dermatitis with different levels of severity. An internationally accepted instrument to assess the severity of IAD in adults with established diagnostic accuracy, agreement, and reliability is needed to support clinical practice and research.

Objectives

To design and psychometrically evaluate the Ghent Global IAD Categorisation Tool (GLOBIAD).

Methods

The design was based on expert consultation using a three-round Delphi procedure with 34 experts from 13 countries. The instrument was tested using IAD photographs reflecting different severity levels in a sample of 823 health professionals in 30 countries. Measures for diagnostic accuracy (sensitivity and specificity), agreement, inter-rater reliability (multi-rater Fleiss kappa), and intra-rater reliability (Cohen's Kappa) were assessed.

Results

The GLOBIAD consists of two categories according to the presence of persistent redness (Cat.1) and skin loss (Cat.2), both subdivided based on the presence of clinical signs of infection. The agreement for differentiating between Cat.1 and Cat.2 was 0.86 [95% confidence interval (CI) 0.86-0.87], with a sensitivity of 90% and a specificity of 84%. The overall agreement was 0.55 (95%CI 0.55-0.56). The Fleiss Kappa for differentiating between Cat.1 and Cat.2 was 0.65 (95%CI 0.65-0.65). The overall Fleiss Kappa was 0.41 (95%CI 0.41-0.41). The Cohen's Kappa for differentiating between Cat.1 and Cat.2 was 0.76 (95%CI 0.75-0.77). The overall Cohen's Kappa was 0.61 (95%CI 0.59-0.62).

Conclusions

The development of the GLOBIAD is a major step forward towards a better systematic assessment of IAD in clinical practice and research worldwide. Further validation is however needed.

This article is protected by copyright. All rights reserved.

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Imatinib-induced pseudoporphyria

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Viable tumor in salvage neck dissections in head and neck cancer: Relation with initial treatment, change of lymph node size and human papillomavirus

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Karlijn van den Bovenkamp, Bart Dorgelo, Maartje G. Noordhuis, Bernard F.A.M. van der Laan, Bert van der Vegt, Hendrik P. Bijl, Jan L. Roodenburg, Boukje A.C. van Dijk, Sjoukje F. Oosting, Ed M.D. Schuuring, Johannes A. Langendijk, Gyorgy B. Halmos, Boudewijn E.C. Plaat
ObjectivesTo identify predictive factors for the presence of viable tumor and outcome in head and neck cancer patients who undergo therapeutic salvage neck dissections.Materials and MethodsRetrospective analysis of 76 salvage neck dissections after radiotherapy alone (n = 22), radiotherapy in combination with carboplatin/5-fluorouracil (n = 42) or with cetuximab (n = 12).ResultsViable tumor was detected in 41% of all neck dissections. Univariate analysis revealed initial treatment with radiotherapy without systemic therapy (OR 6.93, 95%CI: 2.28–21.07, p < .001), increased lymph node size after initial treatment compared to pretreatment CT scan (OR 20.48, 95%CI: 2.46–170.73, p = .005), more extensive neck dissections (OR 8.40, 95%CI: 2.94–23.98, p < .001), and human papillomavirus negative cancer (OR 4.22, 95%CI: 1.10–16.22, p = .036) as predictors of viable tumor. Patients with decreased or stable, but persistently enlarged lymph node size after chemoradiation had a significantly lower chance of viable tumor (OR 0.15, 95%CI: 0.05–0.41, p < .001). Disease-specific 5-year survival was 34% in case of viable tumor, and 78% when no viable tumor was found (p < .001).ConclusionsViable tumor in salvage neck dissections is associated with reduced survival. Radiotherapy alone, human papillomavirus negative cancer and increase in lymph node size, are associated with viable tumor in salvage neck dissections. In case of decreased or stable lymph node size after chemoradiation, watchful waiting could be considered.



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An RNA-seq screen of P. gingivalis LPS treated human gingival fibroblasts

Publication date: Available online 8 January 2018
Source:Archives of Oral Biology
Author(s): Yufeng Xie, Mengjun Sun, Yiru Xia, Rong Shu
Backgroundand objective: In gingival tissues, lipopolysaccharide (LPS) from Porphyromonas gingivalis (P. gingivalis) is the most critical stimulator for inducing inflammatory response. Human gingival fibroblasts (HGFs) are the major constituents of gingival connective tissues. The aim of this study was to investigate P. gingivalis LPS induced whole transcriptional profile in HGFs and the potential crosstalk between microRNAs (miRNAs) and inflammatory cytokines.MethodsRNA-seq was performed on HGFs with and without P. gingivalis LPS treatment. The gene expression of selected inflammatory cytokines and miRNAs induced by LPS at different time points was evaluated by quantitative RT-PCR. The protein expression of chemokines was further confirmed by ELISA.ResultsInterestingly, most of the significantly changed genes (198/204) were up-regulated at 4 h after 10 μg/ml LPS stimulation, including inflammatory cytokines and miRNAs. Confirmed by quantitative RT-PCR, the mRNA levels of IL-1β, IL-6 and IL-8 showed single up-regulation peak (4 h/6 h) after 1 μg/ml and 10 μg/ml LPS treatment. Similarly, 1 μg/ml LPS induced single up-regulation peak (8 h) of miRNA-146a, −146b and −155 expression. However, 10 μg/ml LPS induced the increased expression of miRNA-146a and −155 at both early stage (2 h/4 h) and late stage (24 h).ConclusionTaken together, we investigated P. gingivalis LPS induced whole transcriptional profile, and the different behaviors of miRNA expression induced by different doses of LPS in HGFs.



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Ultrastructural damage in Streptococcus mutans incubated with saliva and histatin 5.

Publication date: Available online 8 January 2018
Source:Archives of Oral Biology
Author(s): A.M. Fernández-Presas, Y. Márquez Torres, R. García González, A. Reyes Torres, I. Becker Fauser, H. Rodríguez Barrera, B. Ruíz García, R. Toloza Medina, J. Delgado Domínguez, J.L. Molinarí Soriano
ObjectiveTo study the ultrastructural alterations induced in Streptococcus mutans (ATCC 25175) incubated with saliva, saliva plus histatin 5 and histatin 5.MethodsS. mutans incubated with saliva histatin 5 or a combination of both were morphologically analyzed and counted. The results were expressed as (CFU)ml⁻¹. Ultrastructural damage was evaluated by transmission electron microscopy. Ultrastructural localization of histatin 5 was examined using immunogold labeling. Apoptotic cell death was determined by flow cytometry (TUNEL).ResultsA decrease in the bacteria numbers was observed after incubation with saliva, saliva with histatin 5 or histatin 5 compared to the control group (p<0.0001). Ultrastructural damage in S. mutans incubated with saliva was found in the cell wall. Saliva plus histatin 5 induced a cytoplasmic granular pattern and decreased the distance between the plasma membrane bilayers, also found after incubation with histatin 5, together with pyknotic nucleoids. Histatin 5 was localized on the bacterial cell walls, plasma membranes, cytoplasm and nucleoids. Apoptosis was found in the bacteria incubated with saliva (63.9%), saliva plus histatin 5 (71.4%) and histatin 5 (29.3%). Apoptosis in the control bacteria was 0.2%.ConclusionsAntibacterial activity against S. mutans and the morphological description of damage induced by saliva and histatin 5 was demonstrated. Pyknotic nucleoids observed in S. mutans exposed to saliva, saliva plus histatin 5 and histatin 5 could be an apoptosis-like death mechanism. The knowledge of the damage generated by histatin 5 and its intracellular localization could favor the design of an ideal peptide as a therapeutic agent.



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SUPRAGINGIVAL AND SUBGINGIVAL MICROBIOTA FROM PATIENTS WITH POOR ORAL HYGIENE SUBMITTED TO RADIOTHERAPY FOR HEAD AND NECK CANCER TREATMENT

Publication date: Available online 8 January 2018
Source:Archives of Oral Biology
Author(s): Elerson Gaetti-Jardim, Ellen Cristina Gaetti Jardim, Christiane Marie Schweitzer, Júlio Cesar Leite da Silva, Murilo Moura Oliveira, Danilo Chizzolini Masocatto, Cauê Monteiro dos Santos
ObjectiveThis case-control study aimed to evaluate the effects of conventional radiotherapy (RT) on the prevalence and populations of oral microorganisms in head and neck cancer patients who did not receive adequate preventive dental care. It was hypothesized that side effects of radiotherapy could be associated with radiation dose, microbiological aspects, and socioeconomic conditions of the patients.DesignTwenty-eight dentate patients with head and neck cancer submitted to RT were included in the study. Radiation dose received varied from 4320 to 7020 cGy. Patients with the same demographic and health conditions, but no history of cancer or antineoplastic treatment were used as controls. Clinical examinations were carried out before RT, 15–22 days after starting RT, immediately after and 6 months after RT. Supra and subgingival biofilms were collected and cultivated onto selective and non-selective media. Isolates were identified by biochemical and physiological characteristics. Stimulated and unstimulated salivary flow rate and saliva buffer capacity were also determined.ResultsMucositis, dermatitis, xerostomia, dysgeusia, dysphagia and candidiasis were common after starting RT and during the treatment period. Xerostomia was followed by a decrease in salivary pH and buffer capacity, which showed association with the increase of cariogenic cocci and yeast populations, which were also associated with deterioration of hygiene. Candida and family Enterobacteriaceae showed increased prevalence with RT, and were associated with the occurrence of mucositis and xerostomia.ConclusionsModifications in oral biofilms of irradiated patients showed association with xerostomia and hygiene conditions, which reinforces the necessity of improving patient compliance to oral health care programs.



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11q23 deletion syndrome (Jacobsen syndrome) with severe bleeding: a case report

11q23 deletion syndrome, also known as Jacobsen syndrome, is characterized by growth retardation, psychomotor retardation, facial dysmorphism, multiple congenital abnormalities, and thrombocytopenia. In 11q23 ...

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Anesthesia for Same Day Discharge After Craniotomy: Review of a Single Center Experience

Same day discharge or outpatient surgery for intracranial procedures has become possible with the advent of image-guided minimally invasive approaches to surgery and availability of short-acting anesthetic agents. In addition, patient satisfaction and the benefits of avoiding hospital stay have resulted in the evolution of neurosurgical day surgery. We reviewed our experience and the available literature to determine the perioperative factors involved which have promoted and will improve this concept in the future. Craniotomy and biopsy for supratentorial brain tumors and surgical clipping of intact cerebral aneurysms have been successfully performed as day surgeries. Patient perceptions and satisfaction surveys have helped in better understanding and delivery of care and successful outcomes. There are major differences in health care across the globe along with socioeconomic, medicolegal, and ethical disparities, which must be considered before widespread application of this approach. Nevertheless, collaborative effort by surgeons, anesthesiologists, and nurses can help in same day discharge of patients after cranial neurosurgery. Veena Sheshadri, MD, Department of Neuroanesthesia and Neurocritical Care, Gleneagles Global Hospitals, Bengaluru, Karnataka, India. All the authors contributed substantially to the conception and design of the manuscript and to the interpretation of data. S.V., V.L., and M.P.: contributed to the literature search, acquisition, and analysis of data. The authors have no funding or conflicts of interest to disclose. Address correspondence to: Lashmi Venkatraghavan, MD, FRCA, FRCPC, Department of Anesthesia, Toronto Western Hospital, University Health Network, University of Toronto, 399 Bathurst St, Toronto, ON, M5T 2S8, Canada (e-mail: lashmi.venkatraghavan@uhn.on.ca). Received May 29, 2017 Accepted November 28, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved

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Innate Sex Bias of Staphylococcus aureus Skin Infection Is Driven by {alpha}-Hemolysin [INFECTIOUS DISEASE AND HOST RESPONSE]

Numerous studies have reported sex bias in infectious diseases, with bias direction dependent on pathogen and site of infection. Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs), yet sex bias in susceptibility to S. aureus SSTI has not been described. A search of electronic health records revealed an odds ratio of 2.4 for S. aureus SSTI in males versus females. To investigate the physiological basis of this bias, we compared outcomes between male and female mice in a model of S. aureus dermonecrosis. Consistent with the epidemiological data, female mice were better protected against SSTI, with reduced dermonecrosis followed later by increased bacterial clearance. Protection in females was disrupted by ovariectomy and restored by short-term estrogen administration. Importantly, this sex bias was mediated by a sex-specific response to the S. aureus–secreted virulence factor α-hemolysin (Hla). Infection with wild-type S. aureus suppressed inflammatory cytokine production in the skin of female, but not male, mice when compared with infection with an isogenic hla deletion mutant. This differential response was conserved following injection with Hla alone, demonstrating a direct response to Hla independent of bacterial burden. Additionally, neutrophils, essential for clearing S. aureus, demonstrated sex-specific S. aureus bactericidal capacity ex vivo. This work suggests that sex-specific skin innate responsiveness to Hla and neutrophil bactericidal capacity play important roles in limiting S. aureus SSTI in females. Understanding the molecular mechanisms controlling this sex bias may reveal novel targets to promote host innate defense against S. aureus skin infection.

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Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development [IMMUNE REGULATION]

The surface receptor FcRIIIA (CD16a) is encoded by the FCGR3A gene and is acquired by human NK cells during maturation. NK cells bind the Fc portion of IgG via CD16a and execute Ab-dependent cell-mediated cytotoxicity, which is critical for the effectiveness of several antitumor mAb therapies. The role of epigenetic regulatory mechanisms controlling transcriptional and posttranscriptional CD16 expression in NK cells is unknown. In this study, we compared specific patterns of DNA methylation and expression of FCGR3A with FCGR3B, which differ in cell type–specific expression despite displaying nearly identical genomic sequences. We identified a sequence within the FCGR3A promoter that selectively exhibits reduced methylation in CD16a⁺ NK cells versus CD16a^– NK cells and neutrophils. This region contained the transcriptional start site of the most highly expressed CD16a isoform in NK cells. Luciferase assays revealed remarkable cell-type specificity and methylation-dependent activity of FCGR3A- versus FCGR3B-derived sequences. Genomic differences between FCGR3A and FCGR3B are enriched at CpG dinucleotides, and mutation of variant CpGs reversed cell-type specificity. We further identified miR-218 as a posttranscriptional negative regulator of CD16a in NK cells. Forced overexpression of miR-218 in NK cells knocked down CD16a mRNA and protein expression. Moreover, miR-218 was highly expressed in CD16a^– NK cells compared with CD16a⁺ NK cells. Taken together, we propose a system of FCGR3A regulation in human NK cells in which CpG dinucleotide sequences and concurrent DNA methylation confer developmental and cell type–specific transcriptional regulation, whereas miR-218 provides an additional layer of posttranscriptional regulation during the maturation process.

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Time-Restricted Feeding Alters the Innate Immune Response to Bacterial Endotoxin [INNATE IMMUNITY AND INFLAMMATION]

An important entraining signal for the endogenous circadian clock, independent of light, is food intake. The circadian and immune systems are linked; forced desynchrony of the circadian clock via nighttime light exposure or genetic ablation of core clock components impairs immune function. The timing of food intake affects various aspects of the circadian clock, but its effects on immune function are unknown. We tested the hypothesis that temporal desynchrony of food intake alters innate immune responses. Adult male Swiss Webster mice were provided with food during the night, the day, or ad libitum for 4 wk, followed by administration of LPS prior to the onset of either the active phase (zeitgeber time [ZT]12: Experiment 1) or the inactive phase (ZT0: Experiment 2). Three hours after LPS administration, blood was collected, and serum was tested for bacteria-killing capacity against Escherichia coli, as a functional assay of immune function. Additionally, cytokine expression was examined in the serum (protein), spleen, and hypothalamus (mRNA). Day-fed mice suppressed bacteria-killing capacity and serum cytokine responses to LPS during the active phase (ZT12). Night-fed mice increased bactericidal capacity, as well as serum and hypothalamic mRNA responses of certain proinflammatory cytokines during the active phase. Only day-fed mice enhanced serum cytokine responses when LPS challenge occurred during the inactive phase (ZT0); this did not result in enhanced bactericidal capacity. These data suggest that mistimed feeding has functional relevance for immune function and provide further evidence for the integration of the circadian, metabolic, and immune systems.

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In This Issue [IN THIS ISSUE]

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Naive CD4+ T Cells Carrying a TLR2 Agonist Overcome TGF-{beta}-Mediated Tumor Immune Evasion [TUMOR IMMUNOLOGY]

TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4⁺ T cells that sequester Pam₃Cys₄ (CD4⁺ T^Pam3) become primed for T_h1 differentiation. CD4⁺ T^Pam3 cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-β–OVA–expressing thymomas, produce high amounts of IFN- and sensitize tumors to PD-1/programmed cell death ligand 1 blockade–induced rejection. In contrast, naive OT2 cells without Pam₃Cys₄ cargo are prone to TGF-β–dependent inducible regulatory Foxp3⁺ CD4⁺ T cell conversion and accelerate tumor growth that is largely unaffected by PD-1/programmed cell death ligand 1 blockade. Ex vivo analysis reveals that CD4⁺ T^Pam3 cells are resistant to TGF-β–mediated gene expression through Akt activation controlled by inputs from the TCR and a TLR2-MyD88–dependent PI3K signaling pathway. These data show that CD4⁺ T^Pam3 cells are capable of T_h1 differentiation in the presence of TGF-β, suggesting a novel approach to adoptive cell therapy.

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A Role of NKR-P1A (CD161) and Lectin-like Transcript 1 in Natural Cytotoxicity against Human Articular Chondrocytes [INNATE IMMUNITY AND INFLAMMATION]

Normal cartilage cells are susceptible to lysis by NK cells. This phenomenon may play a role in immune cartilage destruction; however, the mechanisms of chondrocyte recognition by NK cells remain poorly understood. Therefore, the aim of this study was to reveal a possible role of NKR-P1A/lectin-like transcript 1 (LLT1) interaction in NK cell–mediated cytotoxicity against normal human articular chondrocytes. Chondrocytes were isolated from articular cartilage obtained during talonavicular joint surgery. PBMC or polyclonal NK cells isolated from normal donors served as effector cells. Cell-mediated cytotoxicity against chondrocytes was evaluated by means of 18-h ⁵¹Cr-release assay. Specific mRNA expression was evaluated by classical and quantitative RT-PCR, and proteins were detected by Western blot analysis. We found that lysis of articular chondrocytes by PBMC or polyclonal NK cells was potentiated by stimulation with IL-2. Stimulation of effector cells with IL-2 downregulated mRNA expression of inhibitory NKR-P1A NK cell receptor, and blocking of NKR-P1A with specific mAbs resulted in increased chondrocyte killing. Chondrocytes constitutively expressed LLT1, a ligand of NKR-P1A. LLT1 expression by chondrocytes could be upregulated by IL-1α and TNF. Chondrocyte treatment with IL-1α resulted in their increased resistance to killing by natural cytotoxic cells. This could be reversed by blocking of NKR-P1A. These results show that susceptibility of normal articular chondrocytes to lysis by NK cells is modulated by NKR-P1A/LLT1 interactions. Thus, NKR-P1A/LLT1 interaction might provide some novel target for therapeutic interventions in the course of pathological cartilage injury.

http://ift.tt/2CR72ma

Metabolic Barriers to T Cell Function in Tumors [BRIEF REVIEWS]

The metabolic programs that drive T cell functions are exquisitely sensitive to cell intrinsic and extrinsic factors, allowing T cells to respond in a fine-tuned manner to a variety of immune challenges and conditions. However, many of the factors essential for effector T cell function are perturbed in the tumor microenvironment, where oncogenic mutations drive unrestrained cancer cell growth that leads to excess nutrient consumption, excess waste excretion, and insufficient oxygen delivery. This imposes metabolic constraints on infiltrating cells that result in dysfunction and loss of potential antitumor activity in both naturally occurring as well as tailored T cells introduced as part of immunotherapy. In this review, we highlight the metabolic properties that characterize tumor-infiltrating T cells, the barriers within the metabolic landscape of the tumor microenvironment, and the opportunities and challenges they present in development of new cancer therapeutics.

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Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Understanding the mechanisms of CD4 memory T cell (Tmem) differentiation in malaria is critical for vaccine development. However, the metabolic regulation of CD4 Tmem differentiation is not clear, particularly in persistent infections. In this study, we investigated the role of fatty acid synthesis (FAS) in Tmem development in Plasmodium chabaudi chronic mouse malaria infection. We show that T cell–specific deletion and early pharmaceutical inhibition of acetyl CoA carboxylase 1, the rate limiting step of FAS, inhibit generation of early memory precursor effector T cells (MPEC). To compare the role of FAS during early differentiation or survival of Tmem in chronic infection, a specific inhibitor of acetyl CoA carboxylase 1, 5-(tetradecyloxy)-2-furoic acid, was administered at different times postinfection. Strikingly, the number of Tmem was only reduced when FAS was inhibited during T cell priming and not during the Tmem survival phase. FAS inhibition during priming increased effector T cell (Teff) proliferation and strongly decreased peak parasitemia, which is consistent with improved Teff function. Conversely, MPEC were decreased, in a T cell–intrinsic manner, upon early FAS inhibition in chronic, but not acute, infection. Early cure of infection also increased mitochondrial volume in Tmem compared with Teff, supporting previous reports in acute infection. We demonstrate that the MPEC-specific effect was due to the higher fatty acid content and synthesis in MPEC compared with terminally differentiated Teff. In conclusion, FAS in CD4 T cells regulates the early divergence of Tmem from Teff in chronic infection.

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Myeloid-Derived Suppressor Cells: Immune-Suppressive Cells That Impair Antitumor Immunity and Are Sculpted by Their Environment [BRIEF REVIEWS]

Myeloid-derived suppressor cells (MDSC) are a diverse population of immature myeloid cells that have potent immune-suppressive activity. Studies in both mice and humans have demonstrated that MDSC accumulate in most individuals with cancer, where they promote tumor progression, inhibit antitumor immunity, and are an obstacle to many cancer immunotherapies. As a result, there has been intense interest in understanding the mechanisms and in situ conditions that regulate and sustain MDSC, and the mechanisms MDSC use to promote tumor progression. This article reviews the characterization of MDSC and how they are distinguished from neutrophils, describes the suppressive mechanisms used by MDSC to mediate their effects, and explains the role of proinflammatory mediators and the tumor microenvironment in driving MDSC accumulation, suppressive potency, and survival.

http://ift.tt/2maI7zB

Immune Cell Infiltration and Tertiary Lymphoid Structures as Determinants of Antitumor Immunity [BRIEF REVIEWS]

Limited representation of intratumoral immune cells is a major barrier to tumor control. However, simply enhancing immune responses in tumor-draining lymph nodes or through adoptive transfer may not overcome the limited ability of tumor vasculature to support effector infiltration. An alternative is to promote a sustained immune response intratumorally. This idea has gained traction with the observation that many tumors are associated with tertiary lymphoid structures (TLS), which organizationally resemble lymph nodes. These peri- and intratumoral structures are usually, but not always, associated with positive prognoses in patients. Preclinical and clinical data support a role for TLS in modulating immunity in the tumor microenvironment. However, there appear to be varied functions of TLS, potentially based on their structure or location in relation to the tumor or the origin or location of the tumor itself. Understanding more about TLS development, composition, and function may offer new therapeutic opportunities to modulate antitumor immunity.

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Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity [INNATE IMMUNITY AND INFLAMMATION]

Necroptosis is a form of cell death associated with inflammation; however, the biological consequences of chronic necroptosis are unknown. Necroptosis is mediated by RIPK1, RIPK3, and MLKL kinases but in hematopoietic cells RIPK1 has anti-inflammatory roles and functions to prevent necroptosis. Here we interrogate the consequences of chronic necroptosis on immune homeostasis by deleting Ripk1 in mouse dendritic cells. We demonstrate that deregulated necroptosis results in systemic inflammation, tissue fibrosis, and autoimmunity. We show that inflammation and autoimmunity are prevented upon expression of kinase inactive RIPK1 or deletion of RIPK3 or MLKL. We provide evidence that the inflammation is not driven by microbial ligands, but depends on the release of danger-associated molecular patterns and MyD88-dependent signaling. Importantly, although the inflammation is independent of type I IFN and the nucleic acid sensing TLRs, blocking these pathways rescues the autoimmunity. These mouse genetic studies reveal that chronic necroptosis may underlie human fibrotic and autoimmune disorders.

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Dendritic Cell-Based Cancer Vaccines [BRIEF REVIEWS]

Dendritic cells (DC) are specialized immune cells that play a critical role in promoting an immune response against Ags, which can include foreign pathogenic Ags and self-tumor Ags. DC are capable of boosting a memory T cell response but most importantly they are effective initiators of naive T cell responses. Many years of studies have focused on the use of DC vaccines against cancer to initiate and shape an antitumor-specific immune response and/or boost existing spontaneous antitumor T cell responses. In this study we give a brief overview of DC biology, function, and cellular subsets, and review the current status of the field of DC as cancer vaccines.

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Comparison of outcome measures and complication rates following three different approaches for primary total hip arthroplasty: a pragmatic randomised controlled trial

Total hip arthroplasty is one of the most commonly performed surgical procedures worldwide. There are a number of surgical approaches for total hip arthroplasty and no high-level evidence supporting one approa...

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Induction of Immunosuppressive CD8+CD25+FOXP3+ Regulatory T Cells by Suboptimal Stimulation with Staphylococcal Enterotoxin C1 [INFECTIOUS DISEASE AND HOST RESPONSE]

Superantigens (SAgs) produced by Staphylococcus aureus at high concentrations induce proliferation of T cells bearing specific TCR Vβ sequences and massive cytokinemia that cause toxic shock syndrome. However, the biological relevance of SAgs produced at very low concentrations during asymptomatic colonization or chronic infections is not understood. In this study, we demonstrate that suboptimal stimulation of human PBMCs with a low concentration (1 ng/ml) of staphylococcal enterotoxin C1, at which half-maximal T cell proliferation was observed, induced CD8⁺CD25⁺ T cells expressing markers related to regulatory T cells (Tregs), such as IFN-, IL-10, TGF-β, FOXP3, CD28, CTLA4, TNFR2, CD45RO, and HLA-DR. Importantly, these CD8⁺CD25⁺ T cells suppressed responder cell proliferation mediated in contact-dependent and soluble factor–dependent manners, involving galectin-1 and granzymes, respectively. In contrast, optimal stimulation of human PBMCs with a high concentration (1 μg/ml) of staphylococcal enterotoxin C1, at which maximal T cell proliferation was observed, also induced similar expression of markers related to Tregs, including FOXP3 in CD8⁺CD25⁺ cells, but these T cells were not functionally immunosuppressive. We further demonstrated that SAg-induced TCR Vβ–restricted and MHC class II–restricted expansion of immunosuppressive CD8⁺CD25⁺ T cells is independent of CD4⁺ T cells. Our results suggest that the concentration of SAg strongly affects the functional characteristics of activated T cells, and low concentrations of SAg produced during asymptomatic colonization or chronic S. aureus infection induce immunosuppressive CD8⁺ Tregs, potentially promoting colonization, propagation, and invasion of S. aureus in the host.

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In This Issue [IN THIS ISSUE]

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A Believers Overview of Cancer Immunosurveillance and Immunotherapy [BRIEF REVIEWS]

The field of tumor immunology has grown around the idea that one of the important roles of the immune system is to eliminate cancer. This idea was difficult to reconcile with the accepted notion that the immune system evolved to distinguish self from nonself and therefore tumors derived from self-tissues would not be recognized. Lack of appropriate animal models prevented experimental testing of cancer immunosurveillance. This changed with the realization that the immune system evolved to recognize danger and with the advent of mouse models deficient in one or more immune function, which showed predicted increases in susceptibility to cancer. Simultaneously, technical advances that enabled the study of the human immune system provided data for the existence of tumor-specific T cells and Abs and led to molecular identification of tumor Ags, fully validating the cancer immunosurveillance hypothesis. Immunotherapy designed to strengthen cancer immunosurveillance has achieved unprecedented clinical successes.

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Metformin Mediates Protection against Legionella Pneumonia through Activation of AMPK and Mitochondrial Reactive Oxygen Species [INFECTIOUS DISEASE AND HOST RESPONSE]

In Legionella pneumophila infection, macrophages play a critical role in the host defense response. Metformin, an oral drug for type 2 diabetes, is attracting attention as a new supportive therapy against a variety of diseases, such as cancer and infectious diseases. The novel mechanisms for metformin actions include modulation of the effector functions of macrophages and other host immune cells. In this study, we have examined the effects of metformin on L. pneumophila infection in vitro and in vivo. Metformin treatment suppressed growth of L. pneumophila in a time- and concentration-dependent fashion in bone marrow–derived macrophages, RAW cells (mouse), and U937 cells (human). Metformin induced phosphorylation of AMP-activated protein kinase (AMPK) in L. pneumophila–infected bone marrow–derived macrophages, and the AMPK inhibitor Compound C negated metformin-mediated growth suppression. Also, metformin induced mitochondrial reactive oxygen species but not phagosomal NADPH oxidase–derived reactive oxygen species. Metformin-mediated growth suppression was mitigated in the presence of the reactive oxygen species scavenger glutathione. In a murine L. pneumophila pneumonia model, metformin treatment improved survival of mice, which was associated with a significant reduction in bacterial number in the lung. Similar to in vitro observations, induction of AMPK phosphorylation and mitochondrial ROS was demonstrated in the infected lungs of mice treated with metformin. Finally, glutathione treatment abolished metformin effects on lung bacterial clearance. Collectively, these data suggest that metformin promotes mitochondrial ROS production and AMPK signaling and enhances the bactericidal activity of macrophages, which may contribute to improved survival in L. pneumophila pneumonia.

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Hitting the Target: How T Cells Detect and Eliminate Tumors [BRIEF REVIEWS]

The successes of antitumor immuno-based therapies and the application of next-generation sequencing to mutation profiling have produced insights into the specific targets of antitumor T cells. Mutated proteins have tremendous potential as targets for interventions using autologous T cells or engineered cell therapies and may serve as important correlates of efficacy for immunoregulatory interventions including immune checkpoint blockade. As mutated self, tumors present an exceptional case for host immunity, which has primarily evolved in response to foreign pathogens. Tumor Ags' resemblance to self may limit immune recognition, but key features appear to be the same between antipathogen and antitumor responses. Determining which targets will make efficacious Ags and which responses might be elicited therapeutically are key questions for the field. Here we discuss current knowledge on antitumor specificity, the mutations that provide immunogenic targets, and how cross-reactivity and immunodominance may contribute to variation in immune responses among tumor types.

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A Role of NKR-P1A (CD161) and Lectin-like Transcript 1 in Natural Cytotoxicity against Human Articular Chondrocytes [INNATE IMMUNITY AND INFLAMMATION]

Normal cartilage cells are susceptible to lysis by NK cells. This phenomenon may play a role in immune cartilage destruction; however, the mechanisms of chondrocyte recognition by NK cells remain poorly understood. Therefore, the aim of this study was to reveal a possible role of NKR-P1A/lectin-like transcript 1 (LLT1) interaction in NK cell–mediated cytotoxicity against normal human articular chondrocytes. Chondrocytes were isolated from articular cartilage obtained during talonavicular joint surgery. PBMC or polyclonal NK cells isolated from normal donors served as effector cells. Cell-mediated cytotoxicity against chondrocytes was evaluated by means of 18-h ⁵¹Cr-release assay. Specific mRNA expression was evaluated by classical and quantitative RT-PCR, and proteins were detected by Western blot analysis. We found that lysis of articular chondrocytes by PBMC or polyclonal NK cells was potentiated by stimulation with IL-2. Stimulation of effector cells with IL-2 downregulated mRNA expression of inhibitory NKR-P1A NK cell receptor, and blocking of NKR-P1A with specific mAbs resulted in increased chondrocyte killing. Chondrocytes constitutively expressed LLT1, a ligand of NKR-P1A. LLT1 expression by chondrocytes could be upregulated by IL-1α and TNF. Chondrocyte treatment with IL-1α resulted in their increased resistance to killing by natural cytotoxic cells. This could be reversed by blocking of NKR-P1A. These results show that susceptibility of normal articular chondrocytes to lysis by NK cells is modulated by NKR-P1A/LLT1 interactions. Thus, NKR-P1A/LLT1 interaction might provide some novel target for therapeutic interventions in the course of pathological cartilage injury.

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CCL28-Deficient Mice Have Reduced IgA Antibody-Secreting Cells and an Altered Microbiota in the Colon [MUCOSAL IMMUNOLOGY]

CCL28 induces the migration of IgA Ab-secreting cells (ASCs) via CCR10 and also displays a potent antimicrobial activity in vitro. To explore the role of CCL28 in vivo, we generated CCL28-deficient mice. The mice exhibited a significant reduction and abnormal distribution of IgA ASCs in the lamina propria of the colon. The concentrations of total and Ag-specific IgA in the fecal extracts of CCL28-deficient mice were also drastically reduced. The average amount of IgA secreted by a single IgA ASC derived from the colon was also substantially reduced in CCL28-deficient mice. Furthermore, CCL28 was found to significantly increase the average amount of IgA secreted by a single IgA ASC derived from the colon in vitro. In contrast, the generation of IgA ASCs in Peyer's and cecal patches was not significantly impaired in CCL28-deficient mice. We also found a relative increase in the Class Bacilli in the fecal extracts of CCL28-deficient mice and demonstrated a potent antimicrobial activity of CCL28 against Bacillus cereus and Enterococcus faecalis, both of which belong to Class Bacilli. Thus, CCL28 may also suppress the outgrowth of some bacterial species by its direct antimicrobial activity. Finally, CCL28-deficient mice exhibited a highly aggravated dextran sodium sulfate–induced colitis that was ameliorated by pretreatment with antibiotics. Collectively, CCL28 plays a pivotal role in the homing, distribution, and function of IgA ASCs in the colon and may also affect the intestinal microbiota through its direct antimicrobial activity.

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Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Understanding the mechanisms of CD4 memory T cell (Tmem) differentiation in malaria is critical for vaccine development. However, the metabolic regulation of CD4 Tmem differentiation is not clear, particularly in persistent infections. In this study, we investigated the role of fatty acid synthesis (FAS) in Tmem development in Plasmodium chabaudi chronic mouse malaria infection. We show that T cell–specific deletion and early pharmaceutical inhibition of acetyl CoA carboxylase 1, the rate limiting step of FAS, inhibit generation of early memory precursor effector T cells (MPEC). To compare the role of FAS during early differentiation or survival of Tmem in chronic infection, a specific inhibitor of acetyl CoA carboxylase 1, 5-(tetradecyloxy)-2-furoic acid, was administered at different times postinfection. Strikingly, the number of Tmem was only reduced when FAS was inhibited during T cell priming and not during the Tmem survival phase. FAS inhibition during priming increased effector T cell (Teff) proliferation and strongly decreased peak parasitemia, which is consistent with improved Teff function. Conversely, MPEC were decreased, in a T cell–intrinsic manner, upon early FAS inhibition in chronic, but not acute, infection. Early cure of infection also increased mitochondrial volume in Tmem compared with Teff, supporting previous reports in acute infection. We demonstrate that the MPEC-specific effect was due to the higher fatty acid content and synthesis in MPEC compared with terminally differentiated Teff. In conclusion, FAS in CD4 T cells regulates the early divergence of Tmem from Teff in chronic infection.

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Liver Simulated Allocation Modeling: Were the Predictions Accurate for Share 35?

AbstractBackgroundThe liver simulated allocation model (LSAM) can be used to study likely effects of liver transplant allocation policy changes on organ offers, acceptance, waitlist survival, and posttransplant survival. Implementation of Share 35 in June 2013 allowed for testing how well LSAM predicted actual changes.MethodsLSAM projections for 1 year of liver transplants before and after the Share 35 policy change were compared with observed data during the same period. Numbers of organs recovered, organ sharing, transplant rates, and waitlist mortality rates (per 100 waitlist years) were evaluated by LSAM and compared with observed data.ResultsCandidate, recipient, and donor characteristics in the LSAM cohorts were similar to those in the observed population before and after Share 35. LSAM correctly predicted more accepted organs and fewer discarded organs with Share 35. LSAM also predicted increased regional and national sharing, consistent with observed data, although the magnitude was overestimated. Transplant rates were correctly projected to increase and waitlist death rates to decrease.ConclusionsAlthough the absolute number of transplants was underestimated and waitlist deaths overestimated, the direction of change was consistent with observed data. LSAM correctly predicted change in discarded organs, regional and national sharing, waitlist mortality, and transplants after Share 35 implementation. Background The liver simulated allocation model (LSAM) can be used to study likely effects of liver transplant allocation policy changes on organ offers, acceptance, waitlist survival, and posttransplant survival. Implementation of Share 35 in June 2013 allowed for testing how well LSAM predicted actual changes. Methods LSAM projections for 1 year of liver transplants before and after the Share 35 policy change were compared with observed data during the same period. Numbers of organs recovered, organ sharing, transplant rates, and waitlist mortality rates (per 100 waitlist years) were evaluated by LSAM and compared with observed data. Results Candidate, recipient, and donor characteristics in the LSAM cohorts were similar to those in the observed population before and after Share 35. LSAM correctly predicted more accepted organs and fewer discarded organs with Share 35. LSAM also predicted increased regional and national sharing, consistent with observed data, although the magnitude was overestimated. Transplant rates were correctly projected to increase and waitlist death rates to decrease. Conclusions Although the absolute number of transplants was underestimated and waitlist deaths overestimated, the direction of change was consistent with observed data. LSAM correctly predicted change in discarded organs, regional and national sharing, waitlist mortality, and transplants after Share 35 implementation. Corresponding Author: W. Ray Kim, MD, Division of Gastroenterology and Hepatology, Stanford University, Alway Building, Room M211, 300 Pasteur Drive, Stanford, CA 94305, Phone: 650-725-6511; fax: 650-732-5488; wrkim@stanford.edu Authorship: Aparna Goel was responsible for research design, data analysis, interpretation of data, writing of the paper and critical revision of the manuscript. W. Ray Kim was responsible for research design, interpretation of the data, and critical revision of the manuscript for important intellectual content. Joshua Pyke was responsible for research design, data analysis, interpretation of the data and critical revision of the manuscript for important intellectual content and statistical analysis. David P. Schladt was responsible for research design and critical revision of the manuscript for important intellectual content. Bertram L. Kasiske was responsible for research design and critical revision of the manuscript for important intellectual content. Jon J. Snyder was responsible for data analysis and critical revision of the manuscript for important intellectual content and statistical analysis. John R. Lake was responsible for research design and critical revision of the manuscript for important intellectual content. Ajay K. Israni was responsible for research design and critical revision of the manuscript for important intellectual content. Disclosure: The authors have no conflicts of interest to disclose. Funding: This work was conducted under the support of the Minneapolis Medical Research Foundation, contractor for SRTR, as a deliverable under contract no. HHSH250201500009C (US Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation). As a US Government-sponsored work, there are no restrictions on its use. The views expressed herein are those of the authors and not necessarily those of the US Government. WRK was partially supported by DK 34238/9 and AKI was partially supported by R01 HS 24527. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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The Effects of Short-Term Subnormothermic Perfusion after Cold Preservation on Liver Grafts from Donors after Cardiac Death: An Ex Vivo Rat Model

AbstractBackgroundWe previously reported that short oxygenated warm perfusion before cold storage (CS) had improved the graft viability of rat livers from donors after cardiac death (DCD). In this study, we investigated the effectiveness of short-term oxygenated subnormothermic perfusion for different durations after CS in a rat DCD model.MethodsWe used an isolated perfused rat liver system. In Study 1: the grafts were retrieved from Wistar rats 30min after cardiac arrest (thoracotomy), preserved in CS for 6h, and perfused with oxygenated subnormothermic (20-25°C) Krebs-Henseleit buffer for different durations (0, 15, 30, 60, and 90min groups; n=5 in each). In Study 2: in addition to subnormothermic ex vivo liver perfusion (SELP), after 15min incubation at room temperature, the grafts were reperfused under normothermic condition for 60min as a model of liver transplantation (0, 30, 60, and 90min groups; n=5 in each).ResultsIn Study 1, portal flow, bile production and tissue adenosine triphosphate (ATP) increased with perfusion duration. In Study 2, SELP significantly improved portal flow volume (P

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Ex-situ Organ Preservation: The Temperature Paradigm

No abstract available

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Liver Simulated Allocation Modeling: Were the Predictions Accurate for Share 35?

AbstractBackgroundThe liver simulated allocation model (LSAM) can be used to study likely effects of liver transplant allocation policy changes on organ offers, acceptance, waitlist survival, and posttransplant survival. Implementation of Share 35 in June 2013 allowed for testing how well LSAM predicted actual changes.MethodsLSAM projections for 1 year of liver transplants before and after the Share 35 policy change were compared with observed data during the same period. Numbers of organs recovered, organ sharing, transplant rates, and waitlist mortality rates (per 100 waitlist years) were evaluated by LSAM and compared with observed data.ResultsCandidate, recipient, and donor characteristics in the LSAM cohorts were similar to those in the observed population before and after Share 35. LSAM correctly predicted more accepted organs and fewer discarded organs with Share 35. LSAM also predicted increased regional and national sharing, consistent with observed data, although the magnitude was overestimated. Transplant rates were correctly projected to increase and waitlist death rates to decrease.ConclusionsAlthough the absolute number of transplants was underestimated and waitlist deaths overestimated, the direction of change was consistent with observed data. LSAM correctly predicted change in discarded organs, regional and national sharing, waitlist mortality, and transplants after Share 35 implementation. Background The liver simulated allocation model (LSAM) can be used to study likely effects of liver transplant allocation policy changes on organ offers, acceptance, waitlist survival, and posttransplant survival. Implementation of Share 35 in June 2013 allowed for testing how well LSAM predicted actual changes. Methods LSAM projections for 1 year of liver transplants before and after the Share 35 policy change were compared with observed data during the same period. Numbers of organs recovered, organ sharing, transplant rates, and waitlist mortality rates (per 100 waitlist years) were evaluated by LSAM and compared with observed data. Results Candidate, recipient, and donor characteristics in the LSAM cohorts were similar to those in the observed population before and after Share 35. LSAM correctly predicted more accepted organs and fewer discarded organs with Share 35. LSAM also predicted increased regional and national sharing, consistent with observed data, although the magnitude was overestimated. Transplant rates were correctly projected to increase and waitlist death rates to decrease. Conclusions Although the absolute number of transplants was underestimated and waitlist deaths overestimated, the direction of change was consistent with observed data. LSAM correctly predicted change in discarded organs, regional and national sharing, waitlist mortality, and transplants after Share 35 implementation. Corresponding Author: W. Ray Kim, MD, Division of Gastroenterology and Hepatology, Stanford University, Alway Building, Room M211, 300 Pasteur Drive, Stanford, CA 94305, Phone: 650-725-6511; fax: 650-732-5488; wrkim@stanford.edu Authorship: Aparna Goel was responsible for research design, data analysis, interpretation of data, writing of the paper and critical revision of the manuscript. W. Ray Kim was responsible for research design, interpretation of the data, and critical revision of the manuscript for important intellectual content. Joshua Pyke was responsible for research design, data analysis, interpretation of the data and critical revision of the manuscript for important intellectual content and statistical analysis. David P. Schladt was responsible for research design and critical revision of the manuscript for important intellectual content. Bertram L. Kasiske was responsible for research design and critical revision of the manuscript for important intellectual content. Jon J. Snyder was responsible for data analysis and critical revision of the manuscript for important intellectual content and statistical analysis. John R. Lake was responsible for research design and critical revision of the manuscript for important intellectual content. Ajay K. Israni was responsible for research design and critical revision of the manuscript for important intellectual content. Disclosure: The authors have no conflicts of interest to disclose. Funding: This work was conducted under the support of the Minneapolis Medical Research Foundation, contractor for SRTR, as a deliverable under contract no. HHSH250201500009C (US Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation). As a US Government-sponsored work, there are no restrictions on its use. The views expressed herein are those of the authors and not necessarily those of the US Government. WRK was partially supported by DK 34238/9 and AKI was partially supported by R01 HS 24527. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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The Effects of Short-Term Subnormothermic Perfusion after Cold Preservation on Liver Grafts from Donors after Cardiac Death: An Ex Vivo Rat Model

AbstractBackgroundWe previously reported that short oxygenated warm perfusion before cold storage (CS) had improved the graft viability of rat livers from donors after cardiac death (DCD). In this study, we investigated the effectiveness of short-term oxygenated subnormothermic perfusion for different durations after CS in a rat DCD model.MethodsWe used an isolated perfused rat liver system. In Study 1: the grafts were retrieved from Wistar rats 30min after cardiac arrest (thoracotomy), preserved in CS for 6h, and perfused with oxygenated subnormothermic (20-25°C) Krebs-Henseleit buffer for different durations (0, 15, 30, 60, and 90min groups; n=5 in each). In Study 2: in addition to subnormothermic ex vivo liver perfusion (SELP), after 15min incubation at room temperature, the grafts were reperfused under normothermic condition for 60min as a model of liver transplantation (0, 30, 60, and 90min groups; n=5 in each).ResultsIn Study 1, portal flow, bile production and tissue adenosine triphosphate (ATP) increased with perfusion duration. In Study 2, SELP significantly improved portal flow volume (P

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Particular Role of JAK/STAT3 Signaling in Functional Control of Mesenchymal Progenitor Cells

The role of JAK/STAT3-mediated signaling pathway in the realization of the growth potential of mesenchymal precursor cells was examined in vitro. The stimulating role of JAKs and STAT3 towards proliferating activity of progenitor cells and their different role in the regulation of differentiation of the progenitor elements were demonstrated. Inhibitors of JAKs and STAT3 reduced the yield of fibroblast CFU and their mitotic activity. Blockade of JAKs accelerated and selective inactivation of STAT3 decelerated differentiation of progenitor cells.

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Activation of NK Cells in Mixed Cultures of Wharton’s Jelly Mesenchymal Stromal Cells and Peripheral Blood Lymphocytes

Mesenchymal stromal cells possess immunosuppressive properties that might be used for the therapy of inflammatory diseases of various geneses. The effects of mesenchymal stromal cells depend on their lifetime in the recipient tissues. During heterologous transplantation, mesenchymal stromal cells are eliminated by NK cells. We studied NK cell formation in mixed cultures of Wharton's jelly mesenchymal stromal cells and peripheral blood lymphocytes from an autologous donor. Lymphocytes were activated by a mitogen or IL-2. The lifetime of mesenchymal stromal cells was estimated by MTT test. Cytotoxic activity and phenotype of NK cells were evaluated by flow cytometry. It was found that activation of NK cells depended on IL-2 and was registered on day 2 of incubation with IL-2. In cultures with mitogen-activated lymphocytes, cytotoxicity was observed after 5-6 days. Cytotoxicity of NK correlated with significant decrease in CD16+ and increase in CD56+ NK and with reduction of mesenchymal stromal cell viability. Thus, the main mechanism of elimination of mesenchymal stromal cells is cytotoxicity of NK cells that depended on IL-2 production.

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Relationship between Hedgehog Signaling Pathway and Drug Resistance of Poorly Differentiated Gliomas

The effects of Hedgehog signaling inhibitor (cyclopamine) and activator (Shh) on drug resistance of U251-MG human glioma cells and human astrocyte culture to cisplatin, temozolomide, and doxorubicin were studied. Cyclopamine and Shh modified the drug resistance of U251-MG cells but not of human astrocytes. Experiments with cyclopamine, Shh, and chemical drugs can contribute to detection of the mechanisms of signaling effects on the drug resistance processes, while the experimental data can serve as one of the criteria for choosing individual chemotherapy for patients.

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Immunohistochemical Features of O6-Methylguanine-DNA Methyltransferase Expression during Ovarian Endometriosis

A comparative immunohistochemical study for the expression of O6-methylguanine-DNA methyltransferase (MGMT) was performed in tissues of the eutopic endometrium and ovarian endometriosis. The highest level of MGMT expression in eutopic endometrial tissue was observed in epitheliocyte nuclei during the proliferative phase. In regions of endometriosis the expression of MGMT in epitheliocyte nuclei was shown to increase during stages I and II, but decreased in stages III and IV. The progression of endometriosis was accompanied by a gradual increase of study parameters in the nuclei and cytoplasm of stromal cells. These changes reflect the impairment of DNA reparation, which probably serves as a stage in the development and progression of endometriosis.

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Dynamics of Distribution of Capillaries with Matrix Metalloproteinase-2 and Its Tissue Inhibitor in Rat Brain during Development of Experimental Hypertension

The capillaries containing MMP-2 and its tissue inhibitor TIMP-2 were examined in cerebral cortex and white matter obtained from intact Wistar rats (n=5) and the rats with progressing experimental renovascular hypertension (n=35). In hypertensive rats, the changes in intensity of the immunohistochemical reaction and in the density of capillaries expressing TIMP-2 significantly differed from the corresponding values in MMP-2-positive capillaries, which resulted in pronounced deviation of MMP-2/TIMP-2 index from the control level (especially in cerebral cortex) probably attesting to enhanced risk of complications in cases with arterial hypertension.

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Collagen Implant and Mononuclear Cells of Umbilical Blood Allow the Restore of Movements of Hind Limbs after Removing the Site of Spinal Cord

Replacement of the removal site of the spinal cord on a collagen implant restores the motor function of the hind limbs in rats to the level of movements in the two joints for 8 weeks. After intravenous administration of mononuclear cells of human umbilical blood, recovery accelerated, significantly improved to the level of motion in the three joints, and there is a tendency to improve further recovery of movements.

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Effect of Noopept on Dynamics of Intracellular Calcium in Neurons of Cultured Rat Hippocampal Slices

A neuroprotective and nootropic drug Noopept increased the frequency of spontaneous calcium transients in neurons of CA1 radial layer in cultured rat hippocampal slices. In contrast, the drug exerted no significant effect on intracellular calcium concentration and its dynamics in neurons of hippocampal CA1 pyramidal layer.

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Inducible NO Synthase mRNA Expression and Infiltration of Rats Myocardium with Inflammatory Cells in 2-4 Hours after Modeled Permanent Ischemia or Ischemia/Reperfusion

Expression of inducible NO-synthase mRNA and myocardial infiltration with neutrophils were studied in rats with modeled permanent ischemia and ischemia/reperfusion models. Expression of inducible NO synthase mRNA in the ischemic region increased significantly in 3, 3.5, and 4 h in modeled ischemia/reperfusion and in 3.5 and 4 h in permanent ischemia. Myocardial infiltration with neutrophils was significantly higher than in intact controls throughout the experiment without significant intergroup differences. In non-ischemic myocardium, enhanced expression of inducible NO synthase mRNA and moderate neutrophilic-lymphocytic myocardial infiltration were also observed in 3.5, and 4 h after ischemia.

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Diagnostics of Early Changes in the Immune System Due to Low Concentration of N-Nitrosamines in the Blood

The concentration of N-nitrosamines (N-nitrosodimethylamine and N-nitrosodiethylamine) was measured in blood samples from children after consumption of drinking water with high content of nitrates (main group) or water meeting health standards (reference group). N-nitrosodimethylamine level in the blood from children of the main group differed from that in the reference group by 2.6 times (0.00026±0.00012 and 0.0001±0.00092 mg/dm³, respectively; p<0.05). The specific immune response to N-nitrosodimethylamine exposure was manifested in an increase in the level of specific serum IgG (2 times higher than that in the reference group). An increase in the specific sensitivity to N-nitrosodimethylamine (by the criterion of IgG) was observed in 60.7% subjects. A correlation was found between an increase in the level of IgG to N-nitrosodimethylamine and rise in the concentration of N-nitrosodimethylamine in the blood (R² =0.35; p=0.021). Under these conditions the spontaneous and induced production of arachidonic acid metabolites (leukotrienes) increased by 2.1 times, while the expression of p53 transcription factor (responsible for oncosuppression) decreased by 1.9 times as compared to those in the reference group (p<0.05).

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Connection between Parameters of Erythron System and Myelofibrosis during Chronic Myeloleukemia, Multiply Mieloma, and Chronic Lymphatic Leukemia

Clinical and morphological investigation of myelofibrosis was performed in patients with chronic myeloid leukemia, multiple myeloma, and chronic lymphocytic leukemia by analyzing the morphometric parameters of trepan-biopsy material. The correlation between changes in the parameters of erythron system and distribution of myelofibrosis were analyzed. In patients with chronic myeloid leukemia, multiple myeloma, and chronic lymphocytic leukemia, the maximum suppression of the erythron was observed against the background of severe myelofibrosis. The degree of erythron inhibition correlated with distribution of the fibrous tissue in the bone marrow. In patients with onset of chronic phase of chronic myeloid leukemia and active phase of multiple myeloma, the total number of erythroid cells was lower than in active phase of chronic lymphocytic leukemia irrespective of the degree of myelofibrosis. Erythrocyte count and hemoglobin content in the peripheral blood were lower in patients with multiple myeloma and chronic lymphocytic leukemia in comparison with the corresponding parameters in patients with chronic myeloid leukemia irrespective of the severity of myelofibrosis.

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Cellular Mechanisms of Aortic Valve Calcification

Comparative in vitro study examined the osteogenic potential of interstitial cells of aortic valve obtained from the patients with aortic stenosis and from control recipients of orthotopic heart transplantation with intact aortic valve. The osteogenic inductors augmented mineralization of aortic valve interstitial cells (AVIC) in patients with aortic stenosis in comparison with the control level. Native AVIC culture of aortic stenosis patients demonstrated overexpression of osteopontin gene (OPN) and underexpression of osteoprotegerin gene (OPG) in comparison with control levels. In both groups, AVIC differentiation was associated with overexpression of RUNX2 and SPRY1 genes. In AVIC of aortic stenosis patients, expression of BMP2 gene was significantly greater than the control level. The study revealed an enhanced sensitivity of AVIC to osteogenic inductors in aortic stenosis patients, which indicates probable implication of OPN, OPG, and BMP2 genes in pathogenesis of aortic valve calcification.

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Algorithm of Molecular and Biological Assessment of the Mechanisms of Sensitivity to Drug Toxicity by the Example of Cyclophosphamide

Comparative study of the liver, blood, and spleen of DBA/2JSto and BALB/cJLacSto mice sensitive and resistant to acute toxicity of the cyclophosphamide allowed us to reveal basic toxicity biomarkers of this antitumor and immunosuppressive agent. Obtained results can be used for the development of an algorithm for evaluation of toxic effects of drugs and food components.

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Comparison of Morphology of Adipose Body of the Orbit and Subcutaneous Fat in Humans

We compared histological structure of the orbital and subcutaneous adipose tissue. Quantitative morphometry showed that the mean diameter of adipocytes and their volume density in the orbital adipose tissue were significantly lower than in the subcutaneous fat, while volume density of vessels and elements of the connective tissue in the orbital adipose tissue was higher. Previously known and revealed here differences in the structure of orbital and subcutaneous adipose tissue do not answer the question, whether subcutaneous adipose tissue can be used for replacement of the orbital tissue deficit.

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Experimental Modeling of Alcohol-Induced Liver Cirrhosis in Rats

An experimental model of alcohol-induced liver cirrhosis in white outbred rats was developed: intragastric administration of 40% ethanol (3 g/kg) every other day for 3 weeks and simultaneous intraperitoneal administration of 1% of N-nitrozodimethylamine (5 mg/kg) for 4 consecutive days of each week.

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The Role of Succinate in Regulation of Immediate HIF-1α Expression in Hypoxia

Hypoxia-induced immediate expression of transcription factor HIF-1α in the brain cortex is regulated by succinate produced in both the tricarbonic acid cycle and GABA shunt reactions and is induced by succinate-containing drugs. These facts prove the existence of succinate-dependent signalling regulation involved in immediate and delayed molecular adaptation and increased body resistance to oxygen deficiency, where succinate acts as a signal molecule. The intensity of this process differs in animals with low and high resistance to hypoxia.

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Inactivation of M111 Protein Gene Modifies Streptococcus Pyogenes Interactions with Mouse Macrophages In Vitro

Immunomodulatory properties of S. pyogenes protein M111 were studied on the model of Gurov strain and its isogenic mutant not expressing M protein. Mouse resident peritoneal macrophages were incubated with bacteria and generation of nitroxide and superoxide anions and production of IL-6, IL-10, and IL-17 were evaluated. Protein M111 modified macrophage response: it exhibited antiphagocytic activity, prevented ROS formation, and stimulated the production of anti-inflammatory cytokine IL-10. The results suggested that this protein could serve in the bacteria as a factor suppressing the host defense forces and promoting the realization of the strategy beneficial for pathogens — escape from the host immune defense.

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15-year experience of laparoscopic single anastomosis (mini-)gastric bypass: comparison with other bariatric procedures

Abstract

Background

Laparoscopic single anastomosis (mini-)gastric bypass (LSAGB) has been validated as a safe and effective treatment for morbid obesity. However, data of the long-term outcome remain lacking.

Methods

Between October 2001 and December 2015, 1731 morbidly obese patients who received LSAGB as primary bariatric procedure at the Min-Sheng General Hospital were recruited. Surgical outcome, weight loss, resolution of comorbidities, and late complications were followed, then compared with groups of laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG). All data derived from a prospective bariatric database and a retrospective analysis were conducted.

Results

The average patient age was 33.8 ± 10.4 years with a mean body mass index (BMI) of 40.4 ± 7.7 kg/m². Of them, 70.0% were female while 30.0% were male. Mean operating time, intraoperative blood, and hospital stay of LSAGB were 124.6 ± 38.8 min, 39.5 ± 38.7 ml, and 5.0 ± 4.1 days, respectively. The 30-day post-operative major complication occurred in 30 (1.7%) of LSAGB patients, 16 (2.0%) of LRYGB, and 15 (1.4%) of LSG patients. The follow-up rates at 1, 5, and 10 years were 89.3, 52.1, and 43.6%, respectively. At postoperative 1, 5, and 10 years, the mean percentage of weight loss (%WL) of LSAGB patients were 32.7, 32.2, and 29.1%, and mean BMI became 27, 26.9, and 27 kg/m², respectively. The LSAGB had a higher weight loss than LRYGB and LSG at 2–6 years after surgery. LSG had a lower remission rate in dyslipidemia comparing to LSAGB and LRYGB. The overall revision rate of LSAGB is 4.0% (70/1731) which was lower than the 5.1% in LRYGB and 5.2% in the LSG.

Conclusion

LSAGB is an effective procedure for treating morbid obesity and metabolic disorders, which results in sustained weight loss and a high resolution of comorbidities.

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Update regarding the society of American Gastrointestinal and Endoscopic Surgeons (SAGES) grant distribution and impact on recipient’s academic career

Abstract

Background

Small seed grants strongly impact academic careers, result in future funding, and lead to increased involvement in surgical societies. We hypothesize that, in accordance with the SAGES Research and Career Development committee mission, there has been a shift in grant support from senior faculty to residents and junior faculty. We hypothesize that these junior physician-researchers are subsequently remaining involved with SAGES and advancing within their academic institutions.

Methods

All current and previous SAGES grant recipients were surveyed through Survey Monkey™. Questions included current academic status and status at time of grant, ensuing funding, publication and presentation of grant, and impact on career. Results were verified through a Medline query. SAGES database was examined for involvement within the society. Respondent data were compared to 2009 data.

Results

One hundred and ninety four grants were awarded to 167 recipients. Of those, 75 investigators responded for a response rate 44.9%. 32% were trainees, 43% assistant professors, 16% associate professors, 3% full professors, 3% professors with tenure, and 3% in private practice. This is a shift from 2009 data with a considerable increase in funding of trainees by 19% and assistant professors by 10% and a decrease in funding of associate professors by 5% and professors by 10%. 41% of responders who were awarded the grant as assistant or associate professors had advanced to full professor and 99% were currently in academic medicine. Eighty-two percent indicated that they had completed their project and 93% believed that the award helped their career. All responders remained active in SAGES.

Conclusion

SAGES has chosen to reallocate an increased percentage of grant money to more junior faculty members and residents. It appears that these grants may play a role in keeping recipients interested in the academic surgical realm and involved in the society while simultaneously helping them advance in faculty rank.

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Efficacy of innovative polyglycolic acid sheet device delivery station system: a randomized prospective study

Abstract

Background

Although there have been several reports of treating large post-endoscopic submucosal dissection (ESD) ulcers by covering them with a polyglycolic acid sheet (PGAs), this approach presents problems regarding PGAs delivery. This study assessed the usefulness of a device delivery station system (DDSS) to evaluate the appropriate and rapid PGAs coating method with DDSS.

Methods

Thirty-nine of 41 patients who were diagnosed with early gastric cancer over 20 mm in diameter and pathologically diagnosed with well-differentiated adenocarcinoma were randomly allocated to the following two groups according to delivery method: the conventional PGAs delivery group (C group) (n = 19) and the new DDSS group (DDSS group) (n = 20). The primary outcome was the coating area per minute in the C group and DDSS group (cm²/min).

Results

There were significant differences in the coating time (min), with values of 34.1 (15.0–60.7) vs. 16.85 (11.5–27.2) min for the C group and DDSS group, respectively (p = 0.001). There was also a significant difference in coating area per minute, with values of 0.261 (0.02–1.00) and 0.96 (0.173–2.06) cm²/min for the C group and DDSS group, respectively (p = 0.001). There were four cases of post-ESD bleeding (1–7 days after ESD) in the C group compared with 0 in the DDSS group, which represented a significant difference (p = 0.030).

Conclusions

The DDSS was very useful for rapidly delivering and tightly attaching a PGAs to control post-ESD bleeding.

Trial registration

University Hospital Medical Network (UMIN) 000026377.

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Development of a train-to-proficiency curriculum for the technical skills component of the fundamentals of endoscopic surgery exam

Abstract

Background

The demonstration of competency in endoscopy is required prior to obtaining American Board of Surgery Certification. To demonstrate competency, the resident must pass a national high-stakes cognitive test and a technical skills exam on a virtual reality simulator. The purpose of this preliminary study was to design a proficiency-based endoscopy simulation curriculum to meet this competency requirement.

Methods

This is a mixed methods prospective cohort study at a single academic medical institution. Prior to taking the national exam, surgery residents were required to participate in a skills lab and demonstrate proficiency on 10 simulation tasks. Proficiency was based on time and percent of objects targeted/mucosa seen. Simulation practice time, number of task repetitions to proficiency, and prior endoscopic experience were recorded. Resident's self-reported confidence scores in endoscopic skills prior to and following simulation lab training were obtained.

Results

From January 1, 2016 through August 1, 2017, 20 surgical residents (8 PGY2, 8 PGY3, 4 PGY4) completed both a faculty-supervised endoscopy skills lab and independent learning with train-to-proficiency simulation tasks. Median overall simulator time per resident was 306 min (IQR: 247–405 min). Median overall time to proficiency in all tasks was 235 min (IQR: 208–283 min). The median time to proficiency decreased with increasing PGY status (r = 0.4, P = 0.05). There was no correlation between prior real-time endoscopic experience and time to proficiency. Reported confidence in endoscopic skills increased significantly from mean of 5.75 prior to 7.30 following the faculty-supervised endoscopy skills lab (P = 0.0002). All 20 residents passed the national exam.

Conclusions

In this preliminary study, a train-to-proficiency curriculum in endoscopy improved surgical resident's confidence in their endoscopic skills and 100% of residents passed the FES technical skills test on their first attempt. Our findings also indicate that uniform proficiency was not achieved by real-time experience alone.

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An observational study of the timing of surgery, use of laparoscopy and outcomes for acute cholecystitis in the USA and UK

Abstract

Background

Evidence supports early laparoscopic cholecystectomy for acute cholecystitis. Differences in treatment patterns between the USA and UK, associated outcomes and resource utilization are not well understood.

Methods

In this retrospective, observational study using national administrative data, emergency patients admitted with acute cholecystitis were identified in England (Hospital Episode Statistics 1998–2012) and USA (National Inpatient Sample 1998–2011). Proportions of patients who underwent emergency cholecystectomy, utilization of laparoscopy and associated outcomes including length of stay (LOS) and complications were compared. The effect of delayed treatment on subsequent readmissions was evaluated for England.

Results

Patients with a diagnosis of acute cholecystitis totaled 1,191,331 in the USA vs. 288 907 in England. Emergency cholecystectomy was performed in 628,395 (52.7% USA) and 45,299 (15.7% England) over the time period. Laparoscopy was more common in the USA (82.8 vs. 37.9%; p < 0.001). Pre-treatment (1 vs. 2 days; p < 0.001) and total ( 4 vs. 7 days; p < 0.001) LOS was lower in the USA. Overall incidence of bile duct injury was higher in England than the USA (0.83 vs. 0.43%; p < 0.001), but was no different following laparoscopic surgery (0.1%). In England, 40.5% of patients without an immediate cholecystectomy were subsequently readmitted with cholecystitis. An additional 14.5% were admitted for other biliary complications, amounting to 2.7 readmissions per patient in the year following primary admission.

Conclusion

This study highlights management practices for acute cholecystitis in the USA and England. Despite best evidence, index admission laparoscopic cholecystectomy is performed less in England, which significantly impacts subsequent healthcare utilization.

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Antituberculosis activity, phytochemical identification of Costus speciosus (J. Koenig) Sm., Cymbopogon citratus (DC. Ex Nees) Stapf., and Tabernaemontana coronaria (L.) Willd. and their effects on the growth kinetics and cellular integrity of Mycobacterium tuberculosis H37Rv

Costus speciosus, Cymbopogon citratus, and Tabernaemontana coronaria are herbal plants traditionally used as remedies for symptoms of tuberculosis (TB) including cough. The aims of the present study were to evalu...

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Galega officinalis extract regulate the diabetes mellitus related violations of proliferation, functions and apoptosis of leukocytes

An impaired leukocytes function is the factor causing the susceptibility of patients with diabetes mellitus to infections. The outmost importance for the understanding of the immunological processes involved i...

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Acute effect of Clitoria ternatea flower beverage on glycemic response and antioxidant capacity in healthy subjects: a randomized crossover trial

Clitoria ternatea L., a natural food-colorant containing anthocyanin, demonstrated antioxidant and antihyperglycemic activity. The aim of this study was to determine the effects of Clitoria ternatea flower extrac...

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Acupuncture May Reduce Treatment-Related Joint Pain for Breast Cancer Patients

Joint pain caused by aromatase inhibitors in postmenopausal women with breast cancer can cause some women to stop taking the drugs. Reducing their symptoms may translate into better adherence to therapy.

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Benign prostatic hyperplasia surgical scoring (BPHSS): an novel scoring system for the perioperative outcomes of holmium laser enucleation of the prostate

Abstract

To develop a standardized scoring system, the BPH surgical scoring (BPHSS) system, to quantify the ability to predict the perioperative outcomes resulting from an enlarged prostate. There are two parts included in this study: the retrospective observational study (875 patients treated with holmium laser enucleation of the prostate, HoLEP) and the prospective observational study (111 patient underwent HoLEP). All the outcome data included the following: the basic patient preoperative characteristics, operation time (OT), pre- and post- surgery hemoglobin decrease, Na⁺ variation, hospital stay duration, duration of bladder irrigation, catheterization time, and hospitalization time. The BPHSS, consisting of prostatic volume (PV), prostate-specific antigen (PSA), bladder stones, intravesical prostatic protrusion (IPP), and metabolic syndrome (MetS), was observed regarding the perioperative outcomes. In the retrospective study, patients in high BPHSS group (6–8 points) showed significant increase in the OT (74.61, 95%CI = 16.98–327.84, P < 0.001), hemochrome reduction (416.50, 95%CI = 35.48–4889.88, P < 0.001), hospital stay (1.80, 95%CI = 1.35–2.41, P < 0.001), and bladder irrigation duration (4.04, 95%CI = 1.35–12.10, P = 0.013) compared with the low BPHSS group (0–2 points). In the prospective study, there also existed significant differences between the three scoring grades (P < 0.01) in OT, hemochrome decrease, and the hospital stay. The BPHSS is suitable to predict the perioperative outcomes in patients undergoing HoLEP. It may help urologist to prepare more before surgery to treat the enlarged prostates. Further studies are needed to validate this scoring system in BPH patients in multiple centers.

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Improvements to U.S. Childhood Mortality Rates Have Lagged behind Other Wealthy Nations for the Past 50 Years, New Study Finds

In a new study of childhood mortality rates between 1961 and 2010 in the United States and 19 economically similar countries, researchers report that while there's been overall improvement among all the countries, the U.S. has been slowest to improve.

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Diagnosis and Treatment of Gorham-Stout Disease in Maxillofacial Regions

Purpose: This study was aimed to investigate the clinical features, imaging examination, and treatment of the patients with Gorham-Stout disease (GSD) in maxillofacial region, so as to improve the understanding of GSD. Methods: The medical records of the patients with GSD who were referred to Shanghai Ninth People's Hospital from January 2010 to May 2016 were reviewed. Their ages, lesion location, imaging results, laboratory examination results, treatment, and therapeutic effects were analyzed. Results: A total of 4 cases were included (males 2, females 2). The average onset age was 40 years. GSD attacked the mandible in 2 cases; mandible and temporal bone in 1 case; and mandible, temporal bone, and zygoma in 1 case. All cases were examined by computed tomography (CT), which showed bone resorption and atrophy of soft tissue in involved region. Four patients were given alendronate for treatment. All of them had no significant signs of progress after treatment. Conclusions: GSD can affect one single bone or multiple bones in maxillofacial region. The diagnosis mainly depends on the imaging examinations. Enhanced CT or magnetic resonance imaging is advocated for differential diagnosis of this disease. Alendronate was used with apparent good effect in these patients. Address correspondence and reprint requests to Dr. Baoli Wang, MD, Attending physician, Department of Oral & Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P. R. China; E-mail: baoliwang123456@163.com Received 10 July, 2017 Accepted 1 September, 2017 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Unit Advancement Flap for Lower Lip Reconstruction

Background: Lower lip reconstruction requires consideration of esthetic and functional outcome in selecting a surgical procedure, and reconstruction with local tissue is useful. The authors reconstructed full-thickness defects with a unit advancement flap. Methods: Reconstruction was performed using this method in 4 patients with lower lip squamous cell carcinoma in whom tumor resection with preservation of the mouth angle was possible. The lower lip resection width was 30 to 45 mm, accounting for 50% to 68% of the entire width of the lower lip. The flap was prepared by lateral extension from above the mental unit and matched with the potential wrinkle line of the lower lip in order to design a unit morphology surrounded by the anterior margin of the depressor labii inferioris muscle. It was elevated as a full-thickness flap composed of the orbicularis oris muscle, skin, and mucosa of the residual lower lip from the bilateral sides, and advanced to the defect. Flap transfer was adjusted by small triangular resection of the skin on the lateral side of the mental unit. Results: The postoperative scar was inconspicuous in all patients and there was no impairment of the mouth opening–closing or articulation functions. Conclusions: This was a relatively simple surgical procedure. A blood supply of the flap was stable, and continuity of the orbicularis oris muscle was reconstructed by transferred the residual lower lip advancement flap from the bilateral sides. The postoperative mouth opening–closing function was sufficient, and dentures could be placed from an early phase in elderly patients. The postoperative scar was consistent with the lip unit morphology, being esthetically superior. This procedure may be applicable for reconstruction of defects approximately 1/3 to 2/3 the width of the lower lip where the mouth angle is preserved. Address correspondence and reprint requests to Akihiro Ogino, MD, PhD, Department of Plastic and Reconstructive Surgery, Toho University Omori Medical Center, 6-11-1, Omori-nishi, Ota-ku, Tokyo 143-8541, Japan; E-mail: akihiro.ogino@med.toho-u.ac.jp Received 25 August, 2017 Accepted 23 September, 2017 This article is presented at the 59th Annual Meeting of the Japanese Society of Plastic and Reconstructive Surgery. The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Treatment of Severe Maxillary Hypoplasia With Combined Orthodontics and Distraction Osteogenesis

Distraction osteogenesis (DO) is a technique that allows the generation of new bone in a gap between 2 vascularized bone surfaces in response to the application of graduated tensile stress across the bone gap. Distraction osteogenesis has become a routine treatment of choice to correct skeletal deformities and severe bone defects in the craniofacial complex over the past decade. Distraction osteogenesis has been successfully chosen in lengthening the maxilla and the mandible; in the maxilla and recently in the mandible, the jawbones have been distracted and widened transversely to relieve severe anterior dental crowding and transverse discrepancies between the dental arches. Distraction osteogenesis for maxillary advancement started in 1993 and is now widely used, especially in patients with skeletal Class III malocclusion caused by maxillary hypoplasia. The aim of this study was to present the efficiency of combined orthodontic and DO in the severe maxillary hypoplasia. A 35-year-old Italian man presented to our clinical practice with the chief complaint of esthetic and functionally problems because of skeletal Class III malocclusion with anterior crossbite. Considering that the severity of the skeletal discrepancy is remarkable but compensated by the DO potential, the combined orthodontic and DO treatment was considered adequate, like less invasive and equally effective. It was obtained a good alignment with the upper and lower arch dental alveolar maxillary advancement that allowed to correct the sagittal relationships. The patient was satisfied for the treatment results and had considerable improvement in his self-esteem. Address correspondence and reprint requests to Alessandra Lucchese, DDS, MS, Via Olgettina, 48, 20132 Milan, Italy; E-mail: lcclsn@unife.it Received 13 August, 2017 Accepted 28 September, 2017 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Effect of Surgery First Orthognathic Approach on the Temporomandibular Joint: A Clinical Evaluation

Introduction: Correction of severe malocclusions with skeletal discrepancies requires orthodontic treatment in combination with orthognathic surgery. Even though conventional orthognathic surgery (COS) is a common and well-accepted approach its influence on the signs and symptoms of temporomandibular disorders (TMDs) is still debated. Recently with the introduction of surgery first approach, a different timing for the management of dentoskeletal imbalances has been proposed. The present study is aimed at assessing the relationship between surgery first approach and temporomandibular joint (TMJ) disorders. Methods: The study sample consisted of 24 patients who were selected to be treated with surgery first approach. Clinical follow-ups after surgery were performed every week for the first month, at 3 months, 6 months, and at 1 year. A radiological follow-up was performed at 1 week and at 1 year after the operation with a panorex and a latero-lateral teleradiograph. To assess the effect of surgery first approach on the TMDs signs and symptoms, a clinical assessment was performed 4 days before surgery (T1), 6 months after surgery (T2), and 1 year postoperatively (T3). Results: The results of the authors' study show that pain assessment revealed a general improvement of this symptom in correspondence to TMJ and masticatory muscles except in the masseter and neck region. Also joint noises, TMJ functioning, migraine, and headache underwent a considerable improvement. Conclusion: Surgery first approach is an innovative orthognathic procedure and, by undergoing surgery first approach, patients with pre-existing TMJ dysfunction may experience a significant improvement or even resolution of the TMDs signs and symptoms. Address correspondence and reprint requests to Dr Paolo De Angelis, DDS, Department of Oral and Maxillo-Facial Surgery, Catholic University of the Sacred Heart Medical School, Corso Vittorio Emanuele 28, 63100 Ascoli Piceno, Italy; E-mail: dr.paolodeangelis@gmail.com Received 10 July, 2017 Accepted 30 September, 2017 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Comparison of Tongue-in-Groove and Columellar Strut on Rotation and Projection in Droopy Nasal Tip: Contribution of a Cap Graft

Underrotation of the nasal tip with narrow nasolabial angle is a common nasal deformity that leads to a long nose appearance, named drooping nose. In these patients, there are various techniques described to correct droopy tip and to achieve a desirable nasal tip rotation such as lateral crural steal, lateral crural overlay, tongue-ingroove, columellar strut graft, tip rotation sutures, cephalic trimming, and others. In this study, the effects of tongue-in-groove (TIG) and columellar strut graft (CS) and the contribution of cap graft on nasal tip rotation and projection were evaluated. Twenty-eight consecutive patients who underwent open approach rhinoplasty by the same senior author (ULD) between January 2015 and December 2016 with the diagnosis of septonasal deformity and droopy nasal tip were included. In 9 of these patients nasal tip was constructed with strut graft, in 6 patients with both strut and cap grafts, in 6 patients with TIG technique and in 7 patients with both TIG and cap graft. Standardized right lateral images were taken preoperatively and 6 months postoperatively to use for further assessments. The nasal tip rotation was evaluated by measuring nasolabial angle (NLA) and the nasal projection (NP) was evaluated by using the Goode method. Finally, the postoperative values of NLA and NP at the 6th month were compared with preoperative recorded values in between groups. Each group showed increase at nasal projection; however, significance was present only in CS graft and TIG groups (P=0.011 and P=0.027 relatively). Each 4 groups showed significant increase in nasal tip rotation. In addition, the comparison of percent changes between preoperative and postoperative NP and NLA revealed no difference (P=0.56 and P=0.431 relatively). In conclusion, the authors argued that TIG and CS graft techniques are both reliable methods to correct droopy nasal tip and using additional cap graft over dome area when required is safe and useful. Address correspondence and reprint requests to Uygar Levent Demir, MD, Associate Professor, Department of Otolaryngology, Uludag University Medical School, 16059 Gorukle, Nilufer—Bursa, Turkey, 16059; E-mail: uygardemir@hotmail.com Received 20 July, 2017 Accepted 1 October, 2017 This study was approved by the ethical committee of Medical School. The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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