Systemische Therapien der Psoriasis und Psoriasisarthritis

Zusammenfassung

Die Psoriasis vulgaris ist eine der häufigsten chronischen Hauterkrankungen. Über 25 % der betroffenen Personen benötigen aufgrund der massiven Ausprägung der Symptome und/oder einer deutlichen Einschränkung der Lebensqualität eine wirksame systemische Therapie. Dank intensiverer Forschung und erfolgreicher Zusammenarbeit zwischen akademischen und industriellen Einrichtungen haben sich unsere Behandlungsmöglichkeiten für die Psoriasis in den letzten Jahren enorm erweitert. Insbesondere ermöglichen uns zielgerichtete Therapien eine personalisierte Medizin. Diese Übersichtsarbeit beschreibt das Spektrum der systemischen Therapien bei Psoriasis und Psoriasisarthritis und thematisiert Wirksamkeit, Sicherheit und Besonderheiten der einzelnen Substanzen.

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Pustulöse Psoriasis

Zusammenfassung

Eine Reihe pustulöser Hauterkrankungen teilen klinische, pathogenetische und epidemiologische Aspekte mit der Psoriasis vulgaris, und ihre Einordung als eigene klinische Entitäten oder Unterformen der Psoriasis ist weiterhin umstritten, was sich auch in der Vielzahl ihrer Bezeichnungen widerspiegelt. Hierzu gehören die generalisierte pustulöse Psoriasis mit ihren Sonderformen, die Acrodermatitis continua suppurativa, die akute Pustulosis palmoplantaris, die Psoriasis pustulosa palmoplantaris sowie pustulöse Varianten der vorwiegend durch TNF-Blocker getriggerten paradoxen psoriasiformen Dermatitis. In diesem Beitrag werden Erkenntnisse zu Epidemiologie, klinischem Bild, Pathogenese, Genetik und Therapie dieser pustulösen Hauterkrankungen dargestellt.

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Multiple, schwärzliche, brennende Papeln an beiden Fußsohlen einer 20-jährigen Patientin

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The impact of frailty syndrome and risk scores on emergency cholecystectomy patients

Abstract

Purpose

Cholecystectomy, which is one of the most common surgical procedures, is also performed in the emergency setting. A number of risk scores have been introduced in recent studies; moreover, over the last few years literature has focused on surgical patients with frailty syndrome. The aim of the present study is to evaluate whether frailty syndrome and the risk scores are correlated with morbidity, post-operative hospital stay and the ICU admission rate following emergency cholecystectomy.

Methods

Eighty-five consecutive patients of >65 years of age who underwent cholecystectomy were selected from 2306 emergency procedures for inclusion in the present study. The patients were assessed for frailty syndrome and their scores were calculated on the basis of chart review. Univariate analyses were performed to compare severe frailty patients to intermediate frailty and robust patients. ROC and logistic regression analyses were performed with the end-points of morbidity, hospital stay and ICU admission.

Results

In addition to having worse ASA, inflammatory and risk values than robust patients, frailty syndrome patients also had higher rates of morbidity and ICU admission and longer hospitalization periods. A logistic regression analysis showed that the P-Possum was independently correlated with morbidity. Frailty and open surgery were independently correlated with longer hospitalization, whereas ICU admission was correlated with worse ASA and P-Possum values.

Conclusions

Frailty syndrome significantly impacts the length of hospitalization in patients undergoing emergency cholecystectomy. Although the ORs were limited, the P-Possum value was independently associated with the outcome.

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Are family medicine residents physically active? And do they counsel their chronically ill patients about physical activity? A cross-sectional study among residents of the family medicine joint program, eastern province, Saudi Arabia

2016-05-30T09-42-12Z
Source: International Journal of Medical Science and Public Health
Malak Audah Al Shammari.
Background: Physical activity is a major factor in both preventing chronic illness and in controlling it in already diseased patients. It has been established that a physically active physician may be more likely to counsel patients about the benefits of physical activity and patients tend to adhere to exercise regimens when advised by a physician they think of as a role model. Objective: To determine the amount of physical activity the family medicines residents adhere to and to determine if family medicine residents practice what they counsel to their patients regarding physical activity. Materials and Methods: All family medicine residents in all of the training levels were recruited to take part in the International Physical Activity Questionnaire (IPAQ) survey voluntarily. Levels of physical activity were divided into three categories: low, moderate, and high, according to the guidelines of data processing of the IPAQ. Section two of the survey assessed whether residents in fact counseled patients with chronic prevalent diseases (coronary artery disease, diabetes mellitus, obesity, etc.) about physical activity and the ranking of the most important health determinants according to them. Result: The sample size consisted of 80 participants, all residents of the program from R1 to R4. We have found that the majority >70% of them had low level of physical activity. The majority (96%) did counsel their patients about physical activity especially when the patient had diabetes. Conclusion: Although residents of the joint family medicine program of the eastern province of the Kingdom of Saudi Arabia were not, self-reportedly, physically active themselves, they were active in patient counseling regarding the importance of physical activity in achieving global health and well-being.


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Treatment of plantar fasciitis with dexamethasone with lidocaine hydrochloride

2016-05-30T09-42-12Z
Source: International Journal of Medical Science and Public Health
Sumit Kalra.
Background: Plantar heel pain is a commonly occurring foot complaint. Various electrotherapy modalities are frequently utilized as a treatment. Objective: To determine the effects of a combination of dexamethasone with lidocaine hydrochloride for the treatment of patients with plantar fasciitis (PF). Materials and Methods: A total of 40 patients suffering from PF were divided into two groups; Group A received iontophoresis with distilled water along with 4 mg/mL dexamethasone and 2 cm3 of lidocaine hydrochloride (4% lidocaine hydrochloride), and Group B received iontophoresis with distilled water. Both groups received stretching of plantar fascia and calf muscles, followed by ultrasound for 5 min. Treatment for each patient was for a period of 2 weeks with 3 sessions per week. Result: Group A showed significant decrease in symptoms of PF posttreatment. Conclusion: Iontophoresis with lidocaine hydrochloride showed better results in decreasing symptoms of PF as compared to iontophoresis with distilled water only.


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Foreign body inhalation in children: clinical presentations and x-ray chest findings

2016-05-30T09-42-12Z
Source: International Journal of Medical Science and Public Health
Nisar Hussain Dar, Suhail Amin Patigaroo, Tahir Hussain.
Background: Foreign body aspiration (FBA) is a medical emergency in children. Delay in diagnosis and treatment can cause complications and even deaths are reported. Objective: The aim of this study was to find out clinical features and x-ray findings in patients with FBA. Materials and Methods: A retrospective analysis was done on all patients less than 15 years of age with the discharge diagnosis of FBA from 2011 to 2014 at SMHS Hospital in Kashmir province. Results: Out of 140 patients with FBA, 87 (62%) were male. The mean age was 48 months. The most common clinical findings were history of chocking (77%), decreased breath sounds (42%), wheezing (38%), cough (20%), respiratory distress (15.5%), and fever. CXR was normal in 46% of patients. Air trapping (emphysema) was the most common radiological finding (29.5%) followed by atelectasis (14%) and consolidations (9.2%) and opaque foreign bodies (5.7%). Gram seeds (pulses) were the commonest foreign body (40%). Bronchoscopic removal of foreign body was done successfully in 133 patients (95%). Conclusion: Although FBA in children diagnosed by history, physical examination and radiographic findings, but this finding may be misleading. Negative X-ray chest should not exclude the diagnosis of FBA in children especially with a strong history of FBA. Early bronchoscopic examination will be safe and lifesaving.


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Toward primordial prevention of childhood obesity—predictors and parameters of childhood obesity

2016-05-30T09-42-12Z
Source: International Journal of Medical Science and Public Health
Anil Kumar Paruchuri, Mohammed Faisal, Samiksha Singh.
Background: Overweight children may become overweight adults, particularly if obesity is present in adolescence. There are very much chances of children to become obese if they have obese parents. Parents can contribute both the genes and eating environment for their children and familial patterns of adiposity because of gene-environment interactions. Objective: To find out associations between parental and child overweight and obesity. Materials and Methods: This was a cross-sectional study done in the schools of a city of South India. Children between the ages of 1215 years were included in the study. During the enrollment, study objectives and methodology were explained to each participant, and written consent was taken. Result: There was a poor but statistically significant correlation between childs BMI and fathers BMI (r = 0.226, p = 0.000). Similarly, the correlation between childs BMI and mothers BMI was poor but statistically significant (r = 0.252, p = 0.000). Poor but statistically significant correlation was also observed between BMI and waist-to-height ratio (r = 0.189, p = 0.000) and waisthip ratio (r = 0.127, p = 0.000) of children. Conclusion: The results of this study may assist to identify those children who have more chances to become overweight and obese in adulthood. Parental overweight or obesity is one of the important factors for the development of obesity in the children. Strategies for prevention of overweight and targeted interventions for prevention of the progression of overweight to obesity are required in school-aged children.


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An assessment of the functioning of the Village Health Sanitation and Nutrition Committee in the rural areas of Kamrup district, Assam

2016-05-30T09-42-12Z
Source: International Journal of Medical Science and Public Health
Manjit Das, Jutika Ojah, Rupali Baruah.
Background: The Village Health Sanitation and Nutrition Committee (VHSNC) is a first step toward decentralized planning and community empowerment approach. Objective: To assess the constitution of the VHSNCs, to assess the activities undertaken by them, and to assess the funding and utilization status of the VHSNCs. Materials and Methods: Study designCommunity-based cross-sectional study. Study placeThree blocks of Kamrup district viz, Boko-Bongaon, Hajo, and Sualkuchi. Study periodJuly 1 to October 31, 2015. Study populationThe functionaries of VHSNCs present during visit and the records maintained. Sample sizeTotal 78 VHSNCs were assessed in this study. Sample collection techniqueOut of the total 12 blocks, 3 blocks were selected. Sub-centers (50%) under these three blocks selected and two villages from each SC selected. All the 78 VHSNCs operating in these villages were included in this study. Data collection toolPredesigned and pretested schedule containing both open- and closed-ended questions. Primary data were collected by interview method and secondary data obtained from various records. Results: 55.12% VHSNCs had 11 or more members. Panchayati Raj Institution (PRI) member, Auxiliary Nurse Midwife (ANM), Accredited Social Health Activist (ASHA), Anganwadi Worker (AWW), and Medical officer were members in all of the committees. Only 16.67% of the VHSNCs conducted 1012 meetings in 1 year. 16.67% VHSNCs had maintained and updated the untied fund register. Formation of new committee and new members (96.15%), ASHAs incentive (94.87%), and Anganwadi Center (AWC) repairing (88.76%) were commonly discussed topics in monthly meetings. A majority of 67.93% VHSNCs utilized more than 90% of the funds allotted to them. Conclusion: It was observed that although VHSNCs have been constituted in all of the revenue villages in the study area, there are several lacunae in their organization.


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Infant feeding beliefs and practices among tribal mothers in Nashik district, Maharashtra

2016-05-30T09-42-12Z
Source: International Journal of Medical Science and Public Health
Reshma R Garje, Sunil Kumar Thitame, Konduri V Somasundaram, Laxmi Gautam, Mahesh S Gite.
Background: Breast milk is the safest and nutritious food for infant. Colostrum feeding provides nutrients and immunity to the newborn. Early initiations of breastfeeding and exclusive breastfeeding practices are essential for both infants and mothers. Even though breastfeeding is almost universal in India, culture and tradition exhibit great impact in breastfeeding practice. Objective: To study the beliefs and practice about breastfeeding and identify the impact of selected sociodemographic factors on the infant feeding practices in rural ethnic mothers. Materials and Methods: A cross-sectional study was conducted from December 2014 to April 2015 among 400 rural ethnic mothers having infants and attending Mobile Medical Unit under NRHM in Nasik, Maharashtra. Interview was done by using predesigned, semi-structured questionnaire. Result: The average age of respondents was 22.47 ± 2.58 years; most of them (67.3%) were from the age group 2125 years. Average age at marriage was 17.5 ± 0.81 years, and average age at first pregnancy was 19.04 ± 0.77 years. Almost half (49.3%) of the respondents got married below the age of 18 years, and 75% of them were pregnant with their first baby when they were still at their teenage. Over 55% of the respondent belonged to scheduled tribes category. Majority of the women (42.3%) revealed less than 4 years of schooling, while 13.8% of them never attended school. Majority (61.3%) of the respondents were daily wage laborers. Colostrum feeding was observed in 88.8% study subjects, prelacteal feeding in 17.5%, early initiation of breastfeeding in 70.1%, and exclusive breastfeeding in 83.8%. Conclusion: Even though knowledge and practice of breastfeeding was better, early marriage and early conception were concerns that require attention.


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Local administration of platelet-derived growth factor B (PDGFB) improves follicular development and ovarian angiogenesis in a rat model of Polycystic Ovary Syndrome

Publication date: Available online 30 May 2016
Source:Molecular and Cellular Endocrinology
Author(s): Mariana Di Pietro, Leopoldina Scotti, Griselda Irusta, Marta Tesone, Fernanda Parborell, Dalhia Abramovich
Alterations in ovarian angiogenesis are common features in Polycystic Ovary Syndrome (PCOS) patients; the most studied of these alterations is the increase in vascular endothelial growth factor (VEGF) production by ovarian cells. Platelet-derived growth factor B (PDGFB) and D (PDGFD) are decreased in follicular fluid of PCOS patients and in the ovaries of a rat model of PCOS. In the present study, we aimed to analyze the effects of local administration of PDGFB on ovarian angiogenesis, follicular development and ovulation in a DHEA-induced PCOS rat model. Ovarian PDGFB administration to PCOS rats partially restored follicular development, decreased the percentage of cysts, increased the percentage of corpora lutea, and decreased the production of anti-Müllerian hormone. In addition, PDGFB administration improved ovarian angiogenesis by reversing the increase in periendothelial cell area and restoring VEGF levels. Our results shed light into the mechanisms that lead to altered ovarian function in PCOS and provide new data for potential therapeutic strategies.



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The Zika Effect

Having worked on viruses for over 40 years, I know a fair number of people in the field, and I am amazed at how many of them have started to work on Zika virus. What exactly is attracting virologists to this emerging virus? There are probably many reasons why Zika virus would be of interest t...

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In vivo confocal microscopy efficacy assessment of daylight photodynamic therapy in actinic keratosis patients

Summary

Background

Reflectance confocal microscopy (RCM) is a noninvasive diagnostic technique with an acceptable sensitivity and specificity for actinic keratosis (AK).

Objectives

We evaluated efficacy of daylight photodynamic therapy (DL-PDT) in patients with AK using a new RCM atypia scoring system.

Materials and methods

All patients with AK lesions (Grade I–II) were included in our study (2012–15). Baseline clinical, dermoscopy and RCM evaluations were followed by DL-PDT. In the first follow-up, clinical examination, dermoscopy and RCM imaging of the treated area were carried out. Atypia scoring and cell size measurements were used to compare before and after RCM images.

Results

From 40 lesions (20 patients with mean age of 75·5 years), complete resolution and partial response of the actinic damage was detected in 80% and 17·5% of lesions, respectively. No cellular atypia was seen in the follow-up RCM images of 57·5% of lesions (n = 23), while in 40% of lesions (n = 16) minimal changes to the honeycomb pattern of the epidermis were seen in the follow-up RCM images (atypia score 1). Only one lesion showed minimal or no clinical response, and a persistent moderate amount of atypia in RCM. Furthermore, atypia score and mean cell size decreased significantly in the follow-up DL-PDT RCM images (P < 0·001, P = 0·001, respectively).

Conclusions

RCM features of actinic damage at cellular level have been shown to correlate well with the results of a clinical assessment of AK lesions. This study confirms that in vivo RCM technology might be an additional technique to monitor the efficacy of DL-PDT for AK.

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Comparative Transcriptome profiling provides new insights into mechanisms of androgenetic alopecia progression

Abstract

Androgenetic alopecia (AGA) is the most common progressive form of hair loss that occurs in more than half of men above 50 years ¹. AGA onset is dependent on genetic predisposition and presence of androgen ^{2, 3}. In AGA patients, hair undergoes shortened anagen phase, progressive miniaturization and subsequent vellus transformation of terminal hair follicle.

This article is protected by copyright. All rights reserved.

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Prevalence of Germline Mutations in the Spindle Assembly Checkpoint Gene BUB1B in Individuals with Early-Onset Colorectal Cancer

ABSTRACT

Germline mutations in BUB1B, encoding BUBR1, one of the crucial components of the spindle assembly checkpoint (SAC), have been shown to cause variable phenotypes, including the recessive mosaic variegated aneuploidy (MVA) syndrome, which predisposes to cancer. Reduced levels of the wild-type BUBR1 protein have been linked to the development of gastrointestinal neoplasms. To determine whether mutations in BUB1B are enriched in individuals with colorectal cancer (CRC), we performed amplicon-based targeted next-generation sequencing of BUB1B on germline DNA of 192 individuals with early-onset CRC (≤50 years). None of the individuals was found to be homozygous or compound heterozygous for mutations in BUB1B. However, we did identify two rare heterozygous variants, p.Glu390del and p.Cys945Tyr, in patients who developed CRC at the ages of 41 and 43 years, respectively. Both variants were shown not to affect BUBR1 protein expression levels and protein localization. Since the p.Glu390del variant is located in the BUB3-binding domain, we also performed immunoprecipitation to examine whether this variant affects the binding of BUB1 or BUB3 to BUBR1 but, compared to wild-type BUBR1, no difference was observed. Our data suggest that mutations in BUB1B do not occur frequently in the germline of individuals with CRC and that BUB1B unlikely plays a major role in the predisposition to early-onset CRC. Whether carriers of pathogenic BUB1B mutations, such as the parents of MVA syndrome patients, have an increased risk for cancer remains of interest, as studies in mice have suggested that haploinsufficiency of BUB1B may cause an increase in carcinogen-induced tumours. This article is protected by copyright. All rights reserved.

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IJMS, Vol. 17, Pages 783: Goldfish Leptin-AI and Leptin-AII: Function and Central Mechanism in Feeding Control

In mammals, leptin is a peripheral satiety factor that inhibits feeding by regulating a variety of appetite-related hormones in the brain. However, most of the previous studies examining leptin in fish feeding were performed with mammalian leptins, which share very low sequence homologies with fish leptins. To elucidate the function and mechanism of endogenous fish leptins in feeding regulation, recombinant goldfish leptin-AI and leptin-AII were expressed in methylotrophic yeast and purified by immobilized metal ion affinity chromatography (IMAC). By intraperitoneal (IP) injection, both leptin-AI and leptin-AII were shown to inhibit the feeding behavior and to reduce the food consumption of goldfish in 2 h. In addition, co-treatment of leptin-AI or leptin-AII could block the feeding behavior and reduce the food consumption induced by neuropeptide Y (NPY) injection. High levels of leptin receptor (lepR) mRNA were detected in the hypothalamus, telencephalon, optic tectum and cerebellum of the goldfish brain. The appetite inhibitory effects of leptins were mediated by downregulating the mRNA levels of orexigenic NPY, agouti-related peptide (AgRP) and orexin and upregulating the mRNA levels of anorexigenic cocaine-amphetamine-regulated transcript (CART), cholecystokinin (CCK), melanin-concentrating hormone (MCH) and proopiomelanocortin (POMC) in different areas of the goldfish brain. Our study, as a whole, provides new insights into the functions and mechanisms of leptins in appetite control in a fish model.

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IJMS, Vol. 17, Pages 836: Follicle Loss and Apoptosis in Cyclophosphamide-Treated Mice: What’s the Matter?

With increasing numbers of young female cancer survivors following chemotherapy, chemotherapy-induced fertility loss must be considered. Menstrual disorder and infertility are of particular concern in female cancer patients. We showed that treatment with the alkylating agent cyclophosphamide (CTX) could cause severe primordial follicle loss and growing follicle apoptosis, resulting in loss of ovarian reserve. SPF C57BL/6 female mice were treated with a single dose of 120 mg/kg of CTX or saline as a control, and both sides of ovaries were collected three or seven days after injection. Following CTX treatment, the ovaries were mostly composed of collapsed oocytes and presented marked cortical fibrosis and a reduced number of follicles, especially primordial follicles. The loss of primordial follicles was confirmed by primordial follicle counting, immunohistochemistry and Western blot detection of DDx4/MVH. Follicle apoptosis was tested by a TUNEL assay and the number of TUNEL-positive follicle cells increased, as expected, in CTX-treated mice. Furthermore, expression of APAF-1 and cleaved caspase-3 was also increased after CTX treatment. Analysis of the PI3K/Akt/mTOR signaling pathway showed that CTX increased phosphorylation of Akt, mTOR and downstream proteins without affecting total levels. These results demonstrated that the CTX treatment led to the hyperactivation of the PI3K/Akt/mTOR signaling pathway in ovaries which may be related to primordial follicle loss and growing follicle apoptosis.

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Structural Determinants of Hydration, Mechanics and Fluid Flow in Freeze-dried Collagen Scaffolds

Publication date: Available online 30 May 2016
Source:Acta Biomaterialia
Author(s): G.S. Offeddu, J.C. Ashworth, R.E. Cameron, M.L. Oyen
AbstractFreeze-dried scaffolds provide regeneration templates for a wide range of tissues, due to their flexibility in physical and biological properties. Control of structure is crucial for tuning such properties, and therefore scaffold functionality. However, the common approach of modeling these scaffolds as open-cell foams does not fully account for their structural complexity. Here, the validity of the open-cell model is examined across a range of physical characteristics, rigorously linking morphology to hydration and mechanical properties. Collagen scaffolds with systematic changes in relative density were characterized using Scanning Electron Microscopy, X-ray Micro-Computed Tomography and spherical indentation analyzed in a time-dependent poroelastic framework. Morphologically, all scaffolds were mid-way between the open- and closed-cell models, approaching the closed-cell model as relative density increased. Although pore size remained constant, transport pathway diameter decreased. Larger collagen fractions also produced greater volume swelling on hydration, although the change in pore diameter was constant, and relatively small at ^∼6%. Mechanically, the dry and hydrated scaffold moduli varied quadratically with relative density, as expected of open-cell materials. However, the increasing pore wall closure was found to determine the time-dependent nature of the hydrated scaffold response, with a decrease in permeability producing increasingly elastic rather than viscoelastic behavior. These results demonstrate that characterizing the deviation from the open-cell model is vital to gain a full understanding of scaffold biophysical properties, and provide a template for structural studies of other freeze-dried biomaterials.Statement of significanceFreeze-dried collagen sponges are three-dimensional microporous scaffolds that have been used for a number of exploratory tissue engineering applications. The characterization of the structure-properties relationships of these scaffolds is necessary to understand their biophysical behavior in vivo. In this work, the relationship between morphology and physical properties in the dry and hydrated states was investigated across a range of solid concentrations in the scaffolds. The quantitative results provided can aid the design of scaffolds with a target trade-off between mechanical properties and structural features important for their biological activity.

Graphical abstract

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Modeling the Efficacy of the Extent of Surgical Resection in the Setting of Radiation Therapy for GBM

Summary

Standard therapy for GBM includes maximal surgical resection and radiation therapy. While it is established that radiation therapy provides the greatest survival benefit of standard treatment modalities, the impact of the extent of surgical resection (EOR) on patient outcome remains highly controversial. While some studies describe no correlation between EOR and patient survival even up to total resection, others propose either qualitative (partial vs subtotal vs complete resection) or quantitative EOR thresholds, below which there is no correlation with survival. This work uses a mathematical model in the form of a reaction-diffusion partial differential equation to simulate tumor growth and treatment with radiation therapy and surgical resection based on tumor-specific rates of diffusion and proliferation. Simulation of 36 tumors across a wide spectrum of diffusion and proliferation rates suggests that while partial or subtotal resections generally do not provide a survival advantage, complete resection significantly improves patient outcomes. Furthermore, our model predicts a tumor-specific quantitative threshold below which EOR has no effect on patient survival and demonstrates that this threshold increases with tumor aggressiveness, particularly with the rate of proliferation. Thus, this model may serve as an aid for determining both when surgical resection is indicated as well as the surgical margins necessary to provide clinically significant improvements in patient survival. Additionally, by assigning relative benefits to radiation and surgical resection based on tumor invasiveness and proliferation, this model confirms that (with the exception of the least aggressive tumors) the survival benefit of radiation therapy exceeds that of surgical resection.

This article is protected by copyright. All rights reserved.

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Sensitivities to various EGFR-TKIs of uncommon EGFR mutations L861Q and S768I: what is the optimal EGFR-TKI?

Summary

Most patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and their sensitivities to various EGFR-TKIs have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR-TKIs, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3-L858R), L861Q (Ba/F3-L861Q) or S768I (Ba/F3-S768I) mutations were created and their drug sensitivities to various EGFR-TKIs were examined. Both the Ba/F3-L861Q and Ba/F3-S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3-L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3-L858R cell line. The Ba/F3-L861Q cell line was similarly sensitive and the Ba/F3-S768I cell line was less sensitive to osimertinib, compared with the Ba/F3-L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR-TKI against these uncommon EGFR mutations.

This article is protected by copyright. All rights reserved.

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The Leading Seafood Cuisine of Anisakidosis in Japan

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Editorial Advisory Board

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Cryptococcal Meningitis Treatment Strategies Affected by the Explosive Cost of Flucytosine in the United States: A Cost-effectiveness Analysis

Background. In the United States, cryptococcal meningitis causes approximately 3400 hospitalizations and approximately 330 deaths annually. The US guidelines recommend treatment with amphotericin B plus flucytosine for at least 2 weeks, followed by fluconazole for a minimum of 8 weeks. Due to generic drug manufacturer monopolization, flucytosine currently costs approximately $2000 per day in the United States, with a 2-week flucytosine treatment course costing approximately $28 000. The daily flucytosine treatment cost in the United Kingdom is approximately $22. Cost-effectiveness analysis was performed to determine the value of flucytosine relative to alternative regimens.

Methods. We estimated the incremental cost-effectiveness ratio (ICER) of 3 cryptococcal induction regimens: (1) amphotericin B deoxycholate for 4 weeks; (2) amphotericin and flucytosine (100 mg/kg/day) for 2 weeks; and (3) amphotericin and fluconazole (800 mg/day) for 2 weeks. Costs of care were calculated using 2015 US prices and the medication costs. Survival estimates were derived from a randomized trial and scaled relative to published US survival data.

Results. Cost estimates were $83 227 for amphotericin monotherapy, $75 121 for amphotericin plus flucytosine, and $44 605 for amphotericin plus fluconazole. The ICER of amphotericin plus flucytosine was $23 842 per quality-adjusted life-year.

Conclusions. Flucytosine is currently cost-effective in the United States despite a dramatic increase in price in recent years. Combination therapy with amphotericin and flucytosine is the most attractive treatment strategy for cryptococcal meningitis, though the rising price may be creating access issues that will exacerbate if the trend of profiteering continues.

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Editorial Board

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Sun HY, et al (Clin Infect Dis 2015; 60:36-44)

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Masthead

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Incidence and Prevalence of Opportunistic and Other Infections and the Impact of Antiretroviral Therapy Among HIV-infected Children in Low- and Middle-income Countries: A Systematic Review and Meta-analysis

Background. We conducted a systematic review and meta-analysis to evaluate the incidence and prevalence of 14 opportunistic infections (OIs) and other infections as well as the impact of antiretroviral therapy (ART) among human immunodeficiency virus (HIV)–infected children (aged <18 years) in low- and middle-income countries (LMICs), to understand regional burden of disease, and inform delivery of HIV services.

Methods. Eligible studies described the incidence of OIs and other infections in ART-naive and -exposed children from January 1990 to November 2013, using Medline, Global Health, Embase, Cumulative Index to Nursing and Allied Health Literature, Web of Knowledge, and Literatura Latino Americana em Ciências da Saúde databases. Summary incident risk (IR) and prevalent risk for each OI in ART-naive and ART-exposed children were calculated, and unadjusted odds ratios calculated for impact of ART. The number of OI cases and associated costs averted were estimated using the AIDS impact model.

Results. We identified 4542 citations, and 88 studies were included, comprising 55 679 HIV-infected children. Bacterial pneumonia and tuberculosis were the most common incident and prevalent infections in both ART-naive and ART-exposed children. There was a significant reduction in IR with ART for the majority of OIs. There was a smaller impact on bacterial sepsis and pneumonia, and an increase observed for varicella zoster. ART initiation based on 2010 World Health Organization guidelines criteria for ART initiation in children was estimated to potentially avert >161 000 OIs (2013 UNAIDS data) with estimated cost savings of at least US$17 million per year.

Conclusions. There is a decrease in the risk of most OIs with ART use in HIV-infected children in LMICs, and estimated large potential cost savings in OIs averted with ART use, although there are greater uncertainties in pediatric data compared with that of adults.

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Subscriptions Page

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Reply to Oh

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Table of Contents

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An Adolescent With Fever, Rash, and Altered Mental Status

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15 June News

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Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study

Background. CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized.

Methods. We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5–0.9, 1–2.9, 3–4.9, 5–9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996–2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996–1997, 1998–1999, 2000–2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0–49, 50–99, 100–199, 200–349, 350–499, ≥500 cells/µL) overall and separately according to time since start of ART.

Results. A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2–35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4–16.8) during 5–9.9 years and 14.2 (95% CI, 13.3–15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94–1.00; P = .054) and 1.02 (95% CI, .98–1.07; P = .32) among patients followed for 5–9.9 and ≥10 years, respectively.

Conclusions. After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts.

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Antimicrobial Stewardship: What Works?

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In Utero Tenofovir Exposure Is not Associated With Fetal Long Bone Growth

Background. Despite widespread use of tenofovir disoproxil fumarate (TDF) in pregnant and breastfeeding women, few data exist on fetal bone development after in utero TDF exposure. We evaluated fetal long bone growth in human immunodeficiency virus (HIV)–infected pregnant woman/fetus dyads in Cape Town, South Africa.

Methods. Women were recruited from primary care antenatal services and underwent ultrasonography to determine femur (FLZ) and humerus (HLZ) length z scores. The duration of in utero TDF exposure was calculated in weeks. Linear regression models were applied to assess the associations between the duration of in utero TDF exposure and change in FLZ and HLZ.

Results. A total of 646 woman/fetus dyads contributed 1376 ultrasonographic scans to this analysis: 132 dyads with ≥25 weeks, 326 with 10–24 weeks, and 188 with <10 weeks of TDF exposure. Women receiving TDF for ≥25 weeks were older than those receiving TDF for 10–24 or <10 weeks (median age, 31 vs 28 and 28 years, respectively; P < .01), and had lower HIV RNA levels (median log₁₀ HIV RNA level, 1.59 vs 4.08 and 3.83, respectively; P < .01). Throughout gestation, overall median FLZ and HLZ were 0.30 (interquartile range, –0.03 to 0.63) and 0.22 (–0.26 to 0.59) respectively. In multivariate analysis, there was no association between duration of in utero TDF exposure per 1-week increment and change in FLZ (ß = .00; P = .51) or change in HLZ (ß = .00; P = .40). Results were similar using mixed-effects models.

Conclusions. Although longer follow-up is needed, these in utero data are reassuring and support the continued use of TDF in pregnancy.

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Statin Use and Hospital Length of Stay Among Adults Hospitalized With Community-acquired Pneumonia

Background. Prior retrospective studies suggest that statins may benefit patients with community-acquired pneumonia (CAP) due to antiinflammatory and immunomodulatory effects. However, prospective studies of the impact of statins on CAP outcomes are needed. We determined whether statin use was associated with improved outcomes in adults hospitalized with CAP.

Methods. Adults aged ≥18 years hospitalized with CAP were prospectively enrolled at 3 hospitals in Chicago, Illinois, and 2 hospitals in Nashville, Tennessee, from January 2010—June 2012. Adults receiving statins before and throughout hospitalization (statin users) were compared with those who did not receive statins (nonusers). Proportional subdistribution hazards models were used to examine the association between statin use and hospital length of stay (LOS). In-hospital mortality was a secondary outcome. We also compared groups matched on propensity score.

Results. Of 2016 adults enrolled, 483 (24%) were statin users; 1533 (76%) were nonusers. Statin users were significantly older, had more comorbidities, had more years of education, and were more likely to have health insurance than nonusers. Multivariable regression demonstrated that statin users and nonusers had similar LOS (adjusted hazard ratio [HR], 0.99; 95% confidence interval [CI], .88–1.12), as did those in the propensity-matched groups (HR, 1.03; 95% CI, .88–1.21). No significant associations were found between statin use and LOS or in-hospital mortality, even when stratified by pneumonia severity.

Conclusions. In a large prospective study of adults hospitalized with CAP, we found no evidence to suggest that statin use before and during hospitalization improved LOS or in-hospital mortality.

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Investigation of Legionella pneumophila Outbreak: Effectiveness of Clinical and Genomic Methods

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Fecal Microbial Transplants Reduce Antibiotic-resistant Genes in Patients With Recurrent Clostridium difficile Infection

Background. Recurrent Clostridium difficile infection (RCDI) is associated with repeated antibiotic treatment and the enhanced growth of antibiotic-resistant microbes. This study tested the hypothesis that patients with RCDI would harbor large numbers of antibiotic-resistant microbes and that fecal microbiota transplantation (FMT) would reduce the number of antibiotic-resistant genes.

Methods. In a single center study, patients with RCDI (n = 20) received FMT from universal donors via colonoscopy. Stool samples were collected from donors (n = 3) and patients prior to and following FMT. DNA was extracted and shotgun metagenomics performed. Results as well as assembled libraries from a healthy cohort (n = 87) obtained from the Human Microbiome Project were aligned against the NCBI bacterial taxonomy database and the Comprehensive Antibiotic Resistance Database. Results were corroborated through a DNA microarray containing 354 antibiotic resistance (ABR) genes.

Results. RCDI patients had a greater number and diversity of ABR genes compared with donors and healthy controls. Beta-lactam, multidrug efflux pumps, fluoroquinolone, and antibiotic inactivation ABR genes were increased in RCDI patients, although donors primarily had tetracycline resistance. RCDI patients were dominated by Proteobacteria with Escherichia coli and Klebsiella most prevalent. FMT resulted in a resolution of symptoms that correlated directly with a decreased number and diversity of ABR genes and increased Bacteroidetes and Firmicutes with reduced Proteobacteria. ABR gene profiles were maintained in recipients for up to a year following FMT.

Conclusions. RCDI patients have increased numbers of antibiotic-resistant organisms. FMT is effective in the eradication of pathogenic antibiotic-resistant organisms and elimination of ABR genes.

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Reply to Cassir et al

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Editorial Commentary: The Dawning of Microbiome Remediation for Addressing Antibiotic Resistance

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Clinical characterization and long-term follow-up of Schnitzler syndrome

Summary

Background

Schnitzler syndrome (SchS) is an acquired autoinflammatory disease characterized by chronic urticarial rash in association with monoclonal gammopathy. Patients may progress to lymphoproliferative disorders, but the associated factors and exact risk of progression are still not well defined.

Aim

To characterize the clinical findings, laboratory abnormalities and histopathology of patients with SchS and their respective outcomes.

Methods

We retrospectively reviewed the clinical files and the histological specimens of patients with SchS diagnosed from 1988 to 2015.

Results

Nine patients (two women, seven men) were diagnosed with SchS. Mean age at diagnosis was 61.1 years (range 29–80), with a mean time to diagnosis of 3.7 years and a mean follow-up period of 10.1 years (range 3–25). Four patients displayed an association of fever and arthralgia, and all nine patients consistently showed laboratory markers of inflammation. Serum values of the monoclonal component, IgMκ in eight patients and IgGλ in one patient, progressively increased over time. During follow-up, carried out in association with the haematology department five patients progressed to lymphoproliferative disease, namely, lymphoplasmacytic lymphoma/Waldenström's macroglobulinaemia (n = 4) and diffuse large B-cell lymphoma (n = 1).

Conclusions

SchS is a rare chronic inflammatory disease with a substantial impact on quality of life. Our study highlights the importance of lifelong follow-up for individuals with SchS, owing to the risk of progression to a lymphoproliferative disorder.

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Regulation of H-Ras-driven MAPK signaling, transformation and tumorigenesis, but not PI3K signaling and tumor progression, by plasma membrane microdomains

Regulation of H-Ras-driven MAPK signaling, transformation and tumorigenesis, but not PI3K signaling and tumor progression, by plasma membrane microdomains

Oncogenesis 5, e228 (May 2016). doi:10.1038/oncsis.2016.36

Authors: J V Michael, J G T Wurtzel & L E Goldfinger

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Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the ApcMin/+ model of colon cancer

Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the ApcMin/+ model of colon cancer

Oncogenesis 5, e230 (May 2016). doi:10.1038/oncsis.2016.37

Authors: D R Soto-Pantoja, J M Sipes, G Martin-Manso, B Westwood, N L Morris, A Ghosh, N J Emenaker & D D Roberts

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An ANCCA/PRO2000-miR-520a-E2F2 regulatory loop as a driving force for the development of hepatocellular carcinoma

An ANCCA/PRO2000-miR-520a-E2F2 regulatory loop as a driving force for the development of hepatocellular carcinoma

Oncogenesis 5, e229 (May 2016). doi:10.1038/oncsis.2016.22

Authors: J Huang, J Yang, Y Lei, H Gao, T Wei, L Luo, F Zhang, H Chen, Q Zeng & L Guo

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PTEN negatively regulates mTORC2 formation and signaling in grade IV glioma via Rictor hyperphosphorylation at Thr1135 and direct the mode of action of an mTORC1/2 inhibitor

PTEN negatively regulates mTORC2 formation and signaling in grade IV glioma via Rictor hyperphosphorylation at Thr1135 and direct the mode of action of an mTORC1/2 inhibitor

Oncogenesis 5, e227 (May 2016). doi:10.1038/oncsis.2016.34

Authors: K Bhattacharya, S Maiti & C Mandal

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Migration and invasion is inhibited by silencing ROR1 and ROR2 in chemoresistant ovarian cancer

Migration and invasion is inhibited by silencing ROR1 and ROR2 in chemoresistant ovarian cancer

Oncogenesis 5, e226 (May 2016). doi:10.1038/oncsis.2016.32

Authors: C E Henry, E Llamosas, A Djordjevic, N F Hacker & C E Ford

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Ewing Sarcoma of the External Ear Canal

Background. Ewing sarcoma (ES) is a high-grade malignant tumor that has skeletal and extraskeletal forms and consists of small round cells. In the head and neck region, reported localization of extraskeletal ES includes the larynx, thyroid gland, submandibular gland, nasal fossa, pharynx, skin, and parotid gland, but not the external ear canal. Methods. We present the unique case of a 2-year-old boy with extraskeletal ES arising from the external ear canal, mimicking auricular hematoma. Results. Surgery was performed and a VAC/IE (vincristine, adriamycin, cyclophosphamide alternating with ifosfamide, and etoposide) regimen was used for adjuvant chemotherapy for 12 months. Conclusion. The clinician should consider extraskeletal ES when diagnosing tumors localized in the head and neck region because it may be manifested by a nonspecific clinical picture mimicking common otorhinolaryngologic disorders.

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C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion. Objective: To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients. Methods: We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay. Results: No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB. Conclusion: Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases.
Neurodegener Dis 2016;16:370-372

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Rhus javanica Gall Extract Inhibits the Differentiation of Bone Marrow-Derived Osteoclasts and Ovariectomy-Induced Bone Loss

Inhibition of osteoclast differentiation and bone resorption is a therapeutic strategy for the management of postmenopausal bone loss. This study investigated the effects of Rhus javanica (R. javanica) extracts on bone marrow cultures to develop agents from natural sources that may prevent osteoclastogenesis. Extracts of R. javanica (eGr) cocoons spun by Rhus javanica (Bell.) Baker inhibited the osteoclast differentiation and bone resorption. The effects of aqueous extract (aeGr) or 100% ethanolic extract (eeGr) on ovariectomy- (OVX-) induced bone loss were investigated by various biochemical assays. Furthermore, microcomputed tomography (µCT) was performed to study bone remodeling. Oral administration of eGr (30 mg or 100 mg/kg/day for 6 weeks) augmented the inhibition of femoral bone mineral density (BMD), bone mineral content (BMC), and other factors involved in bone remodeling when compared to OVX controls. Additionally, eGr slightly decreased bone turnover markers that were increased by OVX. Therefore, it may be suggested that the protective effects of eGr could have originated from the suppression of OVX-induced increase in bone turnover. Collectively, the findings of this study indicate that eGr has potential to activate bone remodeling by inhibiting osteoclast differentiation and bone loss.

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Application of Partial Internal Transcribed Spacer Sequences for the Discrimination of Artemisia capillaris from Other Artemisia Species

Several Artemisia species are used as herbal medicines including the dried aerial parts of Artemisia capillaris, which are used as Artemisiae Capillaris Herba (known as "Injinho" in Korean medicinal terminology and "Yin Chen Hao" in Chinese). In this study, we developed tools for distinguishing between A. capillaris and 11 other Artemisia species that grow and/or are cultured in China, Japan, and Korea. Based on partial nucleotide sequences in the internal transcribed spacer (ITS) that differ between the species, we designed primers to amplify a DNA marker for A. capillaris. In addition, to detect other Artemisia species that are contaminants of A. capillaris, we designed primers to amplify DNA markers of A. japonica, A. annua, A. apiacea, and A. anomala. Moreover, based on random amplified polymorphic DNA analysis, we confirmed that primers developed in a previous study could be used to identify Artemisia species that are sources of Artemisiae Argyi Folium and Artemisiae Iwayomogii Herba. By using these primers, we found that multiplex polymerase chain reaction (PCR) was a reliable tool to distinguish between A. capillaris and other Artemisia species and to identify other Artemisia species as contaminants of A. capillaris in a single PCR.

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