PHEOCHROMOCYTOMA, THE GREAT MASQUERADER, PRESENTING AS REVERSIBLE CARDIOMYOPATHY: PRIMUM NON NOCERE.

Background: Pheochromocytoma, the great masquerader, can have a varied spectrum of clinical manifestations. It can often cause a diagnostic challenge despite the availability of modern investigation modalities. Case: We present the case of a 38-year-old male who presented with uncontrolled hypertension for the past 10 years and heart failure for one year. The diagnosis of pheochromocytoma was missed in the initial setting, leading to a biopsy of the retroperitoneal mass. Fortunately, the patient survived the procedure. Subsequently, with the involvement of a multi-disciplinary team, he was optimized for surgery under strict cardiac monitoring. After the complete excision of the tumour, he showed significant improvement not only in his clinical symptoms but also in his cardiac status. Conclusions: This case emphasizes the age-old medical phrase of 'Primum non nocere or first, do no harm'. Any invasive procedure in a pheochromocytoma can lead to a massive release of catecholamines causing a hypertensive crisis, pulmonary oedema, and even cardiac arrest. Any young patient presenting with hypertension or heart failure should be investigated for secondary causes. Cardiomyopathy due to pheochromocytoma is because of catecholamine overload and usually reverses or improves after curative surgery.

In vitro acaricidal activity of Piper longum L. against amitraz resistant Rhipicephalus microplus (Acari: Ixodidae).

The cattle tick, Rhipicephalus microplus Canestrini (Acari: Ixodidae) is one of the most important tick species severely affecting health and causes huge losses to dairy industry. Chemical acaricides are mainly applied for tick control but development of resistance, environmental pollution and contamination of milk and meat products with residues has led to exploration alternative eco-friendly tick control strategies. The dried fruits of Piper longum L. (Indian long pepper, Thippali or Pippali) generally used as flavoring agent have also been shown to have insecticidal property. Different concentrations (0.625%-10%) of alcoholic and aqueous extracts of Piper longum L. were prepared and evaluated for acaricidal activity against amitraz resistant R. microplus adult and larval stages. Against larval stages a dose-dependent mortality response was recorded for both extracts and higher acaricidal property was exhibited by the alcoholic extract with LC50 and LC95 (95% CL) values of 0.488% (0.48-0.49) and 1.39% (1.35-1.44), respectively. Similarly, against adult engorged females, ethanolic extract showed higher acaricidal property with LC50 and LC95 (95% CL) values of 4.67% (4.61-4.74) and 12.38% (12.05-12.73), respectively. Significant (p < 0.05) reduction was recorded in reproductive index of ticks treated and but no effect on hatchability of eggs was recorded in treated groups. The present study establishes acaricidal activity of P. longum fruit extracts against both larval and adult stages of amitraz resistant population of cattle tick.

Anti-calculus efficacy of Periogen® oral rinse in gingivitis patients.

Dental biofilm is a complex, organized microbial community that is the primary etiologic factor for plaque, the most frequently occurring oral contamination for gingivitis, dental caries and periodontal diseases. In dentistry, calculus is a form of hardened dental plaque, caused by precipitation of calcium (Ca) and phosphorous (P) ions deposited from saliva and gingival crevicular fluid. Although the dental biofilm cannot be eliminated, it can be controlled with comprehensive mechanical and chemotherapeutic oral hygiene practices. Chemotherapeutic agents have difficulty penetrating the polysaccharide matrix to reach and affect the microorganisms. The purpose of the present study was to evaluate the anti-calculus efficiency of a mouthwash containing an association of sodium tripolyphosphate, tetrapotassium pyrophosphate, sodium bicarbonate and citric acid in patients affected with gingivitis.

Long-term outcome of trans-sphenoidal surgery for Cushing's disease in Indian patients.

BACKGROUND: The results of trans-sphenoidal surgery (TSS) in Cushing's disease (CD) vary widely depending upon patient characteristics as well as surgical experience. Patients in India are often referred late to referral centers. We studied the rates of remission and endocrine deficiencies after TSS in patients with CD presenting to a referral hospital in India. METHODS: Sixty consecutive patients (45 females, median age 24.5 years) who underwent TSS between 2000 and 2015 were studied. The median (range) duration of follow-up was 40 (3-138) months. Initial and long-term remission and relapse rates and pituitary hypofunction post-TSS were evaluated. RESULTS: Eighteen (30%) patients harbored macroadenomas. Twenty-eight (47%) patients achieved remission in the immediate post-operative period (8 AM serum cortisol < 140 nmol/l), while a higher remission rate was noted at 6 months (39/54 patients, 72%). At 1 year 70% patients and at final follow-up [median duration 40 (range 3-138) months], 58% of patients were in remission. No pre- or post-surgical variables were consistently associated with remission, except for the 8-AM serum cortisol level on the fifth day after surgery. Seven (18%) patients relapsed on follow-up, including five patients who had fifth post-operative day 8 AM serum cortisol < 140 nmol/l. Twelve (25%) patients newly developed hypothyroidism and one (1.6%) patient developed amenorrhoea after TSS. CONCLUSION: Remission rate at 6 months was higher than immediately after TSS. A significant proportion of patients relapsed, thus necessitating life-long follow-up. New-onset hypothyroidism was frequent after TSS.

Human endogenous retroviruses and their implication for immunotherapeutics of cancer.

Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute ∼8% of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically prone to reactivate the expression of HERV elements due to epigenetic dysregulation that accumulate during malignant transformation and when using epigenetic therapies. HERV expression can induce an interferon response due to induction of the viral defense pathway, so-called 'viral mimicry'. By mimicking viral infections, HERVs could function as an 'intrinsic adjuvant', possibly sensitizing cancer cells to immunological recognition. Furthermore, translated HERV elements may in themselves form a valuable pool of tumor-associated antigens. Epitopes derived from HERVs have been recognized by cytotoxic CD8+ T cells, leading to cancer cell recognition. The combination of 'viral mimicry' and T-cell recognition could provide a powerful combination with existing immune stimulatory therapies, such as checkpoint inhibition. This combination is currently being evaluated in clinical trials in a large number of cancers.

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.

This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Cross-regulation among arabinose, xylose and rhamnose utilization systems in E. coli.

Bacteria frequently encounter multiple sugars in their natural surroundings. While the dynamics of utilization of glucose-containing sugar mixtures have been well investigated, there are few reports addressing regulation of utilization of glucose-free mixtures particularly pentoses. These sugars comprise a considerable fraction in hemicellulose which can be converted by suitable biocatalysts to biofuels and other value-added products. Hence, understanding of transcriptional cross-regulation among different pentose sugar utilization systems is essential for successful development of industrial strains. In this work, we study mixed-sugar utilization with respect to three secondary carbon sources - arabinose, xylose and rhamnose at single-cell resolution in Escherichia coli. Our results reveal that hierarchical utilization among these systems is not strict but rather can be eliminated or reversed by altering the relative ratios of the preferred and nonpreferred sugars. Since transcriptional cross-regulation among pentose sugar systems operates through competitive binding of noncognate sugar-regulator complex, altering sugar concentrations is thought to eliminate nonspecific binding by affecting concentration of the regulator - sugar complexes. SIGNIFICANCE AND IMPACT OF THE STUDY: Plant biomass comprises of hexose and pentose sugar mixtures. These sugars are processed by micro-organisms to form products like biofuels, polymers etc. One of the major challenges with mixed-sugar processing by micro-organisms is hierarchical utilization of sugars due to cross-regulation among sugar systems. In this work, we discuss cross-regulation among three secondary carbon sources - arabinose, xylose and rhamnose. Our results show that cross-regulation between pentose sugars is complex with multiple layers of regulation. These aspects need to be addressed for effective design of processes to extract energy from biomass.

Novel tools to assist neoepitope targeting in personalized cancer immunotherapy.

Current cancer immunotherapy approaches utilize the remarkable surveillance capacity of the human immune system, which is capable of recognizing and eliminating cancer cells based on identification of tumor-associated antigens arising as a consequence of the transformation process. Among these, mutational-derived neoepitopes have proved to be powerful targets for tumor elimination and mutational load has been shown to correlate with the clinical response to treatment with checkpoint inhibitors in many different tumor types. This suggests a crucial role for neoepitope recognition in T-cell-mediated tumor eradication. Consequently, strategies to further boost neoepitope recognition, through vaccination or adoptive cell transfer, has received substantial interest. Although such strategies have enormous potential, there are also considerable challenges associated with these approaches. In the present review, we will focus on how novel technological developments can facilitate and improve feasibility and efficacy in neoepitope targeting.

Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria.

The monoclonal anti-immunoglobulin E (IgE) antibody, omalizumab, was the first drug approved for use in patients with chronic idiopathic/spontaneous urticaria (CIU/CSU) who remain symptomatic despite H1 -antihistamine treatment. Omalizumab binds to free IgE, which lowers free IgE levels and causes FcεRI receptors on basophils and mast cells to be downregulated. It has been shown to improve symptoms of CIU/CSU, but its mechanism of action is not currently understood. Potential mechanisms in CIU/CSU include reducing mast cell releasability, reversing basopenia and improving basophil IgE receptor function, reducing activity of IgG autoantibodies against FcεRI and IgE, reducing activity of IgE autoantibodies against an antigen or autoantigen that has yet to be definitively identified, reducing the activity of intrinsically 'abnormal' IgE, and decreasing in vitro coagulation abnormalities associated with disease activity. However, none of these theories alone or in combination fully account for the pattern of symptom improvement seen with omalizumab therapy, and therefore, no one mechanism is likely to be the definitive mechanism of action. Additional research is needed to further clarify the involvement of omalizumab in relieving symptoms associated with the complex, multifactorial pathogenesis of CIU/CSU.

Thermoelectric and Structural Characterization of Al-Doped ZnO/Y2O3 Multilayers.

The influence of Y2O3 nanolayers on thermoelectric performance and structure of 2% Al-doped ZnO (AZO) thin films has been studied. Multilayers based on five 50 nm thick AZO layers alternated with few nanometers thick Y2O3 layers were prepared by pulsed laser deposition on Al2O3 single crystals by alternate ablation of AZO target and Y2O3 target. The number of laser shots on Y2O3 target was maintained very low (5, 10 and 15 pulses in three separate experiments. The main phase (AZO) presents polycrystalline orientation and typical columnar growth not affected by the presence of Y2O3 nanolayers. The multilayer with 15 laser shots of Y2O3 showed best thermoelectric performance with electrical conductivity σ 48 S/cm and Seebeck coefficient S = −82 µV/K, which estimate power factor (S2·σ) about 0.03 × 10−3 W m−1 K−2 at 600 K. The value of thermal conductivity (κ) was found 10.03 W m−1 K−1 at 300 K, which is one third of typical value previously reported for bulk AZO. The figure of merit, ZT = S2·σ·T/κ, is calculated 9.6 × 10−4 at 600 K. These results demonstrated the feasibility of nanoengineered defects insertion for the depression of thermal conductivity.

In vitro assessment of the acaricidal activity of Piper longum, Piper nigrum, and Zingiber officinale extracts against Hyalomma anatolicum ticks.

Ticks and tick-borne diseases are a major constraint for the sustainable cattle industry in the tropical and subtropical regions including the Indian subcontinent. The development of resistance to most of the commonly used acaricides leads to an attempt to screen plant extracts and their combinations for their possible acaricidal activity to develop an eco-friendly tick control alternative. An alcoholic and various aqueous extracts of Piper longum, Piper nigrum and Zingiber officinale and their combinations were evaluated for acaricidal activity against the three-host ixodid tick, Hyalomma anatolicum by larval immersion test using 14-21 days old unfed larvae. The efficacy was assessed by measuring larval mortality (%) and the lethal concentrations for 50% (LC50) and 95% (LC95) with their 95% confidence limits (CL) values were estimated by applying regression equation analysis to the probit transformed data of mortality. A concentration-dependent mortality response was recorded in all extracts prepared from seeds of P. longum and P. nigrum and their combinations. The highest acaricidal property was exhibited by the alcoholic extract of P. longum seeds with the minimum LC50 and LC95 (95% CL) values of 0.071% (0.07-0.072) and 0.135% (0.13-0.14), respectively, followed by alcoholic combinations. Interestingly, no acaricidal activity was recorded in extracts prepared from the rhizome of Z. officinale. The results indicated that the ethanolic extracts of P. longum and P. nigrum and their combinations can be used effectively for tick control in an integrated format.

Definition, aims, and implementation of GA(2) LEN Urticaria Centers of Reference and Excellence.

BACKGROUND: GA²LEN, the Global Allergy and Asthma European Network, has recently launched a program for the development, interaction, and accreditation of centers of reference and excellence in special areas of allergy embedded in its overall quality management of allergy centers of excellence. The first area chosen is urticaria. Urticaria is a common and debilitating condition and can be a challenge for both patients and treating physicians, especially when chronic. Centers of reference and excellence in urticaria (UCAREs) can help to improve the management of hard-to-treat conditions such as urticaria. AIMS: Here, we describe the aims, the requirements and deliverables, the application process, and the audit and accreditation protocol for GA²LEN UCAREs. RESULTS: The main aims of GA²LEN UCAREs are to provide excellence in urticaria management, to increase the knowledge of urticaria by research and education, and to promote the awareness of urticaria by advocacy activities. To become a certified GA²LEN UCARE, urticaria centers have to apply and fulfill 32 requirements, defined by specific deliverables that are assessed during an audit visit. DISCUSSION AND CONCLUSION: The GA²LEN UCARE program will result in a strong network of urticaria specialists, promote urticaria research, and harmonize and improve urticaria management globally.

Status of Competency-Based Medical Education in Endoscopy Training: A Nationwide Survey of US ACGME-Accredited Gastroenterology Training Programs.

OBJECTIVES: The Accreditation Council for Graduate Medical Education (ACGME) emphasizes the importance of medical trainees meeting specific performance benchmarks and demonstrating readiness for unsupervised practice. The aim of this study was to examine the readiness of Gastroenterology (GI) fellowship programs for competency-based evaluation in endoscopic procedural training. METHODS: ACGME-accredited GI program directors (PDs) and GI trainees nationwide completed an online survey of domains relevant to endoscopy training and competency assessment. Participants were queried about current methods and perceived quality of endoscopy training and assessment of competence. Participants were also queried about factors deemed important in endoscopy competence assessment. Five-point Likert items were analyzed as continuous variables by an independent t-test and χ(2)-test was used for comparison of proportions. RESULTS: Survey response rate was 64% (94/148) for PDs and 47% (546/1,167) for trainees. Twenty-three percent of surveyed PDs reported that they do not have a formal endoscopy curriculum. PDs placed less importance (1­very important to 5­very unimportant) on endoscopy volume (1.57 vs. 1.18, P<0.001), adenoma detection rate (2.00 vs. 1.53, P<0.001), and withdrawal times (1.96 vs. 1.68, P=0.009) in determining endoscopy competence compared with trainees. A majority of PDs report that competence is assessed by procedure volume (85%) and teaching attending evaluations (96%). Only a minority of programs use skills assessment tools (30%) or specific quality metrics (28%). Specific competencies are mostly assessed by individual teaching attending feedback as opposed to official documentation or feedback from a PD. PDs rate the overall quality of their endoscopy training and assessment of competence as better than overall ratings by trainees. CONCLUSIONS: Although the majority of PDs and trainees nationwide believe that measuring specific metrics is important in determining endoscopy competence, most programs still rely on procedure volume and subjective attending evaluations to determine overall competence. As medical training transitions from an apprenticeship model to competency-based education, there is a need for improved endoscopy curricula which are better suited to demonstrate readiness for unsupervised practice.

Interval shifts in basophil measures correlate with disease activity in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) significantly impacts the quality of life of those affected through symptoms of pruritus and recurrent skin lesions. In active CSU disease, reduced IgE-mediated basophil histamine release (HR) and basopenia are observed. We sought to examine the relationship between interval changes in basophil measures and shifts in patient-reported disease impairment. Simultaneous symptom and basophil evaluations were completed at two sequential study visits, and interval changes in measures were compared between visits for each subject (n = 38). These measures included Skindex-29, current itch and hives scores, total leukocyte histamine content (an indirect measure of blood basophil presence), and basophil HR in response to anti-IgE and formyl-methionine-leucine-phenylalanine. Overall, interval improvements in disease measures in CSU subjects were associated with increased basophil numbers (total leukocyte histamine content) and IgE-mediated HR. This suggests these measures are potential biomarkers for CSU disease improvement and further implicates a role for basophils in CSU.

Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B.

Inhibitors are an impediment to the effective management of haemophilia B (HB), but there is limited understanding of the underlying genetic risk factors. In this study we aim to understand the role of F9 gene mutations on inhibitor development in patients with HB. Mutations in the F9 gene were identified and HLA typing performed for five boys with severe HB. Data from the CDC Haemophilia B Mutation Project (CHBMP) database were used to assess association between F9 gene mutation type and inhibitor development. Analysis of the CHBMP database showed that larger disruptions in the F9 gene are associated with a higher life-time prevalence of inhibitors. We detected the following mutations in the five subjects, including four novel mutations: Nonsense in three patients (c.223 C>T; p.Arg75* in two siblings, c.553 C>T; p.Glu185*); Splice site in two patients (c.723 + 1 G>A, c.278-27 A>G); Missense in one patient (c.580 A>G, p.Thr194Ala; c.723 G>T; p.Gln241His). Of the two siblings only one responded to immune tolerance induction (ITI). These siblings have identical F9 gene mutations but differ with respect to the HLA alleles. Interestingly, an analysis of peptide-MHC binding affinities shows a significantly higher (one-sided unpaired t-test, P = 0.0018) median affinity for FIX-derived peptides in the sibling that responded to ITI. We conclude that the nature of the F9 gene mutation may be an important risk factor for the development of inhibitors. In addition, the HLA alleles of the individual patients, in conjunction with the mutation type, could be a predictor for the development of inhibitors as well as the response to ITI.

A randomized controlled trial of burping for the prevention of colic and regurgitation in healthy infants.

BACKGROUND: Efficacy of burping in lowering colic and regurgitation episodes in healthy term babies lacks evidence in literature. METHODS: We conducted a randomized controlled trial to compare efficacy of burping versus no-burping in 71 mother-baby dyads in community setting. Primary outcome was reduction in event rates of colic and regurgitation episodes over 3 months. RESULTS: Baseline characteristics were similar in two groups. Difference in incidence rates of colic between the control and burping group was 1.57 episodes/infant/100 weeks [95% confidence interval (CI): -0.63 to 3.76]. There was statistically no significant reduction in colic episodes between burping and non-burping study subjects during 3 months of follow-up (adjusted relative risk 0.64; 95% CI: 0.22-1.86, P-value 0.41). Incidence rate difference of regurgitation episodes/infant/week between burping and control group was 4.36 (95% CI: 4.04 to 4.69) and there was statistically significant increase in burping group (adjusted relative risk 2.05; 95% CI: 1.92-2.18, P-value < 0.0001). CONCLUSIONS: Although burping is a rite of passage, our study showed that burping did not significantly lower colic events and there was significant increase in regurgitation episodes in healthy term infants up to 3 months of follow-up.

Methods report on the development of the 2013 revision and update of the EAACI/GA2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria.

This methods report describes the process of guideline development in detail. It is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS) and is published in Allergy 2014; 69:868-887.