Epac1 Blocks NLRP3 Inflammasome to Reduce IL-1β in Retinal Endothelial Cells and Mouse Retinal Vasculature

Inflammation is an important component of diabetic retinal damage. We previously reported that a novel β-adrenergic receptor agonist, Compound 49b, reduced Toll-like receptor 4 (TLR4) signaling in retinal endothelial cells (REC) grown in high glucose. Others reported that TLR4 activates high-mobility group box 1 (HMGB1), which has been associated with the NOD-like receptor 3 (NLRP3) inflammasome. Thus, we hypothesized that Epac1, a downstream mediator of β-adrenergic receptors, would block TLR4/HMGB1-mediated stimulation of the NLRP3 inflammasome, leading to reduced cleavage of caspase-1 and interleukin-1 beta (IL-1β). We generated vascular specific conditional knockout mice for Epac1 and used REC grown in normal and high glucose treated with an Epac1 agonist and/or NLRP3 siRNA. Protein analyses were done for Epac1, TLR4, HMGB1, NLRP3, cleaved caspase-1, and IL-1β. Loss of Epac1 in the mouse retinal vasculature significantly increased all of the inflammatory proteins. Epac1 effectively reduced high glucose-induced increases in TLR4, HMGB1, cleaved caspase-1, and IL-1β in REC. Taken together, the data suggest that Epac1 reduces formation of the NLRP3 inflammasome to reduce inflammatory responses in the retinal vasculature.

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Polymorphisms of Il-10 (-1082) and RANKL (-438) Genes and the Failure of Dental Implants

Background. Genetic polymorphisms in certain cytokines and chemokines have been investigated to understand why some individuals display implant flaws despite having few risk factors at the time of implant. Purpose. To investigate the association of genetic polymorphisms in interleukin- (IL-) 10 [-1082 region (A/G)] and RANKL [-438 region (A/G)] with the failure of dental implants. Materials and Methods. This study included 90 partially edentulous male and female patients who were rehabilitated with a total of 245 Straumann dental implants. An implant was considered a failure if any of the following occurred: mobility, persistent subjective complaint, recurrent peri-implant infection with suppuration, continuous radiolucency around the implant, probing depth ≥ 5 mm, and bleeding on probing. Buccal mucosal cells were collected for analysis of RANKL438 and IL-10. Results. The implant success rate in this population was 34.4%. The mutant allele (G) in RANKL had an incidence of 52.3% and mutant allele (A) in IL-10 was observed in 37.8%. No statistically significant difference was detected between the failure of the implant and the genotypes and allelic frequencies. Conclusion. No association was detected between the genetic polymorphisms of RANKL (-438) and IL-10 (-1082) and the failure of dental implants in the population studied.

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A Novel Panel of Serum Biomarkers for MPM Diagnosis

Exposure to asbestos is the main cause of malignant pleural mesothelioma (MPM), a highly aggressive cancer of the pleura. Since the only tools for early detection are based on radiological tests, some authors focused on serum markers (i.e., mesothelin). The aim of this study was the evaluation of new serum biomarkers to be used individually or in combination, in order to improve the outcome of patients whose disease would be diagnosed at an earlier stage. Serum and plasma were available from 43 subjects previously exposed to asbestos and 27 MPM patients, all being epithelioid type. All the new markers found differentially expressed in MPM and healthy subjects, by proteomic and genomic approaches, have been validated in the serum by the use of specific ELISA. The combined approach, using tools of genomics and proteomics, is found to be highly innovative for this type of disease and led to the identification of new serum markers in the diagnosis of MPM. These results, if confirmed in a larger series, may have a strong impact in this area, because early detection of this cancer in people at high risk could significantly improve the course of the disease and the clinical approach to an individualized therapy.

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Four questions help predict which patients do not need skin prick test, study finds

Asking people four simple questions can predict those who will have negative results in allergy tests and avoids unnecessary testing, a primary care study has shown.1Symptoms associated with allergic...

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Children’s diabetes control improves but gaps in care remain, audit finds

More than a quarter of children in England and Wales with diabetes now have excellent blood glucose control, while the number said to have poor control has fallen, the latest paediatric audit has...

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The value of systematic contouring of the bowel for treatment plan optimization in image-guided cervical cancer high-dose-rate brachytherapy

Publication date: Available online 27 February 2017
Source:Brachytherapy
Author(s): Antonio L. Damato, Ivan Buzurovic, Mandar S. Bhagwat, Robert A. Cormack, Phillip M. Devlin, Scott Friesen, Jorgen Hansen, Larissa J. Lee, Matthias M. Manuel, Linda P. Cho, Desmond O'Farrell, Akila N. Viswanathan
PurposeTo investigate the dose–volume histogram metrics and optimization results of the contoured bowel in cervical cancer brachytherapy.Methods and MaterialsTreatment plans of cervical cancer patients treated with image-guided high dose rate were retrospectively analyzed with institutional review board approval. In addition to the clinical target volume, rectum, bladder, and sigmoid, the bowel was contoured at the time of planning (Group 1) or at the time of this analysis (Group 2).ResultsThirty-two patients treated with 145 insertions were included. Before optimization, mean ± 1 standard deviation overall bowel minimum dose to the most irradiated 2 cm³ volume of an organ (D2cc) was 67.8 Gyα/β3 ± 13.7 Gyα/β3 (Group 1: 72.6 ± 13.2 Gyα/β3; Group 2: 57.3 ± 8.0 Gyα/β3). Before optimization, one patient in Group 1 presented a bowel D2cc metric exceeding 100 Gyα/β3. After optimization, bowel D2cc mean ± 1 standard deviation was 59.4 ± 6.7 Gyα/β3 (Group 1: 61.4 ± 6.0 Gyα/β3, p < 0.001; Group 2: 55.2 ± 6.5 Gyα/β3, p = 0.026).ConclusionsGiven the potentially high doses and the benefit of optimization in reducing dose to the organs at risk, we recommend consideration of systematic contouring of the bowel when bowel is present in the pelvis.



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Biodegradable polymeric micelles coencapsulating paclitaxel and honokiol: a strategy for breast cancer therapy in vitro and in vivo

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Mammography trends show improved cancer detection, more biopsies

The shift from film to digital technology appears to have improved cancer detection rates for diagnostic mammography, but also has increased the abnormal interpretation rate, which may lead to more women undergoing biopsies for benign conditions,...

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Clinical presentation of patients with spontaneous coronary artery dissection

Background

Spontaneous coronary artery dissection (SCAD) is an infrequent but important cause of myocardial infarction (MI) especially in younger women. However, the clinical presentation and the acuity of symptoms prompting invasive management in SCAD patients have not been described. Understanding these presenting features may improve SCAD diagnosis and management.

Methods

We reviewed SCAD patients who were prospectively followed at the Vancouver General Hospital SCAD Clinic. Their presenting symptoms and unstable features were obtained from detailed clinical histories and hospital admission documentation. Baseline characteristics, predisposing and precipitating conditions, angiographic findings, management strategies, in-hospital, and long-term events were recorded prospectively.

Results

We included 196 SCAD patients who had complete documentation of their presenting symptoms. The majority were women (178/196; 90.8%) and all presented with MI (24.0% STEMI). The most frequent presenting symptom was chest discomfort, reported by 96%. Other symptoms included arm pain (49.5%), neck pain (22.1%), nausea or vomiting (23.4%), diaphoresis (20.9%), dyspnea (19.3%), and back pain (12.2%). Ventricular tachycardia/fibrillation occurred in 8.1% (16/196), with 1.0% having cardiac arrest. The time from symptom onset to hospital presentation was 1.1 ± 3.0 days. NSTEMI patients had longer delay for coronary angiography compared with STEMI (2.0 ± 2.5 days vs. 0.8 ± 1.7 days, P = 0.002). Overall, 34.2% had unstable symptoms upon arrival for coronary angiography. Those with unstable symptoms were more likely to undergo repeat angiography (65.7% vs. 50.4%, P = 0.049), and repeat or unplanned revascularization (14.9% vs. 5.4%, P = 0.033) during acute hospitalization.

Conclusion

Chest discomfort was the most frequent presenting symptom with SCAD and one-third had unstable symptoms prompting urgent invasive angiography. © 2017 Wiley Periodicals, Inc.

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Toxoplasmosis (toxo)

Toxoplasmosis (toxo): An infection caused by a single-celled parasite named Toxoplasma gondii that may invade tissues and damage the brain, especially of the fetus and newborn.

The parasite Toxoplasma gondii is very common (more than 60 million people in the US carry it) but few are aware of it because the immune system often keeps the parasite from causing illness.

The usual symptoms of toxo are similar to flu with fever, fatigue, headache, swollen lymph glands (lymphadenopathy), and muscle aches and pains (myalgia) that may last for a few days to several weeks.

Toxo can be contracted by touching the hands to the mouth after gardening, cleaning a cat's litter box, or anything that came into contact with cat feces. Toxo can also be contracted by eating raw or partly cooked meat, especially pork or lamb, or touching the hands to the mouth after contact with raw or undercooked meat.

Persons with a weakened immune system are at risk for developing a severe case of toxo. At high risk therefore for severe toxo are:

• Children and adults with an inherited immune defect, a
• Anyone with AIDS,
• Anyone receiving systemic (bodywide) chemotherapy,
• Anyone who has received a transplant and is on immunosuppressive therapy (to prevent rejection of their transplant), and
• The fetus and newborn.

Toxoplasma gondii is a well-known teratogen -- an agent that can cause birth defects. If a woman is pregnant when she is infected, the parasite can cross the placenta from her to the baby with sometimes catastrophic consequences.

Children born with toxo (congenital toxoplasmosis) can have mental retardation, convulsions (epilepsy), spasticity, cerebral palsy, and partial or complete deafness and blindness.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Studies of DNA-binding properties of lafutidine as adjuvant anticancer agent to calf thymus DNA using multi-spectroscopic approaches, NMR relaxation data, molecular docking and dynamical simulation

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Hongqin Yang, Peixiao Tang, Bin Tang, Yanmei Huang, Jiawei He, Shanshan Li, Hui Li
The interactions between lafutidine (LAF) and calf thymus DNA (ctDNA) have been investigated both experimentally and theoretically. UV–vis absorption studies confirmed that LAF binds to ctDNA through non-covalent interactions. Fluorescence quenching and time-resolved fluorescence spectroscopy studies showed that the binding of LAF with ctDNA occurred through static quenching mechanism, resulting in the formation of a LAF–ctDNA complex. The binding constants (K) of the complex were found to be around 10³M⁻¹ via NMR relaxation rates and fluorescence data, and the calculated thermodynamic parameters indicated that hydrogen bonds and van der Waals forces played major roles in the binding of LAF to ctDNA. The changes in CD spectra indicated that LAF induced a slight perturbation on the base stacking and helicity of B-DNA. A comparative study of the LAF–ctDNA complex with respect to potassium iodide quenching experiments and competition displacement assays with ethidium bromide, acridine orange, and Hoechst 33258 probes suggested that LAF interacted with ctDNA by minor groove mode. Molecular docking analysis further supported the minor groove binding. Molecular dynamics simulation indicated that LAF depart from the C-G region of DNA, but it can steadily bind with the middle part of DNA composed by A-T base pairs.



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4-O-Sulfation in sea cucumber fucodians contribute to reversing dyslipidiaemia caused by HFD

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Shan Li, Junhui Li, Zijian Zhi, Yaqin Hu, Jian Ge, Xingqian Ye, Ding Tian, Robert J. Linhardt, Shiguo Chen
Fucodians extracted from sea cucumbers (SC-FUCs) possess linear chains with uniform repeating units. Sulfation patterns endow SC-FUCs unique structures and bioactivity. The present study investigated the anti-hyperlipidemic activity of two fucodians isolated from sea cucumbers Pearsonothuria graeffei (fuc-Pg) and Isostichopus badionotus (fuc-Ib). The results indicate fuc-Pg dominated with a 4-O-sulfation pattern shows strong activity in reducing body weight, regulating lipid disorder (TC, TG, HLD-C, and LDL-C level), improving liver function (liver weight, GOP, GPT, and TBA concentrations) and increasing adiponectin level (adiponectin concentration) caused by HFD. However, fuc-Ib dominated with a 2-O-sulfation pattern has only moderate effects. These results suggest that different sulfation pattern may contribute to the differences in the hyperlipidemic activities. Further analysis by quantitative reverse transcription-polymerase chain reaction and Western blot analysis indicate that Fuc-Pg can suppress the expression of CD 36, increase the level of PPARα and decrease the level of CYP7A1, thus, the transportation of fatty acids into liver tissue and lipid metabolism, while fuc-Ib had only limited effects. Our results indicated the sulfation pattern may contribute to anti-hyperlipidemic activity of fucodian, and fuc-Pg dominated with 4-O-sulfation shows better effect and could be further developed as a potential anti-hyperlipidemic food supplement.



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The roles of conserved aromatic residues (Tyr5 and Tyr42) in interaction of scorpion toxin BmK AGP-SYPU1 with human Nav1.7

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Xiangxue Meng, Yijia Xu, Fangyang Wang, Mingyi Zhao, Xue Hou, Yuanyuan Ma, Yao Jin, Yanfeng Liu, Yongbo Song, Jinghai Zhang
Scorpion toxins are invaluable source of therapeutic leads and pharmacological tools which produce influence on the voltage gated sodium channels. In the previous study, our group has reported BmK AGP-SYPU1 (64 amino acids), one scorpion toxin with both potential α-type and β-type scorpion characteristics and analgesic activity in vivo, act as an activator to hNav1.4 and hNav1.5. Additionally, conserved aromatic amino acids Tyr5 and Tyr42 played important roles in bioactivity of BmK AGP-SYPU1 on hNav1.4 and hNav1.5. However, the anti-nonceptitor mechanisms of BmK AGP-SYPU1 referred in vivo have not been clarified yet. The roles of Tyr5 and Tyr42 have still kept unclear in the interaction of BmK AGP-SYPU1 with other VGSCs. In this study, in order to give a deep insight into the relationship of structure and function, the effects of BmK AGP-SYPU1 and its two mutants (Y5F and Y42F) on hNav1.7, which has emerged as a key molecule involved in pain processing, were examined by using Na⁺-specialized fluorescent dye and the whole-cell patch clamp. The data showed that BmK AGP-SYPU1 also displayed as an activator to hNav1.7 with the potential characteristic of α-type and β-type scorpion toxin. Both Tyr5 and Tyr42 were the key amino acids to the functional properties of BmK AGP-SYPU1 when interacting with hNav1.7, and the Tyr42 was involved in the preferences of the toxin to distinct action sites of hNav1.7. On the whole, these data provided more information about the structure of BmK AGP-SYPU1 related to its function upon hNav1.7, and may bring some clues for engineering scorpion toxins to achieve high bioactivity with lower side effects.



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Structure elucidation and immunological activity of a novel glycopeptide from mannatide

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Yanhong Shen, Mengqi Wu, Zhizhen Xu, Yanfei Wan, Li Zhang, Wenqing Zhang, Wei Xia
A water-soluble glycopeptide, designated as MTW, was isolated and purified from crude mannatide by DEAE-Sepharose. MTW showed one symmetrical peak on HPGPC with an average molecular weight of 2.95×10⁴Da. MTW contained 16 kinds of amino acids and the total amino acid content was 0.95%. The structure of polysaccharide moiety of MTW was elucidated based on monosaccharide composition, methylation analysis, partial acid hydrolysis, IR and 1D/2D NMR spectroscopy. The results showed that MTW was a homogeneous glycopeptide including mannose and glucose with a molar ratio of 2:1. The polysaccharide moiety of MTW had a backbone of (1→6)-α-d-Man p residues, which highly branched at O-2 position of (1→2,6)-α-d-Man p residues. The side chains were mainly composed of (1→)-α-d-Man p, (1→2)-α-d-Man p, (1→4)-α-d-Glc p, (1→4,6)-α-d-Glc p residues. The backbone of the polysaccharide moiety of MTW was the same as MT2-A (Li et al. [1]), which was the main component of mannatide, but the side chains of MTW were somewhat different from that of MT2-A. Complement-fixation test indicated that MTW had the same beneficial effect on immunological activity as MT2-A.



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What can we get from varying scan rate in protein differential scanning calorimetry?

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Mojtaba Amani, Ali A. Moosavi-Movahedi, Boris I. Kurganov
Differential scanning calorimetry has many advantages over other techniques to study the thermal stability of proteins due to its direct measurement of thermodynamic parameters. Most proteins undergo irreversible thermal denaturation causing their thermogram to be scan rate dependent. We modeled reversible and irreversible protein thermograms at varying scan rates. The complete Lumry-Eyring model was used to model the irreversible thermograms at various values of T1/2 (temperature at which equilibrium constant equals unity) and T* (temperature at which rate constant equals 1min⁻¹). Our results have shown that the thermal effects of two processes are integrated with decreasing the T* relative to T1/2. It is also shown that the shape of second derivatives of thermograms under different conditions have specific pattern which can be used to judge and estimate the correct model for protein denaturation.



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Editorial Board

Publication date: March 2017
Source:Free Radical Biology and Medicine, Volume 104





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Cryptosporidium-contaminated water disinfection by a novel Fenton process

Publication date: May 2017
Source:Free Radical Biology and Medicine, Volume 106
Author(s): Sina Matavos-Aramyan, Mohsen Moussavi, Hedieh Matavos-Aramyan, Sara Roozkhosh
Three novel modified advanced oxidation process systems including ascorbic acid-, pro-oxidants- and ascorbic acid-pro-oxidants-modified Fenton system were utilized to study the disinfection efficiency on Cryptosporidium-contaminated drinking water samples. Different concentrations of divalent and trivalent iron ions, hydrogen peroxide, ascorbic acid and pro-oxidants at different exposure times were investigated. These novel systems were also compared to the classic Fenton system and to the control system which comprised of only hydrogen peroxide. The complete in vitro mechanism of the mentioned modified Fenton systems are also provided. The results pointed out that by considering the optimal parameter limitations, the ascorbic acid-modified Fenton system decreased the Cryptosporidium oocytes viability to 3.91%, while the pro-oxidant-modified and ascorbic acid-pro-oxidant-modified Fenton system achieved an oocytes viability equal to 1.66% and 0%, respectively. The efficiency of the classic Fenton at optimal condition was observed to be 20.12% of oocytes viability. The control system achieved 86.14% of oocytes viability. The optimum values of the operational parameters during this study are found to be 80mgL⁻¹ for the divalent iron, 30mgL⁻¹ for ascorbic acid, 30mmol for hydrogen peroxide, 25mgL⁻¹ for pro-oxidants and an exposure time equal to 5min. The ascorbic acid-pro-oxidants-modified Fenton system achieved a promising complete water disinfection (0% viability) at the optimal conditions, leaving this method a feasible process for water disinfection or decontamination, even at industrial scales.

Graphical abstract

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Role of Glycine 221 in Catalytic Activity of Hyaluronan-Binding Protein 2 [Enzymology]

Hyaluronan-Binding Protein 2 (HABP2) is a Ca2+-dependent serine protease with putative roles in blood coagulation and fibrinolysis. A G221E substitution, known as the Marburg-I polymorphism, reportedly affects HABP2 function and has been associated with increased risk for cardiovascular disease. However, the importance of Gly-221 for HABP2 activity is unclear. Here, we used G221E, G221A, and G221S mutants to assess the role of Gly-221 in HABP2 catalysis. The G221E variant failed to activate single-chain urokinase-type plasminogen activator (scuPA), and the G221A and G221S variants displayed moderately reduced scuPA-activation. Activity toward the peptide substrate S-2288 was markedly decreased in all HABP2 variants, with G221E being the most defective and G221A the least. In the absence of Ca2+, S-2288 cleavage by wild-type HABP2 was Na+-dependent, with Km decreasing from 3.0 to 0.6 mM upon titration from 0 to 0.3 M Na+. In the presence of 5 mM Ca2+, Km was further reduced to 0.05 mM, but without appreciable contribution of Na+. At physiological concentrations of Na+ and Ca2+, the three HABP2 variants, and particularly G221E, displayed a major Km increase for S-2288. Chemical footprinting revealed that Ile-16 is significantly less protected from chemical modification in G221E than in wild-type HABP2, suggesting impaired insertion of the N-terminus into the G221E protease domain, with a concomitant impact on catalytic activity. Homology modeling suggested that the Glu-221 side chain could sterically hinder insertion of the N-terminus into the HABP2 protease domain, helping to explain the detrimental effects of Glu-221 substitution on HABP2 activity.

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Cyp24a1 attenuation limits progression of BrafV600E-induced papillary thyroid cancer cells and sensitizes them to BRAFV600E inhibitor PLX4720

CYP24A1, the primary inactivating enzyme for vitamin D, is often overexpressed in human cancers, potentially neutralizing the antitumor effects of calcitriol, the active form of vitamin D. However, it is unclear whether CYP24A1 expression serves as a functional contributor versus only a biomarker for tumor progression. In this study, we investigated the role of CYP24A1 on malignant progression of a murine model of BrafV600E-induced papillary thyroid cancer (PTC). Mice harboring wild-type Cyp24a1 (BVECyp24a1-wt) developed PTC at 5 weeks of age. Mice harboring a homozygous deletion of Cyp24a1 (BVECyp24a1-null) exhibited a 4-fold reduction in tumor growth. Notably, we found the tumorigenic potential of BVECyp24a1-null-derived tumor cells to be nearly abolished in immunocompromised nude mice. This phenotype was associated with downregulation of MAPK, PI3K/Akt, and TGF-β signaling pathways and a loss of epithelial-mesenchymal transition (EMT) in BVECyp24a1-null cells, associated with downregulation of genes involved in EMT, tumor invasion and metastasis. While calcitriol treatment did not decrease cell proliferation in BVECyp24a1-null cells, it strengthened antitumor responses to the BrafV600E inhibitor PLX4720 in both BVECyp24a1-null and BVECyp24a1-wt cells. Our findings offer direct evidence that Cyp24a1 functions as an oncogene in papillary thyroid cancer, where its overexpression activates multiple signaling cascades to promote malignant progression and resistance to PLX4720 treatment.

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News and Notices

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Anti-melanoma differentiation-associated protein 5 autoantibodies as a marker for dermatomyositis-associated interstitial lung disease

Linked Article: Matsushita et al. Br J Dermatol 2017; 176:395–402.

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Induced autoimmune bullous diseases

Linked Article: Guerra et al. Br J Dermatol 2017; 176:491–494.

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Intense pulsed light combined with methyl aminolaevulinate for treating actinic keratoses and photoaged skin of the dorsal hands has considerable advantages. However, is it worth the extra expense?

Linked Article: Kohl et al. Br J Dermatol 2017; 176:352–362.

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Image Gallery: Haemophagocytic lymphohistiocytosis in an adult with Langerhans cell histiocytosis

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Towards personalized modification of microbial imbalances

Linked Article: Szabó et al. Br J Dermatol 2017; 176:344–351.

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Image Gallery: PELVIS syndrome

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The treatment of vulval lichen sclerosus in prepubertal girls: a critically appraised topic

Summary

Lichen sclerosus is one of the dermatoses that specifically affects the anogenital skin. It has peaks of incidence in prepubertal girls and postmenopausal women. The objective of this critical appraisal was to review systematically the evidence for efficacy and safety of different treatments. There are no randomized controlled studies of treatment in prepubertal girls and most studies are small case series or case reports. There is little focus on quality of life.

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Severe systemic juvenile xanthogranuloma is an indication for systemic therapy

Linked Article: Maintz et al. Br J Dermatol 2017; 176:481–487.

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Evidence-based management of rosacea

Linked Article: Schaller et al. Br J Dermatol 2017; 176:465–471.

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Neuropeptide PACAP promotes sweat secretion

Linked Article: Sasaki et al. Br J Dermatol 2017; 176:413–422.

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NICE approval of adalimumab for moderate-to-severe hidradenitis suppurativa: the end of the beginning for hidradenitis suppurativa therapeutics?

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Atopic dermatitis and gut microbiota

Linked Article: Nowrouzian et al. Br J Dermatol 2017; 176:439–445.

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Plain language summaries in Simplified Chinese

Linked Article: Thandar et al. Br J Dermatol 2017; 176:330–343.

Linked Article: Køster et al. Br J Dermatol 2017; 176:446–456.

Linked Article: Mohanty et al. Br J Dermatol 2017; 176:403–412.

Linked Article: Steinke et al. Br J Dermatol 2017; 176:363–370.

Linked Article: Kohl et al. Br J Dermatol 2017; 176:352–362.

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More than skin-deep: is basal cell carcinoma a marker for a cancer-prone phenotype?

Linked Article: Ransohoff et al. Br J Dermatol 2017; 176:512–516.

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Fumaric acid esters: a new therapeutic option for skin manifestations in lupus erythematosus?

Linked Article: Saracino and Orteu Br J Dermatol 2017; 176:472–480.

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British Association of Dermatologists’ guidelines for the management of contact dermatitis 2017

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AdDRESSing T-cell responses to antituberculous drugs

Linked Article: Ye et al. Br J Dermatol 2017; 176:378–386.

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Increasing value in research

Linked Article: Thandar et al. Br J Dermatol 2017; 176:330–343.

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Cover Image: Aquagenic wrinkling of the palms: a clue to underlying cystic fibrosis heterozygosity

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Utilization of outreach immunization services among children in Hoima District, Uganda: a cluster survey

The global vaccine action plan 2011–2020 was endorsed by 194 states to equitably extend the benefits of immunization to all people. However, gaps in vaccination coverage remain in developing countries such as ...

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Haemophagocytic syndrome in an adult suffering from pyrexia of unknown origin: an uncommon presentation of tuberculosis: a case report

Tuberculosis is common, can involve various organs of the body and may have diverse presentations. Haemophagocytic syndrome is one of the rare presentations of tuberculosis carrying a very high mortality. Earl...

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“Disȷointed” approach to rare diseases is still failing patients, warn MPs

Many patients in England with rare diseases are still not receiving the right treatment despite a UK wide strategy being launched to improve care more than three years ago, MPs and peers have said.In...

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Gene therapy for primary immune deficiencies: a Canadian perspective

The use of gene therapy (GT) for the treatment of primary immune deficiencies (PID) including severe combined immune deficiency (SCID) has progressed significantly in the recent years. In particular, long-term...

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Conserved functions of the trigger loop and Gre factors in RNA cleavage by bacterial RNA polymerases [Gene Regulation]

RNA cleavage by RNA polymerase (RNAP) is the central step in co-transcriptional RNA proofreading. Bacterial RNAPs were proposed to rely on the same mobile element of the active site, the trigger loop (TL), for both nucleotide addition and RNA cleavage. RNA cleavage can also be stimulated by universal Gre factors, which should replace the TL to get access to the RNAP active site. The contributions of the TL and Gre factors to RNA cleavage reportedly vary between RNAPs from different bacterial species and, probably, different types of transcription complexes. Here, by comparing RNAPs from Escherichia coli (Eco), Deinococcus radiodurans (Dra) and Thermus aquaticus (Taq) we show that the functions of the TL and Gre factors in RNA cleavage are conserved in various species, with important variations which may be related to extremophilic adaptation. Deletions of the TL strongly impair intrinsic RNA cleavage by all three RNAPs and eliminate the inter-species differences in the reaction rates. GreA factors activate RNA cleavage by wild-type RNAPs to similar levels. The rates of GreA-dependent cleavage are lower for ΔTL RNAP variants, suggesting that the TL contributes to the Gre function. Finally, neither the TL nor GreA can efficiently activate RNA cleavage in certain types of backtracked transcription complexes suggesting that these complexes adopt a catalytically inactive conformation probably important for transcription regulation.

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Ex Vivo Human Pancreatic Slice Preparations Offer a Valuable Model for Studying Pancreatic Exocrine Biology [Cell Biology]

A genuine understanding of human exocrine pancreas biology and pathobiology has been hampered by a lack of suitable preparations and reliance on rodent models employing dispersed acini preparations. We have developed an organotypic slice preparation of the normal portions of human pancreas obtained from cancer resections. The preparation was assessed for physiologic and pathological responses to the cholinergic agonist carbachol (Cch) and cholecystokinin (CCK-8), including 1) amylase secretion, 2) exocytosis, 3) intracellular Ca2+ responses, 4) cytoplasmic autophagic vacuole formation, and 5) protease activation. Cch and CCK-8 both dose-dependently stimulated secretory responses from human pancreas slices similar to those previously observed in dispersed rodent acini. Confocal microscopy imaging showed that these responses were accounted for by efficient apical exocytosis at physiologic doses of both agonists and by apical blockade and redirection of exocytosis to the basolateral plasma membrane at supramaximal doses. The secretory responses and exocytotic events evoked by CCK-8 were mediated by CCK-A and not CCK-B receptors. Physiologic agonist doses evoked oscillatory Ca2+ increases across the acini. Supraphysiologic doses induced formation of cytoplasmic autophagic vacuoles and activation of proteases (trypsin, chymotrypsin). Maximal atropine pretreatment that completely blocked all the Cch-evoked responses did not affect any of the CCK-8-evoked responses, indicating that rather than acting on the nerves within the pancreas slice, CCK cellular actions directly affected human acinar cells. Human pancreas slices represent excellent preparations to examine pancreatic cell biology and pathobiology and could help screen for potential treatments for human pancreatitis.

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DNA breaks and chromatin structural changes enhance the transcription of Autoimmune Regulator target genes [Immunology]

The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T-cells by promoting the ectopic expression of tissue-specific genes in thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA-seq, we found that the inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by topoisomerase 1 (TOP1) inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional upregulation to co-occur with the chromatin structural changes within the genomic cluster of carcino-embryonic antigen-like cellular adhesion molecule (CEACAM) genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes.

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Obesity Challenges the Hepatoprotective Function of the Integrated Stress Response to Asparaginase Exposure in Mice [Signal Transduction]

Obesity increases risk for liver toxicity by the anti-leukemic agent asparaginase but the mechanism is unknown. Asparaginase activates the integrated stress response (ISR) via sensing of amino acid depletion by the eukaryotic initiation factor 2 (eIF2) kinase GCN2. The goal of this work was to discern the impact of obesity, alone versus alongside genetic disruption of the ISR, on mechanisms of liver protection during chronic asparaginase exposure in mice. Following diet-induced obesity, biochemical analysis of livers revealed that asparaginase provoked hepatic steatosis that coincided with activation of another eIF2 kinase PERK, a major ISR transducer to ER stress. Genetic loss of Gcn2 intensified hepatic PERK activation to asparaginase yet surprisingly, mRNA levels of key ISR gene targets such as Atf5 and Trib3 failed to increase. Instead, mechanistic target of rapamycin complex 1 (mTORC1) signal transduction was unleashed and this coincided with liver dysfunction reflected by a failure to maintain hydrogen sulfide production or apolipoprotein B100 expression. In contrast, obese mice lacking hepatic activating transcription factor 4 (Atf4) showed an exaggerated ISR and greater loss of endogenous hydrogen sulfide but normal inhibition of mTORC1 and maintenance of apolipoprotein B100 during asparaginase. In both genetic mouse models, expression and phosphorylation of Sestrin2, an ATF4 gene target, was increased by asparaginase, suggesting mTORC1 inhibition during asparaginase is not driven via eIF2-ATF4-Sestrin2. In conclusion, obesity promotes a maladaptive ISR during asparaginase exposure. GCN2 functions to repress mTORC1 activity and maintain ApoB100 protein levels independently of Atf4 expression, whereas hydrogen sulfide production is promoted via GCN2-ATF4 pathway.

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Acute Acinar Pancreatitis Blocks Vesicle-Associated Membrane Protein 8 (VAMP8)-Dependent Secretion Resulting in Intracellular Trypsin Accumulation [Cell Biology]

Zymogen secretory granules in pancreatic acinar cells express two vesicle associated membrane proteins (VAMP), VAMP2 and 8, each controlling 50% of stimulated secretion. Analysis of secretion kinetics identified a first−phase (0 − 2 min) mediated by VAMP2, and second− (2 − 10 min) and third−phases (10− 30 min) mediated by VAMP8. Induction of acinar pancreatitis by supramaximal cholecystokinin (CCK−8) stimulation inhibits VAMP8−mediated second− and third−phase, but not VAMP2−mediated first-phase secretion. Elevation of cAMP during supramaximal CCK-8 mitigates third−phase secretory inhibition and acinar damage caused by the accumulation of prematurely activated trypsin. VAMP8−/− acini are resistant to secretory inhibition by supramaximal CCK−8, and in spite of a 4.5 fold increase in total cellular trypsinogen levels, are fully protected from intracellular trypsin accumulation and acinar damage. VAMP8-mediated secretion is dependent on expression of the early endosomal proteins Rab5, D52 and EEA1. Supramaximal CCK−8 (60 min) caused a 60% reduction in the expression of D52 followed by Rab 5 and EEA1 in isolated acini and in in vivo. The loss of D52 occurred as consequence of its entry into autophagic vacuoles and was blocked by lysosomal cathepsin B and L inhibition. Accordingly, adenoviral overexpression of Rab5 or D52 enhanced secretion in response to supramaximal CCK−8 and prevented accumulation of activated trypsin. These data support that acute inhibition of VAMP8-mediated secretion during pancreatitis triggers intracellular trypsin accumulation and the loss of the early endosomal compartment. Maintaining anterograde endosomal trafficking during pancreatitis maintains VAMP8−dependent secretion thereby preventing accumulation of activated trypsin.

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CDK5/FBW7-dependent Ubiquitination and Degradation of EZH2 Inhibits Pancreatic Cancer Cell Migration and Invasion [Protein Synthesis and Degradation]

Pancreatic cancer is one of the most lethal cancer types. Enhancer of zeste homolog 2 (EZH2) is an oncogenic protein and overexpressed in pancreatic cancer, and EZH2 could be a potential therapeutic target for the treatment of pancreatic cancer. Although significant progress has been made toward understanding the function and deregulation of EZH2 in cancer cells, the post-translational regulation of EZH2 in cancer cells is still unclear. F-box and WD repeat domain-containing 7 (FBW7) acts as a tumor suppressor by targeting multiple oncoprotein substrates for ubiquitination and degradation. Here, we demonstrated that EZH2 was a bona fide substrate of FBW7 in pancreatic cancer cells. We provided evidence that the activated CDK5 kinase was involved in the EZH2 phosphorylation that was required for FBW7-mediated degradation. We further showed that FBW7 suppressed EZH2 activity and inhibited tumor migration and invasion via degradation of EZH2 in pancreatic cancer cells. Furthermore, immunohistochemistry analysis revealed that expression of EZH2 protein negatively correlated with FBW7 protein levels in a cohort of human pancreatic cancer specimens. Collectively, our findings demonstrate FBW7 as a novel E3 ligase of EZH2 regulates of EZH2 protein level in pancreatic cancer and represents a viable strategy for effective treatment of pancreatic cancer.

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Eukaryotic translation initiation factor 4G (eIF4G) coordinates interactions with eIF4A, eIF4B and eIF4E in binding and translation of the barley yellow dwarf virus 3' cap-independent translation element (BTE) [RNA]

Barley yellow dwarf virus (BYDV) RNA, lacking a 5′ cap and a 3′poly(A) tail, contains a cap-independent translation element (BTE) in the 3′untranslated region that interacts with host translation initiation factor eIF4G. To determine how eIF4G recruits the mRNA, three eIF4G deletion mutants were constructed: (i) eIF4G601-1196, containing amino acids 601-1196, including the putative BTE-binding region, and binding domains for eIF4E, eIF4A, eIF4B; (ii) eIF4G601-1488, which contains an additional C-terminal eIF4A-binding domain; and (iii) eIF4G742-1196, which lacks the eIF4E-binding site. eIF4G601-1196 binds BTE tightly and supports efficient translation. The helicase complex, consisting of eIF4A, eIF4B and ATP, stimulated BTE binding with eIF4G601-1196 but not eIF4G601-1488, suggesting that the eIF4A binding domains, may serve a regulatory role, with the C-terminal binding site having negative effects. eIF4E binding to eIF4G601-1196, induced a conformational change, significantly increasing the binding affinity to BTE. A comparison of the binding of eIF4G deletion mutants with BTEs containing mutations, showed a general correlation between binding affinity and ability to facilitate translation. In summary, these results reveal a new role for the helicase complex in 3′ CITE-mediated translation and show that the functional core domain of eIF4G, plus an adjacent probable RNA binding domain mediate translation initiation.

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Novel role for Wnt inhibitor APCDD1 in adipocyte differentiation: implications for diet-induced obesity [Lipids]

Impaired adipogenic differentiation during diet-induced obesity (DIO) promotes adipocyte hypertrophy and inflammation, thereby contributing to metabolic disease. Adenomatosis polyposis coli downregulated 1 (APCDD1) has recently been identified as an inhibitor of Wnt signaling, a key regulator of adipogenic differentiation. Here, we report a novel role for APCDD1 in adipogenic differentiation via repression of Wnt signaling, and an epigenetic linkage between miR-130 and APCDD1 in DIO. APCDD1 expression was significantly upregulated in mature adipocytes as compared to undifferentiated preadipocytes in both human and mouse subcutaneous adipose tissues. siRNA-based silencing of APCDD1 in 3T3-L1 preadipocytes markedly increased expression of Wnt signaling proteins (Wnt3a, Wnt5a, Wnt10b, LRP5, β-catenin), and inhibited expression of adipocyte differentiation markers (C/EBPα, PPARγ and lipid droplet accumulation, while adenovirus-mediated overexpression of APCDD1 enhanced adipogenic differentiation. Notably, DIO mice exhibited reduced APCDD1 expression and increased Wnt expression in both subcutaneous and visceral adipose tissues and impaired adipogenic differentiation in vitro. Mechanistically, we found that miR-130, whose expression is upregulated in adipose tissues of DIO mice, could directly target the 3′-untranslated region of the APCDD1 gene. Furthermore, transfection of a miR-130 inhibitor in preadipocytes enhanced, while a miR-130 mimic blunted, adipogenic differentiation, suggesting that miR-130 contributes to impaired adipogenic differentiation during DIO by repressing APCDD1 expression. Finally, human subcutaneous adipose tissues isolated from obese individuals exhibited reduced expression of APCDD1, C/EBPα and PPARγ as compared to those from non-obese subjects. Taken together, these novel findings suggest that APCDD1 positively regulates adipogenic differentiation, and that its downregulation by miR-130 during DIO may contribute to impaired adipogenic differentiation and obesity-related metabolic disease.

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The leukotriene B4 receptors BLT1 and BLT2 form an antagonistic sensitizing system in peripheral sensory neurons [Signal Transduction]

Sensitization of the heat-activated ion channel Transient Receptor Potential Vanilloid 1 (TRPV1) through lipids is a fundamental mechanism during inflammation-induced peripheral sensitization. Leukotriene B4 is a proinflammatory lipid-mediator whose role in peripheral nociceptive sensitization is to date not well understood. Two major G-Protein-coupled receptors for Leukotriene B4 have been identified: the high affinity receptor BLT1 and the low affinity receptor BLT2. Transcriptional screening for the expression GProtein-coupled receptors in murine dorsal root ganglia showed that both receptors were among the highest expressed in dorsal root ganglia. Calcium imaging revealed a sensitization of TRPV1-mediated calcium increases in a relative narrow concentration range for Leukotriene B4 (100-200 nM). Selective antagonists and neurons from knockout mice demonstrated a BLT1-dependent sensitization of TRPV1-mediated calcium increases. Accordingly, Leukotriene B4 -induced thermal hyperalgesia was mediated through BLT1 and TRPV1 as shown using the respective knockout mice. Importantly, higher Leukotriene B4 concentrations (>0.5 μM) and BLT2 agonists abolished sensitization of the TRPV1-mediated calcium increases. Also, BLT2-activation inhibited protein kinase C- as well as protein kinase Amediated sensitization processes through the phosphatase calcineurin. Consequently, a selective BLT2-receptor agonist increased thermal and mechanical withdrawal thresholds during zymosan-induced inflammation. In accordance with these data immunohistochemical analysis showed that both Leukotriene B4 receptors were expressed in peripheral sensory neurons. Thus, the data show that the two Leukotriene B4 receptors have opposing roles in the sensitization of peripheral sensory neurons forming a self-restricting system.

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Abnormal Breathing Patterns Predict Extubation Failure in Neurocritically Ill Patients

In neurologically injured patients, predictors for extubation success are not well defined. Abnormal breathing patterns may result from the underlying neurological injury. We present three patients with abnormal breathing patterns highlighting failure of successful extubation as a result of these neurologically driven breathing patterns. Recognizing abnormal breathing patterns may be predictive of extubation failure and thus need to be considered as part of extubation readiness.

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Non-Newtonian Comment of Lebesgue Measure in Real Numbers

We would like to generalize to non-Newtonian real numbers the usual Lebesgue measure in real numbers. For this purpose, we introduce the Lebesgue measure on open and closed sets in non-Newtonian sense and examine their basic properties.

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A Rare Case of Stroke Secondary to Iron Deficiency Anemia in a Young Female Patient

Ischemic strokes occur when there is a sudden obstruction of an artery supplying blood flow to an area of the brain, leading to a focal neurological deficit. Strokes can be thrombotic or embolic in etiology and are associated with underlying conditions such as hypertension and atherosclerosis. Possible etiologies of strokes include cardioembolic disease, hematologic disorders, connective tissue disorders, and substance abuse or can be cryptogenic. Most stroke cases are seen in patients over 65 years of age. However, about one-fourth of strokes occur in young adults. Iron deficiency anemia (IDA) has been described as a known cause for strokes in children, but very few case reports describe this association in adults. We describe a 20-year-old female who presented with sudden onset left side weakness. Magnetic Resonance Imaging (MRI) of the brain demonstrated ischemic infarctions. Patient was also found to be severely anemic. Patient had a thorough work-up including Magnetic Resonance Angiography (MRA) of the brain, echocardiogram, and an extensive screen for thrombophilia disorders. This, however, did not demonstrate a clear etiology. As it has been suggested that IDA is a potential cause for stroke, it is possible the stroke in this young patient was attributable to severe IDA.

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Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension

Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined. Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved endothelium-dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1) in endothelial cells. Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries) and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability.

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Central Hyperthermia Treated with Bromocriptine

Introduction. Central hyperthermia is common in patients with brain injury. It typically has a rapid onset with high temperatures and marked fluctuations and responds poorly to antibiotics and antipyretics. It is also associated with worse outcomes in the brain injured patient. Recognizing this, it is important to aggressively manage it. Case Report. We report a 34-year-old male with a right thalamic hemorrhage extending to the midbrain and into the ventricles. During his admission, he developed intractable fevers with core temperatures as high as 39.3°C. Infectious workup was unremarkable. The fever persisted despite empiric antibiotics, antipyretics, and cooling wraps. Bromocriptine was started resulting in control of the central hyperthermia. The fever spikes were reduced to minor fluctuations that significantly worsened with any attempt to wean off the bromocriptine. Conclusion. Diagnosing and managing central hyperthermia can be challenging. The use of bromocriptine can be beneficial as we have reported.

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Simulation of the Effect of Artificial Water Transfer on Carbon Stock of Phragmites australis in the Baiyangdian Wetland, China

How to explain the effect of seasonal water transfer on the carbon stocks of Baiyangdian wetland is studied. The ecological model of the relationship between the carbon stocks and water depth fluctuation of the reed was established by using STELLA software. For the first time the Michaelis-Menten equation (1) introduced the relation function between the water depth and reed environmental carrying capacity, (2) introduced the concept of suitable growth water depth, and (3) simulated the variation rules of water and reed carbon stocks of artificial adjustment. The model could be used to carry out the research on the optimization design of the ecological service function of the damaged wetland.

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Values, Norms, and Peer Effects on Weight Status

This study uses data from the European Social Survey in order to test the Prinstein-Dodge hypothesis that posits that peer effects may be larger in collectivistic than in individualistic societies. When defining individualism and collectivism at the country level, our results show that peer effects on obesity are indeed larger in collectivistic than in individualistic societies. However, when defining individualism and collectivism with individual values based on the Shalom Schwartz universal values theory, we find little support for this hypothesis.

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Consensus Control for a Multiagent System with Time Delays

In this paper, we consider the consensus control problem for a multiagent system (MAS) consisting of integrator dynamics with input and output time delays. First, we investigate a consensus condition for the MAS with a linear controller and without any delay compensation. We then propose a consensus controller with a state predictor to compensate the effect of time delay. The consensus condition for this controller is derived and investigated. Finally, we present an example of solving the consensus control problem for two-wheel mobile robots with feedback loops that pass through a computer network with time delays. To demonstrate the validity of the predictor-based controller, we conduct experiments with two-wheel mobile robots and present the results.

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Deciphering the Roles of Thiazolidinediones and PPAR in Bladder Cancer

The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγ may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγ in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.

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The Optimal Strategies of Risk-Averse Newsvendor Model for a Dyadic Supply Chain with Financing Service

This paper studies the budget-constrained newsvendor problem under risk aversion with financing service and builds a two-stage supply chain decision model on the order quantity and wholesale price. The budget-constrained retailer as a newsvendor faces a nonnegative random demand and the financial institution provides the loan service for the retailer who is risk-averse. This paper first explores the impact of risk aversion on the decisions in financial supply chain. Different from the existing research, we analyze how the financing service of bank loan impacts the risk-averse newsvendor’s decision and how the risk-averse behavior of the retailer influences the optimal strategies in supply chain with CVaR risk measure criterion. It is found that the order quantity decreases in the degree of risk aversion. The optimal order quantity is decreasing in initial budget, wholesale price, and interest rate. It is worth noting that the financing service can improve the profit of the supply chain system when the retailer has a low initial wealth. Finally, to compare with the existing results the theoretical analysis and numerical examples are also illustrated.

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Diversity of Leptospira spp. in Rats and Environment from Urban Areas of Sarawak, Malaysia

Various prevalence studies on Leptospira in animals and humans, as well as environmental samples, had been conducted worldwide, including Malaysia. However, limited studies have been documented on the presence of pathogenic, intermediate, and saprophytic Leptospira in selected animals and environments. This study was therefore conducted to detect Leptospira spp. in rats, soil, and water from urban areas of Sarawak using the polymerase chain reaction (PCR) method. A total of 107 rats, 292 soil samples, and 324 water samples were collected from April 2014 to February 2015. Pathogenic Leptospira was present in 5.6% (6/107) of rats, 11.6% (34/292) of soil samples, and 1.9% (6/324) of water samples. Intermediate Leptospira was present in 2.7% (8/292) of soil samples and 1.9% (6/324) of water samples. Saprophytic Leptospira was present in 10.3% (11/107) of rats, 1.4% (4/292) of soil samples, and 0.3% (1/324) of water samples. From this study, 76 Leptospira spp. were isolated. Based on DNA sequencing, the dominant Leptospira spp. circulating in urban areas of Sarawak are pathogenic Leptospira noguchii, intermediate Leptospira wolffii serovar Khorat, and saprophytic Leptospira meyeri, respectively. Overall, this study provided important surveillance data on the prevalence of Leptospira spp. from rats and the environment, with dominant local serovars in urban areas of Sarawak.

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American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score: a study protocol for the translation and validation of the Dutch language version

Introduction

The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score is among the most commonly used instruments for measuring the outcome of treatment in patients who sustained a complex ankle or hindfoot injury. It combines a clinician-reported and a patient-reported part. A valid Dutch version of this instrument is currently not available. Such a translated and validated instrument would allow objective comparison across hospitals or between patient groups, and with shown validity and reliability it may become a quality of care indicator in future. The main aims of this study are to translate and culturally adapt the AOFAS Ankle-Hindfoot Score questionnaire into Dutch according to international guidelines, and to evaluate the measurement properties of the AOFAS Ankle-Hindfoot Score-Dutch language version (DLV) in patients with a unilateral ankle or hindfoot fracture.

Methods and analysis

The design of the study will be a multicentre prospective observational study (case series) in patients who presented to the emergency department with a unilateral ankle or hindfoot fracture or (fracture) dislocation. A research physician or research assistant will complete the AOFAS Ankle-Hindfoot Score-DLV based on interview for the subjective part and a physical examination for the objective part. In addition, patients will be asked to complete the Foot Function Index (FFI) and the Short Form-36 (SF-36). Descriptive statistics (including floor and ceiling effects), internal consistency, construct validity, reproducibility (ie, test–retest reliability, agreement and smallest detectable change) and responsiveness will be assessed for the AOFAS DLV.

Ethics and dissemination

This study has been exempted by the Medical Research Ethics Committee (MREC) Erasmus MC (Rotterdam, the Netherlands). Each participant will provide written consent to participate and remain anonymised during the study. The results of the study are planned to be published in an international, peer-reviewed journal.

Trial registration number

NTR5613. pre-result.

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Effectiveness of the Gold Standard Programme compared with other smoking cessation interventions in Denmark: a cohort study

Objectives

We compared the effectiveness of the Gold Standard Programme (a comprehensive smoking cessation intervention commonly used in Denmark) with other face-to-face smoking cessation programmes in Denmark after implementation in real life, and we identified factors associated with successful quitting.

Design

Prospective cohort study.

Setting

A total of 423 smoking cessation clinics from different settings reported data from 2001 to 2013.

Participants

In total, 82 515 patients were registered. Smokers ≥15 years old and attending a programme with planned follow-up were included. Smokers who did not want further contact, who intentionally were not followed up or who lacked information about the intervention they received were excluded. A total of 46 287 smokers were included.

Interventions

Various real-life smoking cessation interventions were identified and compared: The Gold Standard Programme, Come & Quit, crash courses, health promotion counselling (brief intervention) and other interventions.

Main outcome

Self-reported continuous abstinence for 6 months.

Results

Overall, 33% (11 184) were continuously abstinent after 6 months; this value was 24% when non-respondents were considered smokers. The follow-up rate was 74%. Women were less likely to remain abstinent, OR 0.83 (CI 0.79 to 0.87). Short interventions were more effective among men. After adjusting for confounders, the Gold Standard Programme was the only intervention with significant results across sex, increasing the odds of abstinence by 69% for men and 31% for women. In particular, compliance, and to a lesser degree, mild smoking, older age and not being disadvantaged were associated with positive outcomes for both sexes. Compliance increased the odds of abstinence more than 3.5-fold.

Conclusions

Over time, Danish smoking cessation interventions have been effective in real life. Compliance is the main predictor of successful quitting. Interestingly, short programmes seem to have relatively strong effects among men, but the absolute numbers are very small. Only the comprehensive Gold Standard Programme works across sexes.

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Analysis of the time and workers needed to conduct systematic reviews of medical interventions using data from the PROSPERO registry

Objectives

To summarise logistical aspects of recently completed systematic reviews that were registered in the International Prospective Register of Systematic Reviews (PROSPERO) registry to quantify the time and resources required to complete such projects.

Design

Meta-analysis.

Data sources and study selection

All of the 195 registered and completed reviews (status from the PROSPERO registry) with associated publications at the time of our search (1 July 2014).

Data extraction

All authors extracted data using registry entries and publication information related to the data sources used, the number of initially retrieved citations, the final number of included studies, the time between registration date to publication date and number of authors involved for completion of each publication. Information related to funding and geographical location was also recorded when reported.

Results

The mean estimated time to complete the project and publish the review was 67.3 weeks (IQR=42). The number of studies found in the literature searches ranged from 27 to 92 020; the mean yield rate of included studies was 2.94% (IQR=2.5); and the mean number of authors per review was 5, SD=3. Funded reviews took significantly longer to complete and publish (mean=42 vs 26 weeks) and involved more authors and team members (mean=6.8 vs 4.8 people) than those that did not report funding (both p<0.001).

Conclusions

Systematic reviews presently take much time and require large amounts of human resources. In the light of the ever-increasing volume of published studies, application of existing computing and informatics technology should be applied to decrease this time and resource burden. We discuss recently published guidelines that provide a framework to make finding and accessing relevant literature less burdensome.

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Onset seasons and clinical outcomes in patients with Stanford type A acute aortic dissection: an observational retrospective study

Objectives

To evaluate the association of onset season with clinical outcome in type A acute aortic dissection (AAD).

Design

A single-centre, observational retrospective study.

Setting

The study was conducted in Fuwai Hospital, the National Centre for Cardiovascular Disease, Beijing, China.

Participants

From 2008 to 2010, a set of consecutive patients with type A AAD, confirmed by CT scanning, were enrolled and divided into four groups according to onset season: winter (December, January and February), spring (March, April and May), summer (June, July and August) and autumn (September, October and November). The primary end points were in-hospital death and all-cause mortality during follow-up.

Results

Of the 492 cases in this study, 129 occurred in winter (26.2%), 147 in spring (29.9%), 92 in summer (18.7%), and 124 in autumn (25.2%). After a median follow-up of 20.4 months (IQR 9.7–38.9), the in-hospital mortality in cases occurring in autumn was higher than in the other three seasons (23.4% vs 8.4%, p<0.01). Long-term mortality was comparable among the four seasonal groups (p=0.63). After adjustment for age, gender and other risk factors, onset in autumn was still an independent factor associated with increased risk of in-hospital mortality (HR 2.05; 95% CI 1.15 to 3.64, p=0.02) in addition to surgical treatment. Further analysis showed that the seasonal effect on in-hospital mortality (autumn vs other seasons: 57.4% vs 27.3%, p<0.01) was only significant in patients who did not receive surgical treatment. No seasonal effect on long-term clinical outcomes was found in this cohort.

Conclusions

Onset in autumn may be a factor that increases the risk of in-hospital death from type A AAD, especially in patients who receive conservative treatment. Immediate surgery improves the short-term and long-term outcomes regardless of onset season.

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Improving outcomes from high-risk surgery: a multimethod evaluation of a patient-centred advanced care planning intervention

Introduction

Patients who are frail, have multiple comorbidities or have a terminal illness often have poor outcomes from surgery. However, sole specialists may recommend surgery in these patients without consultation with other treating clinicians or allowing for patient goals. The Patient-Centred Advanced Care Planning (PC-ACP) model of care provides a framework in which a multidisciplinary advanced care plan is devised to incorporate high-risk patients' values and goals. Decision-making is performed collaboratively by patients, their family, surgeons, anaesthetists, intensivists and surgical case managers. This study aims to evaluate the feasibility of this new model of care, and to determine potential benefits to patients and clinicians.

Methods and analysis

After being assessed for frailty, patients will complete a patient–clinician information engagement survey pretreatment and at 6 months follow-up. Patients (and/or family members) will be interviewed about their experience of care pretreatment and at 3 and 6 months follow-ups. Clinicians will complete a survey on workplace attitudes and engagement both preimplementation and postimplementation of PC-ACP and be interviewed, following each survey, on the implementation of PC-ACP. We will use process mapping to map the patient journey through the surgical care pathway to determine areas of improvement and to identify variations in patient experience.

Ethics and dissemination

This study has received ethical approval from Townsville Hospital and Health Service HREC (HREC/16/QTHS/100). Results will be communicated to the participating hospital, presented at conferences and submitted for publication in a peer-reviewed MEDLINE-indexed journal.

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Understanding the Models of Community Hospital rehabilitation Activity (MoCHA): a mixed-methods study

Introduction

To understand the variation in performance between community hospitals, our objectives are: to measure the relative performance (cost efficiency) of rehabilitation services in community hospitals; to identify the characteristics of community hospital rehabilitation that optimise performance; to investigate the current impact of community hospital inpatient rehabilitation for older people on secondary care and the potential impact if community hospital rehabilitation was optimised to best practice nationally; to examine the relationship between the configuration of intermediate care and secondary care bed use; and to develop toolkits for commissioners and community hospital providers to optimise performance.

Methods and analysis

4 linked studies will be performed. Study 1: cost efficiency modelling will apply econometric techniques to data sets from the National Health Service (NHS) Benchmarking Network surveys of community hospital and intermediate care. This will identify community hospitals' performance and estimate the gap between high and low performers. Analyses will determine the potential impact if the performance of all community hospitals nationally was optimised to best performance, and examine the association between community hospital configuration and secondary care bed use. Study 2: a national community hospital survey gathering detailed cost data and efficiency variables will be performed. Study 3: in-depth case studies of 3 community hospitals, 2 high and 1 low performing, will be undertaken. Case studies will gather routine hospital and local health economy data. Ward culture will be surveyed. Content and delivery of treatment will be observed. Patients and staff will be interviewed. Study 4: co-designed web-based quality improvement toolkits for commissioners and providers will be developed, including indicators of performance and the gap between local and best community hospitals performance.

Ethics and dissemination

Publications will be in peer-reviewed journals, reports will be distributed through stakeholder organisations. Ethical approval was obtained from the Bradford Research Ethics Committee (reference: 15/YH/0062).

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Blood venous sample collection: Recommendations overview and a checklist to improve quality

Publication date: Available online 27 February 2017
Source:Clinical Biochemistry
Author(s): Davide Giavarina, Giuseppe Lippi
The extra-analytical phases of the total testing process have substantial impact on managed care, as well as an inherent high risk of vulnerability to errors which is often greater than that of the analytical phase. The collection of biological samples is a crucial preanalytical activity. Problems or errors occurring shortly before, or soon after, this preanalytical step may impair sample quality and characteristics, or else modify the final results of testing.The standardization of fasting requirements, rest, patient position and psychological state of the patient are therefore crucial for mitigating the impact of preanalytical variability. Moreover, the quality of materials used for collecting specimens, along with their compatibility, can guarantee sample quality and persistence of chemical and physical characteristics of the analytes over time, so safeguarding the reliability of testing. Appropriate techniques and sampling procedures are effective to prevent problems such as hemolysis, undue clotting in the blood tube, draw of insufficient sample volume and modification of analyte concentration. An accurate identification of both patient and blood samples is a key priority as for other healthcare activities. Good laboratory practice and appropriate training of operators, by specifically targeting collection of biological samples, blood in particular, may greatly improve this issue, thus lowering the risk of errors and their adverse clinical consequences.The implementation of a simple and rapid check-list, including verification of blood collection devices, patient preparation and sampling techniques, was found to be effective for enhancing sample quality and reducing some preanalytical errors associated with these procedures. The use of this tool, along with implementation of objective and standardized systems for detecting non-conformities related to unsuitable samples, can be helpful for standardizing preanalytical activities and improving the quality of laboratory diagnostics, ultimately helping to reaffirm a “preanalytical” culture founded on knowledge and real risk perception.



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The current peer review system is unsustainable-awaken the paid reviewer force!

Publication date: Available online 27 February 2017
Source:Clinical Biochemistry
Author(s): Eleftherios P. Diamandis




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NT-proBNP is increased in differentiated thyroid carcinoma patients and may predict cardiovascular risk

Publication date: Available online 27 February 2017
Source:Clinical Biochemistry
Author(s): Esther N. Klein Hesselink, Anouk N.A. van der Horst-Schrivers, Iwan C.C. van der Horst, Stephan J.L. Bakker, Anneke C. Muller Kobold, Adrienne H. Brouwers, Geertruida H. de Bock, Jourik A. Gietema, Robin P.F. Dullaart, Thera P. Links, Joop D. Lefrandt
IntroductionChronic suppression of TSH in patients treated for differentiated thyroid carcinoma (DTC) may induce cardiac damage and increase risk for cardiovascular events and premature mortality. We aimed to compare circulating concentrations of N-terminal pro Brain Natriuretic Peptide (NT-proBNP) of DTC patients with controls, and to investigate whether higher NT-proBNP is associated with an increased risk for cardiovascular events and all-cause mortality in DTC patients.MethodsSerum NT-proBNP levels were determined in 266 DTC patients, median 10.4 [IQR 4.1–18.5] years after DTC diagnosis, and compared to 798 age- and sex-matched controls. Using multivariable Cox regression analyses, the association of NT-proBNP with cardiovascular events and all-cause mortality was determined. Hazard ratios (HR) and 95% confidence intervals (CIs) were expressed per SD increase of log-transformed NT-proBNP.ResultsMean age±SD of DTC patients and controls was 54.8±14.5 and 54.8±12.8years, respectively; 74% were women. Median NT-proBNP level was 70 [40–119] ng/L for DTC patients vs. 49 [25–89] ng/L for controls (p<0.001). During median follow-up of 8.6 [6.6–9.0] years, 30 DTC patients (11.4%) had a cardiovascular event and 38 (14.4%) died. Higher NT-proBNP was associated with an increased risk for cardiovascular events and all-cause mortality, age- and sex-adjusted HRs (95% CIs) 3.22 (2.17–4.79) and 1.61 (1.17–2.23), respectively. In further models with adjustment for cardiovascular risk factors, NT-proBNP remained independently associated with outcome.ConclusionNT-proBNP levels are elevated in patients with DTC, and are associated with an increased risk for cardiovascular events and all-cause mortality. Determination of NT-proBNP may identify DTC patients at increased cardiovascular risk, who could benefit from more stringent cardiovascular risk surveillance.



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Enteric fever: Resurrecting the epidemiologic footprints

Yatish Agarwal, Dipendra K Gupta, Ravindra S Sethi

Astrocyte 2016 3(3):153-161

A genetically monomorphic, human-restricted bacterial pathogen that causes 21 million cases of typhoid fever and 200,000 deaths each year, predominantly in southern Asia, Africa, and South America, Salmonella enterica subspecies serovar Typhi has a long and colored evolutionary history. Based on studies relating to the population genetic structure of Typhi by mutation discovery within 200 gene fragments from a globally representative strain collection of 105 strains, researchers have drawn up a phylogenetic tree for Salmonella typhi. It is surmised that the first ancestral strains of the bacteria appeared somewhere in Indonesia between 43000 and 10000BC. That despite the passage of millennia of years since the setting up of its first footprints on Mother Earth, Salmonella typhi has persisted as a highly homogeneous tribe, may have much to do with the asymptomatic carrier state in humans that they can dig into to survive. This process of neutral evolution and genetic buffering in Typhi coupled with the relatively more recent adaptive evolution, a sequel of rapid transmission of phenotypic changes through acute infections, has led to production of its antibiotic-resistant strains has made the task of public health physicians even more daunting and complex. These chronicles dwell on the historical truths and multihued accounts relating to the epidemiology of a disease that once changed the course of European history, battles, and wars, and, narrates, how, over time, the bacteriologists, pharmacologists, and physicians of the times came up trumps against the slayer bacteria.

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Role of soluble transferrin receptor and soluble transferrin receptor index in diagnosing iron deficiency anemia in patients with chronic kidney disease

Dipendra Kumar Gupta, Rajeev Krishna Choudhary, Monica Sharma, Sumita Saluja, Bhupender Gupta

Astrocyte 2016 3(3):125-130

Background: Approximately 25–38% of chronic kidney disease (CKD) patients with anemia suffer absolute or functional iron deficiency. This deficiency is estimated and monitored primarily through two iron indices, viz., transferrin saturation (TSAT) and serum ferritin. However, both these parameters suffer from several lacunae and search continues to establish more true measures. This study enquires into the role of soluble transferrin receptors (sTfR) and ratio of sTfR and log ferritin index (sTfR index) as potential measures of the true iron status in patients. Material and Methods: This prospective cross-sectional study comprised a total of 126 CKD patients with anemia on erythropoietin (EPO) undergoing hemodialysis (HD). Of these 126 patients, 55 had iron deficiency anemia (IDA). Estimations of serum iron, TSAT, serum ferritin, and sTfR and sTfR, indices were performed in each patient. Bone marrow aspiration (BMA) was carried out to determine cellularity, cytomorphology, and myeloid: erythroid (M/E) ratio, and was stained with Prussian blue stain. The results of the bone marrow iron status were taken as the gold standard. Subsequently, receiver operating characteristic (ROC) curve analysis was carried out to assess the discriminative power of the sTfR and sTfR indices for evaluation of iron status in patients with CKD. Results: The cut-off value of sTfR index at its maximum sensitivity (71.8%) and specificity (62%) was found to be 1.39, whereas that of sTfR at its maximum sensitivity (63.6%) and specificity (64.8%) was 3.00. Statistically significant correlations were found between sTfR index (Pearson correlation (r) = –0.379) and serum iron (r = –0.38; P < 0.01), TSAT (r = –0.31; P < 0.01), and serum ferritin (r = –0.399; P < 0.01). sTfR was found to correlate significantly (r = –0.445) with serum iron (P < 0.01), TSAT (r = –0.365; P < 0.01), and hemoglobin (r = –0.179; P = 0.04) but not with serum ferritin (r = 0.12; P = 0.153). Conclusion: sTfR and sTfR index values are useful tools for assessment of iron status in patients with CKD, however, they are at best complementary to the existing indices of serum ferritin and TSAT. Between sTfR and sTfR index, the latter has a greater discriminating power.

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Tetralogy of fallot with absent pulmonary valve with anomalous origin of the right pulmonary artery from ascending aorta

Varun V Nivargi, Vihita Kulkarni, CN Makhale

Astrocyte 2016 3(3):171-173

A 12 year old boy presented with history of cyanotic congenital heart disease with dyspnea on exertion since last 9 years. Patient was diagnosed as a case of Tetralogy of Fallot 5 years before he came to us and he had underwent a palliative Blalock Taussig Thomas shunt for the same. An intracardiac repair was attempted 4 years back which was abandoned due to unknown reasons. His symptoms persisted after the two procedures. On admission to our hospital a detailed echocardiogram was done that showed Tetralogy of Fallot with absent pulmonary valve with post stenotic dilatation of left pulmonary artery and an anomalous origin of right pulmonary artery from ascending aorta with a blocked B-T shunt. A high risk intracardiac repair was advised.

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Gender differences in the accuracy of stress 99mTc-sestamibi myocardial perfusion imaging

Deepa Kumar, Ravinder S Sethi, Sandeep Bansal, Padma A Namgyal, Aditi K Sehgal, Tajamul S Malik

Astrocyte 2016 3(3):131-136

Introduction: Coronary artery disease (CAD) is a leading cause of death in both women and men worldwide. There is under-recognition and under-diagnosis of CAD as a cause of high mortality rates in women. There is paucity of data regarding comparison of sensitivity, specificity, and accuracy of myocardial perfusion imaging-single photon emission computed tomography (MPI-SPECT) study in women and men in Indian population. Hence, this study was carried out to compare the sensitivity, specificity, and accuracy of MPI in women and men in the Indian population. Material and Methods: This retrospective study included 275 patients, 49 women and 226 men. Only patients who had coronary angiography (CAG) done within 6 months of the stress 99mTc-sestamibi MPI-SPECT study were included in the study. Two arbitrary cut-off points on CAG, i.e., ≥50% and ≥70% were used for the determination of extent of CAD. Results: Considering CAG as the gold standard with ≥50% coronary stenosis as the cut-off criteria for significant stenosis, the overall sensitivity, specificity, and accuracy, respectively, of MPI- SPECT was 80%, 65%, and 72% in women and 82%, 70%, and 76% in men (P value not significant). Considering ≥70% coronary stenosis as the cut off criteria for significant stenosis, the overall sensitivity, specificity, and accuracy, respectively, of MPI-SPECT was 88%, 57%, and 66% in women and 87%, 59%, and 70% in men (P value not significant). No significant difference was found in the sensitivity, specificity, and accuracy of left anterior descending, left circumflex artery, and right coronary artery coronary vessels among women and men for both ≥50% and ≥70% coronary stenosis as the cut off criteria. Conclusion: 99mTc-sestamibi MPI-SPECT has comparable sensitivity, specificity, and accuracy for the detection of CAD in women as it does in men.

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Hemorrhagic metastasis to brain from a primary mucoepidermoid carcinoma of esophagus

Yatish Agarwal, Sagar Tomar, Amit Kumar, Avneet S Chawla, Vinod Gupta, Poonam Khambra

Astrocyte 2016 3(3):165-167

Primary esophageal cancers rarely metastasize to the brain. On the rare occasion that such an event occurs, the histological cell type is mostly a squamous cell carcinoma. These brain metastases are picked up on contrast computed tomography typically as multiple ring enhancing hypodense lesions. In the histological spectrum of esophageal cancers, a mucoepidermoid carcinoma is rather rare. The possibility of it metastasizing to the brain is rarer still. That such a metastatic lesion be hemorrhagic is truly atypical, yet this case in point uncovers such an event, where an upper esophageal mucoepidermoid carcinoma in a 55-year-old male led to a hemorrhagic metastasis in the vermis of the cerebellum.

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Role of uric acid therapy in prevention of early ischemic stroke progression

KC Rakshith, Saumya H Mittal, ZK Misri, Shivanand Pai

Astrocyte 2016 3(3):137-138

Objective: To study the role of uric acid (UA) in the outcome of thrombolysis after stroke. Materials and Methods: Our observational study was conducted over 5 years at the KMC Hospital, Mangalore from July 2011 to July 2016. All patients above the age of 18 years presenting to the hospital within 4.5 hours of stroke onset were included into the study. The patients' stroke severity was calculated by National Institute of Health Stroke Scale (NIHSS) score, whereas the outcome was measured by modified Rankin Scale (mRS) score. The patients were divided into good outcome, poor outcome, and expired groups of patients depending on the mRS score (<3, ≥3 but <6, and 6, respectively). UA in the blood was measured and recorded in all the included patients. At the end of the study, significance was calculated by standard statistical methods. Results: A total of 71.9% patients were found to have a good outcome, 24.2% patients had poor outcome, and the rest were in the expired group of patients. Among the good outcome patients, UA was found to be 4.6 ± 1.4 mg/dL, in the poor outcome group UA was 3.7 ± 1.1 mg/dL, and in expired group UA was 3.2 ± 0.6 mg/dL (P = 0.002). Conclusion: Our results suggest that UA has neuroprotective actions and can predict a good outcome among patients undergoing thrombolysis.

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Of medical curricula and gen-next physicians

Yatish Agarwal, Bipin Batra

Astrocyte 2016 3(3):121-124



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Factors affecting knee flexion in primary total knee arthroplasty

Nilay Chhasatia, M Ravikumar, D Dhanalakshmi

Astrocyte 2016 3(3):139-141

Background: The two main measures of a successful primary total knee arthroplasty (TKA) are relief from pain and increase in the range of motion. Because the lifestyle in the Indian subcontinent requires bending of knee beyond 90° during the course of numerous daily chores, the range of knee flexion achieved following surgery is an important clinical outcome measure. This outcome can, however, be influenced by several variables. Objective: This study tried to analyze the possible difference in the postoperative knee flexion among patients undergoing primary TKA and establish the interrelationship among different covariates. Materials and Methods: Thirty-three patients of primary TKA were recruited in the study. Newly operated cases were followed up till 6 months postoperatively. Knee flexion as a part of knee society scoring was carried out as a part of the follow-up. The results obtained were suitably analyzed using the standard statistical tools. Results: Knee flexion in patellar resurfaced post-TKA group (114.17 ± 9.42; P = 0.01) was significantly higher than that in patellar nonresurfaced post-TKA group. Patients who were used to employing some kind of support while negotiating stairs had significantly worse pain scores (41.11 vs. 48.33; P = 0.007] and reduced knee flexion (105.56 vs. 119.17; P = 0.001) compared to those who did not use any support. Compared to males, females were more likely to use support while negotiating stairs (Wald chi square = 4.151, P = 0.04 OR = 8.0). Among all post-TKA patients, males were found to have a greater degree of knee flexion than females (120 vs. 105.37; P = 0.002). No significant difference in knee flexion was observed among age groups and type of arthritis or side of the operated knee. Conclusions: Patellar resurfacing and male sex was associated with a greater degree of post-TKA knee flexion in the study participants.

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Acquired vulvar lymphangioma circumscriptum

Aditi Sobti, Derrick Aw Chen Wee, Kong Bing Tan

Astrocyte 2016 3(3):162-164

Lymphangioma circumscriptum is a benign dilatation of lymph channels localized to the skin and subcutaneous tissues. This dermatological condition is generally found localized to the oral mucosa, tongue, proximal parts of arms and legs, groin, axilla, and trunk. Primary vulvar involvement is very rare. This report dwells on a 61-year-old female presenting with multiple itchy translucent warty papules on the left vulva. These lesions had been present for the past 3 years, and were gradually increasing in number and size. She had undergone a hysterectomy for uterine carcinoma 13 years ago, and had subsequently developed lymphedema of the left leg. Histopathologic examination of the biopsied vulvar papule demonstrated hyperkeratotic epidermis and dilatation of thin-walled lymph vessels in superficial dermal papillae. The physiopathological features helped clinch the diagnosis of vulvar lymphangioma circumscriptum.

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Pursuing a flexible approach to tympanomastoidectomy: Benefits of a tailor-made strategy in squamosal otitis media

Isha Preet Tuli, Anirudh Sarkar

Astrocyte 2016 3(3):142-147

Introduction: The keystone of definitive management in active squamosal chronic otitis media (COM) is surgical correction. Numerous surgical strategies are in vogue, and the choice of surgery is largely governed by the underlying anatomic and pathologic condition. Of recent, much interest has focused on adopting a flexible approach which combines a number of sequential steps that aim to eradicate the disease and reconstruct the hearing apparatus in a single stage procedure, rather than following a traditional approach of modified radical mastoidectomy. Patients and Methods: This randomized, prospective double-blind study comprised 30 patients of various ages and both sexes, diagnosed with a unilateral or bilateral active squamosal chronic otitis media (COM). Of them, 12 (40%) patients were submitted to canal-wall down mastoidectomy, whereas 18 (60%) underwent a canal-wall up procedure. Each patient was followed up for a period of 6 months. The success of the procedure was measured in terms of achieving dry ear; a successful uptake of graft; and improvement in hearing. Results: Post surgery, at the end of 6 weeks, a dry ear was achieved in 25 (83.33%) patients, while the graft was taken up well in 29 (96.67%) patients. At 6 months, the number of patients with dry ear grew to 27 (90%), while the graft was taken up well in 28 (93.33%) patients. Two (6.66%) patients had graft failure. Of the 12 patients with canal-wall down procedure, 9 (75%) patients recorded a hearing improvement of air bone gap (ABG) ≤30 dBHL, while among the 18 patients who had a canal-wall up procedure, 94% had a hearing improvement of ABG ≤ 30 dBHL. Conclusion: Pursuing a flexible approach to tympanomastoidectomy offers a number of distinct benefits. Because the procedure is tailored to the gravity of otologic disease recognized intraoperatively, it fosters a total eradication of the disease and allows a suitable reconstruction of the auditory mechanism. Because the procedure is completed in a single stage, it reduces the time, effort, cost, and discomfort to the patient, while also diminishing the expense and burden on the public healthcare facility.

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