The Role of PI3K/Akt and ERK in Neurodegenerative Disorders

Abstract

Disruption of Akt and Erk-mediated signal transduction significantly contributes in the pathogenesis of various neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's diseases, Huntington's disease, and many others. These regulatory proteins serve as the regulator of cell survival, motility, transcription, metabolism, and progression of the cell cycle. Therefore, targeting Akt and Erk pathway has been proposed as a reasonable approach to suppress ND progression. This review has emphasized on involvement of Akt/Erk cascade in the neurodegeneration. Akt has been reported to regulate neuronal toxicity through its various substrates like FOXos, GSK3β, and caspase-9 etc. Akt is also involved with PI3K in signaling pathway to mediate neuronal survival. ERK is another kinase which also regulates proliferation, differentiation, and survival of the neural cell. There has also been much progress in developing a therapeutic molecule targeting Akt and Erk signaling. Therefore, improved understanding of the molecular mechanism behind the regulatory aspect of Akt and Erk networks can make strong impact on exploration of the neurodegenerative disease pathogenesis.

http://bit.ly/2BcLvCz

Reply to the Letter to the Editor of Fei Jia et al. concerning “Comparison of combined anterior–posterior approach versus posterior-only approach in neuromuscular scoliosis: a systematic review and meta-analysis” by Shao ZX, et al. [Eur Spine J; (2018) 27(9): 2213–2222]

http://bit.ly/2sYmZAj

TiO 2 nanotube arrays modified with nanoparticles of platinum group metals (Pt, Pd, Ru): enhancement on photoelectrochemical performance

Abstract

Highly ordered TiO₂ nanotube arrays (TiO₂ NTs) were synthesized by anodization method using a titanium foil and further modified with nanoparticles (Ø = 2~10 nm) of three platinum group metals (that is, platinum, palladium, and ruthenium) through potentiostatic pulsed electrodeposition method to obtain the composite material. Compared with pure TiO₂ NTs, all the three composite samples (M-TiO₂ NTs, M = Pt, Pd, Ru) showed different enhancement effects on the light responses, as well as different photoelectrochemical performances. In this study, the performance of M-TiO₂ NTs, which worked as photoanode and cathode, was investigated. Ru-TiO₂ exhibited the best degradation yield (~ 85.8%) when applied as photoanode under visible light illumination, which indicated the platinum group metal could also be induced under visible irradiation, not just served as the co-catalyst. M-TiO₂ NTs as cathode were evaluated under the hydrogen evolution reaction (HER). The three M-TiO₂ NT electrodes showed an improved efficiency over pure TiO₂ NTs, while Pt-TiO₂ NTs performed even better (without any sacrificial agent) with higher Faradic efficiency than platinum electrode in the photoelectrocatalytic hydrogen production, which could be explained by the uniform and fine metal nanoparticles on the surface of TiO₂ NTs to offer abundant active sites for the reaction.

Graphical abstract

In this paper, TiO2 nanotube arrays loaded with nanoparticles of platinum group metals have been explored on their enhancement of photoelectrocatalytic activity. Platinum group metals served as co-catalyst in the surface of TiO2 nanotubes and show great variations in different reactions.

http://bit.ly/2Gds9Ap

Pathogens, Vol. 8, Pages 20: Antibacterial Activities of Herbal Toothpastes Combined with Essential Oils against Streptococcus mutans

Pathogens, Vol. 8, Pages 20: Antibacterial Activities of Herbal Toothpastes Combined with Essential Oils against Streptococcus mutans

Pathogens doi: 10.3390/pathogens8010020

Authors: Özgü İlkcan Karadağlıoğlu Nuran Ulusoy Kemal Hüsnü Can Başer Azmi Hanoğlu İrem Şık

In recent years, people have become more conscious about the side-effects of fluoride toothpastes and herbal products have drawn attention as alternatives in the struggle against caries. Studies have focused on the benefits of essential oils obtained from herbs because of their antibacterial effects. The aim of this study was to evaluate and compare the antibacterial activity of Origanum dubium and Cinnamomum cassia oils combined with herbal toothpastes against Streptococcus mutans. The antibacterial activity of the test materials was determined using the agar well diffusion method before and after the addition of essential oils. We tested the efficacy of Splat Organic and Splat Biocalcium against S. mutans (12 mm and 11 mm, respectively) doubled in combination with Origanum dubium (23 mm for both toothpastes) and tripled with Cinnamomum cassia (38 mm and 36 mm, respectively). Jack N’ Jill toothpaste, which did not initially show any antibacterial effect, exhibited the largest inhibition zones after the addition of the essential oils (38 mm for Origanum dubium and 39 mm for Cinnamomum cassia). The results of this study pointed out that herbal toothpastes exhibit statistically higher antibacterial activity against Streptococcus mutans (p < 0.05) than their initial forms after the addition of essential oils.

from Genes Mutations Carcinogenesis via alexandrossfakianakis on Inoreader http://bit.ly/2B9HiiH

Funding for imaging AI companies tops $1.2B

Investor money continues to surge into start-up companies that are developing...

Read more on AuntMinnieEurope.com

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from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2G2thHF

Verification of image quality and quantification in whole-body positron emission tomography with continuous bed motion

Abstract

Objective

Whole-body dynamic imaging using positron emission tomography (PET) facilitates the quantification of tracer kinetics. It is potentially valuable for the differential diagnosis of tumors and for the evaluation of therapeutic efficacy. In whole-body dynamic PET with continuous bed motion (CBM) (WBDCBM-PET), the pass number and bed velocity are key considerations. In the present study, we aimed to investigate the effect of a combination of pass number and bed velocity on the quantitative accuracy and quality of WBDCBM-PET images.

Methods

In this study, WBDCBM-PET imaging was performed at a body phantom using seven bed velocity settings in combination with pass numbers. The resulting image quality was evaluated. For comparing different acquisition settings, the dynamic index (DI) was obtained using the following formula: [P/S], where P represents the pass number, and S represents the bed velocity (mm/s). The following physical parameters were evaluated: noise equivalent count at phantom (NEC_phantom), percent background variability (N_10 mm), percent contrast of the 10 mm hot sphere (Q_{H, 10 mm}), the Q_{H, 10 mm}/N_10 mm ratio, and the maximum standardized uptake value (SUV_max). Furthermore, visual evaluation was performed.

Results

The NEC_phantom was equivalent for the same DI settings regardless of the bed velocity. The N_10 mm exhibited an inverse correlation (r < − 0.89) with the DI. Q_H,10 mm was not affected by DI, and a correlation between Q_H,10 mm/N_10 mm ratio and DI was found at all the velocities (r > 0.93). The SUV_max of the spheres was not influenced by the DI. The coefficient of variations caused by bed velocity decreased in larger spheres. There was no significant difference between the bed velocities on visual evaluation.

Conclusion

The quantitative accuracy and image quality achieved with WBDCBM-PET was comparable to that achieved with non-dynamic CBM, regardless of the pass number and bed velocity used during imaging for a given acquisition time.

http://bit.ly/2G2JvAQ

Assessment of fragile histidine triad expression in ameloblastoma, odontogenic keratocyst and dentigerous cyst

Vanishri Chandrashekhar Haragannavar, Anand S Tegginamani, Shashidara Raju, Shailesh Kudva, Celestina Dawn Peter, DK Shruthi

Indian Journal of Pathology and Microbiology 2019 62(1):3-6

Background: FHIT (Fragile histidine triad) a member of tumor suppressor family, has been extensively studied in many solid tumors including head and neck squamous cell carcinoma. Among all head and neck cyst and tumors odontogenic lesions account approximately 3%-9%. The molecular pathogenesis of these lesions is less explored. Defects in cell cycle regulators and tumor suppressor genes could result in the development of odontogenic cyst and tumors. Hence, we aimed to determine the significant role of a tumor suppressor gene FHIT in most commonly occurring odontogenic lesions mainly ameloblastoma, odontogenic keratocyst and dentigerous cyst. Subjects and Methods: Immunohistochemical analysis of FHIT was done in ameloblastoma, odontogenic keratocyst, dentigerous cyst and dental follicle. Interpretation of the stained slides were done using standard scoring criteria by two pathologist. The results were subjected for statistical analysis. Results: Expression of FHIT varied among the groups, with highest negative expression in ameloblastoma 44.4% followed by odontogenic keratocyst 14% and 100%positive expression was seen in dentigerous cyst. The expression levels between the groups were statistically insignificant. Conclusion: The varied expression or negative expression of FHIT could be considered as an indicator for aggressive behavior and transformation of preneoplastic/cystic epithelium.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2BaJuGQ

Intraosseous ganglion of the distal tibia: Clinical, radiological, and histopathological highlights

Ridhi Sood, Rajnish Garg, Harpreet Kaur, Neena Sood

Indian Journal of Pathology and Microbiology 2019 62(1):183-184



from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2Trxfg4

Tumor budding in laryngeal carcinoma

Sumeyye Ekmekci, Ulku Kucuk, Seda Kokkoz, Ebru Cakir, Murat Gumussoy

Indian Journal of Pathology and Microbiology 2019 62(1):7-10

Background: Tumor budding was defined as a single cancer cell or a cluster of fewer than five cancer cells in the stroma of the invasive tumor margin. It has been suggested as a prognostic factor in various cancers, such as esophageal, lung, colorectal, and endometrial. There are only a few studies about the prognostic signifi cance of tumor budding in laryngeal carcinomas. Materials and Methods: A total of 81 patients with laryngeal carcinoma diagnosed between 2011 and 2016 and treated by partial or total laryngectomy were evaluated. Clinicopathologic parameters were correlated with the presence and grade of tumor budding. Results: The study was consisted of 77 (95.1%) male and 4 (4.9%) female patients. The mean age of the patients was 60.2 years (min: 42 and max: 78). Median follow-up time was 25 months (min: 7 and max: 54) (SD ±11.5). Histopathologic diagnosis was squamous cell carcinoma (SCC) in all patients. Of the 62 cases showing budding, 2 (3.2%) were stage 1, 12 (19.4%) stage 2, 16 (25.8%) stage 3, and 32 (51.6%) were stage 4. Fifteen cases with budding (24.2%) showed lymphovascular invasion (LVI). None of the nonbudding cases had LVI and perineural invasion (PNI). Statistical analysis revealed that LVI and PNI were signifi cantly associated with budding (P = 0.017 and P = 0.012). Among the tumors showing budding, 37% had lymph node metastasis (LNM). In nonbudding cases 15% had LNM. There was a statistically significant correlation between LNM and budding (P = 0.017). None of the parameters correlated with grade of tumor budding statistically. Conclusion: The results of this study suggest that tumor budding might be used as a prognostic factor in laryngeal SCCs.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2Bhzpbb

Extramedullary plasmacytoma of tonsil: an unusual site

Ritesh Sachdev, Manoj Tayal, Shalini Goel, Rashi Sharma, Dheeraj Gautam

Indian Journal of Pathology and Microbiology 2019 62(1):167-168



from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2ToB1H5

Effectuation to Cognize malignancy risk and accuracy of fine needle aspiration cytology in salivary gland using “Milan System for Reporting Salivary Gland Cytopathology”: A 2 years retrospective study in academic institution

Veer Karuna, Priya Gupta, Monika Rathi, Kriti Grover, Jitendra Singh Nigam, Nidhi Verma

Indian Journal of Pathology and Microbiology 2019 62(1):11-16

Background: To accost things in a particular disciple, egress related to Fine Needle Aspiration Cytology (FNAC) and to standardize reporting pattern, a framework "Milan System for Reporting Salivary Gland Cytopathology" (MSRSGC) has been sponsored. Aim: Aim of this study was to evaluate the potency of salivary gland FNAC reported under Milan guidelines, to calculate malignancy risk, and to compare the preoperative cytological diagnoses with the postoperative histopathological diagnoses. Settings and Design: This was a retrospective study over a period of 2 years (May 2016 to April 2018), which was classified according to Milan system and correlation with histopathology. Furthermore, the risk of malignancy was calculated for all the diagnostic categories. Materials and Methods: FNAC were analyzed on 105 patients with palpable salivary gland. Results were distributed into six categories. About 76 cases were surgically treated and resected tissues were submitted for histopathological examination. Statistical Analysis: The various diagnostic values of the procedure were calculated using the standard formula. Results: We reviewed 105 salivary gland FNA samples and recorded interpretations according to the proposed standardized six categories. Among them, category IV (neoplastic) had more cases (57.14%). The rates of malignancy in histology were as follows: (1) nondiagnostic, 0.0%; (2) nonneoplastic, 0.0%; (3) atypia of undermined significance, 50.00%; (4a) benign, 02.44%; (4b) uncertain malignant potential, 33.33%; (5) suspicious for malignancy, 100%; and (6) malignancy, 93.33%. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of Milan system came out to be 85.00%, 98.14%, 94.44%, 94.64%, and 94.59%, respectively. Conclusion: The six-tier diagnostic categories of the Milan system helps in triaging patients with salivary gland swelling and thus facilitate individualized management.

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Undifferentiated embryonal sarcoma of the liver in elderly: Case report and review of the literature

Gunter Gerson, José Telmo Valença, Juliana M Cavalcante, River De Alencar Bandeira Coêlho

Indian Journal of Pathology and Microbiology 2019 62(1):129-131

Sarcomas are rare lesions of the liver and represent <1% of primary liver tumors. Embryonic sarcoma (undifferentiated) of the liver is a rare and aggressive malignant tumor that usually occurs in children with a peak incidence between 6 and 10 years. In adults, it is extremely rare with only 13 cases described in patients older than 40 years and 68 cases reported in patients older than 15 years. There is a slight predominance of females in adults. With an emphasis on morphological and immunohistochemical features, as well as on clinical data and imaging studies, we present this case report, in addition to extensive literature review on the topic.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2TrfygD

Immunohistochemical and morphometrical evaluation of well-differentiated thyroid tumor of uncertain malignant potential

Dareen A Mohamed, Maha M Shamlola

Indian Journal of Pathology and Microbiology 2019 62(1):17-23

Context: Well-differentiated tumor of uncertain malignant potential (WDT-UMP) were encapsulated follicular pattern tumors with diffuse equivocal or focal unequivocal papillary thyroid carcinoma (PTC) type nuclear changes without definite invasion. These tumors are suggested to be borderline in its nature. Immunohistochemistry by CD56, P63, and CK19 are common markers used in differentiation between benign and malignant thyroid tumor. Computerized nuclear morphometry is an inexpensive objective and reproducible tool to evaluate histological features of thyroid tumors. Aims: To categorize WDT-UMP using combined nuclear morphometry and immunohistochemistry of CD56, P63, and CK19. Subjects and Methods: We used CD56, P63, and CK19 immunostaining and mean nuclear area and perimeter morphometry on 20 cases of WDT-UMP, 25 cases malignant thyroid tumors, and 25 cases benign thyroid lesions. Statistical Analysis Used: Student's t-test (Unpaired), analysis of variance (ANOVA) test, and Chi-square tests by SPSS V. 20. Results: Significant differences were obtained between WDT-UMP and benign group according to the three markers, but no significant difference between WDT-UMP and malignant group. The mean nuclear area and mean nuclear perimeter were significantly higher in WDT-UMP group in comparison with the benign group while there were no significant differences with the malignant group. Conclusion: WDT-UMP are intermediate lesions differing from benign lesions of the thyroid and sharing some criteria with PTC to a certain extent.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2BcQLpA

SETTLE tumor of thyroid: Oldest case in literature

Hamsa Nandini, Vivek Shetty, Akhila Lakshmikantha, HV Sunil, Subramanian Kannan

Indian Journal of Pathology and Microbiology 2019 62(1):175-177



from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2TlarPi

From Editor's desk

Ranjan Agrawal

Indian Journal of Pathology and Microbiology 2019 62(1):1-2



from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2TohWF6

A study of morphological prognostic factors in colorectal cancer and survival analysis

S Poornakala, NS Prema

Indian Journal of Pathology and Microbiology 2019 62(1):36-42

Context: Globally, colorectal cancer (CRC) is one of the leading causes of cancer death. Many Asian countries experience an increasing incidence of CRC due to changes in diet and lifestyle. Many pathological prognostic factors other than the tumor-node-metastasis (TNM) staging reflect the biological behavior of tumor tissue and influence the treatment and survival. Aims: The aim is to evaluate: (1) Various morphological prognostic factors of colorectal cancer, (2) the correlation of the prognostic factors with survival, and (3) the prognostic factors with independent prognostic significance. Settings and Design: Descriptive study conducted in a tertiary care center in Kerala. Materials and Methods: Five hundred and eighty-seven resected specimens of CRC received from January 1, 2007 to October 31, 2012 were studied for various morphological prognostic factors. Overall survival and disease-free survival were obtained by Kaplan Meier survival analysis. Cox regression analysis was performed to identify the predictors of survival. Results: CRC incidence was higher in the age group 40–60 years and males were dominant. Rectum was the common site with bleeding per rectum as a common symptom. Predominant tumors had ulcerative gross configuration, size ≤5 cm and were free of transverse, radial margin involvement. Majority of tumors were well-differentiated adenocarcinoma with invasion beyond muscularis propria, without vascular, perineural invasion, and lymph node involvement and were in Stage II. The overall and disease-free 3-year survival rates were 89.1% and 88%, respectively. Among the eight significant factors in univariate analysis, tumor histology, depth of invasion, and perineural invasion were found to have independent prognostic significance in multivariate analysis. Conclusions: In addition to the TNM staging, other morphological prognostic factors should be given importance, while considering the patients for adjuvant therapy to improve the survival rates in CRC.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2BcQwuG

Sclerosing polycystic adenosis: A case report with review of the literature

Sreelekha Appasani, Preethi Thattaruparambil Ramadas, Jayapriya Gangadharan, Anitha Mathews

Indian Journal of Pathology and Microbiology 2019 62(1):136-138

Sclerosing polycystic adenosis (SPA) is primarily a disease of major salivary glands. It was recognized as a distinct morphologic entity by Smith et al. in 1996. To best of our knowledge, 67 cases of SPA are reported in English literature. Here, we describe a case of SPA showing classic histomorphological features, involving the parotid gland of a 17-year-old girl. It was diagnosed as mucoepidermoid carcinoma at a peripheral hospital and was referred to our center. Histologically, it was well circumscribed and composed of lobules, separated by hyalinized stroma. Lobules showed adenosis, foci of acinic cell hyperplasia, and intraductal epithelial proliferation. Immunohistochemistry with p63 highlighted myoepithelial layer around every duct, acinus, and also in foci showing epithelial hyperplasia. There was no evidence of malignancy. Awareness of SPA, a benign rare entity, is essential to avoid misdiagnosing it as other common salivary gland tumors which it may mimic.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2TpEKnP

Expression and immune recognition of polypeptides derived from Hepatitis C virus structural proteins

Alyaa S. Abdel Halim, Mohamed R Mohamed, Fatma F. Abdel Hamid, Amr M Karim

Indian Journal of Pathology and Microbiology 2019 62(1):43-48

Background: Hepatitis C virus (HCV) is characterized by a high degree of nucleotide sequence variability between genotypes. This variability extends to functional and immunological determinants. Serological tests using antigenic segments derived from the HCV polyprotein have been used for the diagnosis of HCV infection. However, available diagnostic Kits do not necessarily take type variability into consideration and are not optimized for HCV genotype 4a (HCV4a), the predominant genotype in Egypt. Aim: The aim of this study was to express some HCV4a-derived polypeptides in order to identify those with immunodiagnostic utility. Materials and Methods: Six sequential/overlapping genomic segments encoding 100–266 amino acid peptides from the core (peptide 1), envelope 1 (E1; peptide 2), envelope 2 (E2; peptides 4, 5, and 6), and E1/E2 (peptide 3) regions of the HCV4apolyprotein were selected for in vitro expression as glutathione S-transferase-fusion proteins. The immunoreactivity of the expressed peptides was evaluated against sera from HCV-infected/uninfected individuals using dot blot, western blot, and enzyme-linked immunosorbent assay. Results: The expressed polypeptides were recognized by HCV-infected sera from 20 patients, while showing no immunoreactivity toward uninfected serum. Peptide 1 derived from the core protein was found to be the most immunoreactive. Conclusion: Expressed polypeptides hold good potential for use in the development of improved HCV immunodiagnostics.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2B9FdTV

Neu Laxova syndrome

Tanima Dwivedi, Manasi Gosavi

Indian Journal of Pathology and Microbiology 2019 62(1):149-152

NeuLaxova syndrome (NLS) is a rare congenital abnormality involving multiple systems. Until date, only 60 cases of this syndrome have been reported in the literature. A stillborn fetus from a 23-year-old female with bad obstetrics history and consanguinity marriage, presented at 41 weeks gestation and not appreciating fetal movements for the past 3 days. Ultrasound examination revealed the absence of fetal cardiac activity and features of growth retardation. The fetus was sent for pathological examination. At autopsy, fetus had ichthyosis over the scalp and face, depressed nasal bridge, low set ears, microcephaly, slopping forehead, wide interdigital spaces, edema of hands and feet, hypoplastic penis, right leg showed congenital talipes equinovarus and left leg showed rocker bottom foot. On dissection, all organs were in situ. Both lungs were hypoplastic, brain was atrophied, and heart showed right ventricle hypertrophied. A diagnosis of NLS was made. Genetic counseling and early serial ultrasound examination should be performed at high-risk families because of its autosomal recessive mode of inheritance. Early diagnosis of the disease may offer termination of the pregnancy as an option. The prognosis is poor, and the affected newborns are either stillborn or die immediately after birth.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2Toi6w1

Immunohistochemistry and morphometric analysis of pelviureteric junction complexes in children with hydronephrosis

Pradyumna Pan, Neeraj Sachdeva

Indian Journal of Pathology and Microbiology 2019 62(1):49-53

Aim: The study aimed to analyze the musculature and innervations of pelviureteric junction (PUJ) complex and upper ureter by morphometry and immunohistochemistry in surgically resected specimens of PUJ obstruction and compares the findings with normal controls. Materials and Methods: Specimens of the PUJ were obtained from twenty patients with hydronephrosis due to PUJ obstruction undergoing surgical treatment in this unit from 2013 to 2015. In the control group, seven PUJ complexes were taken from patients who had nephrectomy due to trauma and Wilms tumor. The sections were stained with H and E stain and elastic von Gieson stain. For immunohistochemistry, the tissue sections were immunostained by an indirect immunoperoxidase method for S-100 and neuron-specific enolase. Results: Histopathologically, the predominant arrangement of muscle fibers was layered, i.e., a thick circular layer surrounded by two longitudinal layers on either side in PUJ of obstruction patients. S-100 immunoreactivity in the muscle layer showed dense neural innervation in PUJ complex of obstructed patients. Conclusions: Circular enhanced musculature may cause a sphincter-like activity with holding up of urine. The higher density of neuronal expression in PUJ might be responsible for causing constant contraction and intrinsic obstruction.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2B86mqz

Sialadenoma papilliferum of the hard palate: A rare case report

Saede Atarbashi-Moghadam, Ali Lotfi, Mohammad Moshref, Sepideh Mokhtari

Indian Journal of Pathology and Microbiology 2019 62(1):163-164

Sialadenoma papilliferum (SP) is a rare benign salivary gland tumor with unclear cell origin. This report presents a new case of SP of the hard palate occurring in a 50-year-old female. The lesion was completely excised, and the microscopic features were consistent with SP. The knowledge of this rare entity contributes to proper diagnosis and prevents unnecessary radical surgery and treatment.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2Tppjfz

Differential expression of cyclin E, p63, and Ki-67 in gestational trophoblastic disease and its role in diagnosis and management: A prospective case–control study

Asaranti Kar, Chandraprava Mishra, Priyadarshini Biswal, Tushar Kar, Sasmita Panda, Subhasini Naik

Indian Journal of Pathology and Microbiology 2019 62(1):54-60

Background: Gestational trophoblastic disease (GTD) constitutes a spectrum of tumors and tumor-like conditions, characterized by proliferation of pregnancy-associated trophoblastic tissue of progressive malignant potential. It is very difficult to differentiate these complex groups of lesions basing on histomorphology alone. Immunohistochemistry (IHC) with cyclin E, P63, and Ki-67 has a definite role in the identification of different trophoblasts and entities of GTD and also in the determination of biological behavior. Aims: The aim of this study is to find the differential expression of cyclin E, p63, and Ki-67 in normal placenta, hydropic abortus (HA), and various entities of GTD. Design and Settings: A prospective case–control study conducted in a government medical college. Methods: Total 96 cases, divided into Group A (48 histologically confirmed cases of GTD) and Group B (controls comprising 8 HA and 40 normal placentas of different trimesters), were studied. The histological samples were subjected to IHC using cyclin E, Ki-67, and p63. Statistical Analysis: Results were analyzed using SPSS statistical method. Results: Among the three immunomarkers used, Cyclin E and Ki-67 show statistically significant difference (P < 0.05) when compared between GTD and control groups, but it was insignificant for p63 (P = 0.369). Strong staining intensity of cyclin E and Ki-67 is seen in complete moles, choriocarcinoma, and placental site trophoblastic tumor. Conclusion: This study was done to evaluate the role of cell cycle regulatory proteins such as cyclin E and p63 and proliferation marker Ki-67 in the detection of various trophoblasts and differential diagnosis of the lesions associated with them.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2BgtnHN

Relationship between obesity and health problems in help-seeking military veterans

Background

UK Armed Forces (UK AF) veterans may be particularly vulnerable to obesity and its comorbid physical and mental health problems.

Aim

To examine the relationship between body mass index (BMI), physical health problems, mental health disorders and sociodemographic characteristics in UK AF veterans engaged in psychological treatment.

Methods

Information regarding veteran BMI, demographic characteristics, physical health conditions and mental health problems was collected and analysed using univariate and multivariate regression analyses. Rates of veteran obesity were also compared with the UK general population.

Results

Of the 384 help-seeking veterans, 37.5% (n=151) were overweight (BMI 26–30) and 35.5% (n=143) were obese. Obesity in help-seeking male veterans was two to four times higher than that of the general population of UK. Higher scores on measures of anger and common mental health problems were significantly associated with greater BMI. Problems with physical systemic functioning and mobility were also significantly associated with greater BMI.

Conclusions

The results indicate that treatment-seeking UK AF veterans exhibit higher levels of obesity compared with the general population, and clinically significant physical and mental comorbidities. The findings highlight a need for mental health services to offer treatments that effectively integrate physical and mental healthcare in the treatment of people with mental health problems.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2CWbpKM

Hierarchical process using Brier Score Metrics for lower leg injury risk curves in vertical impact

Introduction

Parametric survival models are used to develop injury risk curves (IRCs) from impact tests using postmortem human surrogates (PMHS). Through the consideration of different output variables, input parameters and censoring, different IRCs could be created. The purpose of this study was to demonstrate the feasibility of the Brier Score Metric (BSM) to determine the optimal IRCs and derive them from lower leg impact tests.

Methods

Two series of tests of axial impacts to PMHS foot–ankle complex were used in the study. The first series used the metrics of force, time and rate, and covariates of age, posture, stature, device and presence of a boot. Also demonstrated were different censoring schemes: right and exact/uncensored (RC-UC) or right and uncensored/left (RC-UC-LC). The second series involved only one metric, force, and covariates age, sex and weight. It contained interval censored (IC) data demonstrating different censoring schemes: RC-IC-UC, RC-IC-LC and RC-IC-UC-LC.

Results

For each test set combination, optimal IRCs were chosen based on metric–covariate combination that had the lowest BSM value. These optimal IRCs are shown along with 95% CIs and other measures of interval quality. Forces were greater for UC than LC data sets, at the same risk levels (10% used in North Atlantic Treaty Organisation (NATO)). All data and IRCs are presented.

Conclusions

This study demonstrates a novel approach to examining which metrics and covariates create the best parametric survival analysis-based IRCs to describe human tolerance, the first step in describing lower leg injury criteria under axial loading to the plantar surface of the foot.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2S0LewP

Artificial intelligence and the radiologist: the future in the Armed Forces Medical Services

Artificial intelligence (AI) involves computational networks (neural networks) that simulate human intelligence. The incorporation of AI in radiology will help in dealing with the tedious, repetitive, time-consuming job of detecting relevant findings in diagnostic imaging and segmenting the detected images into smaller data. It would also help in identifying details that are oblivious to the human eye. AI will have an immense impact in populations with deficiency of radiologists and in screening programmes. By correlating imaging data from millions of patients and their clinico-demographic-therapy-morbidity-mortality profiles, AI could lead to identification of new imaging biomarkers. This would change therapy and direct new research. However, issues of standardisation, transparency, ethics, regulations, training, accreditation and safety are the challenges ahead. The Armed Forces Medical Services has widely dispersed units, medical echelons and roles ranging from small field units to large static tertiary care centres. They can incorporate AI-enabled radiological services to subserve small remotely located hospitals and detachments without posted radiologists and ease the load of radiologists in larger hospitals. Early widespread incorporation of information technology and enabled services in our hospitals, adequate funding, regular upgradation of software and hardware, dedicated trained manpower to manage the information technology services and train staff, and cyber security are issues that need to be addressed.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2CVzKAm

The impact of body mass index on perioperative outcomes after robotic liver resection

Abstract

High body mass index (BMI) is associated with other multiple comorbidities such as non-alcoholic fatty liver disease, steatohepatitis, liver cirrhosis, and cardiopulmonary diseases, which can impact the perioperative outcomes following liver resection. We aimed to study the impact of BMI on perioperative outcomes after robotic liver resection. All the patients undergoing robotic liver resection between 2013 and 2017 were prospectively followed. The patients were divided into three groups (BMI < 25, BMI 25–35, BMI > 35 kg/m²) for illustrative purposes. Demographic and perioperative outcome data were compared. Data are presented as median (mean ± SD). Thirty-eight patients underwent robotic hepatectomy, 73% were women, age was 58 (57 ± 17.6) years, and ASA class was 3 (3 ± 0.5). Indications for surgery were neoplastic lesions in 34 patients (89%), hemangioma in two patients (6%), fibrous mass in one patient (2.5%), and focal nodular hyperplasia in one patient (2.5%). 32% of the patients underwent right or left hemihepatectomy, 21% underwent sectionectomy, 5% underwent central hepatectomy and the reminder underwent non-anatomical liver resection. Operative time was 261 (254.6 ± 94.3) min. Estimated blood loss was 175 (276 ± 294.8) ml. Length of hospital stay was 3 (5 ± 4.9) days. By regression analysis of the three BMI groups, estimated blood loss, rate of postoperative complication, rate of conversion, need for transfusion, length of ICU stay, and length of hospital stay did not have a significant relationship with BMI. A total of five patients (13%) experience complications. Four patients had complications that were nonspecific to liver resection, including acute renal injury, respiratory failure, and enterocutaneous fistula. One patient had bile leak, treated with ERCP stenting. No mortality was seen in this study. Obesity should not dissuade surgeons from utilizing minimally invasive robotic approach for liver resection. Robotic technique is a safe and feasible in patients with high BMI. The impact of BMI on outcomes is insignificant.

http://bit.ly/2MJUMGG

North‐south gradient of mesothelioma and asbestos consumption‐production in the United States‐Progresses since the 1st asbestos partial ban in 1973

Background

Temporal trends and broad geographical distributions of asbestos use and the incidence of malignant mesothelioma (MM) in the US still need to be studied.

Methods

Data on asbestos consumption and production between 1900 and 2015 and MM mortality and incidence rates between 1975 and 2015 in the US were examined. Spatial distributions of MM mortality and incidence rates and their association with climate zone were analyzed.

Results

Decline of MM incidence and mortality rates in the US occurred about 20 years after the peak of asbestos consumption‐production in 1973. There are apparent north‐south (N‐S) gradients in MM mortality and incidence rates in the US.

Conclusion

Recent decline of MM incidence and mortality rates in the US may be associated with reduced US asbestos consumption. N‐S MM gradients between 1999 and 2015 were likely related to larger asbestos requirements in building materials in the northern states.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2DOj27J

MiR-5571-3p and miR-135b-5p, derived from analyses of microRNA profile sequencing, correlate with increased disease risk and activity of rheumatoid arthritis

Abstract

Objectives

This study aimed to investigate microRNA (miRNA) expression profiles in synovium tissues of rheumatoid arthritis (RA) patients by RNA sequencing and to evaluate the values of dysregulated miRNAs in RA diagnosis and monitoring.

Methods

Thirty RA patients who underwent knee arthroscopy and 30 controls with knee trauma who underwent surgery were consecutively recruited, and synovium tissue samples of both groups were obtained during surgeries. In the exploration part, miRNA and mRNA expression profiles of 3 RA samples and 3 control samples were detected using RNA sequencing then followed by bioinformatic analyses. In the validation part, 5 candidate miRNA levels were detected by quantitative polymerase chain reaction (qPCR) in 30 RA patients and 30 control patients.

Results

In the exploration part, 78 miRNAs and 1582 mRNAs were upregulated while 40 miRNAs and 1295 mRNAs were downregulated in synovium tissue samples of RA patients compared with those of controls. Furthermore, enrichment analyses revealed that these dysregulated miRNAs and mRNAs were mainly implicated in immune activities and inflammatory diseases such as leukocyte migration, complement activation, and RA. In the validation part, qPCR assay revealed that miR-5571-3p and miR-135b-5p expressions were increased in RA patients compared with those in controls and disclosed good predictive values for RA risk with high area under the curves (AUCs). Besides, both miR-5571-3p and miR-135b-5p levels were positively correlated with disease activity and inflammation level of RA.

Conclusions

Analyses of miRNA expression profiles by sequencing indicate that miR-5571-3p and miR-135b-5p correlate with increased RA risk and activity.

http://bit.ly/2G2oZjx

A novel WDR62 missense mutation in microcephaly with abnormal cortical architecture and review of the literature

Abstract

Autosomal recessive primary microcephaly (MCPH) is a group of rare neurodevelopmental diseases with severe microcephaly at birth. One type of the disorder, MCPH2, is caused by biallelic mutations in the WDR62 gene, which encodes the WD repeat–containing protein 62. Patients with WDR62 mutation may have a wide range of malformations of cortical development in addition to congenital microcephaly. We describe two patients, a boy and a girl, with severe congenital microcephaly, global developmental delay, epilepsy, and failure to thrive. MRI showed hemispherical asymmetry, diffuse pachygyria, thick gray matter, indistinct gray-white matter junction, and corpus callosum and white matter hypoplasia. Whole exome sequencing revealed the same novel homozygous missense mutation, c.668T>C, p.Phe223Ser in exon 6 of the WDR62 gene. The healthy parents were heterozygous for this mutation. The mutation affects a highly conserved region in one of the WD repeats of the WDR62 protein. Haplotype analysis showed genetic relatedness between the families of the patients. Our findings expand the spectrum of mutations randomly distributed in the WDR62 gene. A review is also provided of the brain malformations described in WDR62 mutations in association with congenital microcephaly.

http://bit.ly/2CZFqct

Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines

Summary

The latex from Euphorbia tirucalli is used in Brazil as a folk medicine for several diseases, including cancer. Recently, we showed a cytotoxic activity of E. tirucalli euphol in a wide range of cancer cell lines. Moreover, we showed that euphol inhibits proliferation, motility and colony formation in pancreatic cancer cells, induces autophagy and sensitizes glioblastoma cells to temozolomide cytotoxicity. Herein, we report in vitro activity of three semi-synthetic ingenol compounds derived from E. tirucalli, IngA (ingenol-3-trans-cinnamate), IngB (ingenol-3-hexanoate) and IngC (ingenol-3-dodecanoate), against a large panel of human cancer cell lines. Antineoplastic effects of the three semi-synthetic compounds were assessed using MTS assays on 70 cancer cell lines from a wide array of solid tumors. Additionally, their antitumor potential was compared with known compounds of the same class, namely ingenol-3-angelate (Picato®) and ingenol 3,20-dibenzoate and in combination with standard chemotherapeutic agents. We observed that IngA, B, and C exhibited dose-dependent cytotoxic effects. Amongst the semi-synthetic compounds, IngC displayed the best activity across the tumor cell lines. In comparison with ingenol-3-angelate and ingenol 3,20-dibenzoate, IngC showed a mean of 6.6 and 3.6-fold higher efficacy, respectively, against esophageal cancer cell lines. Besides, IngC sensitized esophageal cancer cells to paclitaxel treatment. In conclusion, the semi-synthetic ingenol compounds, in particular, IngC, demonstrated a potent antitumor activity on all cancer cell lines evaluated. Although the underlying mechanisms of action of IngC are not elucidated, our results provide insights for further studies suggesting IngC as a putative therapy for cancer treatment.

http://bit.ly/2MHZULh

Transgenic versus conventional corn: fate of fumonisins during industrial dry milling

Abstract

The aim of this study was to compare the fate of fumonisins in transgenic and non-transgenic corn during industrial dry milling. For this purpose, whole corn samples and their fractions (germ, pericarp, endosperm, corn meal, and grits) were collected from one of the major Brazilian milling plants, totaling 480 samples. There was no significant difference (p > 0.05) between mean fumonisin (FB₁ + FB₂) levels in transgenic (1130 μg/kg) and non-transgenic (920 μg/kg) whole corn. However, in non-transgenic germ, endosperm and corn meal fraction fumonisin levels were higher (2940 μg/kg, 250 μg/kg and 190 μg/kg, respectively) than in transgenic fractions (2180 μg/kg, 130 μg/kg and 85.0 μg/kg, respectively). Furthermore, the highest percentages of fumonisins were distributed in the germ, corresponding to about 87 and 76% of the total fumonisins present in the whole corn from non-transgenic and transgenic hybrids, respectively. Concerning the endosperm from non-transgenic and transgenic corn, approximately, 23% and 13% of the total fumonisins were retained after the dry milling. Further processing in corn meal (300 to 420 μm particle size) and grits (590 to 1190 μm) decreased the percentages of remaining fumonisins to 4% and 2% (transgenic) and 10% and 3% (non-transgenic corn), respectively. These results suggested that fumonisin concentration was higher in outer and inner non-transgenic fractions when compared to transgenic ones and that the fate of fumonisins during the industrial dry milling could be affected by the transgenic status. However, it was not possible to conclude that the difference was exclusively due to this variable.

http://bit.ly/2SgBT3s

First report of Fusarium foetens as a mycotoxin producer

Abstract

Fusarium foetens, a pathogen of Begonia plants, has been recently described as a new fungal species. This Fusarium species causes a destructive vascular wilt disease which leads to the death of the plant. Moreover, Fusarium species are known to produce a huge variety of secondary metabolites such as mycotoxins and phytotoxins. Here, we studied the toxicogenic profile of one F. foetens strain, isolated from maize, employing two methods based on the use of ultra-performance liquid chromatography coupled to mass spectrometry-ion trap-time of flight detection. The mycotoxins beauvericin and fusaric acid were detected in a pure culture of F. foetens. In addition, four fusaric acid analogs (10,11-dihidroxyfusaric acid, hydroxyfusaric acid, dehydrofusaric acid, and a hydroxylated unsaturated fusaric acid analog) were tentatively identified on the basis of their accurate mass and fragmentation patterns. Therefore, these preliminary data indicate that F. foetens isolated from maize is able to produce Fusarium mycotoxins including beauvericin and fusaric acid.

http://bit.ly/2GeP2U6

Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines

Summary

The latex from Euphorbia tirucalli is used in Brazil as a folk medicine for several diseases, including cancer. Recently, we showed a cytotoxic activity of E. tirucalli euphol in a wide range of cancer cell lines. Moreover, we showed that euphol inhibits proliferation, motility and colony formation in pancreatic cancer cells, induces autophagy and sensitizes glioblastoma cells to temozolomide cytotoxicity. Herein, we report in vitro activity of three semi-synthetic ingenol compounds derived from E. tirucalli, IngA (ingenol-3-trans-cinnamate), IngB (ingenol-3-hexanoate) and IngC (ingenol-3-dodecanoate), against a large panel of human cancer cell lines. Antineoplastic effects of the three semi-synthetic compounds were assessed using MTS assays on 70 cancer cell lines from a wide array of solid tumors. Additionally, their antitumor potential was compared with known compounds of the same class, namely ingenol-3-angelate (Picato®) and ingenol 3,20-dibenzoate and in combination with standard chemotherapeutic agents. We observed that IngA, B, and C exhibited dose-dependent cytotoxic effects. Amongst the semi-synthetic compounds, IngC displayed the best activity across the tumor cell lines. In comparison with ingenol-3-angelate and ingenol 3,20-dibenzoate, IngC showed a mean of 6.6 and 3.6-fold higher efficacy, respectively, against esophageal cancer cell lines. Besides, IngC sensitized esophageal cancer cells to paclitaxel treatment. In conclusion, the semi-synthetic ingenol compounds, in particular, IngC, demonstrated a potent antitumor activity on all cancer cell lines evaluated. Although the underlying mechanisms of action of IngC are not elucidated, our results provide insights for further studies suggesting IngC as a putative therapy for cancer treatment.

http://bit.ly/2MHZULh

De-Hankelization of singular spectrum analysis matrices via L 1 norm criterion

Abstract

This paper proposes to employ the L₁ norm criterion to perform the de-Hankelization in the singular spectrum analysis (SSA). In particular, the represented values of the off-diagonals in the two-dimensional SSA matrices are found via minimizing the L₁ norm errors of the vectors defining as the absolute differences between the off-diagonal vectors and the vectors with all their elements being the represented values. This results to reduce the total number of the large-valued elements in the error vectors. Also, this paper guarantees to achieve the exact perfect reconstruction of the original signal. As the formulated problem is a standard linear programming problem, the solution could be efficiently found via the simplex method. The computer numerical simulations verify the results.

http://bit.ly/2S1RQv3

Pediatric nodular fasciitis at the roof of the optic canal causing decreased vision: case report and review of the literature

Abstract

We present a 3-year-old girl with decreased visual acuity of the left eye. Radiological studies revealed a mass lesion at the roof of the left optic canal with bony erosion, which compressed the left optic nerve. Gross total resection of the mass and decompression of the optic canal were performed. Histopathological study was consistent with nodular fasciitis. This is the first report of nodular fasciitis at the roof of the optic canal in a young child. Nodular fasciitis compressing the optic nerve should be included in differential diagnoses of optic neuropathy in young children.

http://bit.ly/2UxjKeV

Antibacterial effects of iron oxide (Fe 3 O 4 ) nanoparticles: distinguishing concentration-dependent effects with different bacterial cells growth and membrane-associated mechanisms

Abstract

Nowadays, the influence of nanoparticles (NPs) on microorganisms attracts a great deal of attention as an alternative to antibiotics. Iron oxide (Fe₃O₄) NPs' effects on Gram-negative Escherichia coli BW 25113 and Gram-positive Enterococcus hirae ATCC 9790 growth and membrane-associated mechanisms have been investigated in this study. Growth specific rate of E. coli was decreased, indicating the bactericidal effect of Fe₃O₄ NPs. This inhibitory effect of NPs had a concentration-dependent manner. The reactive oxygen species together with superoxide radicals and singlet oxygen formed by Fe₃O₄ NPs could be the inhibition cause. Fe₃O₄ NPs showed opposite effects on E. hirae: the growth stimulation or inhibition was observed depending on NPs concentration used. Addition of NPs altered redox potential kinetics and inhibited H₂ yield in E. coli; no change in intracellular pH was determined. Fe₃O₄ NPs decreased H⁺-fluxes through bacterial membrane more in E. coli than in E. hirae even in the presence of DCCD and increased ATPase activity more in E. hirae than in E. coli. Our results showed that the Fe₃O₄ NPs demonstrate differentiating effects on Gram-negative and Gram-positive bacteria likely due to the differences in bacterial cell wall structure and metabolic peculiarities. Fe₃O₄ NPs of different concentrations have no hemolytic (cytotoxic) activity against erythrocytes. Therefore, they can be proposed as antibacterial agents in biomedicine, biotechnology, and pharmaceutics.

http://bit.ly/2t2uztG

Enhanced production and identification of antioxidants in in vitro cultures of the cacti Mammillaria candida and Turbinicarpus laui

Abstract

Cacti are an important source of metabolites but present limitations for their commercial exploitation, like slow growth and a decrease of wild populations. An alternative to obtain their biocompounds without affecting the natural environment are the in vitro culture techniques. We established in vitro cultures from Mammillaria candida Scheidweiler and Turbinicarpus laui Glass and Foster and used different stresses to increase metabolites and antioxidant activity. The cultures were exposed to 1.25% polyethylene glycol to induce a moderate drought stress, 50 g L⁻¹ sucrose to generate an osmotic stress, chitosan (1.25 to 5 mg mL⁻¹) to simulate a biotic attack, or to UV light. Chitosan was the best elicitor improving 1.5 times the concentration of phenolics, 9 to 10 times the content of flavonoids and betalains, and 16% the antioxidant activity in M. candida suspensions. In T. laui suspensions, this elicitor duplicates the flavonoids content and antioxidant activity. The antioxidant levels in elicited suspensions increased 5 to 10 times in relation to plant tubercles. Eleven compounds were identified in M. candida suspensions being digalloyl rhamnoside and epicatequin gallate the most abundant; in the T. laui suspensions, 16 compounds were detected and the most abundant were 17-decarboxi neobetanin and derivatives of luteolin. Thus, cacti in vitro culture is an efficient system to obtain high level of metabolites of biological interest.

http://bit.ly/2MKQEWI

Apatinib, a novel VEGFR inhibitor plus docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR: a phase I trial

Summary

Background This phase I trial was primarily conducted to determine the maximum tolerated dose (MTD) of apatinib combined with docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR who have failed to first-line platinum-based chemotherapy, and to evaluate the safety and tolerability of apatinib plus docetaxel. Methods This was a single-center, open-label, dose-escalating phase I trial. The study used a standard 3 + 3 dose escalation design with the primary aim of determining the MTD. Twelve patients with advanced lung adenocarcinoma were enrolled, the primary endpoint was safety. Two doses of apatinib, 250 mg/day (level 1) and 500 mg/day (level 2), were evaluated in combination with 60 mg/m² doxetacel every 3 weeks. Six patients have been treated at levels 1 and 2, respectively. Optimal dose of apatinib was determined by dose-limiting toxicity (DLT). Results Six patients have been treated at levels 1 and 2. At level 1, one of six patients experienced grade 3 acneiform rash as DLTs. At level 2, two patients experienced grade 3 hypertension and one experienced grade 3 nasal bleeding. MTD and recommended dose for phase II study was 250 mg/day. Most frequent adverse events of any grade were bilirubin elevation, hypertension, alanine aminotransferase elevation, transglutaminase elevation, hand foot syndrome and fatigue. The median progression-free survival was 2.76 month. Moreover, three patients had developed progressive disease and the mean duration of response was 2.79 months. Conclusion Apatinib plus docetaxel was well tolerated and showed promising efficacy in advanced lung adenocarcinoma. This combination therapy may represent a potent therapeutic option for advanced lung adenocarcinoma patients with wild-type EGFR.

http://bit.ly/2UyJHuN

Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo

Summary

We generated a nitric oxide (NO)-releasing derivative of the anti-HIV protease inhibitor lopinavir by linking the NO moiety to the parental drug. We investigated the effects of lopinavir and its derivative lopinavir-NO on melanoma cell lines in vitro and in vivo. Lopinavir-NO exhibited a twofold stronger anticancer action than lopinavir in vitro. These results were successfully translated into syngeneic models of melanoma in vivo, where a significant reduction in tumour volume was observed only in animals treated with lopinavir-NO. Both lopinavir and lopinavir-NO inhibited cell proliferation and induced the trans-differentiation of melanoma cells to Schwann-like cells. In melanoma cancer cell lines, both lopinavir and lopinavir-NO induced morphological changes, minor apoptosis and reactive oxygen species (ROS) production. However, caspase activation and autophagy were detected only in B16 cells, indicating a cell line-specific treatment response. Lopinavir-NO released NO intracellularly, and NO neutralization restored cell viability. Treatment with lopinavir-NO induced only a transient activation of Akt and inhibition of P70S6 kinase. The results of this study identify lopinavir-NO as a promising candidate for further clinical trials in melanoma and possibly other solid tumours.

http://bit.ly/2sZ68NO

Evaluation des Zungengrunds bei OSAS unter elektrischer Stimulationstherapie des N. hypoglossus

Zusammenfassung

Hintergrund

Die nächtliche elektrische Stimulationstherapie des Nervus hypoglossus von Patienten mit obstruktivem Schlafapnoesyndrom (OSAS) ist eine vergleichsweise junge Therapieform. Verlaufsdaten zu Auswirkungen auf die Zungengrundmorphologie unter langfristiger Stimulationstherapie liegen nicht vor.

Fragestellung

Im Rahmen dieser Studie erfolgte die sonografische Evaluation der Zunge bei Patienten mit OSAS vor und nach der Implantation eines Hypoglossusstimulationssystems. Ziel war es, die Durchführbarkeit der Methode zu zeigen sowie erste Hinweise auf Veränderungen der Zungengrundmorphologie unter Therapie zu erhalten.

Material und Methoden

Bei sieben Patienten mit OSAS (m = 5, w = 2, 60,14 ± 12,5 J, Zeit unter Stimulationstherapie 296,43 ± 92,04 Tage) wurden vor und 12 Monate nach Implantation eines einseitigen Stimulationssystems des N. hypoglossus (ImThera Aura 6000™) mittels Ultraschall (GE Vivid S6, 4 MHz, Konvexsonde) die Zunge und der Zungengrund vermessen.

Ergebnisse

12 Monate nach Implantation hatte sich die gemessene Distanz zwischen beiden Aa. linguales an ihrer Eintrittsstelle in den Zungengrund verringert (MW vor Implantation 3,844 ± 0,397 cm; MW nach 12 Monaten 3,591 ± 0,302; p = 0,037). Alle anderen Parameter wiesen keine statistisch auffällige Veränderung auf.

Diskussion

Ultraschall kann ein sinnvolles Hilfsmittel bei der Evaluation von Patienten mit OSAS sein. Die klinische Bedeutung der beobachteten Messwerte ist noch unklar. Eine langfristige Verkleinerung des Zungengrunddurchmessers durch die Stimulationstherapie scheint möglich zu sein.

http://bit.ly/2GdZ6g2

Cultural competence in family practice and primary care setting

Raman Kumar, Sudip Bhattacharya, Neha Sharma, Arulmani Thiyagarajan

Journal of Family Medicine and Primary Care 2019 8(1):1-4

In primary care settings, cultural perception and competence attitude are imperative as notion of health, illness, sickness, and care means different to different people. The knowledge of cultural beliefs and customs facilitate healthcare providers to afford improved care and helps to avert misunderstandings among care provider's staff, patients, and their families. It is a very useful approach in family practice towards improving the health care to racial/ethnic minor groups and reducing the disparities.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2CZkH8V

Rio Declaration: Global peace – A prerequisite for attainment of sustainable development goals

Raman Kumar

Journal of Family Medicine and Primary Care 2019 8(1):5-6

The representatives of the WONCA Young Doctors Movement met face to face for the first time in Rio de Janeiro on 2nd November 2016 and unanimously adopted the Rio Declaration 2016 calling for global peace.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2S2CMxa

Parotid gland swelling after upper gastrointestinal endoscopy

Sangey C Lamtha, Uma Rai, Parvez T Hassan

Journal of Family Medicine and Primary Care 2019 8(1):274-275

Upper gastrointestinal (UGI) endoscopy is a routine procedure done in field of gastroenterology. It is a safe procedure which can be done with or without sedation with rare post procedure complications. Our case illustrates that parotid gland swelling is a uncommon event post upper g.i endoscopy and it a benign event which resolves on its own.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2D11C67

Minimum data set (MDS) based trauma registry, is the data adequate? An evidence-based study from Odisha, India

Sanghamitra Pati, Rinshu Dwivedi, Ramesh Athe, Pramod Kumar Dey, Subhashisa Swain

Journal of Family Medicine and Primary Care 2019 8(1):7-13

Background: In majority of the low- and middle-income countries (LMICs), the societal cost of injuries are alarming. The severity and magnitude of the road traffic injuries (RTI) in India are not estimated accurately due to the lack of availability of data. The data are limited on the aspects such as demographics, cause, severity of injury, processes of care, and the final outcome of injuries. This study aimed to determine the feasibility of setting up a sustainable trauma registry in Odisha, India, and to determine the demographics, mechanism, severity, and outcomes of injury reported to the facilities/hospital. Materials and Methods: A prospective observational study was conducted at Srirama Chandra Bhanja Medical College and Hospital (SCB-MCH), Cuttack, India. Injured patients who reported/admitted to the emergency department were observed, and data were collected by using a minimum data set (MDS) developed by the World Health Organization (WHO). Data were collected for a period of one month in June 2015. Observations were collected on 20 variables. The completeness of data collection ranged from 60% (19 variables) to 70% (23 variables) out of total 33 variables. Results: This study uses 145 cases of injury reported in SCB-MCH. Out of the total reported population at the trauma registry, about 21% were females. Nearly 45% of the injury occurred on road/street. RTI accounted for 36.6% of injury. Out of the total admitted cases, 2.8% died in the emergency department, 11% were discharged to home, and 7.6% left against medical advice. Majority of the respondents have reported single injuries (77%). Head injuries were more common and severe among majority of the reported cases (44.1%), followed by neck injury (28.3%) and chest (15.9%). Conclusions: This study indicates the challenges in obtaining complete data on injury. Data were missing in terms of admission, discharge, and Glasgow Comma Scale (GCS) among the studied population. This study suggests that individual GCS scoring should be done instead of total GCS scoring in each trauma patient. By collection and storage of adequate data, better policy decisions can be implemented, which will minimize and prevent trauma cases and maximize the utilization of the available resources.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2S0abIF

The effect of short-term exposure to red and blue light on the autonomic tone of the individuals with newly diagnosed essential hypertension

Pratibha Modi, Kamlesh Jha, Yogesh Kumar, Tribhuwan Kumar, Ramji Singh, Abhilasha Mishra

Journal of Family Medicine and Primary Care 2019 8(1):14-21

The research study aimed to study the effect of short term exposure to light basically red, blue and white on the autonomic tone of essential hypertensive individuals. The objective was to find out the baseline cardiac autonomic function along with the effect of these lights on the cardiac autonomic function among them. Till date few if any study have been conducted upon the individuals with certain disorder as common as essential hypertension. This was a cross sectional observational study conducted in the institute itself that included 77 newly diagnosed hypertensive subjects who willingly participated in the study. After written informed consent, brief history taking with the help of self-made questionnaire and clinical examination, they were randomized to different intervention groups (IG) namely IG I (red) IG II (blue) and IG III (white). HRV analysis of the last 5-6 minutes of both the baseline and color exposure was finally analyzed using MS Excel version 13 and Graph Pad Prism version 7.05. Different HRV parameters have been found to be affected differently on different color exposures. Red has shown to have an impact, mainly on the sympathetic system whereas white showed a dominant vagal component thus acting as a parasympathetic regulator. On one hand, where no conclusive result was found on blue light exposure, white light showed the most prominent results affecting various time and frequency components of HRV like SDRR, TP, LF etc. The present study, both, contradicts as well as supports various other works done on the similar area of interest. One reason of such high variation in different results is because HRV is itself a very dynamic function affected by even a slight change in both the internal and external environment of the subject. As artificial lights of various colors are part and parcel of the aesthetics and designing of most of the work environment all over world, it is very pertinent to study its impact upon human health status. The outcome of the study may play a decisive role in the diagnostics and therapeutics of essential hypertension in days to come. Furthermore, on the basis of the present findings, a future study could be undertaken with bigger data base addressing the limitations of the present study to find some conclusive evidence in the area highlighted.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2S4NHGN

Prevalence and patterns of peripheral neuropathy in patients of rheumatoid arthritis

Nidhi Kaeley, Sohaib Ahmad, Monika Pathania, Rajesh Kakkar

Journal of Family Medicine and Primary Care 2019 8(1):22-26

Background: Rheumatoid arthritis (RA) is an autoimmune disorder characterized by involvement of multiple small and large joints with multisystem extra-articular manifestations. Peripheral neuropathy is known extra-articular manifestation of RA with the incidence of around 39.19% as per previous studies. Early diagnosis and treatment of peripheral neuropathy has been shown to improve both physical and functional disabilities of patients with RA. Objectives: The primary objective was to study prevalence and patterns of peripheral neuropathy in patients with RA. The secondary objective was to study demographic, clinical parameters, disease severity, and extra- articular manifestations in patients with RA with and without peripheral neuropathy. Materials and Methods: Consecutive patients of RA were recruited. Detailed clinical examination and electrophysiological tests were done to diagnose peripheral neuropathy. The demographic and clinical parameters were noted and tabulated. Student's t-test was used to analyze continuous variable, whereas Chi-square test was used for analysis of categorical variables. Results: Of 89 patients with RA, 75.28% (n = 67) patients had peripheral neuropathy electrophysiologically, whereas 20.89% (14 patients of 67) had superficial touch sensory loss on examination. Subclinical neuropathy was present in 50.74% (n = 34) of patients. Statistically significant association between the presence of neuropathy and age of the patients, disease duration, use of disease-modifying antirheumatoid drugs, disease severity (disease activity score-28), and presence of subcutaneous nodules (P < 0.05). Conclusion: Patients with RA, especially elderly patients, should undergo electrophysiological testing to rule out peripheral neuropathy. Electrophysiological study is a diagnostic and gold standard tool to diagnose subclinical neuropathy in patients with RA. Presence of peripheral neuropathy in these patients has been found to be significantly associated with deteriorating health status, pain scores, and presence of extra-articular manifestations.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2RXNwNf

Prevalence and risk factors of anemia among pregnant women attending a public-sector hospital in Bangalore, South India

J Vindhya, Anita Nath, G V. S. Murthy, Chandra Metgud, B Sheeba, V Shubhashree, P Srinivas

Journal of Family Medicine and Primary Care 2019 8(1):37-43

Background: Anemia affects almost two-thirds of pregnant women in developing countries and contributes to maternal mortality and low birthweight. According to the National Family Health Survey-4 reports, maternal anemia continues to be a public health problem. Objective: To study the prevalence of anemia and its risk factors among pregnant women attending a public-sector hospital. Materials and Methods: This study was nested within an ongoing cohort study "ÇASCADE" which is exploring the effect of prenatal exposure to maternal cortisol and psychological distress on infant development in Bangalore. The respondents were enrolled from the antenatal clinic at Jayanagar General Hospital, which is a sub-district hospital. A total of 280 women who fulfilled the eligibility criteria were enrolled. Results: The prevalence of anemia was observed to be 33.9%; proportion of mild and moderate anemia was almost similar (48.4 and 49.5%). The mean hemoglobin level of all the participants was 11.33 ± 1.460 g/dl. The mean hemoglobin level concentration was high during early gestation with a slight decrease by 21–24 weeks. Prenatal depression but not anxiety appeared to be a strong predictor of anemia on bivariate as well as multivariate analysis. No association was observed with socio-demographic and obstetric variables. Conclusion: The burden of maternal anemia was considerably high in the study population. Although iron-folic acid supplementation is available under the national health program to address this issue, it is important to consider and address other risk factors when designing and implementing target interventions for anemia control in selected populations.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2S2CLt6

Bridging therapy for achalasia in a second trimester pregnant patient

Zachary S Neubert, Edward T Stickle

Journal of Family Medicine and Primary Care 2019 8(1):289-297

We present the case of a 28-year-old female who presented for primary care at 22-week gestation with type II achalasia and worsening solid/liquid dysphagia leading to pregnancy weight loss. Considering that durable therapies such as surgical myotomy and pneumatic dilatation have considerable risk, botulinum A toxin injection was selected as a temporizing bridging therapy. She had an uncomplicated post procedure course and had significant rapid improvement in dysphagia symptoms, which enabled her to progress to normal peripartum weight. This case highlights the need for early recognition of achalasia and an unique niche for use of botulinum toxin A as a temporizing therapy in this risk averse population.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2CZSI96

Knowledge and attitude about emergency contraception among Saudi women of childbearing age

Malak S Alharbi, Ahmad S Almujil, Fatma F Alreshid, Emad H Kutbi

Journal of Family Medicine and Primary Care 2019 8(1):44-48

Context: Emergency contraception (EC) use is rare in Saudi Arabia. Aims: The aim of this study is to determine the knowledge, attitude, and practice of EC among Saudi women of childbearing age. Settings and Design: This study is a cross-sectional descriptive study using a survey questionnaire tool. Materials and Methods: We conducted a survey of married women of childbearing age (18–45 years) attending the Obstetrics and Gynecology Clinic at Riyadh, Saudi Arabia between January and April 2018. Statistical Analysis Used: Pearson's Chi-square test is used for this study. Results: This study included 370 of 525 (70.5%) women, with a mean age of 32.3 ± 6.3 years. Of these, 117 (31.6%) knew how to prevent pregnancy after unprotected sex, and 62 knew about EC. Forty-two women (67.7%) thought EC should be widely advertised, and 30 (48.4%) thought it should be made available even without prescription. Forty-seven women (75.8%) said that they were not shy to ask for EC, and 37 (59.7%) claimed that both partners should decide about the use of EC. The most common reason for not using EC was medical concerns (n = 30, 48.4%). Thirty three (53.2%) of the 62 women with knowledge about EC would use it immediately after sex. Knowledge, awareness, and use of EC were significantly correlated with higher monthly income, educated women, having three or more children, and working women. Conclusions: Among Saudi women, knowledge, awareness, and use of EC remain low, although a positive attitude for future use of EC exists. Health information campaigns are necessary to reach women, particularly those of low socioeconomic status, less educated women, and housewives to explain EC, its availability, and its proper use.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2S2ApKw

Early onset type 2 diabetes mellitus in a Saudi child misdiagnosed as type 1 diabetic: A case report

Hassan M Al-Musa

Journal of Family Medicine and Primary Care 2019 8(1):313-315

Objective: To report a Saudi young patient with early onset type 2 diabetes, who was misdiagnosed for 6 years as type 1 diabetic. Case Report: A Saudi male aged 18-year old presented with uncontrolled diabetes. He was diagnosed 6 years earlier to have type 1 diabetes mellitus. He was kept insulin, but he was not compliant to treatment and his blood glucose kept on fluctuating and not controlled. He came to our diabetes center for management of his uncontrolled diabetes. There was no past history of hospitalization. His father was type 2 diabetic. His body mass index was 46.7 kg/m2. His glycosylated hemoglobin (HbA1c) level was 9.9%. Immune dysfunction was evaluated using serum antibody levels of glutamic acid decarboxylase, which proved to be negative (0.7 U/mL), while serum C-peptide level was not low (2.2 ng/mL). Therefore, the patient was diagnosed as early onset type 2 diabetic, not type 1 diabetic. The patient was advised to start physical exercise through daily walking for at least 1 h. The dietitian planned a strict diet plan for him to follow. Insulin injections and Metformin tablets were started. The patient received detailed health education on nature and management of his condition. After 4 months, his body mass index became 39.4 kg/m2 and his HbA1c became 6%. Insulin was stopped, and he was advised to continue on metformin, the diet, and daily walking. Two months later, his body mass index was 37.7 kg/m2 and his HbA1c became 5.41%. Conclusions: Early onset type 2 diabetes should be suspected among obese children with symptoms of diabetes. Proper health education and patient's compliance to medication, diet, and physical activity are essential for successful management of early onset type 2 diabetes. Moreover, primary care physicians need to be aware that type 2 diabetes is not necessarily adult-onset.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2CZSA9C

A cross-sectional study of knowledge regarding rabies among attendees of anti-rabies clinic of a teaching hospital, Jaipur

Priyanka Kapoor, Vaseem Naheed Baig, Sudhanshu Kacker, Mahima Sharma, Mohit Sharma

Journal of Family Medicine and Primary Care 2019 8(1):194-198

Background: Being a fatal and 100% preventable disease, all efforts must be made by the health system to prevent even a single case of rabies. By assessing the knowledge of people regarding rabies prevention, we can make plans and policies for its prevention. The aim of this study was to assess the knowledge regarding rabies among attendees of anti-rabies clinic of a teaching hospital, Jaipur. Methods: This observational cross-sectional study was conducted among attendees of anti-rabies clinic, Govt. R.D.B.P. Jaipuria hospital, Jaipur from February 2018 to July 2018. A total of 107 participants were included in the study. Data was collected using preformed questionnaire. Continuous data were expressed in mean and standard deviation and count data were expressed in proportion. Results: In our study population, only 22.5% respondents had good knowledge, 56% had fair, and 21.5% had poor knowledge. Fatality of rabies was known to 68.2% of participants. One fourth of the participants knew that rabies is not curable, however, approximately 83% knew that it is preventable. Fifty-six percent of the participants were aware about washing the bite wound with soap and water. Approximately one-third (36%) of the participants knew that it is an infectious disease, however, only 7.5% knew that saliva, vomitus, tear, and urine of rabies patient may have rabies virus. Approximately 15% of the attendees had a wrong concept that a single injection is sufficient for immunization. Conclusion: Although this study was done at a teaching hospital, lack of knowledge is still a big issue in urban population as well. This study concludes that knowledge regarding rabies should be highlighted in national programs of India to acknowledge Indian population regarding fatal rabies.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2CZSqiw

Barriers to exclusive breastfeeding in rural community of central Gujarat, India

Dinesh J Bhanderi, Yogita P Pandya, Deepak B Sharma

Journal of Family Medicine and Primary Care 2019 8(1):54-61

Context: Exclusive breastfeeding (EBF) in first the 6 months of life is the most effective way to satisfy nutritional and psychological needs of a baby. However, EBF rate for India remained low at 54.9% during 2015–2016. It is therefore essential to understand the reasons for such a low EBF rate in the country so that appropriate interventions can be developed and implemented. Objectives: (1) To estimate the prevalence of EBF in rural community of central Gujarat and (2) to identify barriers to EBF in this community. Materials and Methods: A community-based cross sectional study was conducted among mothers of 330 infants of age 6 months to 1 year using pretested questionnaire. Two-stage cluster sampling technique was used to select the sample. χ2 test, t-test, and logistic regression were applied to assess the significance of associations. Results: EBF rate in the studied population was detected to be 49.7%. Early marriage of parents, less educated parents, male child, Christian religion, working mother, less number of antenatal visits, operative delivery, late initiation of breastfeeding, not feeding colostrum, lack of knowledge about EBF, and poor counseling of mother regarding EBF were identified as barriers to EBF. Conclusion: Prevalence of EBF was found to be lower than the national average in the rural community of central Gujarat. Effective strategies at local, state, and national levels should aim at addressing the barriers to EBF that are identified in this study.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2RXByTT

Preintensive care: Thrombolytic (streptokinase or tenecteplase) in ST elevated acute myocardial infarction at peripheral hospital

Himmatrao S Bawaskar, Pramodini H Bawaskar, Parag H Bawaskar

Journal of Family Medicine and Primary Care 2019 8(1):62-71

Background: Coronary artery disease is a major cause of death in India. Sudden death preceded by chest pain is due to acute myocardial infarction. Villagers are aware and afraid of chest pain. Majority of chest pain victims attend the primary physician in golden hours. Hence, primary doctors can play important role for early thrombolysis and salvage the myocardium from irreversible injury. This study determined year mortality in a patient who received the rapid thrombolysis at primary care hospital (streptokinase or tenecteplase) at rural setting. Setting: Peripheral General Hospital Mahad on Mumbai–Goa highway. Patients and Methods: Patients with typical chest pain with electrocardiogram showed ST segment elevated myocardial infarction (STEMI) with or without risk factors admitted from 2005 to march 2016 were studied. Details clinically studied: time interval between chest pain to hospital, hospital to needle time, reperfusion and arrhythmias. Time required for regression of elevated ST segment, a response to thrombolytic (streptokinase or tenecteplase) therapy, is studied. Results: Total 244 patient reported with chest pain of these 35 cases brought dead with history of chest pain and convulsive moment before they died. Of these, 209 patients had acute STEMI. Of these, 162 received streptokinase (STK) and 47 received tenecteplase (TNP)]. Analysis of STK Vs TNP patients 18 (11.11%) versus 3 (6.38%) (P = 0.361) died during the treatment. Around 17 (18.49%) vs 5 (10.63%) (P = 0.941) did not show signs of reperfusion, respectively. Re infarction occurred during hospitalization 3 (2.5%) versus 3 (6.38%) (P = 0.094) cases. Around 12 (7.40%) versus 0% (P = 0.072) died at the end of 12 months of thrombolytic therapy. Conclusion: Thrombolysis of STEMI within golden hours improved the reperfusion. However, 1-year fatality is significance with streptokinase as compared with tenecteplase.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2S1JrI1

Apatinib, a novel VEGFR inhibitor plus docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR: a phase I trial

Summary

Background This phase I trial was primarily conducted to determine the maximum tolerated dose (MTD) of apatinib combined with docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR who have failed to first-line platinum-based chemotherapy, and to evaluate the safety and tolerability of apatinib plus docetaxel. Methods This was a single-center, open-label, dose-escalating phase I trial. The study used a standard 3 + 3 dose escalation design with the primary aim of determining the MTD. Twelve patients with advanced lung adenocarcinoma were enrolled, the primary endpoint was safety. Two doses of apatinib, 250 mg/day (level 1) and 500 mg/day (level 2), were evaluated in combination with 60 mg/m² doxetacel every 3 weeks. Six patients have been treated at levels 1 and 2, respectively. Optimal dose of apatinib was determined by dose-limiting toxicity (DLT). Results Six patients have been treated at levels 1 and 2. At level 1, one of six patients experienced grade 3 acneiform rash as DLTs. At level 2, two patients experienced grade 3 hypertension and one experienced grade 3 nasal bleeding. MTD and recommended dose for phase II study was 250 mg/day. Most frequent adverse events of any grade were bilirubin elevation, hypertension, alanine aminotransferase elevation, transglutaminase elevation, hand foot syndrome and fatigue. The median progression-free survival was 2.76 month. Moreover, three patients had developed progressive disease and the mean duration of response was 2.79 months. Conclusion Apatinib plus docetaxel was well tolerated and showed promising efficacy in advanced lung adenocarcinoma. This combination therapy may represent a potent therapeutic option for advanced lung adenocarcinoma patients with wild-type EGFR.

http://bit.ly/2UyJHuN

Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo

Summary

We generated a nitric oxide (NO)-releasing derivative of the anti-HIV protease inhibitor lopinavir by linking the NO moiety to the parental drug. We investigated the effects of lopinavir and its derivative lopinavir-NO on melanoma cell lines in vitro and in vivo. Lopinavir-NO exhibited a twofold stronger anticancer action than lopinavir in vitro. These results were successfully translated into syngeneic models of melanoma in vivo, where a significant reduction in tumour volume was observed only in animals treated with lopinavir-NO. Both lopinavir and lopinavir-NO inhibited cell proliferation and induced the trans-differentiation of melanoma cells to Schwann-like cells. In melanoma cancer cell lines, both lopinavir and lopinavir-NO induced morphological changes, minor apoptosis and reactive oxygen species (ROS) production. However, caspase activation and autophagy were detected only in B16 cells, indicating a cell line-specific treatment response. Lopinavir-NO released NO intracellularly, and NO neutralization restored cell viability. Treatment with lopinavir-NO induced only a transient activation of Akt and inhibition of P70S6 kinase. The results of this study identify lopinavir-NO as a promising candidate for further clinical trials in melanoma and possibly other solid tumours.

http://bit.ly/2sZ68NO

Bispecific anti-CD3 x anti-B7-H3 antibody mediates T cell cytotoxic ability to human melanoma in vitro and in vivo

Summary

Inhibition of the B7-H3 immune checkpoint is reported to limit the tumor growth of B7-H3⁺ tumors. In this study, we demonstrated B7-H3 expression in human melanoma cells, including a primary culture and several cell lines. Furthermore, we investigated whether B7-H3 could serve as a target for T cell-mediated immunotherapy against melanoma. The cytotoxic capacity of activated T cells (ATCs) armed with an anti-CD3 x anti-B7-H3 bispecific antibody (B7-H3Bi-Ab) to melanoma cells was measured using a bioluminescent signal through a luciferase reporter on tumor cells. In contrast to unarmed ATCs, B7-H3Bi-Ab-armed ATCs exhibited increased cytotoxicity against melanoma cells at effector/target ratios from 1:1 to 20:1. Moreover, B7-H3Bi-Ab-armed ATCs secreted more interferin-gamma (IFN-γ), accompanied by higher levels of activating marker CD69 and CD25 expression. Infusion of B7-H3Bi-Ab-armed ATCs suppressed melanoma growth in a xenograft mouse model. Taken together, our results indicate that B7-H3Bi-Ab-armed ATCs may be a promising approach to immunotherapy for melanoma patients.

http://bit.ly/2UyJAPT

Endonuclease and redox activities of human apurinic/apyrimidinic endonuclease 1 have distinctive and essential functions in IgA class switch recombination [Immunology]

The base excision repair (BER) pathway is an important DNA repair pathway and is essential for immune responses. In fact, it regulates both the antigen-stimulated somatic hypermutation (SHM) process and plays a central function in the process of class switch recombination (CSR). For both processes, a central role for apurinic/apyrimidinic endonuclease 1 (APE1) has been demonstrated. APE1 acts also as a master regulator of gene expression through its redox activity. APE1's redox activity stimulates the DNA-binding activity of several transcription factors, including NF-kB and a few others involved in inflammation and in immune responses. Therefore, it is possible that APE1 has a role in regulating the CSR through its function as a redox coactivator. The present study was undertaken to address this question. Using the CSR-competent mouse B cell line CH12F3 and a combination of specific inhibitors of APE1's redox (APX3330) and repair (compound #3) activities, APE1-deficient or -reconstituted cell lines expressing redox-deficient or endonuclease-deficient proteins, and APX3330-treated mice, we determined the contributions of both endonuclease and redox functions of APE1 in CSR. We found that APE1's endonuclease activity is essential for IgA-class switch recombination. We provide evidence that the redox function of APE1 appears to play a role in regulating CSR through the interleukin-6 signaling pathway and in proper IgA expression. Our results shed light on APE1's redox function in the control of cancer growth through modulation of the IgA CSR process.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2To0v7B

Engineering a murine cell line for the stable propagation of hamster prions [Neurobiology]

Prions are infectious protein aggregates that cause several fatal neurodegenerative diseases. Prion research has been hindered by a lack of cellular paradigms for studying the replication of prions from different species. Although hamster prions have been widely used to study prion replication in animals and within in vitro amplification systems, they have proven challenging to propagate in cultured cells. Since the murine catecholaminergic cell line CAD5 is susceptible to a diverse range of mouse prion strains, we hypothesized that it might also be capable of propagating non-mouse prions. Here, using CRISPR/Cas9-mediated genome engineering, we demonstrate that CAD5 cells lacking endogenous mouse PrP expression (CAD5-PrP-/- cells) can be chronically infected with hamster prions following stable expression of hamster PrP. When exposed to the 263K, HY, or 139H hamster prion strains, these cells stably propagated high levels of protease-resistant PrP. Hamster prion replication required absence of mouse PrP, and hamster PrP inhibited the propagation of mouse prions. Cellular homogenates from 263K-infected cells exhibited prion seeding activity in the RT-QuIC assay and were infectious to naïve cells expressing hamster PrP. Interestingly, murine N2a neuroblastoma cells ablated for endogenous PrP expression were susceptible to mouse prions, but not hamster prions upon expression of cognate PrP, suggesting that CAD5 cells either possess cellular factors that enhance or lack factors that restrict the diversity of prion strains that can be propagated. We conclude that transfected CAD5-PrP-/- cells may be a useful tool for assessing the biology of prion strains and dissecting the mechanism of prion replication.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2BfmTZF

A Streptococcus aquaporin acts as peroxiporin for efflux of cellular hydrogen peroxide and alleviation of oxidative stress [Gene Regulation]

Aquaporins (AQPs) are transmembrane proteins widely distributed in various organisms and facilitate bidirectional diffusion of water and uncharged solutes. The catalase-negative bacterium Streptococcus oligofermentans produces the highest H2O2 levels reported to date, which has to be exported to avoid oxidative stress. Here, we report that a S. oligofermentans aquaporin functions as a peroxiporin facilitating bidirectional transmembrane H2O2 transport. Knockout of this aquaporin homolog, So-AqpA, reduced H2O2 export by approximately 50% and increased endogenous H2O2 retention, as indicated by the cellular H2O2 reporter HyPer. Heterologous expression of So-aqpA accelerated exogenous H2O2 influx into Saccharomyces cerevisiae and Escherichia coli cells, indicating that So-AqpA acts as a H2O2-transferring aquaporin. Alanine substitution revealed Phe40 as a key residue for So-AqpA–mediated H2O2 transport. Northern blotting, qPCR, and luciferase reporter assays disclosed that H2O2 induces a >10-fold expression of So-aqpA. Super-resolution imaging showed that H2O2 treatment increases So-AqpA protein molecules per cell by 1.6- to 3-fold. Inactivation of two redox-regulatory transcriptional repressors, PerR and MntR, reduced H2O2-induced So-aqpA expression to 1.8- and 4-fold, respectively. Electrophoretic mobility shift assays determined that MntR, but not PerR, binds to the So-aqpA promoter, indicating that MntR directly regulates H2O2-induced So-aqpA expression. Importantly, So-aqpA deletion decreased oxic growth and intraspecies competition and diminished the competitive advantages of S. oligofermentans over the caries pathogen Streptococcus mutans. Of note, So-aqpA orthologs with the functionally important Phe40 are present in all streptococci. Our work has uncovered an intrinsic, H2O2-inducible bacterial peroxiporin that has a key physiological role in H2O2 detoxification in S. oligofermentans.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2B9jRGf

Mutations in the DNMT3A DNA methyltransferase in AML patients cause both loss and gain of function and differential regulation by protein partners [Molecular Bases of Disease]

Eukaryotic DNA methylation prevents genomic instability by regulating the expression of oncogenes and tumor-suppressor genes. The negative effects of dysregulated DNA methylation are highlighted by a strong correlation between mutations in the de novo DNA methyltransferase gene DNA methyltransferase 3 alpha (DNMT3A) and poor prognoses among acute myeloid leukemia (AML) patients. We show here that clinically observed DNMT3A mutations dramatically alter enzymatic activity, including mutations that lead to 6-fold hypermethylation and 3-fold hypomethylation of the human cyclin-dependent kinase inhibitor 2B (CDKN2B or p15) gene promoter. Our results provide insights into the clinically observed heterogeneity of p15 methylation in AML. Cytogenetically normal AML (CN-AML) constitutes 40–50% of all AML cases and is the most epigenetically diverse AML subtype with pronounced changes in non-CpG DNA methylation. We identified a subset of DNMT3A mutations that enhance the enzyme's ability to perform non-CpG methylation by 2–8 fold. Many of these mutations mapped to DNMT3A regions known to interact with proteins that themselves contribute to AML, such as thymine DNA glycosylase (TDG). Using functional mapping of TDG–DNMT3A interactions, we provide evidence that TDG and DNMT3-like (DNMT3L) bind distinct regions of DNMT3A. Furthermore, DNMT3A mutations caused diverse changes in the ability of TDG and DNMT3L to affect DNMT3A function. Cell-based studies of one of these DNMT3A mutations (S714C) replicated the enzymatic studies and revealed that it causes dramatic losses of genome-wide methylation. In summary, mutations in DNMT3A lead to diverse levels of activity, interactions with epigenetic machinery components and cellular changes.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2TwV5He

Quality Assurance in Interventional Radiology: Post-procedural Care

Abstract

Purpose of Review

To review best practices to improve the quality of patient service in the field of interventional radiology after performing the procedure.

Recent Findings

The aim of this paper is to highlight aspects of post-procedural care such as effective communication, post-procedural management of the patient, handling of obtained specimens, post-procedural follow-up, tracking outcomes, and education to assist the interventionalist in providing comprehensive quality post-procedural care.

Summary

Post-procedural communication, follow-up, and outcome tracking are essential elements in the quality assurance of an Interventional Radiology service.

http://bit.ly/2HK9izo

Quality Assurance in Interventional Radiology: Preprocedural Care

Abstract

Purpose of Review

To review best practices to improve the quality of patient service in the field of interventional radiology prior to performing the procedure.

Recent Findings

We highlight a checklist of elements that have a potential for improvement and contribution to overall quality of patient care from the time of taking the consult, until the time of the procedure. Our check list includes establishing appropriateness of the procedure, reducing waiting times, patient-centered care, patient education, shared decision making, establishing expectations, informed consent, managing the patient's medication list, preprocedure diet, prevention of CIN, prevention of contrast reactions, pain control and sedation, and coagulation status and hemostasis risk. Several consensus guidelines are referenced in this chapter. However, individual patients and clinical scenario vary and determine which guideline to follow or modify based in clinical judgment.

Summary

The clinic is a key component of success in any Interventional Radiology practice, as it provides the space for consultation, patient education, and preprocedural planning.

http://bit.ly/2t0AY8N

The role of lamin A/C in mesenchymal stem cell differentiation

Abstract

Lamin A/C is the major architectural protein of cell nucleus in charge of the nuclear mechanosensing. By integrating extracellular mechanical and biochemical signals, lamin A/C regulates multiple intracellular events including mesenchymal stem cell (MSC) fate determination. Herein, we review the recent findings about the effects and mechanisms of lamin A/C in governing MSC lineage commitment, with a special focus on osteogenesis and adipogenesis. Better understanding of MSC differentiation regulated by lamin A/C could provide insights into pathogenesis of age-related osteoporosis.

http://bit.ly/2BbxVPK

Perspektiven 2025 – ein Positionspapier der Deutschen Gesellschaft für Innere Medizin

Dtsch med Wochenschr 2019; 144: 207-212
DOI: 10.1055/a-0799-5146

Anlässlich des 200. Geburtstag ihres Gründers, Friedrich Theodor von Frerichs, setzt sich die Deutsche Gesellschaft für Innere Medizin (DGIM) mit dem vorliegenden Papier Perspektiven für ihre Arbeit in den kommenden Jahren, die durch Herausforderungen für Medizin und Wissenschaft geprägt sein werden. Basierend auf den 10 als zentral erfassten, kritisch beleuchteten Themenbereichen – Ärzte als Forscher, „Klug entscheiden", digitale Medizin, Ökonomisierung der Medizin, Aus- und Weiterbildung, demografischer Wandel und Multimorbidität, internistische Systemmedizin, Infektiologie und Hygiene, Intensivmedizin und Notaufnahme sowie Pflege und medizinische Assistenzberufe – soll das Papier die grundlegenden Positionen der Fachgesellschaft darlegen.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2MHJy5u

Fortschritte bei der Systemischen Sklerose

Dtsch med Wochenschr 2019; 144: 189-193
DOI: 10.1055/a-0652-2488

Von der Pathogenese zu neuen therapeutischen Zielen Das adaptive Immunsystem scheint für die Pathogenese entscheidend. Insbesondere dürften Autoantikörper, die das angeborene und adaptive Immunsystem regulieren, eine wesentliche Rolle spielen. Das frühe Erkennen von Organkomplikationen Schäden entstehen in den ersten 5 Jahren nach Beginn des Raynaud-Syndroms. Daher ist ein kontinuierliches Screening auf Organschäden nötig; die frühe Zuweisung in Zentren wird empfohlen. Bei Polymerase-III-Ak muss an ein paraneoplastisches Syndrom gedacht werden. Die kardiale Beteiligung ist prognostisch wichtiger als zuvor vermutet. Besseres Verstehen der Krankheitslast Die Systemische Sklerose (SSc) besitzt eine Vielzahl von wenig bekannten Symptomen wie Inkontinenz, Juckreiz und beeinträchtigt in der Regel die Lebensqualität deutlich. Die Letalität der Systemischen Sklerose D ie Mehrzahl der Patienten stirbt an der Erkrankung oder an deren Folgen, wobei neben der Lungenfibrose und der pulmonalen arteriellen Hypertonie die kardiale Beteiligung die knapp 10 %ige Sterblichkeit innerhalb von 2 Jahren verursacht. Durch frühes Erkennen von ventrikulären Tachykardien kann der plötzliche Herztod verhindert werden. Neues zur Therapie der Systemischen Sklerose Frühe und intensive Therapien und die Behandlung in Zentren sind nötig. Bei früher diffuser SSc ist eine autologe Stammzelltransplantation zu erwägen. Eine Reihe Substanzen befindet sich derzeit in Phase-III-Studien. Viele SSc-Patienten sind untertherapiert.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2sWUDXg