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25th July 2020 @ 10:00 am – 4:00 pm Europe/London Timezone
Doncaster Wool Market
Doncaster DN1 1BN
Doncaster DN1 1BN
Join us on Sat 25 July, this will be our Summer event celebrating women owned businesses for a unique shopping day in the town centre at Doncaster's New Wool Market. MNFW is proud to support women-owned businesses and over the last few years have collaborated with some amazing retailers, products and services offered by local independent women. Come along to our Shopping Day and support your local independent businesses, enjoy the whole day out with amazing specialist street food from around the world at the revamped Wool Market.
If you would like to apply for a stall at this event: https://forms.gle/A7qXwEnSZKASPiQ46


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The importance of metabolite profiling of a new drug is well-recognized. Elucidation of drug metabolite information is crucial due to the fact that drug metabolites can be toxic at certain levels, have a greater pharmacodynamic effect than the parent drug, interfere with concomitant medication, and impact liver function. In drug discovery, liquid chromatography (LC) combined with electrospray ionization (ESI) mass spectrometry (MS) has become the method of choice for obtaining rapid metabolic information due to its ease of use, exceptional selectivity, and applicability, even toward thermally labile polar metabolites, such as glucuronides, sulfates, and glutathione conjugates.
However, in LC/ESI-MS the analyte sensitivity is dependent upon the nature of the analyte, as well as the mobile-phase properties, such as organic solvent and electrolyte contents.
It is accepted that a mobile phase with a higher composition of organic solvents improves the ionization efficiency, especially in the case of negative polarities. However, achieving the desired chromatographic separation of metabolites may require the use of mobile phases that may not be ideal for ESI. Altering solvent properties by post-column addition of a modifier can be an effective technique to improve sensitivity. Post-column addition of an organic modifier stabilizes the spray and allows enhancement of sensitivity without affecting the chromatographic separation.
An attractive aspect of the post-column addition is that the LC part is completely decoupled from the ionization region, which allows the use of an assortment of modifiers.
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And be not conformed to this world: but be ye transformed by the renewing of your mind, that ye may prove what is that good, & acceptable, & perfect, will of God."Romans 12:2
Mind Power 365 (The Blessed Factory)
Thursday, May 10, 2012
Bible Verse of The Day: Philippians 4:19
Bible Verse of The Day: It is Written, And my God will supply all your needs according to His riches in glory in Christ Jesus. Philippians 4:19 Feel free to leave your prayer requests in the comment section. Have a blessed day!
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text: 10 fantastic degrees to study on the Gold Coast January 2017 Boasting more than 200 international and domestic education providers including three major universities, the Gold Coast is being recognised globally for its education offerings. Shannon Willoughby, CEO of Study Gold Coast says it is no accident the Gold Coast is being positioned as an education destination of choice. She says Study Gold Coast is using the sector to raise the profile of the city both nationally and internationally. "The growth of the education sector is a key part of further diversifying the Gold Coast economy,'' says Willoughby. "Not so long ago tourism was the only drawcard for the city and it became trapped in boom and bust cycles. Now, the city is growing larger, the economy is diversifying and the economy is becoming much more stable." Willoughby says the education industry is now Australia's third largest export industry and globally Australia is the third most sought after education destination in the world. Study Gold Coast is working to ensure the city receives its fair share of international students. With this in mind, More Gold Coast has chatted to the city's three universities to uncover some of the most popular and innovative courses on offer to students… Bachelor of Speech Pathology (SCU): Speech pathologists assess and treat adults and children exhibiting acquired or congenital disorders of speech, fluency, voice, language and swallowing. This distinctive degree at Southern Cross University educates students to become knowledgeable, skilled, empathetic, ethical and innovative professionals who are able to provide effective assessment and intervention for people of different ages. Bachelor of Pedorthics (SCU): Pedorthics is about keeping people mobile and getting the best performance from their feet, footwear or orthoses. Southern Cross University is the first in Australia to offer a Bachelor qualification in this field. Bachelor of Criminology and Criminal Justice (Griffith) This is a specialised degree that teaches about the causes of crime and society's response through the justice system to address them. It offers graduates career opportunities in policing and security, intelligence, probation and parole, child protection, crime analysis, courts and justice services, crime prevention and regulatory agencies. Southern Cross University Gold Coast campus Bond University, Architecture Building Gold Coast Bachelor of Biomedical Science (Griffith) A Biomedical Science degree offers students an understanding of health and the methods for diagnosing and treating disease. It is also one of a growing number of study environments using virtual reality technology to provide students with a truly immersive learning environment. The degree prepares graduates for work in hospitals, health departments, medical research institutes, university and government research organisations, and in the pharmaceutical, diagnostic, biotechnology and other health-related industries. Bachelor of Paramedicine (Griffith) Demand for paramedics in South-East Queensland and Northern NSW currently exceeds supply and this degree prepares graduates for positions in this important field of community health. Through the degree, students are trained to work as a paramedic in a range of traditional and non-traditional settings and are skilled in clinical decision-making, problem-solving and critical thinking. They learn about human body systems, paramedic practice, emergency treatment of disease and response to trauma. Master of Nutrition and Dietetic Practice (Bond) All Bond University's Master of Nutrition and Dietetic Practice students complete an international nutrition project abroad to obtain a global perspective on nutrition and dietetics. Projects and activities focus on the entrepreneurial practice of nutrition and dietetics to develop business management, media and marketing skills. Bachelor of Actuarial Science (Bond) Emerging as a key growth sector of the 21st century, actuarial science applies elements of economics, finance, statistics and advanced mathematics to interpret, manage and evaluate risk. The Bachelor of Actuarial Science – developed and taught by Professor Terence O'Neill, one of Australia's leading academic authorities in the field – is an innovative and immersive program that combines advanced mathematics, statistics, data analytics, actuarial risk theory, finance, economics and accounting with large-scale, real-life commercial data analysis to develop techniques for the management of risk and business decision making. Students will gain unparalleled access to Bond Business School's two financial trading rooms and 40 Bloomberg terminals – the most of any university in Australia. Juris Doctor (JD) (Bond) Bond's The Juris Doctor program is an approved degree for purposes of admission as a barrister or solicitor in all Australian jurisdictions. And in conjunction with further study, the program can be used to gain admission internationally, making it immensely popular with our large cohort of Canadian law students. Students learn Legal research and analysis, Legal writing and drafting, Negotiation and dispute resolution, Advocacy and oral presentation and Client interviewing and communication. Bachelor of Interactive Media & Design (Bond) The Bachelor of Interactive Media and Design program prepares communicators and designers for careers in the dynamic field of interactive media applied to a wide range of applications. The degree is founded on the growing market power of the creative industries, which are based on design, web and procedural communications. Specialisations within the degree include computer games and digital media design, advertising, film and television as well as communication. All students have complete access to the awesome Level Up Lab and Computing Lab which are specifically tailored for the development of desktop, mobile and console applications. These include virtual reality, augmented reality, 3D printing, websites, apps and games. Master of Advertising (Bond) Throughout the Master of Advertising program, students will be actively involved in the day-to-day requirements and challenges of developing commercial campaign concepts and design communication initiatives for clients in a studio-based learning environment. Students have complete access to the Upper Basement Studio and other facilities which feature designated work areas, brainstorming spaces, a "chill out" zone and up to date design software and equipment easily accessible. Student working in the Bond University Architecture Building Bachelor of Architectural Studies (Bond) Students of the Bachelor of Architectural Studies (BAS) have complete access to the brand new architecture building, designed by Sir Peter Cook and Gavin Robotham of CRAB Studio, London – the Abedian School of Architecture. A strong studio culture is driven by student collaboration, social engagement, and consistent one-on-one interaction with academic staff. The Workshop and Digital Fabrication Lab provides opportunities in design as part of the new generation of architecture. Share Facebook Twitter Google plus Email


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Mindless in-play wagering encourages corruption in sports, McGauran says
Racing Australia's chief executive Peter McGauran has reportedly lobbied the Federal government demanding that a loophole in Australia's interactive gambling law concerning in-play wagering be closed.
McGauran told The Australian newspaper that Racing Australia believes "mindless" in-play betting has opened the door to corruption in sports even further.
Major Australian bookmakers have exploited a loophole that allows for live betting over the telephone by utilising advanced technology and a requirement that customer's switch on the microphone on their device when utilising in-play betting offers.
McGauran's submission was made to the government review headed by NSW premier Barry O'Farrell on the interactive gambling act.
"It's an integrity and an economic issue," McGauran told The Australian.
"There would be significant migration of revenue from traditional racing wagering to sports betting to in-play, which is mindless repetitions in front of a big screen that for many is reminiscent of poker machines.
"Apart from the clear and immediate threat to integrity from illegal online bookmaking, the revenue loss over time will significantly damage one of Australia's leading industries and its 200,000 employees."
Other recommendations submitted by the organisation included ISP blocking of offshore, unlicensed gambling operators and payment service restrictions. Racing Australia also wants a match fixing and corruption in sport task force to be established.
Online Casino News Courtesy of Infopowa


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Thursday 24 May, 7.30 pm - Church in Rougemont
Pablo VALETTI violin
Petr SKALKA cello
Céline FRISCH harpsichord
Sonatas by Francesco Maria Veracini, Domenico Scarlatti, Francesco Geminiani & Pietro Locatelli
One of the leading Baroque ensembles, "Café Zimmermann" first earned its reputation performing Bach's instrumental music. For their concert in Rougemont the three "pillars" of the ensemble, all trained at the Schola Cantorum in Basle, have prepared an intimate and colorful voyage to Italy, where the trio sonata and other principal forms of Baroque music originated.
Friday 25 May, 2 pm - Church in Rougemont
Youngsters singing for other youngsters
Henri FARGE direction
N. N. violins
Veronika KUIJKEN harpsichord
Madrigals by Monteverdi
Following concerts with the Ministrings three years ago, the Maîtrise two years ago, and the Orchestra Piccolo last year, students from the Lausanne Conservatory are "back in the trenches" this year to demonstrate their passion to other youngsters. These are advanced choir singers who have come to perform under the direction of the former choir director of Radio-France.
Free admission – information and reservations at the Tourist Office
Friday 25 May, 7.30 pm - Church in Rougemont
The "Four Seasons" and other Italian concertos
I VIRTUOSI DELLE MUSE (8 musicians)
Jonathan GUYONNET violin
Stefano MOLARDI harpsichord & direction
Antonio Vivaldi: "The Four Seasons"; Concerto in G Minor RV 156
Antonio Caldara: Introduzione alla Passione
Archangelo Corelli: Trio Sonata Op. 3 No. 4
Georg Friedrich Haendel: Suite "Fortunate Florindo"
Nicola Porpora: Concerto Op. 2 No. 5
This is not the first performance of the "Four Seasons" at "La Folia": the performance of the renowned Barocchisti in 2004 is followed this year by the new rising star among Italian Baroque ensembles. Founded in Cremona in 2004, "I Virtuosi delle Muse" recently signed with EMI Classics. At the heart of their concert programme are the works of a number of Italian musical geniuses.
Saturday 26 May, 11 am - Church in Rougemont
Harpsichord Recital: from Frescobaldi to Bach
Jovanka MARVILLE harpsichord
Works by Giovanni Battista Ferrini, Girolamo Frescobaldi, Georg Friedrich Haendel, Domenico Scarlatti & Johann Sebastian Bach
It is the king of instruments at "La Folia", the one with which everything began. The magnificent harpsichords belonging to our president Jean-Michel Chabloz have a rendezvous this year with Jovanka Marville, professor at the Lausanne University of Music (HEM). A student of Christiane Jaccottet (as well as "our" Ruedi Lutz for improvisation), she has prepared a musical voyage through Baroque Europe that begins at the court in Mantua and will end in Northern Germany.
Saturday 26 May, 7.30 pm - Church in Rougemont
Monteverdi, body and soul
Michel CORBOZ direction
A collection of madrigals and excerpts from Selva Morale by Claudio Monterverdi
Is it necessary to introduce the Lausanne Vocal Ensemble? Founded in 1961 by Michel Corboz, this outstanding choral ensemble first established its international reputation with much-praised recordings of Monteverdi and is thus a "logical" choice to perform at the 12th edition of the festival with its particular emphasis on Mantua this year. The ensemble will be coming with an assortment of sacred and profane works by the Italian composer in a colorful homage which unites heaven and earth.
Sunday 27 May, 7.30 pm - Chruch in Rougemont
"Il canto delle lagrime" – approaching Monteverdi's "Lamento d'Arianna"
Raquel ANDUEZA song
Bérengère SARDIN harp
Yves RECHSTEINER harpsichord
Approaching Claudio Monteverdi's "Lamento d'Arianna" – excerpts from:
Claudio Monteverdi: 7th book of Madrigals; Scherzi Musicali
Girolamo Frescobaldi: 1st and 2nd books of Toccatas
Salomone Rossi: various books of Sinfonias, Gagliards & Courantes
Orfeo is well known, but Arianna has been lost: the only part of this opera that has survived is Monterverdi's masterpiece the "Lamento d'Arianna", whose success gave birth to a veritable musical genre that bridged the 17th century. Yves Rechtsteiner has created an original concert programme centering around this Lamento and contemporary composers from the court in Mantua such as Frescobaldi and Salomone Rossi.
Monday 28 May, 11 am - Church in Rougemont
Italian Improvisations
Ruedi LUTZ (harpsichord, organ, keyboard) improvises on music from the court in Mantua with three students from the Schola Cantorum Basiliensis:
Alice BORCIANI soprano
Eva SALADIN violin
Sam CHAPMAN lute & theorbo
The festival's favorite child will never stop surprising us! He is coming to Rougemont this year in the same costume that delighted us in 2001: as professor for improvisation at the Schola Cantorum Basiliensis, the prestigious school to whom the festival owes so much. "Primus inter pares", he is coming to the 12th edition of the festival with three of his students ready to weave their themes around music from the court in Mantua.
Monday 28 May, 4 pm - Church in Rougemont
«Il cieco miraculoso» – Conrad Paumann at the court of the house of Gonzaga
Guillermo PÉREZ organetto & direction
David CATALUNYA clavicymbalum
Andrés Alberto GOMEZ organ
Angélique MAUILLON Gothic harp
Viva Biancaluna BIFFI vielle & song
The ensemble "Tasto solo" has made a specialty of rediscovering the repertoire for Gothic keyboard instruments from the 14th and 15th centuries. Each of the apparitions is a sensation for the ears as well as for the eyes, for one rarely has the opportunity to admire such "mechanical" marvels. The ensemble comes with a programme centering around one its "warhorses", Conrad Paumann, one of the first composers from the tradition of the great German school.
Monteverdi, Mantoue & Italy
The theme of the festival each year is not an end in itself, a self-imposed restriction to creating a programme, but more of a guiding light that lends a unique color to each edition of the event. "La Folia" is a venue that has made it is possible to encounter early music in all of its facets, a series of concerts over an extended Whitsunday weekend, each "an earful" in itself. The previous festivals offered tours of the great musical traditions in Europe, taking listeners to Flanders, Austria, Bohemia and even to… Switerland! This year we are initiating a series of festivals dedicated to some of the most significant courts in music history: towns where enlightened princes maintained chapels and composers over a number of generations, nurturing the finest of Europe's music during their golden ages. The first stopover in this extended journey is in Mantua in northern Italy. The duchy here was led by the Gonzaga family, later the Ganzaga-Nevers family, from the 15th to the 18th century. This little city-state, later annexed by the duchy of Milan, enjoyed its golden age from the 16th to the 17th centuries, particularly during the reign of Vincent I, who accompanied Claudio Monteverdi in the production of his greatest masterpieces.
As usual we have prepared this sojourn in Italy together with faithful friends of "La Folia" as well as with a number of new faces whose talents it is a pleasure to be able to share with you: the young ensemble "I Virtuosi delle Muse" is coming with their breathtaking interpretation of Vivaldi's "Four Seasons"; Céline Frisch and Pablo Valetti's celebrated "Café Zimmermann" will be present in its trio formation; the ensemble "Tasto Solo", which has earned recognition for their rediscovery of very early keyboard music; and it is a great pleasure finally to be able to greet Michel Corboz and his Lausanne Vocal Ensemble in Rougemeont with a tailor-made Monteverdi programme.
It was "love at first sight" in 2001, and since then no edition of "La Folia" has been possible without the bright, friendly, informal presence of harpsichordist Ruedi Lutz, master of improvisation and incomparable "entertainer". As for our Bach edition last year, he will be coming to the festival this year with three of his students from the Schola Cantorum Basiliensis. And finally, last but not least, budding artists will be contributing to the festive atmosphere with a first-class polyphonic programme made to measure around Monteverdi and the court in Mantua, young vocalists from the Lausanne Conservatory under the direction of Henri Farge.
We would like to take this opportunity to thank all of our patrons, sponsors, partners, friends, benefactors and you, our faithful audiences, for without you "La Folia" simply would not exist!


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Carabeth Benson, 82, of Galesburg, died at 2:06 a.m. Tuesday, July 28, 2020, at home.
She was born June 27, 1938, in Biggsville, the daughter of Earl M. and Martha H. (Dunham) Plummer. She married to Jack L. Savidge on December 29, 1965. He preceded her in death on February 10, 1984. She later married Warren "Tim" Benson on October 14, 1984, in Dahinda. He preceded her in death on February 8, 2007.
She is survived by a step son, Cam (Crystal) Junkin of Arizona; two step daughters, Carol (Walt) Foster of Canada and Kim (John) Linn of Wyoming; six grandchildren; 11 great grandchildren; a brother, Douglas Mac (Annella) Plummer of Galesburg; three sisters, Earleen Farrell, Dorothy (Ray) Pickrel, and Susan Perschnick, all of Galesburg; a foster brother, Randy (Linda) Edwards of Utah; and many nieces and nephews. She was preceded in death by her parents and a sister, Nancy Craig.
Carabeth worked at Galesburg Midwest Credit Union for 30 years before retiring. She was a former member of Dahinda United Methodist Church. She graduated from Galesburg High School in 1956 and then Youngs Beauty School. Carabeth enjoyed collecting antiques.
Graveside service will be 11 a.m. Monday, August 3, 2020, in Oak Lawn Memorial Gardens. There will be no visitation. Memorial contributions may be made to a charity of the donor's choice. Hinchliff-Pearson-West Funeral Directors and Cremation Services Galesburg Chapel is handling arrangements for the family. Online condolences may be made at www.h-p-w.com.
To send flowers to the family or plant a tree in memory of Mrs. Carabeth (Plummer) Benson, please visit our floral store.
Donor's Choice


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No-brainer: Tigers moving RHP prospect Sandy Baez to bullpen
Detroit — The question isn't so much why the Tigers' are transitioning right-handed pitching prospect Sandy Baez from starter to reliever, it's what took them so long to do it?
The Tigers' Double-A affiliate Erie announced Thursday that Baez, 24, was moving to the bullpen — a move orchestrated by the general manager Al Avila and vice president of player development David Littlefield.
"He performed well in relief when he came up to Detroit," Littlefield said. "And he'd done well in the bullpen in spring training. He has a great arm and he's got some weapons. We just think that with the way things are right now, we're going to try him in the bullpen and see how things go."
Baez, who as an emergency call-up pitched 4.1 innings of no-hit relief June 4 against the Yankees, has scuffled as a starter at Double-A. He was 1-7 with a 5.31 ERA and a 1.467 WHIP in 15 starts.
Those numbers are not indicative of his skill-set. As a starter, his fastball velocity was averaging 94.7 mph. That will play up toward 96 mph in shorter innings out of the bullpen. He also has a slider and split-fingered pitch.
From an organizational point of view, Baez's quickest path to the big leagues is as a reliever.
The Tigers sent Warwick Saupold back to Toledo on Wednesday night and purchased the contract of right-hander Victor Alcantara. Right-handers Drew VerHagen and Johnny Barbato are on the disabled list.
Closer Shane Greene is also on the disabled list.
Beyond that, seven of the club's top 10 prospects are starting pitchers, including No. 1 prospect Franklin Perez, who is finishing his rehab starts and could be in the rotation at Erie soon.
Given all those variables, moving Baez to the bullpen is a no-brainer — for the Tigers and for Baez.


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IFC and Stock Exchanges around the World Ring the Bell for Gender Equality
IFC, a member of the World Bank Group, is partnering with over 70 stock exchanges around the world to "Ring the Bell for Gender Equality"—an initiative linked with International Women's Day that promotes increased women's participation in the global economy to catalyze sustainable and inclusive private sector growth.
Accelerating the pace of reforms to ensure gender equality could yield enormous benefits, with the potential to increase global gross domestic product by $12 trillion in the next six years, according to a McKinsey Global Institute report.
"The business case is compelling and IFC research has recently highlighted that correcting gender imbalances could lead to important economic gains in developing countries," said Ethiopis Tafara, IFC Vice President & General Counsel, Legal, Compliance Risk and Sustainability. "Failing to tap into all human capital represents a significant lost opportunity to boost growth," he said.
Examples include increasing the flow of private equity and venture capital to women-owned businesses in emerging markets beyond the current 7 percent and accelerating the pace of women ascending to board and senior leadership positions.
The 2019 Ring the Bell for Gender Equality marks the fifth year of the partnership, which encourages participating stock exchanges to signal their commitment to gender equality by advocating for better gender balance and prioritizing diversity in their own corporate structures. This can include implementing women-friendly workplace policies, developing female-oriented investment products, reporting to shareholders on diversity practices, encouraging or requiring listed companies to disclose gender metrics, and increasing the number of women on their boards and in senior leadership.
"Stock exchanges represent a powerful alliance to push for equitable economic opportunities and promote gender equality as part of a broader emphasis on environment, social and governance issues," said Mary Porter Peschka, Director for ESG at IFC. "As business leaders, entrepreneurs, employees and consumers, women are fundamental to inclusive growth," she said.
IFC's support for gender-smart business solutions include working with companies in developing countries to generate opportunities for women that also contribute to the bottom-line. The institution leverages its relationship with over 2,000 financial institutions and private equity funds to expand access to finance for female entrepreneurs.
It also promotes good corporate-governance practices such as board diversity. IFC has over 30 percent female representation among nominee directors on the boards of its own investee companies today and aims to increase that rate to 50 percent by 2030.
The "Ring the Bell for Gender Equality" event is a partnership of IFC, Sustainable Stock Exchanges Initiative (SSE), UN Global Compact, UN Women, Women in ETFs, and the World Federation of Exchanges.
About IFC
IFC—a sister organization of the World Bank and member of the World Bank Group—is the largest global development institution focused on the private sector in emerging markets. We work with more than 2,000 businesses worldwide, using our capital, expertise, and influence to create markets and opportunities in the toughest areas of the world. In FY18, we delivered $23.3 billion in long-term financing for developing countries, leveraging the power of the private sector to help end poverty and boost shared prosperity.


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The proportions of your business and safety measure hope acquire by blogging is another consideration. Whatever is exclusive. If your business has something interesting state he on a consistent basis, especially when it will invite comments from others, then response is generally yes, yet every situation is various and must be evaluated to your pros, cons, and what your business hopes to gain from a blog presence.
When considering which one is the most important, what's going to help in which make more money from your online business, as compared to trying choose on one would be to other, take into consideration that using both PPC and good seo may be just what you ought to accomplish great traffic and excellent conversions. Objective is to boost your main point here. Let seo and PPC interfere to achieve that.
Images may alter as well when the mouse hoovers over it. This is great if you'd like to show visitors your image may be the portal to a new screen. Possess apply this though you'll be wanting the roll-over to be subtle and instant. So use light weight photos that load quickly and fiddle with gradient settings and color changes. Usually the roll-over image glance very very similar to the original.
Now that you know, what area perform on, Document How you want to address the unexpressed needs. Start complete study of the actual marketplace and evolve a clear and simple plan for that portal and some tips it is poised a person the readers.
This has gained popularity in web design since can be of sitios web.0. The new web functionality means new wonderful landmarks like uploading, dynamic content and animated. Prime examples of web 2.0 sites are YouTube, Flickr and Twitter. Insurance coverage the new functionality will be here web design have applied rounded edges to a great deal of their designs and not done well in some cases. I guess it boils down to extra of your design whether you should use rounded edges. Avoid them or use all of them 3px radius (small curve) if you would like your site to be very slim and clean looking. Too a more bubbly, kids look use rounded edges on everything and expand the radius as well.
D) Keep All Options before The eye area and then, COMPARE THEM:Try to discover as many Agencies and then, do a comparison on the cornerstone of their offerings. Compare and get the most-appropriate digital agency. Now, is actually because not that difficult. Or, is here? just ensure a person simply have merely the trusted companies on your list, when doing the variety.
The TAGS on your page hold a key to key word prominence. Assist you maximise SEO on web site its crucial to incorperate your keywords inside your Page Titles, Descriptions and Keywords tag cloud. Also make sure that your body content contains your keywords – but don't go 'stuffing' crazy! The remainder traditional marketing, good happy with a clear sales message will build conversion price ranges.


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Niveus adds new service line
Niveus Consulting Group is proud to announce they have added a new service line for clients.
- DFK news
- 09 October 2019
Niveus Consulting Group is proud to announce they have added a new service line for clients.
In response to the current market trends and to build on the synergies of the group, in addition to accounting, tax and transfer pricing services, Niveus Consulting Group will also provide legal services to its clients as of 1 October 2019. The new business line (Niveus Legal Services) will be supported by an associated law firm headed by Adam Fischer.
Adam has been a Hungarian lawyer since 2012. He studied at a top law university in Hungary; he also obtained a business management BA degree. Adam worked at Baker & McKenzie for almost 4 years; then he went to a top tier Hungarian boutique law firm. His primary field is commercial law, with a strong focus on tax law. He also represents clients during court procedures, including both commercial and tax disputes.
Niveus Consulting Group is now able and happy to assist you with any Hungarian legal issues, should it be the establishment of a company, a dispute with a business partner or simply some legal advice to clarify the Hungarian law.
Feel free to contact Niveus Consulting Group partners or Adam directly at [email protected]
To find out more about Niveus Consulting Group visit their website ww.niveus.hu/en/


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Hypothesis and Theory ARTICLE
Perforinopathy: a spectrum of human immune disease caused by defective perforin delivery or function
- 1Killer Cell Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
- 2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
- 3Cancer Cell Death Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
Congenital perforin deficiency is considered a rare cause of human immunopathology and immune dysregulation, and classically presents as a fatal illness early in infancy. However, we propose that a group of related disorders in which killer lymphocytes deliver only partially active perforin or a reduced quantum of wild-type perforin to the immune synapse should be considered part of an extended syndrome with overlapping but more variable clinical features. Apart from the many rare mutations scattered over the coding sequences, up to 10% of Caucasians carry the severely hypomorphic PRF1 allele C272 > T (leading to A91V mutation) and the overall prevalence of the homozygous state for A91V is around 1 in 600 individuals. We therefore postulate that the partial loss of perforin function and its clinical consequences may be more common then currently suspected. An acute clinical presentation is infrequent in A91V heterozygous individuals, but we postulate that the partial loss of perforin function may potentially be manifested in childhood or early adulthood as "idiopathic" inflammatory disease, or through increased cancer susceptibility – either hematological malignancy or multiple, independent primary cancers. We suggest the new term "perforinopathy" to signify the common functional endpoints of all the known consequences of perforin deficiency and failure to deliver fully functional perforin.
Perforin (PRF, encoded by the PRF1 gene) is a pore-forming toxin (1, 2) stored in the secretory granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells (collectively known as cytotoxic lymphocytes, CLs) (3). During an immune response, CLs form an immune synapse (IS) with various types of antigen-presenting cell, and release PRF and granzyme serine proteases into the synaptic cleft (4). The extracellular milieu of the IS (high calcium and neutral pH) promotes perforin membrane binding and insertion culminating in pore formation (5, 6), an indispensable requirement for granzymes to enter the target cell cytoplasm and trigger a multitude of cell death signaling pathways (7–12).
A Spectrum of Clinical Presentations Reflecting Functional PRF Deficiency
It was first appreciated around the turn of this century that the complete loss of perforin activity results in a fatal, autosomal recessive immunoregulatory disorder of infancy (median age of onset <12 months), familial hemophagocytic lymphohistiocytosis (FHL) (13), which can be cured only by heterologous bone marrow transplantation (14). The inability to clear antigen-presenting cells by impaired CLs causes an uncontrolled activation and expansion of CD4+ and CD8+ T cells that secrete high levels of interferon-γ. This cytokine is central to disease pathogenesis, as it leads to macrophage activation and secondarily to the overproduction of pro-inflammatory cytokines by these cells. This in turn is manifested clinically as intractable fever, liver and spleen enlargement, and hemophagocytosis in the bone marrow and lymphoid organs, leading to severe anemia and leukopenia (15). It is generally thought that macrophage activation and infiltration in bone marrow leads to hemophagocytosis in FHL patients. Recently, it was shown that interferon-γ specifically potentiated phagocytosis of erythrocytes by macrophages, thus suggesting a key mechanism for anemia in these patients (16). Variations in clinical presentation stem in part from the fact that there are up to five independent genetic causes of primary FHL and related syndromes (4). Linkage analyses have identified four genetic causes that account for 80–90% of FHL, while a further locus mapping to Chr 9 is yet to be defined (17). Inactivating perforin mutations are responsible for approximately 50% of all cases (type 2 FHL, FHL2), while mutations in three other genes, UNC13D, STX11, and STXBP2 (FHL3, 4, and 5 respectively) impair or ablate the delivery of perforin to the IS (18–21). Thus, all the causes of FHL are causally linked by the failure to deliver sufficient active perforin to the IS.
Natural killer cells (innate immunity) and CTLs (adaptive immunity) were first recognized for their key role/s in the defense against viruses; more recently these cells have also been appreciated as being critical for immune surveillance against a variety of malignancies, particularly those of hematopoietic origin (22, 23) or of multiple cancers in the same individuals (24). Both these roles reflect the importance of perforin in initiating the apoptosis of dangerous cells, either those harboring an intracellular pathogen, or possessing the potential for uninhibited growth and spread, to the detriment of the host. Given this, it is perhaps surprising that (infantile) FHL rarely presents with overwhelming sepsis syndrome caused by viral infection (with the rare exceptions of persistent or fulminant Epstein–Barr virus infection) and almost never with malignancy. Thus, most cases of FHL are not manifested directly through the consequences of failed "target cell death" but rather, indirectly, through an apparent skewing of the immune response toward exaggerated cytokine secretion, the second major type of effector function of CTL/NK cells.
Recent work on CTL/NK cells has highlighted their regulation of various inflammatory pathways through their cross-talk with other components of the immune system (25–27); the consequent aberrations in inflammatory responses leading from failed perforin production can occur in response to known human pathogens, although a specific pathogen that triggers the onset of FHL is rarely identified. These phenomena strongly indicate that perforin and the pathways that synthesize and deliver it to the IS play a more fundamental role in immune homeostasis, centered more particularly on adaption of the neonate to the myriad "non-pathogenic" antigenic stimuli he/she will encounter after leaving the womb. In this context, we postulate it is the failure to clear "constitutive" antigen-presenting cells through perforin-dependent (largely granzyme-mediated) cell death that induces the increased secretion of interferon-γ from the killer lymphocyte, in turn provoking severe dysregulation of pro-inflammatory and chemokine cascades in by-stander cells. The molecular and cellular mechanisms causally linking failed target cell apoptosis and the hypersecretion of interferon-γ are of fundamental importance to the pathophysiology of perforinopathies, and ought to be the focus of intensive research. The consequential effects on macrophages, including secondary pro-inflammatory cytokine secretion and grossly increased macrophage phagocytic activity are the major manifestations of disease and are most marked when perforin activity is completely abolished, but less so if some residual perforin activity persists, for example due to inheritance of perforin missense mutation/s that are not completely inactivating. This theme is taken up again below, as we believe that the variable clinical presentations probably flow on from this fact. While this paper focuses on perforin, it has also been noted for some time that granzymes (for example, granzymes A and M) can influence inflammatory pathways (25, 27), sometimes in a perforin-dependent manner, and at other times without the need for perforin to be present. While the significance of granzyme-mediated inflammatory pathways for human health are yet to be defined and hyper- (or hypo-) inflammatory syndromes are not yet described, future research should keep this possibility in mind. This is particularly so because granzyme genes can show considerable polymorphism, both in mice (28) and humans (29).
On the basis that congenital defects in CTL/NK that influence the secretion of active perforin may become clinically evident at various stages of life, we would like to propose that this group of disorders be considered as perforinopathies under three subheadings: acute, subacute, and chronic, depending on the stage of disease onset (Table 1). As alluded to above, earlier presentations tend to reflect cytokine-mediated immunopathology; later in life, a patient may present more cryptically with relatively weaker inflammatory manifestations or none at all (Figure 1). We think it is quite likely that clinicians managing these less urgent clinical presentations may not have previously considered perforinopathy in the differential diagnosis, particularly in children presenting with a variety of inflammatory disorders beyond infancy.
Figure 1. All of the clinical presentations of perforin deficiency (including the failure to deliver active perforin into the immune synapse) result from failed killing of an antigen-presenting cell. Early in life, the clinical manifestations are more likely to reflect cytokine hypersecretion due to chronic stimulation of CD4 and CD8 CTLs and NK cells, resulting in disordered immune hemostasis affected both the lymphoid and myeloid compartments. Later in life, hyper-inflammatory presentations are less likely, and the clinical scenario is more likely to reflect failure to clear dangerous target cells, particularly virus-infected cells and neoplastic cells.
Acute Presentations of Perforinopathy – FHL
For the purpose of this discussion, we define acute perforinopathy as that resulting in a clinical presentation prior to the age of 24 months, with median of approximately 9 months (this may vary depending on the genetic cause of FHL). As discussed above, the pathogenesis involves a cascade of downstream events following on from the inability of NK cells and CTL to present functional perforin and, therefore, kill a cognate target cell. Affected infants typically present with "classic" FHL and meet all or most of the criteria described in HLH-2004 (15). The diagnosis is confirmed by the loss of NK cytotoxicity (which is convenient to test, as the NK cells of healthy individuals display constitutive, pathogen-independent cytotoxicity) and identification of mutations in candidate genes (PRF1, UNC13D, STX11, STXBP2). Affected infants are typically very unwell, and may require admission to a high-dependency or intensive care unit; given the autosomal recessive inheritance of most of these disorders, a sibling may have previously been similarly affected, while parents are almost always unaffected carriers. Patients first have their condition stabilized, and are then prepared for heterologous bone marrow transplantation, the only potentially curative therapy (14, 15).
Acute perforinopathy is caused by detrimental mutations in PRF1 or in proteins responsible for its delivery from the lumen of cytotoxic granules to the IS, UNC13D, STX11, or STXBP2 (4). The molecular basis of many disease-causing PRF1 mutations has been investigated directly using recombinant expression systems (23, 30–33), and is supported by the X-ray crystal structure of perforin (1). In contrast, the biochemical bases of pathological mutations in the other three proteins, Munc13-4, Syntaxin11, and Munc18-2, remain largely unexplored due to the lack of sufficiently informative experimental systems. As a result, the loss of molecular function is predicted (34, 35), either on the basis of undetectable NK cell activity and/or severely reduced protein expression due to degradation. In the context of an early onset FHL (acute perforinopathy), the known structural and cellular defects correlate well with disease severity. Indeed, in the case of PRF1, genuinely "null" mutations are most commonly caused by nonsense or frame-shift mutations and in-frame deletions that completely abrogate function. By contrast, a careful genotype-phenotype analysis has revealed that only about 50% of missense mutations ever reported resulted in a complete loss of perforin function, either due to direct interference with a critical functional domain or unscheduled post-translational modifications such as glycosylation (30, 36). The remaining PRF1 missense mutations were more commonly associated with atypical presentations of FHL or with seemingly unrelated pathologies (immunoregulatory or otherwise) in older children, adolescents, and even adults, who did not necessarily presented with FHL at all (23, 37). If residual perforin activity delays the clinical onset beyond the age of 12 months, we term the presentation "subacute."
Sub-acute Presentations of Perforinopathy
Sub-acute perforinopathies have a wide spectrum of manifestations, all of which are all caused by a partial ("sub-total") loss of CL cytotoxicity due to bi-allelic mutations in one of the four genes described above. Unlike the acute form of the disease, sub-acute perforinopathies may be difficult to diagnose due to their generally milder and more "patchy" clinical presentations, an intermittent clinical course, a range of ages of onset and their frequent response to non-specific immune-suppressive or immune-ablative therapies (38, 39). These patients are more likely to present with a precipitating infection or with an isolated inflammatory manifestation such as pneumonitis that can lead the treating clinician away from the underlying diagnosis. While the only curative therapy for such patients is still ultimately bone marrow transplantation, combination drug therapy may induce remissions of variable duration. These non-curative interventions may be the only available therapies that influence disease outcome, but they have frequent unwanted effects such as opportunistic infection, growth retardation, and bone marrow suppression. Alleviating symptoms that might have categorized them as FHL patients might also delay diagnosis in both the patient and their younger siblings (38). Considering the fact that "classic" FHL is relatively rare and commonly described in infants or very young children, we believe sub-acute perforinopathies may be under-diagnosed, and thus may delay consideration of curative stem cell transfer as a definitive treatment option.
How common are sub-acute perforinopathies? The inevitable answer is "We do not know." Due to the lack of direct functional data on Munc13-4, syntaxin 11, and Munc18-2 mutations, we will discuss perforin deficiency as a paradigm for partial loss of CL function. The first indication that bi-allelic perforin mutations may lead to atypical FHL came from the observation that individuals who inherit two mutant alleles of PRF1, one of which is the common polymorphism C272 > T, encoding the ostensibly conservative Ala91Val (A91V) substitution, presented at an older age than "classic" FHL, and with variable symptoms (13, 38, 39). The initial suggestion that the "polymorphism" may be pathogenic was initially met with skepticism, due largely to the very high frequency of the allele among Caucasians (8–17% are heterozygotes) and the rareness of early onset FHL, which was considered at that time to be the only authentic manifestation of the disease (40). However, over the next several years, additional clinical research and biochemical studies have confirmed the original prediction that the A91V substitution is a genuine mutation that impacts severely on perforin structure and function (31, 41). While a prospective cohort study has never been reported, it is nonetheless clear from many reported case studies that inheritance of A91V in the homozygous state or its co-inheritance with a genuinely null allele is very strongly associated with atypical FHL or other immunopathologies that are delayed compared with "classic" disease (sub-acute perforinopathies). In the largest epidemiological studies reported to date [involving over 2,600 healthy individuals – (42–44)], healthy A91V homozygotes have been reported only in one study (42); every other reported case of A91V homozygocity was invariably associated with a pathology. However, the statistical power of these studies linking the genotype with disease has been insufficient to achieve significance. Based on the Mendelian inheritance of perforin mutations, it is predicted that at least 1 in 600 Caucasian individuals should be homozygous for A91V. Assuming strong penetrance of an associated immunopathology in these individuals, such a perforinopathy would be almost 100 times as common as classic ("acute") FHL. Remarkably, at this frequency, A91V-related immune deficiency would rank among the most common congenital disorders; it would be approximately four times as frequent as cystic fibrosis and at a par with Down syndrome.
Is partial perforin deficiency a common phenomenon, and is it caused only by A91V? A retrospective analysis of all reported cases of FHL associated with bi-allelic PRF1 mutations uncovered a previously unappreciated dichotomy: half of the patients who carried at least one missense mutation in PRF1 presented "acutely," with a FHL-like syndrome before the age of 12 months, while the remaining 50% had significantly delayed FHL, or presented with other, seemingly unrelated pathologies (23, 37, 45). Most of these patients either developed hematological malignancies (usually beyond the age of 10 years, which we consider to be a "chronic" presentation) or presented with unusual or protracted viral infections (23, 46, 47). Critically, biochemical analysis of multiple missense mutations associated with atypical FHL has led to the realization that partial perforin deficiency results from perforin misfolding: all reported cases of atypical, delayed FHL had some recoverable perforin-mediated cytotoxicity in vitro (23). Structural studies recently supported these findings, as wild-type perforin was shown to be a thermo-labile protein, with a melting temperature (the temperature at which the protein denatures and starts to lose function) only slightly above 40°C (5). Even though this analysis was conducted in vitro, this finding has raised the intriguing possibility that the protracted, cytokine-induced fever of FHL might further aggravate the disease by accentuating the protein misfolding defect. Given the diversity of clinical presentation that encompasses cancer, atypical onset of viral infections, and attenuated FHL-like syndromes, it is likely that a significant proportion of sub-acute perforinopathies go undiagnosed.
Identification of missense mutations that confer partial activity for the proteins encoded by the UNC13D, STX11, and STXBP2 genes may broaden the spectrum of recognized sub-acute perforinopathies. A number of non-synonymous polymorphisms in these genes have already been cataloged in single nucleotide polymorphism (SNP) databases, and future studies will determine whether any of these variations can affect the rate and/or efficiency of secretory granule exocytosis and membrane fusion, steps that ultimately determine the amount of perforin secreted into the IS and its rate of delivery.
Chronic Presentations of Perforinopathy
We consider chronic perforinopathies to be disease states that represent as a spectrum of immune-mediated diseases associated with monoallelic mutations in FHL-related genes. The presentations typically do not have a strong resemblance to classic FHL and may include blood cancers and macrophage activation syndrome in patients with juvenile rheumatoid arthritis. Typically, age of onset will be beyond 5 years of age. In addition, some studies have reported an association of PRF1 polymorphisms and the outcome of allogeneic bone marrow transplantation. All of these associations are contentious, as studies that find no link outnumber those supporting such an association.
Once again, the most reliable and "testable" information comes from the analysis of PRF1 polymorphisms, as the functional consequence of mutations is well understood. Considering the fact that hundreds of FHL patients with known genetic defects have been diagnosed around the world since 1999, the number of their family members who are known carriers of monoallelic mutations, should exceed 1,000. This is a significant cohort of unrelated individuals, who may be potentially investigated in prospective longitudinal studies on immune surveillance of infections and cancer and for dysregulated immune homeostasis.
An association between presumed partial CL deficiency due to monoallelic A91V perforin polymorphism, and acute lymphoblastic leukemia or macrophage activation syndrome, has been demonstrated in several studies that have necessarily involved a limited number of individuals (48, 49), but no statistical difference was observed in follow up studies when larger cohorts of patients were examined (24, 43). The likely reason for this apparent discrepancy may be the relatively low statistical power of smaller studies. Another possibility is that a partial deficiency of CL function may predispose more strongly to a specific subtype of malignancy or other pathology. For example, while the largest analysis of patents with acute lymphoblastic leukemia did not reveal an enrichment of A91V carriers compared to healthy controls, a subset of the ALL patients who also had BCR-ABL translocations were more likely to carry the A91V allele than the control group (43). Similarly, in a study that retrospectively examined patients who had been diagnosed with more than one primary malignancy during their lifetime, a significant proportion of patients diagnosed with both melanoma and B cell lymphoma were carriers of A91V or another perforin mutation that is partly inactivating (R28C), than those who had been diagnosed with either disease alone (24).
We have tried to explore the molecular basis for how a monoallelic mutation might adversely affect overall cytotoxic function in an inherited condition classically considered to be recessive. Molecular analysis has revealed that A91V has a partial dominant-negative effect on the function of wild-type perforin; partly misfolded perforin might interfere with the expression or trafficking of normal perforin through the endoplasmic reticulum/Golgi to the secretory granules (31, 50). Once wild-type and misfolded perforin molecules are "mixed" and stored together, it is easy to imagine that perforin pores with a heterogeneous composition of monomers might have disproportionately poor function. We also speculate that in heterozygous individuals, the wild-type allele may be under-expressed relative to the mutated allele, thus further diminishing overall CL function. This possibility needs to be formally excluded, but has been described for many other polymorphic genes [e.g., Ref. (51)].
Further analysis of CL function in patients with immune-mediated disease is warranted, particularly employing recent advances in single-cell microscopy technology, which may reveal CL deficiencies that would otherwise remain undetected in cell population-based experiments (6). Such technologies may validate the more common statistical approaches, where for example, the frequency of a PRF1 mutation in cancer patients is compared to that in healthy controls. In acute perforinopathy, there is a clear causal relationship between the disease phenotype and the patient's genotype, but this is not the case in cancer (even assuming a clinician considered testing for perforin genotype, which would be unusual). Rather, most chronic perforinopathies are likely to present "indirectly." In cancer, the PRF1 gene [and, most likely, UNC13D, STX11, and STXBP2 (52)] would be considered to be a tumor suppressor gene, but is not the cause of malignancy per se and is certainly not the only causal factor. Rather, impaired perforin function reduces the surveillance of cancerous cells, which were generated through an unrelated genetic event. This notion raises a question of what constitutes an appropriate control in these studies. Since the hypothesis is that carriers of monoallelic mutation(s) in PRF1 or related genes predispose to immune-mediated diseases with uncertain age of onset, taking a "snapshot" of a healthy population may underestimate the impact of mutations. In contrast, it was recently shown that individual differences between the cytotoxic activity of NK cells (and cytotoxic T cells) are much smaller than previously thought (6). This opens an avenue for "personalized" analysis of CL function that may shed light on predisposition of an individual to an immune pathology, prospectively and retrospectively.
In this discourse, we have proposed the term "perforinopathy" to denote the wide and diverse spectrum of manifestations of perforin deficiency, both temporal and clinical. Early (acute) clinical presentations are often fatal and usually represent dysregulated immune homeostasis and the resultant hypercytokinemia ("cytokine storm") and hemophagocytosis consequent on macrophage activation. Sub-acute presentations still occur in infancy/early childhood, may typically have a more benign course that is still principally inflammatory and may accompany other pathologies such as juvenile idiopathic arthritis or virus infection. Chronic manifestations of perforin deficiency may appear as late as adulthood, and the principal cause of symptoms is the failure to clear specific dangerous cells, particularly pre-malignant cells. Hematopoietic malignancies seem to be a common outcome, and some patients may present well into adulthood with more than one primary cancer: early onset malignant melanoma and lymphoma is the commonest combination we have observed. Although most of the data supporting our proposed "classification" is centered on our knowledge of PRF1 gene mutations, we hope that this paper will stimulate further study on polymorphisms and mutations of other genes that play a role in delivering functional perforin to the target cell.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by Program, Project, and Fellowship grants from the National Health and Medical Research Council (NHMRC) of Australia, and a project grant from the Cancer Council Victoria. We thank Kevin Thia for technical assistance in preparation of this manuscript.
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45. Voskoboinik I, Dunstone MA, Baran K, Whisstock JC, Trapani JA. Perforin: structure, function, and role in human immunopathology. Immunol Rev (2010) 235:35–54. doi:10.1111/j.0105-2896.2010.00896.X
46. Beaty AD, Weller C, Levy B, Vogler C, Ferguson WS, Bicknese A, et al. A teenage boy with late onset hemophagocytic lymphohistiocytosis with predominant neurologic disease and perforin deficiency. Pediatr Blood Cancer (2007) 50:1070–2. doi:10.1002/pbc.21438
47. Katano H, Ali MA, Patera AC, Catalfamo M, Jaffe ES, Kimura H, et al. Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation. Blood (2004) 103:1244–52. doi:10.1182/blood-2003-06-2171
48. Cannella S, Santoro A, Bruno G, Pillon M, Mussolin L, Mangili G, et al. Germline mutations of the perforin gene are a frequent occurrence in childhood anaplastic large cell lymphoma. Cancer (2007) 109:2566–71. doi:10.1002/cncr.22718
49. Santoro A, Cannella S, Trizzino A, Lo Nigro L, Corsello G, Arico M. A single amino acid change A91V in perforin: a novel, frequent predisposing factor to childhood acute lymphoblastic leukemia? Haematologica (2005) 90:697–8.
50. Brennan AJ, Chia J, Browne KA, Ciccone A, Ellis S, Lopez JA, et al. Protection from endogenous perforin: glycans and the C terminus regulate exocytic trafficking in cytotoxic lymphocytes. Immunity (2011) 34:879–92. doi:10.1016/j.immuni.2011.04.007
51. Gartner JJ, Parker SC, Prickett TD, Dutton-Regester K, Stitzel ML, Lin JC, et al. Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma. Proc Natl Acad Sci U S A (2013) 110:13481–6. doi:10.1073/pnas.1304227110
52. Machaczka M, Klimkowska M, Chiang SC, Meeths M, Muller ML, Gustafsson B, et al. Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations. Haematologica (2013) 98:760–4. doi:10.3324/haematol.2012.073098
Keywords: perforin, perforinopathy, granzyme, NK cell, protein misfolding, FHL, immune deficiency
Citation: Voskoboinik I and Trapani JA (2013) Perforinopathy: a spectrum of human immune disease caused by defective perforin delivery or function. Front. Immunol. 4:441. doi: 10.3389/fimmu.2013.00441
Received: 02 October 2013; Paper pending published: 25 October 2013;
Accepted: 25 November 2013; Published online: 12 December 2013.
Edited by:Konrad Krzewski, National Institutes of Health, USA
Reviewed by:Jos W. M. Van Der Meer, Radboud University Nijmegen Medical Centre, Netherlands
Emily Mace, Baylor College of Medicine, USA
Copyright: © 2013 Voskoboinik and Trapani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ilia Voskoboinik and Joseph A. Trapani, Research Division, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC 3002, Australia e-mail: firstname.lastname@example.com; email@example.com


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Balance: something I truly truly struggle with! I never could get myself to workout and then have a few glasses of wine with some friends, or enjoy a meal out without having to look up the nutrition information prior to the meal. Because I'm beginning such a strict diet soon for prep, I've decided to live a little…and living is AMAZING. After killing a good back and bi workout last night followed by some HIIT Cardio, I was able to relax most of the day and enjoy a night out with friends that involved a few glasses of wine, nachos, and more than enough laughter. I usually spend my free time (and in this, two weeks of free time due to no schooling or work) by working out and hoarding myself up in my room avoiding all possible human interaction. And maybe that's what some people need and enjoy. Personally, I think having that social interaction occasionally is something I once thrived off of as a child and really need to have happen again. Staying up until 2AM driving around listening to god know what is playing on the radio with some of the closest friends possible is a great remedy for any type of sadness you're feeling.
How I've been keeping the balance in my life:
- Working out, 5-6 days a week
- indulging once a day—whether it be in a piece of dark chocolate, a glass of wine, a good book, or a 30 minute nap. I don't go overboard but sometimes you need to treat yourself
- Eating healthy 80% of the time while still enjoying the occasional treats…. such as a cookie pie my roommate whipped up last week!
- Not saying no to plans…unless you truly no you just cannot attend. Your friends invite you to a concert that starts in 3 hours and you have no other plans/obligations? HECK YES YOURE GOING!!
What does balance mean to you?


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Sellwood's 'Bertie Lou's': One of Portland's last true diners
In the corner of Sellwood where Spokane Street meets S.E. 17th is a quirky breakfast café called Bertie Lou's.
It's not any bigger than a studio apartment, and is built onto the front of a house. It offers seven tables – in addition to a half-moon-shaped counter with its backless stools, where customers can converse with the short-order cooks who are busy in the kitchen.
Waitresses have to squeeze through customers and other staff while delivering a steaming plate of ham steak and eggs, or perhaps a three-cheese omelet sprinkled with pepper jack cheese. Arriving customers have to wait for a seat outside on the sidewalk, since there isn't any room inside for a waiting area.
Bertie Lou's opened in 1945, a time when over 97,000 men were working at Portland's Kaiser Shipyards. Many of the workers were boarding in Clackamas County, and had to travel through Sellwood on their way to work – so it wasn't unusual for Bertie Lou's to be their first stop before the horn signaled the start of their day at the 'yards.
As reported in one of our previous history stories in THE BEE, the now-gone Kellogg Creek Housing Development opened in 1942, with over 100 homes occupying the land, and was just a mere twenty blocks south of Bertie Lou's. It was almost a daily ritual for workers coming and going from the Kellogg housing area at all times of the day and night to stop in for a bite at Bertie Lou's. In addition to breakfast, the diner served lunch from noon until 8 p.m.
When it opened, the little luncheonette had only nine seats and a counter, with no tables available for extra seating. Customers often ordered a brown-bag lunch to go, stopped for a quick morning coffee to start their workday, or to end the evening with a piece of pie.
According to local legend, H.E. Hall presented the dainty diner as a graduation present to his two daughters. The café was named in their honor – Bertie and Lou. But there the mystery deepens. In a 1945 December issue of the THE BEE, an ad for the eatery announces "I'm hurrying to Bertie Lews for a meal that really hits the spot." Either it was a typo by the newspaper, or the owner of the business decided to rename it Bertie Lou's in the following year. Whatever the case may be, the name today remains what it was in 1946.
Small in size, the space rented by Howard Hall was only 10 by 20 feet, so he didn't have to invest much capital in furnishing the restaurant. A barber shop adjacent to Bertie Lou's run by John Rekart was established in the 1930's, and continued until the café arrived. If the lunch counter at Bertie's was backed up with waiting customers, you could always put your name on the wait list, dash next door and get a haircut, and get back in the nick of time for your breakfast order.
If that origin story is true, evidently the girls weren't as elated over their graduation gift as H.E Hall intended – because, after three years, a new owner had taken over the business. After the end of World War II, the Kaiser Shipyards had been shut down, most of its employees had been laid off, and the workers – female and male – had gone elsewhere. The industrial and factory workers who once patronized Bertie's Diner left the state, or relocated to another section of the city closer to their new jobs.
The new owners had a similar last name, but were not related to Howard Hall. Fred and Clarice Hill struggled to keep the restaurant running for a brief time, until Betty Shaw turned up to buy them out. Betty, who was operating the diner in 1950 with her husband Jasper, would become one of the neighborhood's most memorable ladies – working behind the counter, and serving longtime residents, for the next 29 years. Bertie Lou's was the family-friendly establishment where folks gathered for weekend brunch, or shared coffee with a friend, or grabbed an empty stool for a slice of the award-winning County Fair apple pie.
Back during the war, Betty herself had worked in the shipyards as a welder, and previously had grown up in the Oak Grove neighborhood, south of Milwaukie. It wouldn't be surprising to many that Bertie Lou's was the first place she stopped before off heading out to her own job the shipyards. Sitting at the counter with a hot beverage in hand, she may well have dreamed of owning her own restaurant, and making sure that homemade pie was on the menu.
Now, with Betty and Jasper in charge, Bertie Lou's became a Sellwood institution over the years. Baked pies were a lunchtime specialty, and were kept in a three-tiered glass case at the end of the tiny customer counter. Helping build her reputation as a character, many residents who visited the café remarked on her caustic attitude. If a customer was too demanding when placing an order, or brought a herd of undisciplined children into to the café, she would simply refuse to serve them a meal. Apparently, Betty wasn't worried about restaurant reviews when she was on duty, but people still continued to support her neighborhood café.
Betty continued to run Bertie Lou's well into her seventies, when her health and her busy work schedule started catching up with her. She began to start looking for a potential new proprietor who would keep the longtime restaurant in the neighborhood, and wouldn't change the name.
Eventually Janet Taylor, who had waitressed there for six years and had worked with Betty, decided to buy the classic diner. But Betty died before the sale papers could be signed, and it looked like the popular café that everyone knew might have to close. Worse yet, Betty and Jasper had no relatives to inherit their possessions, so all of their property was simply willed to friends.
But, happily, these friends of Betty's happened to be the boss of Janet's husband, Jeff. Knowing that Betty had indeed wished the Taylors to purchase her café, a contract was prepared to sell them Bertie Lou's as well as the house that was attached to the rear of the tiny restaurant.
So, by 1980, the Taylors were the new owners, and Janet became the waitress, assistant cook, and bookkeeper for the business. Janet spent endless hours baking and preparing the food in their attached house, destined to be served from the diner's kitchen the next morning.
As mentioned in the "Living" section of the Oregonian newspaper in 1987, Janet offered homemade buttermilk biscuits and cinnamon rolls to morning customers. However, the menu was changing from homestyle lunches to food typically found in the fast-serve restaurants of the time – sandwiches, soups, and hamburgers – and everything on the menu was available for less than $5.00. The breakfast specialty became the "Famous Monty's Omelet", which consisted of hamburger, tomatoes, and onions, without any cheese. But once again, change was on the way.
In 1985, Harriet Fasenfest rented Bertie Lou's from the Taylor family. Fasenfest overhauled the old standard breakfast of hotcakes and hash browns, introducing some of her favorite recipes, which included blueberry and gingerbread pancakes. Customers were treated to unconventional items like scrambled eggs with smoked salmon, pancakes with apple compote, and even lemon waffles. Weekends found a line forming at the glass door composed of people who didn't even live in the community, but wanting to taste the sensational new breakfasts. Although a single mother, with one child and absolutely no restaurant experience, Fasenfest took the Sellwood and Westmoreland diners by storm.
Menus were decorated in pink and aqua, and orders were taken by a waitstaff dressed in the same colors. Gone was the atmosphere of an old diner with a grumpy waitress who wore a dirty apron. Harriet Fasenfest changed Bertie Lou's from being "just a diner" into a top gourmet experience!
The energetic and creative Fasenfest planned on turning the tiny café into a franchise, envisioning a succession of small diners built across the country to be called "Harriet's Eat Now Café". She was successful in establishing the "Groundswell Café" and two "Harriet's Eat Now Cafés" in Portland. One of the Harriet's Eat Now Cafés was also located in Sellwood, and the other was in Old Town in Northwest Portland.
For the previous 40 years the little luncheonette could only offer nine built-in stools for its customers, with no tables available at which to sit down. Fasenfest decided that Bertie Lou's needed a total makeover, and that this could only be accomplished by opening up the southern section of the structure that once housed various barbershops, a chimney sweep, an electrical store, and other assorted shops throughout its history. The additional space gained by the expansion increased the customer serving area by one third, and clientele no longer left in haste because of the long wait time for an available seat at the counter.
Alas, Fasenfest's career and entrepreneurial skills in Portland were doomed to end suddenly. Now that Bertie Lou's was successfully drawing customers as it once did, Janet Taylor decided to return and take over the café that she had rented out to Harriet on a temporary basis. When Harriet Fasenfest found herself unable to purchase the diner, she moved to Georgia with her new husband, where she continued her career in the restaurant field, along with gardening, teaching, and writing.
Entering the 1990's, more of Portland's small diners began closing, as fast food restaurants such as McDonalds, Burger King, Burgerville, and Mike's Drive In nearby on 17th Avenue as well as in Milwaukie, grew in popularity. Many new customers preferred sitting alone at a table with their computers rather than having a casual get together with family and friends.
In 2001, Robert Erickson bought the tiny café from Alexandria Osmer, who had by then operated Bertie's for five years. Robert was intrigued that, over its 55-year history, in good times and bad, Bertie Lou's had always drawn a crowd.
He revamped the menu, adding Eggs Benedict, Omelets, and Scramble specialties, and created a campy menu with the expectation that customers would read it from front to back. "I wanted a menu for customers who weren't sure what they wanted to eat, but would know what to order once they finished reading it," he explained in a recent phone interview.
This writer's favorite is the "Reverend Mike special". The story goes that Mike was a cook at Bertie Lou's, but also an ordained minister. And reportedly, Reverend Mike even performed a wedding at the café. Considering the space available in the café, the guest list must have been very short.
Today, the latest owner, Daniel Gaard, tells us that he came on board as a weekend cook working for Robert at Bertie Lou's. During his years as right-hand man to the owner, Robert kept suggesting to Daniel that he buy Bertie Lou's, and continue its tradition of being one of Portland's last little diners in the city. He finally did, and he hasn't changed much on the menu, in the belief that he shouldn't be changing things that the customers come for. "And, if visitors want to know what the daily special is, they'll have to stop by the café," he says.
In the summertime, additional tables and wooden benches are available for customers outside on the sidewalk, where 15 to 20 guests can be served. But beware – they do fill up fast because, as we all know, when the sun comes out in Oregon, outside seating is at a premium. So as you see, Bertie Lou's is much more than just a breakfast or lunch stop; it's a place to sit down and find out about the person sitting next to you. And Daniel and his waitstaff can fill you in on the latest local events and happenings in the community. The little diner is full of stories and tales. As Robert Erickson remarks, "When you dine at Bertie Lou's, you get a feel of what the Sellwood community is like."
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Vacancy summary
Reference: 06635 Job Type: Permanent Date Posted: 6 April 2017
Vacancy summary
Reference: 06635
Job Type: Permanent
Date Posted: 6 April 2017
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Wednesday, 19 October 2011
REVIEW: Staley/Pavel Strength seminar
If you've got any interest in training & are vegan or veggie you may not like Charles Staley's nutritional view. When he was with Iron radio he was a member of PETA (Please Eat The Animals, not the other one) & some of his more controversial out bursts may have tainted your view on him. That being said, I'd suggest you open your mind his training views. His 'big idea' EDT (escalating density training) is a very useful way to train many clients (or yourself) if you are looking for physique changes. The basic premise is pretty simple, so as an example lets take a kettlebell snatch (as that was used in the seminar), you do sets of 5 for fifteen minutes, once you can no longer do sets of 5, drop to sets of 4, then set of 3 when you can no longer do 4, down to sets of 1 rep if you have to. You rest as much as you need between sets, but stop at 15 minutes. The idea is to do more reps each time you repeat that 15 minute workout over the weeks. Obviously there's a lot more to it than that, but that is the framework. You must keep the form tight, but that's really it, doing more in a set time frame. He also teaches Olympic lifting (I will be reviewing another Staley seminar, this time on Olympic lifting quite soon). Staley is a clear speaker & has quite a few training ideas you might find useful...I just wouldn't ask him any nutritional advice or he might annoy you a bit!
Pavel Tsatsouline (generally just called Pavel) is someone who knows movement. He's best known for kettlebells, but he's worked with powerlifters, sports people, fighters etc., basically everyone out there. He does have 'his style' which is stories about Russia & thankfully doesn't use the whole 'comrade' term as much as he used to (I find it a little off-putting). He has some very insightful thoughts on training & fixing training issues (I wish I was as fast, for me I often have to sit down & think about things before an answer comes to me). Some of the ideas like "Same but different", that is instead of doing a whole pile of different exercises find a few & try variation. So, using deadlift as an example, you could do conventional deadlift, sumo, rack pulls, standing on blocks, using bands or chains, using a trap bar, using a Jefferson lift or hack deadlift (I didn't even think of the last 2 myself & I've thought about deadlift a little!) can improve your lift, as they work the same motor pathways, but are different, so SAME motor patheways, DIFFERENT exact movement, so you will continue to improve, without risking overuse & not risk boredom either, the important point is not to pick just any movement, but one that works a weak point in your lift. Even hand position (for example a snatch grip), or foot position (sumo, conventional, close stance) also can be used just to make things a little different & so you can reap rewards.
There was a lot in this seminar. I will be watching it again I suspect as it was an information dense product. I enjoyed it quite a lot & learnt quite a few things I can put into practice in the near future.
You can get hold of the seminar at Dragon door (or you can do like mate & search about for a cheaper copy as they are out there).
Posted by Vegan Bodybuilding at 11:59
Labels: exercise, kettlebell, review, training
1 comment:
Than you for what I thought was a fair review
- 31 October 2013 at 12:04
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I am running Accordance 10.4.3 on MacBook Pro with Yosemite 10.10.1 and have had it installed on this machine for 2 yrs or so now.
Yesterday I enabled Dropbox synch on my iPad and iPhone and it seemed to work fine for User Notes.
However today, when I do a Dropbox Sync I get the above message and the notes aren't updating on my devices...
The file "XX" reads "RuelNotes (Mike Rue's conflicted copy)
Help? Thanks.