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leyhejuhyunghan · 2 years ago

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nature “CRISPR ‘cousin’ put to the test in landmark heart-disease trial, Gene therapy test launches pivotal year for precise genome-editing technique known as base editing.”, The Cas9 directs the base-editing enzyme to the right location in the genome, reduce PCSK9 activity, Religious & Biblical Studies - Brill Publishing The Tree of Life, Pippa Salonius, Chapter 12 The Tree of Life in Medieval Iconography, George Dunlop Leslie (English, 1835-1921), Matilda - Dante, Purgatorio, Canto 28, 1859, Wadsworth Atheneum Museum of Art James Abbott McNeill Whistler (American, 1834 -British, 1903), Coast of Brittany (Alone with the Tide), 1861, Female Artists in History Gabriele Münter (German, 1877-1962), Interieur mit Weinachtsbaum (Interior with Christmas Tree), ca. 1912-14, Christie’s., Staffelsee, 1932, Schloss Elmau im Winter, 1933, Staffelsee, 1934, Straßendurchstich im Winter (Naturstudie. Station Berggeist Schnee), 1935, Ketterer Kunst.

https://www.nature.com/articles/d41586-022-01951-1?utm_term=Autofeed&utm_campaign=nature&utm_medium=Social&utm_source=Facebook&fbclid=IwAR19if0Lw95-fmOUpShQi2bDonT5OS1or_WlUAGuwUKTVczRN4VDOCGwgKk#Echobox=1657906344 https://brill.com/view/book/edcoll/9789004423756/BP000013.xml https://www.facebook.com/photo/?fbid=10150948780782151&set=a.10150724112537151 https://www.facebook.com/photo/?fbid=407819374713153&set=a.334687465359678 https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/3125262201091981/

https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/3056631941288341/ https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/1714278678857014/ https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/1714289802189235/ https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/1827048414246706/

NEWS

15 July 2022

CRISPR ‘cousin’ put to the test in landmark heart-disease trial

Gene therapy test launches pivotal year for precise genome-editing technique known as base editing.

Heidi Ledford

https://www.nature.com/articles/d41586-022-01951-1?utm_term=Autofeed&utm_campaign=nature&utm_medium=Social&utm_source=Facebook&fbclid=IwAR19if0Lw95-fmOUpShQi2bDonT5OS1or_WlUAGuwUKTVczRN4VDOCGwgKk#Echobox=1657906344 A clinical trial that recently treated its first participant will test whether base-editing — a genome-editing method related to the CRISPR–Cas9 system — can safely be used to make precise, single-letter changes to a DNA sequence in a cholesterol-regulating gene without breaking both strands of DNA first, as CRISPR–Cas9 would do.

This study will be followed by another base-editing trial, slated to treat its first participant later this year, that will aim to treat sickle-cell disease, a genetic blood disorder.

In CRISPR–Cas9 genome editing, the Cas9 enzyme breaks both strands of DNA at the site that is to be edited. The cell’s DNA-repair processes stitch the strands back together, but sometimes make mistakes. This means that a range of DNA sequence changes are possible with each edit.

Base editing, by contrast, avoids cutting both strands of the DNA by coupling a Cas9 protein that cuts only one strand of DNA, rather than both, to another enzyme that chemically converts one DNA letter to another. The Cas9 directs the base-editing enzyme to the right location in the genome; the other enzyme then acts on that site, ideally producing only one edit.

Lower cholesterol

The trial announced this week will use a base editor to convert an adenine base (A) to a guanine one (G) in the DNA encoding a protein called PCSK9, a key regulator of blood cholesterol levels. The approach, developed by Verve Therapeutics in Cambridge, Massachusetts, aims to reduce the amount of functional PCSK9 in people with a condition called heterozygous familial hypercholesterolaemia, which causes high cholesterol and can lead to heart disease. Disabling PCSK9 has been shown to reduce cholesterol levels and cut the risk of heart disease, and several therapies already on the market reduce PCSK9 activity.

“It could be very promising,” says Piter Bosma, who studies liver diseases at the Amsterdam University Medical Centers. Bosma points to preclinical results in macaques (Macaca fascicularis) published last year, which showed that the treatment reduced blood levels of PCSK9 by 81% and lowered blood cholesterol levels with no apparent harmful side effects1. Another study in macaques by Schwank and his colleagues also found that the treatment was safe2.

In and out

The Verve trial aims to edit cells directly in the body. The team has encased the base-editing components — messenger RNA encoding the enzyme needed to alter DNA, and an extra snippet of RNA that will direct the enzymes to the correct location — in lipid nanoparticles, similar to those used in the formulation of mRNA COVID-19 vaccines. The nanoparticles will be concentrated in the liver, a key site of PCSK9 production.

By contrast, the upcoming sickle-cell trial will use base editing to alter DNA in blood stem cells that have been removed from the body. The edited cells will then be reinfused into participants. The trial will be conducted by Beam Therapeutics, also based in Cambridge, which collaborated with Verve to develop the cholesterol base-editing therapy. Other base-editing therapies are being developed to treat conditions such as leukaemia; a rare metabolic condition called glycogen storage disease; and Stargardt’s disease, which can cause blindness. And other CRISPR-derived approaches are being readied for their own foray into the clinic. Alternative Cas enzymes have been discovered that can edit RNA rather than DNA. Schwank says that his lab has mostly moved on from base editing, to a technique called prime editing, which offers more precision: “It’s all moving fast.”

doi: https://doi.org/10.1038/d41586-022-01951-1

Religious & Biblical Studies - Brill Publishing

* Prize Winner *

Dr Pippa Salonius, Adjunct Professor at Monash University, Australia, has won the 2022 Constant Mews Early Career Publication Prize for her chapter The Tree of Life in Medieval Iconography, as published in The Tree of Life (Ed. Douglas Estes). Congratulations!

The prize is awarded biennially by the Australia and New Zealand Association for Medieval and Early Modern Studies for "the best article-length scholarly work in Constant’s broad areas of scholarly interest: the medieval history of religions, intellectual history, and textual editing and translation."

The chapter is now freely accessible until 31 July 2022: http://ow.ly/U5Ym50JGvKf

The Tree of Life

Series: Themes in Biblical Narrative, Volume: 27

E-Book ISBN: 9789004423756

Publisher: Brill

Print Publication Date: 05 Mar 2020

Chapter 12 The Tree of Life in Medieval Iconography

In: The Tree of Life

Author: Pippa Salonius

Type: Chapter

Pages: 280–343

DOI: https://doi.org/10.1163/9789004423756_014

https://brill.com/view/book/edcoll/9789004423756/BP000013.xml Restricted Access Introduction

Restricted Access Chapter 1 The Tree of Life in Ancient Near Eastern Literature

Restricted Access Chapter 2 The Tree of Life in Ancient Near Eastern Iconography

Restricted Access Chapter 3 The Tree of Life in Genesis

Restricted Access Chapter 4 The Tree of Life in Proverbs and Psalms

Restricted Access Chapter 5 The Tree of Life in Jewish-Christian Legendary Texts

Restricted Access Chapter 6 The Tree of Life in Ancient Apocalypse

Restricted Access Chapter 7 The Tree of Life in Enochic Literature

Restricted Access Chapter 8 The Tree of Life in the Apocalypse of John

Restricted Access Chapter 9 The Tree of Life in Early Christian Literature

Restricted Access Chapter 10 The Tree of Life in Philo

Restricted Access Chapter 11 The Tree of Life in Gnostic Literature

Full Access Chapter 12 The Tree of Life in Medieval Iconography

Restricted Access Chapter 13 The Tree of Life in the North

Restricted Access Chapter 14 The Tree of Life in Modern Theological Thought

Restricted Access Conclusion Chapter 12 The Tree of Life in Medieval Iconography

In: The Tree of Life

Author: Pippa Salonius

Type: Chapter

Pages: 280–343

DOI: https://doi.org/10.1163/9789004423756_014 Abstract

Throughout Europe and Byzantium, from North Africa and the Holy Land to the British Isles and Scandinavia, the tree of life flourished in the imagery of the medieval Church, where visual metaphors of vegetation and growth conveyed such complex notions as the duel nature of Christ and his role in human salvation. Building on Mesopotamian tradition the tree united human and divine realms as axis mundi. At the center of Paradise in the Hebrew Bible, the Christian tree was associated with the wood of the cross as an image of renewal, which, located in Jerusalem, stood at the center of the Christian world. Using a broad selection of images, this survey explores the tree of life and its symbolism across medieval Christendom. https://brill.com/view/book/edcoll/9789004423756/BP000013.xml?body=contentsummary-43177

At the center of the plate the stylized budding cross is rooted in a mound of earth, from where it stretches upwards to touch the dove of the Holy Spirit hovering above.13 Four rivers flowing from its base confirm that it is the tree of life in the garden of Eden (Genesis 2:9–10).14 The center of the cross is inscribed with the words ‘ZΩH’ (Life) and ‘ΦΩC’ (Light) that intersect at the letter Ω. Both the image and the words at its center reference John 8:12, “Again Jesus spoke to them, saying, ‘I am the light of the world: whoever follows me will not walk in darkness, but will have the light of life.’ ”

The Christian tree of life in the midst of the garden is inextricably linked with the Jewish tradition, with its roots buried deep in Jewish Scripture and legend on the one hand and the Mesopotamian cosmic tree with its fruits of immortality on the other.15 Conceived as a mystical path to God, the tree of life is central to the Kabbalah, a form of Jewish mysticism and theosophy that can be traced to thirteenth-century texts.16 It was associated with judgement, life after death, the Messiah and the new Jerusalem in the early prophetic writings in the books of Ezekiel, Zechariah, in the Psalms and the Proverbs.17 Images of it can be found decorating many of the terracotta lamps found in Palestinian and Roman graves and on stone slabs in the Jewish catacombs from the first centuries AD.18 The earliest image of a tree in a Jewish context appeared in the third-century wall painting above the Holy Ark in the synagogue in Dura Europos. In this position the tree emphasizes the rabbinical view of the Torah as the tree of life.19 It was a path to righteousness and its ascending vegetative growth suggests the Midrash; “And by the tree of life the souls of the righteous are going up and down to heaven and from heaven to the garden of Eden, like a man going up and down a ladder.”20 Use of arboreal motifs on early Christian sarcophagi suggests their dependence on eastern Jewish funerary art (fig. 12.5).21

Associating the cross with the tree of life attests to the crucifixion as an act of victory.37 An idea exquisitely rendered by the literary image of the cross blossoming after Christ’s death in a twelfth-century version of the legend of the Holy Rood (Oxford, Bodleian Library, MS Bodley 343).38 Jacobus de Voragine disseminates the story of the cross and lends support to the idea of it flowering in his extremely popular medieval sourcebook the Legenda aurea (c. 1260), where he explains that the name of Christ’s birthplace ‘Nazareth’ means ‘flower.’39 The idea that wood of some form was taken from paradise is rooted in Jewish tradition. In close proximity and affinity with Jewish culture, the Syrian church began using crosses with vegetative designs drawn from nature as early as the mid-fourth century.40 In fact the tale of Adam and Eve leaving paradise with seeds or a twig from the tree of life, which Seth then planted at Adam’s grave and grew into the tree of the cross may have originated in Syria.41 The legend is still alive in the oral tradition of the Ethiopian Church, where foliate crosses transmit a lifegiving image of Christian salvation. The story was known in Europe by the twelfth-century, together with other more obscure versions, such as the story of Moses, who cut his staff from the tree of life in paradise.42

With its roots buried deep in the authority of the Hebrew Bible, the Christian image of the tree of life springs from Genesis 2:9, where together with the tree of knowledge of good and evil, it is located at the center of the garden of Eden.43 It appears regularly in illustrations of the Fall of Man, as seen on the San Isidoro Reliquary in the Museo de la Basilica de San Isidoro de León (c. 1063) (fig. 12.9).44

As one of the earliest surviving manuscript illuminations of Bonaventure’s Lignum vitae, the Durham example suggests that illustrated models of the text had reached as far as the British Isles by the last quarter of the thirteenth century.

The first images of Bonaventure’s Lignum vitae may well have drawn on the visual tradition of the Tree of Jesse and in some illustrations the two iconographic models are fused (fig. 12.14).110 An image of natural continuity, every single element can be seen as parts relating to a whole, with reference to Christ.111 The Franciscan Life of Christ, which quickly established Christ on the cross as the focal figure in its branches, exploits the same arboreal referencing system that expressed both ‘continuity of line and the community of lineage’ so effectively.112 In fact, later in the fourteenth century the mendicant orders privileged the tree of life as a metaphor of community and belonging in the images of their orders known as ordensstammbäume. The earliest surviving example of this development was painted by the Master of the Dominican Effigies in the Dominican Convent of Santa Maria Novella in Florence (fig. 12.24).113 George Dunlop Leslie (English, 1835-1921), Matilda - Dante, Purgatorio, Canto 28, 1859, Wadsworth Atheneum Museum of Art James Abbott McNeill Whistler (American, 1834 -British, 1903), Coast of Brittany (Alone with the Tide), 1861, Female Artists in History Gabriele Münter (German, 1877-1962), Interieur mit Weinachtsbaum (Interior with Christmas Tree), ca. 1912-14, Christie’s., Staffelsee, 1932, Ketterer Kunst., Schloss Elmau im Winter, 1933, Staffelsee, 1934, Ketterer Kunst., Straßendurchstich im Winter (Naturstudie. Station Berggeist Schnee), 1935, Ketterer Kunst. Christa Zaat

July 12, 2012

George Dunlop Leslie (English genre painter) 1835 - 1921

Matilda - Dante, Purgatorio, Canto 28, 1859

oil on canvas

20¼ x 36½ in. (51.4 x 92.7 cm.)

signed with monogram and dated 1859 (lower right), and further signed and inscribed 'G D Leslie. 2 Abercorn Place St Johns wood No 2' (on the reverse)

private collection https://www.facebook.com/photo/?fbid=10150948780782151&set=a.10150724112537151

'For thou, Lord, hast made me glad through thy work; I will triumph in the works of thy hands' - Psalm XCII, 4

Lot Notes

The painting illustrates Dante's Purgatorio, Canto 28, in which the poet, accompanied by Virgil and Statius, penetrates the Garden of Eden and encounters

A lady, wandering through the wood alone,

Singing and culling flower after flower,

Wherewith her pathway was all painted o'er.

In Canto 33 the lady is given the name of Matelda (sic), and she is usually identified as Matilda, Countess of Tuscany (1046-1115), a great heiress of the house of Canossa who was renowned for her fortitude in the face of many adversities. In Dante's poem she represents the Active and Beatrice the Contemplative Life.

G.D. Leslie was the son of C.R. Leslie, R.A. (1794-1859), the Anglo-American painter who specialised in literary genre and was the biographer of John Constable. Born in 1835, G.D. Leslie studied under his father before entering the Royal Academy Schools. He began to exhibit at the R.A. in 1857, and for a few years was profoundly influenced by the Pre-Raphaelites. Matilda, which was exhibited in 1860, when the artist was twenty-five, is an outstanding example. Rich in meticulously-handled naturalistic detail inspired by Dante's graphic account of the Garden of Eden, it is almost a textbook illustration of Pre-Raphaelite and Ruskinian principles. Cosmo Monkhouse, publishing the picture in 1883, described it as coming 'nearer to what the public reckons as Pre-Raphaelite than any other of the works we print: for (it is) "purist" in feeling and filled with almost infinite detail of grass and leaf and flower'. Sixteen years later Percy Bate included it in The English Pre-Raphaelite Painters, his pioneering study of the movement.

Although the Pre-Raphaelites' earliest works, exhibited within a year or two of the Brotherhood's foundation in 1848, had provoked a bitterly hostile reaction from the critics, it was not long before taste began to change. This was partly due to the sheer appeal of the pictures themselves, especially those of Millais, and partly to the advocacy of John Ruskin, who came to the Brothers' defence in two letters to the Times in May 1851 and went on to champion them in a pamphlet (1851), in the Edinburgh Lectures (1853), and in the third volume of Modern Painters (1854). Leslie was one of many young artists who succumbed to these influences and experienced a brief Pre-Raphaelite phase before moving on to develop a less demanding style, whether this was more classical, more Aesthetic, or simply more conventional. His later speciality was domestic genre in the Aesthetic mode. Pot Pourri, a fine example exhibited at the R.A. in 1874, in which two young women in 'Queen Anne' dress make the eponymous mixture in oriental bowls within a tightly-structured and delicately-toned composition, was sold in these Rooms on 27 November 2002 , lot 13, (£446,650). By the time he painted Matilda in 1859, Leslie was already living in St John's Wood, and he was to become a prominent member of the St John's Wood Clique, a group of artists, also including Philip Calderon, W.F. Yeames, Henry Stacy Marks and others, who all favoured genre subjects, whether of a pathetic or frivolous kind. However in 1884 he left the area, settling at Wallingford in Berkshire, where he found many subjects for landscapes.

Dante's Vision of Matilda gathering Flowers had also been the subject of a watercolour by D.G. Rossetti, executed for Ruskin in 1855. The watercolour itself is lost, but a related pen-and-ink drawing exists in the Ashmolean Museum (fig. 1). This was the moment when Ruskin was still a passionate admirer of Rossetti's work, and was encouraging him to illustrate the poet whom he regarded as 'the great prophetic exponent of the heart of the Middle Ages'. Matilda gathering Flowers was one of seven watercolours based on the Purgatorio that he commissioned from Rossetti, and was a pair to a subject from Canto 27, Dante's Vision of Rachel and Leah, now in the Tate Gallery.

It would be interesting to know if Leslie was aware of these watercolours, and if they inspired him to tackle the Matilda subject himself. It seems highly likely since Ruskin was on close terms with the Leslie family, and had already praised earlier works by George in Academy Notes. Moreover, although the composition of Leslie's picture has little in common with Rossetti's corresponding design (fig. 1), Leslie shows Dante, Virgil and Statius standing in the distance contemplating Matilda in much the same way that Rossetti had shown Dante watching the two girls in his Rachel and Leah. It may also be noted, for what it is worth, that Leslie's picture was entitled Dante's Leah when it was published in the Magazine of Art in 1883 and again when Percy Bate reproduced it in 1899.

The picture was one of two, both rather similar in conception, that Leslie exhibited at the R.A. in 1860. The other (no. 588) was entitled Meditation, and, like Matilda, was accompanied in the catalogue by a quotation from one of the Psalms (no. XCIV). The pictures were commended by Tom Taylor writing in his capacity as art critic on the Times. 'Two figures by Mr G.D. Leslie - one called 'Matilda' from Dante's Purgatorio, a lady reclining (sic) in a green garden on the edge of a pool starred with water lillies; the other a meditative figure in a similar landscape - without the water - show at once a power of faithful landcape painting and a thoughtful and graceful feeling for female form and character, which promise well for this young painter's future. The fault of both pictures is a want of keeping between landscape and figures, and a certain rawness and over-emphasis, the result of honest painstaking not yet matured by study and practice'.

The pictures were hung in the North Room, not far from Whistler's At the Piano (Taft Museum, Cincinnatti), a revolutionary work in this context which inevitably excited much comment.

Matilda was bought direct from the artist by John Hamilton Trist (1811-1891), a Brighton wine-merchant who formed a large collection of works by the Pre-Raphaelites and their contemporaries. The collection was considered worthy of an article in the Magazine of Art in 1883, and by the time Trist died it consisted of well over a hundred items. The artists represented included Rossetti, Burne-Jones, Madox Brown, Leighton, Alma-Tadema, Albert Moore, Legros, George Heming Mason and many others, but Trist's favourite artist was Arthur Hughes, by whom he owned some twenty examples. One of the most important, Silver and Gold, was sold in these Rooms on 25 October 1991 (lot 50). There were two works by George Dunlop Leslie in the collection, the other being Marguerite, a work of 1866.

At Trist's sale in 1892, Matilda was one of a number of pictures that were bought in by the family (Silver and Gold was another). In 1899 it was published by Bate, and in 1905 it was lent to an exhibition at the Whitechapel Art Gallery. When J.H. Trist's son, Herbert Hardwick Trist, died in 1935, the picture passed to his widow, who sold it at Christie's two years later. At this date it was still accompanied by the original receipt, but this has since been lost.

* * *

George Dunlop Leslie was an English genre painter, author and illustrator. Leslie was born in London, the son of notable genre painter Charles Robert Leslie. Leslie lived early on in St John's Wood (London), and was part of the St John's Wood Clique, a group of artists who favoured light-hearted genre subjects. His early works, such as "Mathilda" (1860) showed the strong influence of the Pre-Raphaelites, but he settled into a more academic, aesthetic, style of painting with the aim of showing "pictures from the sunny side of English domestic life". He often used children as subjects and his work was praised by John Ruskin for its portrayal of the "sweet quality of English girlhood”.

Wadsworth Atheneum Museum of Art

July 12 at 9:42 AM

“Alone with the Tide”, James Abbott McNeill Whistler’s first ever seascape, is the subject of our next Spotlight exhibition, opening August 4.⁣

⁣

In 1861 Whistler spent three months on the coast of Brittany in northern France to recover from rheumatic fever, and while there he painted “Alone with the Tide.” This painting and related letters by the artist will be brought together to tell the story of Whistler’s early masterpiece.⁣

⁣

(#Whistler was born in Lowell, MA #onthisday in 1834.⁣)

⁣

Image: “Coast of Brittany” (Alone with the Tide), 1861. Oil on canvas. In memory of Willian Arnold Healy, given by his daughter, Susie Healy Camp https://www.facebook.com/photo/?fbid=407819374713153&set=a.334687465359678 https://en.wikipedia.org/wiki/James_Abbott_McNeill_Whistler

Female Artists in History

December 11, 2021

Gabriele Münter (German painter) 1877 - 1962

Interieur mit Weinachtsbaum (Interior with Christmas Tree), ca. 1912-14

oil on canvas

88.3 x 72.7 cm. (34.75 x 28.63 in.)

with Nachlass stamp (on the reverse)

private collection

Catalogue Note Christie's

Peter Walter and Dr. Isabelle Jansen will include this work in their forthcoming Gabriele Münter catalogue raisonné. https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/3125262201091981/

Female Artists in History

September 21, 2021

Gabriele Münter (German painter) 1877 - 1962

Staffelsee, 1932

oil on board

33.1 x 44.5 cm. (13 x 17.5 in.)

signed and dated in lower left, rear of board once more signed in blue chalk and inscribed "96/4 XII.31" in pencil

private collection https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/3056631941288341/

Catalogue Note Ketterer Kunst

Spirited Murnau landscape with a view of Staffelsee.

Clearly contoured forms in bright colors.

Continuation of the characteruistc "Blaue Reiter" style.

After longer stays in Berlin and Paris Gabriele Münter returned to Murnau in 1931 and planned to stay for good. In context of this decision she planned to rebuild the "Russen-Haus". After the completion of the conversion she rewarded the architect with this painting of her much beloved Staffelsee. The relationship with the art historian Johannes Eichner helped her to regain inner peace which gave her a chance to develop her art. Münter stated she wanted to see the landscape "large and simple" and thus she attained a very mature conception. This work offered here is typical of her style that began to form in Murnau and its surroundings as early as in the 1910s. Forms are connected by broken colors and become part of a larger master plan and the previously favored strong contours make way for a barely perceptible accentuation. Münter’s clear form language must be seen as the result of a longer readjustment process that kept the artist from walking into the trap of too great a love for details for all her life. Female Artists in History

May 23, 2016

Gabriele Münter (German painter) 1877 - 1962

Schloss Elmau im Winter, 1933

oil on panel

32.9 x 41 cm. (12.9 x 16.1 in)

with estate stamp "Gabriele Münter Nachlass" on verso as well as inscribed (by artist?) "7/33 16. I. 33 n. Zch [nach Zeichnung]".

with two small labels, numbered "L 285" and "1050" respectively.

private collection https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/1714278678857014/

Catalogue Note Ketterer Kunst Sale: 380 Modern Art, June 04. 2011 in Munich Lot 47

Gabriele Münter received her first art lessons at the 'Damen-Kunstschule' (Ladies Art School) in Düsseldorf and then attended the Society of Woman Artists as M. Dasio's and A. Jank's pupil. Then she went to Munich where she visited the private art school 'Phalanx' which was run by Wassily Kandinsky. In 1904 Münter and Kandinsky began travelling together: to Holland, Italy, France - where they met Rousseau and Matisse - and elsewhere. Stylistically she now distanced herself from Impressionism and her works began showing Fauve and Expressionist influences. In 1908 she and Kandinsky began leading a calmer life in their apartment in Munich. They often met with Klee, Marc, Macke, Jawlensky and Marianne von Werefkin. The country house Münter bought in Murnau provided an ideal working environment. In 1909 the artist began painting glass, a medium which would later also be adopted by Kandinsky, Marc, Macke and Campendonk. Münter was a member of the 'Neue Künstlervereinigung München' for two years and in 1911 she joined the 'Blaue Reiter', the artist group founded by Kandinsky and Marc. She was interested in Kandinsky's development towards abstract art, but her own works continued to be figurative. Her landscapes, figurative scenes and portraits show a reduction to the essential with an inclination towards humorous characterization. When war broke out, Münter and Kandinsky at first moved to Switzerland. Münter, however, decided a year later to go to Stockholm, where she separated from Kandinsky. In late autumn 1917 she moved to Copenhagen. She traveled a lot during the 1920s and spent some time in Munich, Murnau, Cologne and Berlin. After 1931 she spent most of her time in Murnau and Munich.

In the reclusiveness of Murnau, far away from the Munich and Berlin art scenes, Gabriele Münter developed a painting style that, based on her own experience and taken to calmer paths, never denied her artistic roots. Gabriele Münters later partner Dr. Johannes Eichner described this process as follows: "The art of Gabriele Münter does not reflect anything of the jaggedness of the outward existence. Neither the maladies nor the disasters of our century tempted her or incited her views. [..] Deeply rooted in nature, in comparison with which personal fates, contemporary events and mankinds lapses are mere ripples on the surface, Gabriele Münters painting has an air of the eternal. Fundamental changes, stages of development and revolutions cannot be found in her oeuvre since 1908 " (Gabriele Münter, Werke aus 5 Jahrzehnten, ex. cat. Braunschweiger Kunstverein 1950, no page).

In 1956 she received the Culture Prize of the City of Munich. The year 1960 saw the first exhibition of Münter's work in the US, followed in 1961 by a large show in the Mannheim Kunsthalle. The artist died in her house at Murnau on 19 May 1962. [KD]

Female Artists in History

October 5, 2016

Gabriele Münter (German painter) 1877 - 1962

Staffelsee, 1934

oil on cardboard

33.1 x 40.7 cm. (13 x 16 in.)

signed and dated lower left. With a monogrammed dedication by Gabriele Münter on verso

additionaly inscribed "Staffelsee" on verso presumably by a hand other than that of the artist on verso and dated as well as with an inscription regarding the work's origin by the previous owner

private collection

Catalogue Note Ketterer Kunst Sale: 368 Modern Art, June 12. 2010 in Munich Lot 59

https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/1714289802189235/

Female Artists in History

December 26, 2016

Gabriele Münter (German painter) 1877 - 1962

Straßendurchstich im Winter (Naturstudie. Station Berggeist Schnee), 1935

oil on cardboard

33 x 41 cm. (12.9 x 16.1 in.)

signed and dated lower right. Verso inscribed in circle with work number "17/35" and dated "1. III.", as well as with a label with the stamped number "592"

private collection

Catalogue Note Ketterer Kunst Sale: 428 Modern Art, Dec. 03./05. 2015 in Munich Lot 277

The landscape of the Ammergau mountains, which Gabriele Münter found right in front of her doorstep, inspired her to ever new atmospheric landscapes. Bold and experimental in design and coloring during her early period and with a stronger feel for reality later on as a result of her new concept of interpretation. Münter's depictions are statements of her love for the landscape: She avoids any kind of heroic notion as it is often ascribed to mountain landscapes. She sort of rounds the mountains and thus allows a peaceful atmosphere. In large and swiftly painted color fields, preferrably in Münter's beloved blue, she renders her view of a calm lower Alps landscape, in which a small wooden house makes for the focal point. https://www.facebook.com/female.artists.in.history/photos/a.1456056671345884/1827048414246706/

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agappediagnostics · 3 years ago

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LIPOPROTEIN (a) or Lp(a) – IS’T THE MOST IMPORTANT CARDIAC MARKER IN EARLY HEART ATTACKS?

Lipoprotein (a), or LP(a), is a large lipoprotein particle made by the liver. It includes particle similar to LDL & two proteins known as Apo B & Apo A. The Apo A particle is a very sticky protein particle, considered to be involved in the clotting system & it’s addition can be likened to adding a patch of Velcro on to a normal LDL particle. Lp(a) is a highly heritable biomarker independently associated with atherosclerotic cardiovascular disease especially at younger age.

LP(a) is not routinely measured in general practice earlier, but family screening for high levels is very important as its concentration is genetically determined or it’s hereditary & difficult to control with drugs. A Lp(a) test is used to check for risk of stroke, heart attack, or other heart diseases. It’s usually tested in people who have certain risk factors, such as a family history of heart disease.

Current recommendations from the European Atherosclerosis Society are to screen people who are at intermediate, moderate or high risk of developing cardiovascular system disorders (CVS), like premature CVS, family history of premature CVS, family history of elevated LP(a), familial hypercholesterolaemia, those with recurrent CVS, despite optimum medical treatment.

People with high Lp(a) levels are much more prone to accumulating fatty deposits in the arteries, known as atherosclerosis, making them at very higher risk for blockages in the leg arteries & narrowing of the heart's aortic valve (aortic stenosis) & heart attacks.

Normal values of Lp(a) are below 30 mg/dL. As per US guidelines, elevated Lp(a) is defined as ≥ 50 mg/dL is considered a “risk-enhancing” factor that can be used to determine proper lifestyle changes or treatment.

Lp(a) concentrations predict incident atherosclerotic cardiovascular disease-among middle-aged adults within primary & secondary prevention contexts, with a linear risk gradient across the distribution. Concentrations are slightly variable across racial subgroups, but the associated risk appears to be very similar.

TAILPIECE: If Lp(a) is higher, you should immediately change your lifestyle accordingly without fail, to be in safer side, so that all other lipid parameters like Cholesterol, LDL, TGL are well controlled. Agappe, your best partner in diagnostics, serves you with Lp(a) & other lipid profile reagents in Fully automatic clinical chemistry analysers & Nephelometry platforms like Mispa i2 & Mispa i3 protein analyzers.

https://www.agappe.com/in/blog-details/260

#lipoprotein cardiacmarker heartattack hearthealth proteins HealthArticle AgappeDiagnostics

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ffrepos · 6 years ago

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PATH3305 - UWA

Medical Genetics (2018, Sem 1)

Unit coordinator: Dr Clayton Fragall

L1-7 (Mid Sem 1): pp. 4-5 (Organisation of Human Genome) 14 & 17 (Human Genetic Variation) 20-21, 31-32 (Mechanisms of Mutation) 35-36 (Cytogenomics) 37-42** (Population Genetics)

L9-16 (Mid Sem 2): pp. 3-4, 9-10: Interpret thermal curve (Detection of Genetic Variation) 16: No. of exomes sequenced (Overview of NGS) 19-20, 23-25, 27, 29-30 (Phenotypic consequences of genetic variants) 36, 47: Understand all the detection methods & in which situations should each method be used; pros & cons (DNA CNVs: Methods of Detection & Disease)

CNV Detection summary table

48, 50-54: Prevalence of CML & ALL, special cases (Cancer cytogenomics) 55, 57-58 (Pharmacogenetics) 65 (Genetic diagnostic strategies)

L17-22: pp. 1-3: Risk factors (Familial Hypercholesterolaemia) 5-6: Inheritance pattern of hypoalphalipoproteinemia & FHBL (Rare lipid disorders) 11-13, 16: Diseases screened and screening methods (Newborn screening) 17-25: Understand mutational hotspots, causative genes & upregulation treatment (Finding disease genes & Genetic muscle diseases) 26: Introduces many concepts for PATH3308 (Investigating Therapies for NMD)

L23-24: pp. 1-3: Starred items (Mitochondrial Genetics) 4-7: Just appreciate that these are very complicated (Mitochondrial Diseases)

L25-26: See starred items in summary slides (Psychiatric Genetics)

L27: p.1 (Epigenetic Variation)

#PATH3305 #medical genetics #pathology #Frankie #UWA #human genome #mutation #NGS #FH #DMD #population genetics #cytogenomics #genetics #summary #table

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lupine-publishers-scsoaj · 4 years ago

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Bempedoic Acid a Small Molecule Drug Process and Synthesis, Innovation And /Or Advantages, Development Status And /Or Regulatory Status| Lupine Publishers

Journal of Surgery| Lupine Publishers

Abstract

Bempedoic acid (ETC-1002), a small molecule drug, promotes low density lipoprotein (LDL) receptor mediated clearance of LDL-cholesterol (LDL-C) by inhibition of adenosine triphosphate citrate lyase (ACL), a mechanism complementary to those of existing lipid-modifying therapies. Bempedoic acid is a pro-drug activated specifically within the liver where it inhibits ACL, a regulatory checkpoint within the cholesterol biosynthesis pathway. By inhibiting ACL, bempedoic acid reduces cholesterol synthesis in liver cells and triggers compensatory LDL receptor upregulation. Inhibiting ACL with bempedoic acid complements other mechanisms targeted by current therapies, resulting in additional lowering of LDL-C, without leading to increases in adverse events (AEs).b In the phase III clinical trials (NCT02666664, NCT02991118) of patients with high cardiovascular risk and elevated LDL-C not adequately controlled by their current therapy, patients are given a daily dose of 180 mg bempedoic acid as an oral tablet, whilst remaining on ongoing lipid-modifying therapy. The present paper describes the process and synthesis, innovation and /or advantages, development status and /or regulatory status of Bempedoic acid.

Keywords: Cardiovascular Disease; Hyperlipidemia; ETC-1002; Low Density Lipoprotein Cholesterol; Synthesis; Statin Associated Muscle Symptoms; Statin Intolerance; Regulatory Status

Introduction

The current standard of care for patients with hypercholesterolaemia is primarily statins which can reduce LDL-C. However, some patients, particularly those with heterozygous familial hypercholesterolaemia, coronary heart disease (CHD), CHD-risk equivalents, and other clinical manifestations of atherosclerotic cardiovascular disease [1] (ASCVD), require additional LDL cholesterol lowering on top of what can be achieved with maximum tolerated statin therapy. Additionally, there are patients who are unable to tolerate statins due to adverse advents such as muscle pain, or increased blood glucose. There is an unmet medical need for patients unable to achieve sufficient reduction in LDL cholesterol with existing treatment options and thus remain at increased risk of cardiovascular disease and the consequences thereof. Bempedoic acid requires activation by a specific enzyme acyl-CoA synthatase (ACSVL1), which is largely restricted to the liver. Therefore, it is believed that unlike statins, myotoxicity is unlikely to occur with bempedoic acid because it does not inhibit cholesterol biosynthesis in skeletal muscle due to the absence of ACSVL1 in these cells. The effect of bempedoic acid is additivenot redundant-to that of statins, because the target of bempedoic acid, ACL, is a distinct regulatory checkpoint on the cholesterol biosynthesis pathway than HMG-CoA reductase, the primary target of statins. Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme does not present in skeletal muscle, inhibits ATP-citrate lyase [2], an enzyme upstream of βhydroxy β-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Statins are widely prescribed for lowering LDL-cholesterol (LDL-C) and reducing the risk of cardiovascular disease. However, many patients are statin intolerant and unable to achieve sufficient LDL-C lowering due to muscle-related side effects. Bempedoic acid (ETC-1002)’s mechanism of action is similar to that of statins, but because it does not inhibit the cholesterol biosynthesis pathway in skeletal muscle, myotoxicity is unlikely to occur. ETC-1002 was first discovered at the original Esperion Therapeutics, which was acquired by Pfizer in 2004 and subsequently spun-out as Esperion Therapeutics in 2008 along with ETC-1002 and other assets. Esperion continues development of ETC-1002 [3], which is currently in phase III trials as an LDL-Clowering agent in patients with hypercholesterolemia. This review discusses the drug candidate’s mechanism of action, effects, safety and clinical data. This paper explaining how the process of synthesis was carried and conclusion of Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. a) The phase 3 CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Serenity clinical trial demonstrates the lipid‐lowering efficacy of bempedoic acid, a first‐ in-class, prodrug, small-molecule inhibitor of ATP-citrate lyase, among patients with established statin intolerance and elevated low-density lipoprotein cholesterol who were receiving stable background therapy. b) Muscle-related symptoms contributed to the history of statin intolerance for almost all patients. c) Although bempedoic acid acts on the same cholesterol biosynthesis pathway as statins, the muscle-related adverse event rate in CLEAR Serenity with bempedoic acid, which is not activated in skeletal muscle, did not differ from placebo, even among patients who had experienced muscle-related symptoms while on statin therapy [4].

Development Status And/or Regulatory Designations

Bempedoic acid does not currently have Marketing Authorisation in the EU/UK for any indication. Bempedoic acid or bempedoic acid with ezetimibe in a fixed-dose combination are in phase III clinical trials for the treatment of primary hypercholesterolaemia [5] (heterozygous familial and nonfamilial) or mixed dyslipidaemia in patients who are statin-intolerant, or for whom a statin is contraindicated. Bempedoic acid monotherapy and bempedoic acid with ezetimibe in a fixed-dose combination is also in phase III clinical trials for the treatment of primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia in patients unable to reach LDL-Cholesterol goals with the maximum tolerated dose as an adjunct to diet in combination with a statin or statin with other lipid lowering therapies. Esperion Therapeutics was founded in April 2008 by former executives of, and investors in, the original Esperion Therapeutics which was founded in July 1998 and was bought by Pfizer for $1.3 billion in 2004 and then spun out in 2008. ETC-1002 was first discovered at the original Esperion [5], and Esperion subsequently acquired the rights to it from Pfizer in 2008. Esperion own the exclusive worldwide rights to ETC-1002. Preparation Bempedoic acid [5,6] was prepared by condensation of 1,5-dibromopentane (I) with ethyl isobutyrate (II) by means of LDA in THF in the presence of DMPU at −78 °C to give ethyl 7-bromo-2,2-dimethylheptanoate (III), which is dimerized with tosylmethyl isocyanide (IV) in the presence of NaH and Bu4NI in DMSO to yield diethyl 8-isocyano-2, 2,14,14-tetramethyl-8-(tosyl) pentadecanedioate (V). Reaction of intermediate (V) with aqueous HCl in CH2Cl2 affords 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid diethyl ester (VI), which is hydrolyzed with aqueous KOH in refluxing EtOH/H2O to provide the dicarboxylic acid ESP-15228 (VII) (1-4). Ketone (VII) is finally reduced by means of NaBH4 in MeOH (1). Scheme 1[6].

7-Bromo-2,2-Dimethylheptanoic Acid Ethyl Ester

7-Bromo-2,2-dimethylheptanoic acid ethyl ester [5]

Under argon atmosphere and cooling with an ice-bath, a solution of lithium diisopropylamide in THF (1.7 L, 2.0 M, 3.4 mol) was slowly dropped into a solution of 1,5- dibromopentane (950 g, 4.0 mol) and ethyl isobutyrate (396 g, 3.4 mol) in THF (5 L) while keeping the temperature below +5 DC. The reaction mixture was stiπed at room temperature for 20 h and quenched by slow addition of saturated ammonium chloride solution (3L). The resulting solution was divided into three 4-L portions. Each portion was diluted with saturated ammonium chloride solution (5L) and extracted with ethyl acetate (2 ‘2L). Each 4-L portion of ethyl acetate was washed with saturated sodium chloride solution (2L), 1 N hydrochloric acid (2L), saturated sodium chloride solution (2L), saturated sodium bicarbonate solution (2L), and saturated sodium chloride solution (2L). The three separate ethyl acetate layers were combined into a single 12-L portion, dried over magnesium sulfate, and concentrated in vacuo to give the crude material (1.7L) which was purified by vacuum distillation. Two fractions were obtained: the first boiling at 88 – 104 °C / 0.6 ton (184.2 g), the second at 105 – 120 °C / 1.4 ton (409.6 g) for atotal yield of 60 %. 1H NMR (300 MHz, CDC13 / TMS): δ (ppm): 4.11 (q, 2 H, J = 7.2 Hz), 3.39 (t, 2 H, J = 6.8 Hz), 1.85 (m, 2 H), 1.56 – 1.35 (m, 4 H), 1.24 (t, 3 H, J = 7.2 Hz), 1.31 – 1.19 (m, 2 H), 1.16 (s, 6 H). 13C NMR (75 MHz, CDCI3 /TMS): δ (ppm): 177.9, 60.2, 42.1, 40.5, 33.8, 32.6, 28.6, 25.2, 24.2, 14.3. HRMS (El, pos): Calcd. for CπH22Brθ2 (MH+ ): 265.0803, found: 265.0810.6.18.

2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester

Under Air atmosphere, to a solution of 7-bromo-2,2- dimethylheptanoic acid ethyl ester5 (26.50 g, 100 mmol), tetra-nbutylammonium iodide (3.69 g, 10 mmol) and p- toluenesulfonyl methyl isocyanide (9.80 g, 50 mmol) in anhydrous DMSO (300 mL) was added sodium hydride (4.80 g, 20.5 mmol, 60 % dispersion in mineral oil) at 5 – 10o C The reaction mixture was stiπed at room temperature for 20 h and quenched with ice-water (300 mL). The product was extracted with dichloromethane (3D 100 mL). The combined organic layers were washed with water (200 mL), half-saturated NaCl solution 100 mL), and saturated NaCl solution (200 mL), dried over MgS04, and concentrated in vacuo to get the crude 8-isocyano-2,2,14,14-teframethyl-8-(toluene-4- sulfonyl)-pentadecanedioic acid diethyl ester (36.8 g) as an orange oil, which was used in the next step without purification. To a solution of this crude product (36.8 g) in dichloromethane (450 mL) was added concentrated hydrochloric acid (110 mL) and the mixture was stiπed at room temperature for 1h. The solution was diluted with water (400 mL) and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with saturated NaHC0 solution (2 x 150 mL) and saturated NaCl solution (150 mL). The organic solution was dried over Na2S04 and concentrated in vacuo. The residue was subjected to column chromatography (silica gel, hexanes: ethyl acetate = 11:1) to give 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (12.20 g, 66 % over two steps) as a colorless oil. l H NMR (300 MHz, CDC13 /TMS): δ (ppm): 4.11 (q, 4 H, J – 6.9 Hz), 2.37 (t, 4 H, J – 7.5 Hz), 1.58 – 1.47 (m, 8 H), 1.35 – 1.10 (m, 8 H), 1.24 (t, 6 H, J = 7.2 Hz), 1.15 (s, 12 H). 13C NMR (75 MHz, CDC13/TMS): δ (ppm): 211.6, 178.3, 60.5, 43.1, 42.5, 40.9, 30.1, 25.5, 25.1, 24.1, 14.7. HRMS (LSIMS, nba): Calcd. for C23 IL3 O5 (MH+ ): 399.3110, found: 399.3129.

8-OXO-2,2,14,14-Tetramethylpentadecanedioic Acid

A solution of KOH (25 g) in water (50 mL) was added to a solution of 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester [6] (10.69 g, 155 mmol) in ethanol (400 mL), then heated at reflux for 4 h. After cooling, the solution was evaporated to a volume of ca. 50 mL and diluted with water (800 mL). The organic impurities were removed by extracting with dichloromethane (2 x 200 mL). The aqueous layer was acidified to pH 2 with concentrated hydrochloric acid (50 mL) and extracted with methyl tert. -butyl ether (MTBE, 3 x 200 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the crude product (9.51 g) as an oil. Crystallization from hexanes / MTBE (50 mL: 25 mL) afforded 8-oxo-2,2,14,14- teframethylpentadecanedioic acid (6.92 g, 79 %) as waxy, white crystals. M.p.: 83 – 84 °C. 1H NMR (300 MHz, CDCI3 /TMS): δ (ppm): 12.03 (s, 2 H), 2.37 (t, 4 H, J = 7.3 Hz), 1.52 – 1.34 (m, 8 H), 1.28 – 1.10 (m, 8 H), 1.06 (s, 12 H). 13C NMR (75 MHz, CDCI3 /TMS): δ (ppm): 210.5, 178.8, 41.7, 41.2, 29.1, 25.0, 24.4, 23.1. HRMS (LSIMS, gly): Calcd. for C19H3505 (MH+ ): 343.2484, found: 343.2485

8-Hydroxy-2.2.14,14-Tetramethylpentadecanedioic Acid

Under nitrogen atmosphere, sodium borohydride (0.06 g, 1.6 mmol) was added to a stiπed solution of 8-oxo-2,2,14,14- tetramethylpentadecanedioic acid (1.18 g, 3.4 mmol) in methanol (50 mL) at 0 °C. The reaction progress was momtored by thin layer chromatography (silica; hexanes: ethyl acetate = 50: 50). Additional sodium borohydride was added after 1h (0.48 g, 13 mmol). After 8 h, the reaction mixture was hydrolyzed with water (50 mL) and acidified with concentrated hydrochloric acid (3 mL) to pH 1. The solution was diluted with water (50 mL) and exfracted with dichloromethane (4 x 25 mL). The combined organic layers were washed with saturated sodium chloride solution (2 x 30 mL), dried over magnesium sulfate, concentrated in vacuo, and dried in high vacuo to give 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (0.7 g, 60 %) as a very viscous oil. 1 H NMR (300 MHz, CDC13 /TMS): δ (ppm): 7.42 (br. s, 3 H), 3.59 (br. s, 1 H), 1.65 – 1.00 (m, 20 H), 1.18 (s, 12 H). 13C NMR (75 MHz, CDC13 /TMS): δ (ppm): 184.5, 71.8, 42.1, 40.5, 37.0, 29.8, 25.2, 25.1, 24.9, 24.8. HRMS (FAB): Calcd. for Cι9 H3705 (MH+ ): 345.2635, found: 345.2646. HPLC: 83.8 % purity. Keto-substituted hydrocarbons with 11−19 methylene and bis-terminal hydroxyl and carboxyl groups have been synthesized and evaluated in both in vivo and in vitro assays for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats [Crl:(ZUC)-faBR] following 1 and 2 weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ketone functionality and the gem dimethyl or methyl/aryl substituents. Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g,14c), and the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f,14f). Compound 14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with a minimum effective dose of 30 mg/kg/day. Compound 10g dose-dependently modified non-HDL-cholesterol, triglycerides, and no esterified fatty acids, with a minimum effective dose of 10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2−3 times higher than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels was observed.

Only Keto Compd Described 2,2,14,14-Tetramethyl-8-oxopentadecanedioic Acid [6] (10g).

According to the procedure given for 10f, 9g (8.54 g, 21.4 mmol) was saponified with KOH (85%, 4.53 g, 68.6 mmol) in EtOH (13 mL) and water (5 mL) at reflux for 4 h. The solid product obtained after usual workup was recrystallized from Et2 O/hexanes (50 mL/50 mL), affording 10g (4.16 g, 57%) as colorlessneedles. Mp: 82−83 °C. 1 H NMR (CDCl3 ): δ 11.53 (br, 2H), 2.39 (t, 4H, J = 7.3), 1.60−1.50 (m, 8 H), 1.30−1.20 (m, 8 H), 1.18 (s, 12 H). 13C NMR (CDCl3 ): δ 211.7, 185.0, 42.8, 42.3, 40.4, 29.7, 25.1, 24.8, 23.8. HRMS (LSIMS, gly): calcd for C19H35O5 (MH+ ) 343.2484, found 343.2444. HPLC: Alltima C-8 column, 250 × 4.6 mm, 5 μm; 60% acetonitrile/40% 0.05 M KH2 PO4 , flow rate 1.0 mL/min; RI, tR 6.50 min, 92.6% pure. Bempedoic acid is an oral medicinal product that is in clinical development for the treatment of people with primary hypercholesterolaemia or mixed dyslipidaemia [7-9] with high cardiovascular risk. Abnormal levels of lipids in the blood characterises dyslipidaemia. High levels of cholesterol in the blood (hypercholesterolemia) may be caused by genetic defects as seen in familial hypercholesterolaemia or may occur when genes and other factors such as lifestyle habits interact, as seen in non-familial hypercholesterolaemia. Most people with hypercholesterolaemia have mildly or moderately increased low-density lipoprotein cholesterol (LDL-C) levels (often considered the “bad” cholesterol that may cause blockages of blood vessels). Elevated levels of LDL-C increase the risk of cardiovascular disease, which is responsible for many deaths and disabilities. Bempedoic acid lowers LDL-C via a different mechanism of action and offers the potential advantage of reduced muscular adverse effects when compared to statins which are the current standard of care. Bempedoic acid is being developed for patients at high cardiovascular risk who are unable to reach LDL-C goals with the maximum tolerated dose of statins. The effect of bempedoic acid is additive-not redundant-to that of statins, and if licensed, may offer additional and effective treatment option to use in combination with dietary changes and other lipidmodifying therapies to treat primary hypercholesterolaemia or mixed dyslipidaemia. Bempedoic acid is claimed in U.S. Patent No. 7,335,799 that is scheduled to expire in December 2025, which includes 711 days of patent term adjustment, and might be eligible for a patent term extension period of up to five years. U.S. Patent Nos. 9,000,041, 8,497,301 and 9,624,152 claim methods of using bempedoic acid. PRODUCT: Bempedoic acid.

Bempedoic Acid (Esperion Therapeutics, Inc.)

With a targeted mechanism of action, bempedoic acid is a firstin-class, orally available, once-daily ACL inhibitor that reduces cholesterol biosynthesis and lowers elevated levels of LDL-C by up-regulating the LDL receptor, [10] but with reduced potential for muscle-related side effects. Completed Phase 1 and 2 studies in more than 800 patients treated with bempedoic acid have produced clinically relevant LDL-C lowering results of up to 30 percent as monotherapy, approximately 50 percent in combination with ezetimibe, and an incremental 20+ percent when added to stable statin therapy.

Mechanism of Action

In November 2016, we announced the publication of “Liverspecific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis,” by Stephen L. Pinkosky, our Associate Director of Translational Research and Biology, et al., in Nature Communications. The paper systematically outlines the experiments and analyses undertaken by us and our collaborators to fully understand the mechanism of action for how bempedoic acid reduces LDL-C, including its specificity for the liver. Bempedoic acid is a prodrug that once activated, inhibits ACL, an enzyme upstream of HMG-CoA reductase [11,12], (the molecular target of statins) in the cholesterol synthesis pathway. Like statins, bempedoic acid decreases cholesterol synthesis in the liver, which results in decreased intracellular cholesterol, up-regulation of LDL receptor activity and increased LDL-C clearance from the blood. Although bempedoic acid and statins both inhibit cholesterol synthesis in the liver, an important differentiating feature is that, unlike statins, bempedoic acid is inactive in skeletal muscle. Specifically, bempedoic acid is a prodrug which requires activation by a specific enzyme, very long-chain acyl-CoA synthetase, or ACSVL1, to convert bempedoic acid to its CoA activated form. This enzyme is present in the liver but not in skeletal muscle. Therefore, bempedoic acid does not inhibit the cholesterol biosynthesis pathway in skeletal muscle, thus providing a mechanistic basis for reduced potential for muscle-related adverse effects. Bempedoic acid has been shown to provide incremental lowering of LDL-C when used in combination with both ezetimibe and statins at all doses [13]. Fixed Dose Combination Bempedoic Acid and Ezetimibe (BA+EZ) In the second quarter of 2016, the Food and Drug Administration, or FDA, accepted our submission of an Investigational New Drug, or IND, application for the fixed dose combination of bempedoic acid 180 mg and ezetimibe 10 mg, or BA+EZ, which is in development for the same indications as bempedoic acid monotherapy [14,15] (LDL-C lowering and CV risk reduction). We recently completed a bioavailability study and a formulation of BA+EZ has been selected for manufacturing, development and, if approved, commercialization. We expect to announce clinical development and regulatory plans for BA+EZ in the first half of 2017.

Cardiovascular Disease and Elevated LDL-C

Cardiovascular disease, which results in heart attacks, strokes and other cardiovascular events, represents the number one cause of death and disability in western societies. The American Heart Association, or AHA, estimates that approximately 800,000 deaths in the United States were caused by cardiovascular disease in 2013. Elevated LDL-C is well-accepted as a significant risk factor for cardiovascular disease and the CDC estimates that 78 million U.S. adults have elevated levels of LDL-C. A consequence of elevated LDL-C is atherosclerosis, which is a disease that is characterized by the deposition of excess cholesterol and other lipids in the walls of arteries as plaque. The development of atherosclerotic plaques often leads to cardiovascular disease. The risk relationship between elevated LDL-C and cardiovascular disease was first defined by the Framingham Heart Study, [15] which commenced in 1948 to define the factors that contributed to the development of cardiovascular disease. The study enrolled participants [16].

(Esperion Therapeutics, Inc)

a) Licenses

In April 2008, we entered into an agreement with Pfizer pursuant to which we acquired a worldwide, exclusive, fully paidup license from Pfizer to certain patent rights owned or controlled by Pfizer relating to bempedoic acid, and we granted Pfizer a worldwide, exclusive, fully paid-up license to certain patent rights owned or controlled by us relating to development programs other than bempedoic acid. The license to us covers the development, manufacture and commercialization of bempedoic acid. We may grant sublicenses under the license. Under the license agreement, Pfizer is restricted from making, using, developing or testing any of the compounds claimed under the same patents that claim or cover the composition of matter of bempedoic acid. [17], Neither party is entitled to any royalties, milestones or any similar development or commercialization payments under the license agreement, and the licenses granted are irrevocable and may not be terminated for any cause, including intentional breaches or breaches caused by gross negligence [18]. Intellectual Property of Esperion Therapeutics, Inc. As of December 31, 2016, our patent estate, including patents we own or license from third parties, on a worldwide basis, included approximately 25 issued United States patents and four pending United States patent applications and 23 issued patents and 15 pending patent applications in other foreign jurisdictions. Of our worldwide patents and pending applications, only a subset relates to our small molecule program which includes our lead product candidate, bempedoic acid. Bempedoic acid is claimed in U.S. Patent No. 7,335,799 that is scheduled to expire in December 2025, which includes 711 days of patent term adjustment, and may be eligible for a patent term extension period of up to five years. U.S. Patent Nos. 9,000,041 and 8,497,301 claim methods of treatment using bempedoic acid. We also have a pending U.S. patent application directed to bempedoic acid. There are currently three issued patents and four pending application in countries outside the United States that relate to bempedoic acid [19].

Overall Safety Observations (Esperion Therapeutics, Inc statement)

To date, in completed studies, over 800 patients have been treated with bempedoic acid for periods of up to 12 weeks at maximum repeated doses of 240 mg per day. Bempedoic acid has been safe and well-tolerated with no dose-limiting side effects identified to date in our ongoing or completed clinical studies. No clinical safety trends have emerged to date.

Conclusion

The synthesis of Bempedoic acid was prepared by condensation of 1,5-dibromopentane with ethyl isobutyrate by means of LDA in THF in the presence of DMPU at −78 °C to give ethyl 7-bromo-2,2-dimethylheptanoate , which is dimerized with tosylmethyl isocyanide in the presence of NaH and Bu4NI in DMSO to yield diethyl 8-isocyano-2, 2,14,14-tetramethyl-8-(tosyl) pentadecanedioate . Reaction of intermediate with aqueous HCl in CH2 Cl2 affords 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid diethyl ester, which is hydrolysed with aqueous KOH in refluxing EtOH/H2O to provide the dicarboxylic acid ESP-15228 (1-4). Ketone is finally reduced by means of NaBH4 in MeOH (1). Esperion announced new details about its phase 3 program for bempedoic acid, its unique oral, once-daily cholesterol-lowering compound. The company said the phase 3 program would include patients with hypercholesterolemia on any statin at any dose, including those with LDL levels not adequately controlled on current statin therapy in intolerant” patients unable to take even low doses of statins. Bempedoic acid does not currently have Marketing Authorisation in the EU/UK for any indication. Bempedoic acid or bempedoic acid with ezetimibe in a fixed-dose combination are in phase III clinical trials for the treatment of primary hypercholesterolaemia (heterozygous familial and nonfamilial) or mixed dyslipidaemia in patients who are statin-intolerant, or for whom a statin is contraindicated. Bempedoic acid monotherapy and bempedoic acid with ezetimibe in a fixed-dose combination is also in phase III clinical trials for the treatment of primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia in patients unable to reach LDL- Cholesterol goals with the maximum tolerated dose as an adjunct to diet in combination with a statin or statin with other lipid lowering therapies.

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pharmaphorumuk · 4 years ago

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Regeneron’s cholesterol drug evinacumab claims February FDA date

The FDA has started a speedy review of Regeneron’s ANGPTL3-targeting antibody evinacumab for a rare, inherited disorder that dramatically raises the risk of heart disease.

The cholesterol-lowering drug has been classed as a breakthrough therapy for homozygous familial hypercholesterolaemia (HoFH) by the FDA, which is due to deliver a decision on the marketing application by 11 February after a truncated six-month review.

HoFH affects around 1,300 people in the US, says the biotech, and raises cholesterol levels in the blood to very high levels. As a consequence, people with the condition can develop cardiovascular disease very early, even in childhood in some cases, despite aggressive treatment with cholesterol-lowering drugs like statins and PCSK9 inhibitors.

Evinacumab (formerly REGN1500) was developed after scientists discovered that people with genetic profiles that reduced ANGPTL3 gene activity had significant lower levels of LDL cholesterol, and a decrease in the risk of developing heart disease,

If approved, it will sit alongside Sanofi-partnered PCSK9 inhibitor Praluent (alirocumab) – which has underperformed since its launch in 2015 – in Regeneron’s emerging cardiovascular franchise.

The ANGPTL3 antibody has been filed for approval in the US and Europe on the back of the phase 3 ELIPSE trial, which tested the antibody in 65 HoFH patients already being treated with statins, PCSK9 inhibitors and other drugs like ezetimibe.

Adding in Regeneron’s antibody resulted in a 49% drop in cholesterol levels from the start of the study compared to patients sticking with their current therapy alone, according to results presented earlier this year at the American College of Cardiology’ congress in March.

The FDA awarded evinacumab breakthrough status in 2017 on the strength of phase 2 data which also showed that the antibody could achieve impressive 50% reductions in LDL cholesterol, as well as cutting blood lipids like triglycerides, in HoFH patients.

There’s no data showing that the drug can reduce progression to heart disease yet, but it’s widely believed that cutting blood lipids can reduce that risk.

Not all patients with HoFH are the same however as there are multiple genes involved in the disease, including those for LDL receptors, apolipoprotein B and PCSK9.

Crucially, Regeneron’s drug seems to work even in so-called ‘null-null’ patients, which have very low levels of receptors that remove LDL cholesterol from the blood and so progress to cardiovascular complications very quickly.

Evinacumab may not be so significant commercially however, at least in the near term, although it will likely be able to command higher pricing than Praluent due to the rarity of HoFH. Analysts put peak US sales in the region of $200 million to $400 million.

Once tipped as blockbusters, Praluent and a rival PCSK9 drug from Amgen – Repatha (evolocumab) – have struggled to gain sales momentum in the much larger population of people with other forms of high cholesterol, and have yet to crack the $1 billion sales threshold, even when their sales are combined.

They now also face the threat of competition from Novartis PCSK9 rival inclisiran, which offers much less frequent dosing.

Evinacumab is expected to be a smaller product, thanks to the tiny population affected by the ultra-rare indication, although Regeneron will be able to detail using the same salesforce that sells Praluent, reducing the cost of rollout if approved.

The biotech is also running trials that could end up expanding its use into patients with heterozygous familial hypercholesterolaemia (HeFH) – a less severe inherited disorder – as well as for patients with non-inherited forms of high cholesterol who can’t meet treatment targets with a statin and PCSK9 inhibitor.

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from https://pharmaphorum.com/news/regenerons-cholesterol-drug-evinacumab-claims-february-fda-date/

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lapakhobi · 5 years ago

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Mengetahui penyebab masalah kolesterol dan tekanan darah tinggi

PENYEBAB TEKANAN DARAH & KOLESTEROL

1. Faktor Genetik

Familial hypercholesterolaemia merupakan kolesterol tinggi yang dialami secara turun temurun dalam keluarga. Lakukan pengecekan kadar kolesterol sejak usia anak-anak.

2. Malas berolahraga/bergerak.

kurang aktif bergerak dan malas berolahraga bisa meningkatkan risiko Anda mengalami kondisi ini. Apalagi jika hal ini didukung…

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#akibat kolesterol #herbal kolesterol #manfaat essenzo moringa honey #masalah kolesterol #meredakan darah tinggi #obat kolesterol #solusi darah tinggi #solusi kolesterol #tekanan darah tinggi #testimoni madu essenzo

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siva3155 · 5 years ago

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300+ TOP DOCTOR Interview Questions and Answers

DOCTOR Interview Questions for freshers experienced :-

1) Explain who is Doctor? A physician is someone who practices medicine to treat illnesses and injuries. Physicians go to medical school to be trained. They typically hold a college degree in medicine. Physicians once made house calls to treat patients at home, but now mostly see patients in their offices or in hospitals. Physicians may also work for schools, companies, sports teams, or the military. Physicians are often assisted by nurses or other staff. 2) How doctor treat patients? Physicians treat patients by diagnosing them, or figuring out what is wrong. When Physicians diagnose a patient, they begin by asking questions about the patient's symptoms such as fever, headache, or stomach ache. They may ask other questions about things like past illnesses or family members who have been sick. They will then examine the patient, often looking at different parts of the body and listening to the heart and lungs with a stethoscope. Sometimes they may need to collect blood, use an x-ray machine, or use other tools to look for things they cannot see when examining the patient. Usually, when they have gathered enough information, a doctor can make a diagnosis and then prescribe a treatment. Often they prescribe . 3) Who is a specialists doctor? Some doctors specialise in a certain kind of medicine. These physicians are called specialists. They may only treat injuries to a certain part of the body, or only treat patients who have certain diseases. For example, there are physicians who specialise in diseases of the stomach or intestines. Other physicians are "general practitioners" or "family practitioners". This means that they do a little bit of everything. They try to deal with as much of a patient's health problems as they can without sending them to a specialist. A doctor who performs surgery is called a surgeon. 4) How communication skills help patient? Once a patient begins developing trust in a doctor, the chances of him/her recovering increases as his/her confidence in the doctor goes up and s/he begins to believe that s/he can recover. 5) Why doctors should learn communication skills? Communication skills play a major role in developing patient-doctor relationship. And miscommunication could lead to clashes with relatives/friends of patients over care given to the latter. 6) What is Venous thrombosis? There are numerous extra-gastrointestinal manifestations of inflammatory bowel disease that occur in both ulcerative colitis and Crohn's disease, such as uveitis, conjunctivitis, arthritis, pyoderma gangrenosum and erythema nodosum. Some occur primarily in Crohn's, such as gallstones and renal stones due to the area of bowel affected, while patients with ulcerative colitis are more likely to develop primary sclerosing cholangitis and venous thromboses. 7) What is Azathioprine? Azathioprine takes a number of months to exert its anti-inflammatory effect and therefore has a limited role in the acute management of Crohn's disease, though it can be started at the time of an acute flare of Crohn's. 8) What is Bendroflumethiazide? Treatment of hypercalcaemia can include fluid rehydration, loop diuretics, bisphosphonates, steroids, salmon calcitonin and chemotherapy. In clinical practice intravenous fluids are the first-line agent used to treat hypercalcaemia, both rehydrating the patient and helping to lower the calcium levels. This is combined with the co-administration of bisphosphonates such as pamidronate, which exert their maximal effect 5-7 days after administration. 9) What is Ceftriaxone? A cephalosporin such as ceftriaxone is first-line treatment in patients with streptococcal meningitis. Benzylpenicillin would be more appropriate if Neisseria meningitidis was suspected. 10) What is Anti-Histone antibody? In induced SLE anti-histone antibody is present in 90% of patients, although this is not specific for the condition. Anti-nuclear antibody is positive in 50% of patients as opposed to 95% of patients with idiopathic SLE.

DOCTOR Interview Questions 11) What is C-reactive protein? In SLE the erythrocyte sedimentation rate is classically raised while C-reactive protein levels can stay normal and therefore CRP is also not as useful as the other investigations to monitor disease activity and progression. 12) What are the parameters of life-threatening asthma? Peak expiratory flow rate of Tachycardia: heart rate > 100 beats per minute Inability to complete sentences with one breath 14) What is terbutaline 10 mg nebulised In the management of asthma, patients should be sitting upright in bed and receiving 100% oxygen. Salbutamol is given at a dose of 5 mg nebulised, not 500 micrograms. Ipratropium bromide and steroids should then be considered. 15) Medical Abbreviations part 19: TFTs - thyroid function tests U - units UC - ulcerative colitis V/Q - ventilation/perfusion WCC - white cell count 16) Medical Abbreviations part 18: RBBB - right bundle branch block SIADH - syndrome of inappropriate ADH secretion SLE - systemic lupus erythematosus STEMI - ST-elevation myocardial infarction STD 17) Medical Abbreviations part 17: p.r.n. - pro re nata PSA - prostate-specific antigen PSC - primary sclerosing cholangitis PSGN - post-streptococcal glomerulonephritis RAS - renal artery stenosis 18) Medical Abbreviations part 16: PaO2 - partial pressure of oxygen PCA - patient-controlled analgesia PCI - primary coronary intervention PCP - Pneumocystis carinii pneumonia PCR - polymerase chain reaction 19) Medical Abbreviations part 15: --> NICE 1) Formerly: National Institute for Clinical Excellence 2) Currently: National Institute for Health and Clinical Excellence --> NMDA - N-methyl-D-aspartate --> NSAIDs - non-steroidal anti-inflammatory --> NSTEMI - non-ST-elevation myocardial infarction --> PaCO2 - partial pressure of carbon dioxide 20) Medical Abbreviations part 14: MRI - magnetic resonance imaging MRSA - methicillin-resistant Staphylococcus aureus MSH - melanocyte-stimulating hormone NAC - N-acetylcysteine NG - nasogastric 21) Medical Abbreviations part 13: LFT - liver function test LTOT - long-term oxygen therapy MCV - mean cell volume MHC - major histocompatibility complex MMSE - mini mental state examination 22) Medical Abbreviations part 12: J - joules JVP - jugular venous pressure LBBB - left bundle branch block LDH - lactate dehydrogenase LDL - low-density lipoprotein 23) Medical Abbreviations part 11: HONKC - hyper-osmolar non-ketotic coma HSP - Henoch-Schnlein purpura HUS - haemolytic uraemic syndrome IV - intravenous IVDU - intravenous user 24) Medical Abbreviations part 10: HAART - highly active antiretroviral treatment hCG - human chorionic gonadotrophin HDL - high-density lipoprotein HDU - High-Dependency Unit HLA - human leukocyte antigen 25) Medical Abbreviations part 9: G6PD - glucose-6-phosphate dehydrogenase GCS - Glasgow coma scale GFR - glomerular filtration rate GORD - gastro-oesophageal reflux disease GTN - glyceryl trinitrate 26) Medical Abbreviations part 8: FEV1 - forced expiratory volume in 1 second FFP - fresh frozen plasma FH - familial hypercholesterolaemia Fi(O)2 - fraction of inspired oxygen FVC - forced vital capacity 27) Medical Abbreviations part 7: DVT - deep vein thrombosis ERCP - endoscopic retrograde cholangiopancreatography ESR - erythrocyte sedimentation rate F1 - Foundation year 1 doctor F2 - Foundation year 2 doctor 28) Medical Abbreviations part 6: CPAP - continuous positive airway pressure (ventilation) CPR - cardiopulmonary resuscitation CRP - C-reactive protein CSF - cerebrospinal fluid dsDNA - double-stranded DNA 29) Medical Abbreviations part 5: CDT - Clostridium difficile toxin CIN - cervical intraepithelial neoplasia CLL - chronic lymphocytic leukaemia COMT - catechol-O-methyltransferase COPD - chronic obstructive pulmonary disease 30) Medical Abbreviations part 4: BCG - bacille Calmette-Guerin BHL - bilateral hilar lymphadenopathy BMI - body mass index BNP - B-type natriuretic peptide CEA - carcinoembryonic antigen 31) Medical Abbreviations part 3: AMT - abbreviated mental test ANA - antinuclear antibody ANCA - anti-neutrophil cytoplasmic antibody APACHE - acute physiology and chronic health evaluation AST - aspartate aminotransferase 32) Medical Abbreviations part 2: ADH - antidiuretic hormone AFB - acid-fast bacilli AIDS - acquired immunodeficiency syndrome ALP - alkaline phosphatase ALT - alanine aminotransferase 33) Medical Abbreviations part 1: AF - atrial fibrillation aFP - alpha-fetoprotein ABG - arterial blood gas ACE - angiotensin-converting enzyme ACTH - adrenocorticotrophic hormone 34) How many childrens affected with asthma in UK? Asthma affects over 5 million individuals in the UK. Approximately 1 million children are affected. 35) Can medication is known to cause hypokalaemia? The medication is most likely to be a selective 2-agonist such as salbutamol, which leads to a tremor, palpitations, headaches and hypokalaemia at high doses. Washing the mouth after administration of inhaled steroids is recommended, no matter what dose is given. Atrovent is the trade name for ipratropium bromide, which is more useful in chronic obstructive pulmonary disease than in asthma, although it can be used in an acute asthma attack. 36) Patient feeling randomly sick with headaches. What could it be? Persistent headaches are not something that can be ignored, as this could be your body trying to send you a signal that there is something wrong. Often, the history and description of the headache can be quite helpful as you attempt to determine what is the cause of your headaches so that you can know how to get better. If your headaches are associated with certain movements, activities, foods, or other triggers, than this can serve as a clue to you and your doctor to help you feel better. If, on the other hand, your symptoms are somewhat predictable and come on in the same way, then it is also possible to use this information to diagnose the type of headache, which then gets you closer to getting some help with your pain and other symptoms. Migraines are classically associated with light sensitivity, nausea and vomiting, and intractable and incapacitating pain. People with migraines may have a family history of them, and they may have an aura, or symptoms that routinely come before the headache and let them know it is coming. 37) Why should be pain in neck? There are times that infections can happen in the neck, and these infections can be very serious because of the number of important structures that run through the neck. Some of these include nerves that are relevant to moving some of the muscles of your upper extremities, and others are the very important arteries and veins that run through your neck to and from your head. Often, if people have an infection, they will also have symptoms of an infection, such as a high fever, swelling, redness, etc. These can be more common in those with a history of injecting, as this allows serious and dangerous bacteria direct access to the rest of the body through the arteries and veins. If it has been a while since your last injection, then it may make an infection less likely. Swelling and pain can also happen from muscle spasms that come with poor posture or increased exertion out of the norm. There are also some other possible explanations. 38) Why do in some cases patients feel chest, neck and hands flush? Certainly the thought of carcinoid syndrome is something that crosses the mind in hearing about your symptoms. That is, however, a rather rare process that would be unusual for most people to have. In such a situation, it is good to describe your symptoms and your concerns to your doctor so that he or she can test for the possibility of something as serious or as rare as that condition. There are many other possible explanations, however, many of which are much more common. It is not unusual for some people to have changes of flushing and some of the other feelings that you describe when they are in stressful or unusual situations. Some of this can sometimes be understood in context of the response that some people have to loud noises or fright, ie, they can faint. This reaction is one extreme on the spectrum of a vagal reaction that can occur in some. On a less extreme note, other can have some of the same symptoms you describe without having something as notable as a syncopal episode. There are often things that can be done to help. 39) Suppose if a patient have abnormal blood on his underwear how you deal? Abnormal bleeding can have many different causes, but you have provided some valuable information. First, we have to clarify where exactly the bleeding is coming from. While vaginal bleeding is perhaps the most likely, both the urinary tract and the GI tract can also be a source of bleeding. Either of those would have different causes and explanations, with infections and small sources of bleeding such as hemorrhoids being among the most common reasons for abnormal or untimely bleeding. With regards to vaginal bleeding, there is a clue that is suggested by the fact that the blood is bright red in color. In general, this can reflect fresher blood that has not started to be broken down. It may also suggest blood that is coming from a source further down the vaginal tract, although that is not necessarily true. There are different conditions that can affect the vaginal or uterine lining and are common explanations for symptoms such as you describe. There are also tumors that can result in abnormal bleeding, and these tumors can be both benign and malignant. 40) Suppose if patient have unbearable neck to shoulder pain only while on his period. What could it be? This is a somewhat interesting phenomenon that will take more visits to your doctor to help explain. Your OB/GYN is likely a good place to start, as he or she will be best positioned to help sort out the hormonal element to your symptoms. Another option might be a neurologist or spine surgeon, either of which may be able to help with your symptoms at the level of your neck. An ear nose and throat surgeon may offer some other insight that could be helpful. Whichever you choose, the approach to your problem will likely be different. Primary care and medical doctors are more likely to use lab work and your symptoms to help arrive at an answer, and may use medications empirically to see what helps to make you better. A surgeon, on the other hand, is more likely to listen to your symptoms, complete an exam, and recommend imaging and other anatomic studies that can help to determine what is causing your symptoms. The pain may have a component of something that changes on a monthly basis with your menstrual cycle. This could be a swelling, or even something as simple as a change in the blood flow. 41) Suppose if patient having chronic neck pain for 4 days. Medication and RMT massage have done nothing, pain is 10/10 now. What could it be? It is not normal for pain to become so severe and fail to respond in any way to conservative therapy, and so your doctor should discuss this with you in more detail to make sure that there is nothing serious that is causing your symptoms. Neck and muscle spasms can be common in some people with a history of c spine injury or trauma, and can be severe and debilitating. They should not be a new onset symptom for most people, however, unless you have had some precipitating event. Massage and things to help the muscles relax is often a great idea to help with some of the mild aches and pains that we can have from time to time, and the fact that you had no improvement is worrisome. Your doctor may entertain other possible explanations for this pain in addition to trauma and misuse injuries. He or she may decide it is important to get some imaging and complete a physical exam looking for things that might be amiss. Shooting pain can be a concern for nerve injury. 42) Suppose if I am patient of acid reflux, how can I get rid off? Fortunately, there are things that can be done to help with reflux. The most obvious answer is some of the many medications that are available to help reduce stomach acid. Some of the least expensive and most effective are even available over the counter, but should be used after discussing your symptoms with your doctor. There are some medications, such as ranitidine and other anti histamine medications (H2 blockers as they are sometimes called), that can be very effective for many people and have a very mild side effect profile. They are most effective when taken as directed, and the efficacy does tend to decrease if they are not timed appropriately with regards to the meals. Other excellent medications are those that are known as proton pump inhibitors, or PPIs, which can be even more effective. The over the counter doses are effective for most people, but in severe cases prescription strength doses can also be used. These medications also have relatively mild side effects, but should be discussed with your doctor. In addition to these medications, lifestyle changes should be tried before any medications. These can be found suggested in many places. Please speak with your doctor. DOCTOR Questions and Answers pdf Download Read the full article

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queenketouk · 5 years ago

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56 today 🎉... Time to celebrate!!! Not because it's my birthday, but because it was 18 years ago that I ditched statins despite a grim prognosis due to FH (Familial Hypercholesterolaemia). Doctors insisted that the neuro-muscular debility I suffered from day 1 of statination was not a side effect of the drugs (liars), that I'd lost my mind, and that with a sky-high cholesterol like mine I wouldn't reach my 40s. Scary stuff, considering I was 38 then... only 2 years 😱 left! But I decided to do it my way. No statins ❇️, fewer carbs ❇️, then keto♥️♥️♥️. Hippocrates would have been proud that I chose food as my medicine 😁. Today, 18 years later, my TC, HDL and LDL are high, but trygs are low, and so is CrP. Even my GP (reluctantly and with great reservations about keto... lol) had to admit that I'm as fit as a fiddle, and NOT at metabolic risk, despite FH. I weigh 52 kg (115 lb) and take ZERO meds - not even occasional pain killers or anti-inflammatories, as I never get aches & pains, colds or headaches. Do I care or worry about my TC (10.3 mmol/L, or 400 mg/dL) being mind-blowingly high? Nope 😁. My body clearly needs it. I WILL FOREVER BE INDEBTED to the few intelligent and unbiased doctors who opened my eyes by disclosing the cholesterol myth, the true cause of CVD and the statins damage crisis. THANK YOU♥️. THANK YOU♥️. THANK YOU♥️. https://www.instagram.com/p/B1vrw7bo1Dq/?igshid=1b7nznok2cv8j

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chimeperson23-blog · 5 years ago

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Very high LDL and no cardiovascular disease – at all!

12th May 2018

[A classic black swan]

If your hypothesis is that all swans are white, the discovery of one black swan refutes your hypothesis. That is how science works. Or at least that is how science should work. In the real world, scientists are highly adept at explaining away contradictions to their favoured hypotheses. They will use phrases such as, it’s a paradox. Or, inform you that you didn’t measure the correct things, or there are many other confounding factors – and suchlike.

Anyway, accepting that the finding of someone with a very high LDL level, and no detectable atherosclerosis, will always be dismissed – in one way or another – I am still going to introduce you to a ‘case history’ of a seventy-two-year-old man with familial hypercholesterolaemia, who has been studied for many, many, years. Try as they might, the researchers have been unable to discover any evidence for cardiovascular disease (CVD) – of any sort.

In the past, I have spoken to many people with very high LDL and/or total cholesterol levels who are CVD free, even in very old age. The mother of a friend of mine has a total cholesterol of level of 12.5mmol/l (483mg/dl). She is eighty-five, continues to play golf and has not suffered from any cardiovascular problems.

However, none of these people had been studied in any detail. Which means that they can, and are, dismissed as irrelevant ‘anecdotes’. Yes, the widely used and highly exasperating phrase that I often encounter is that ‘the plural of anecdote is not data’. This, of course, is completely untrue, or at least it is untrue if you start dismissing detailed individual cases as anecdote.

Whilst an anecdote may simply be a story, often second hand, a case history represents a painstaking medical history, including biochemical and physiological data. In reality, the plural of case histories is data. That is how medicine began, and how most medical breakthroughs have been made. We look at what happens to real people, over time, we study them, and from this we can create our hypotheses as to how diseases may be caused and may then be cured.

So, a single case is NOT an anecdote, and cannot be lightly dismissed with a wave of the hand and a supercilious smirk.

In fact, the man who is the subject of this case history has written to me on a few occasions, to tell me his story. I have not written anything about him before, as I knew his case was going to be published, and I did not want to stand on anyone’s toes. With that in mind, here we go.

The paper was called ‘A 72-Year-Old Patient with Longstanding, Untreated Familial Hypercholesterolemia but no Coronary Artery Calcification: A Case Report.’ 1

The subject has a longstanding history of hypercholesterolemia. He was initially diagnosed while in his first or second year as a college student after presenting with corneal arcus and LDL-C levels above 300 mg/dL [7.7mmol/l]

He reports that pharmacologic therapy with statins was largely ineffective at reducing his LDL-C levels, with the majority of lab results reporting results above 300 mg/dL and a single lowest value of 260 mg/dL while on combination atorvastatin and niacin. In addition to FH-directed therapy, our subject reports occasionally using baby aspirin (81 mg) and over-the-counter Vitamin D supplements and multivitamins.

In the early 1990s, our patient underwent electron beam computed tomography (EBCT) imaging for CAC following a series of elevated lipid panels. Presence of CAC (coronary artery calcification) was assessed in the left main, left anterior descending, left circumflex, and right coronary arteries and scored using the Agatston score.

His initial score was 0.0, implying a greater than 95% chance of absence of coronary artery disease. Because of this surprising finding, he subsequently undertook four additional EBCT tests from 2006 to 2014 resulting in Agatston scores of 1.6, 2.1, 0.0, and 0.0, suggesting a nearly complete absence of any coronary artery calcification. In February of 2018, he underwent multi-slice CT which revealed a complete absence of coronary artery calcification.

So, here we have a man who has an LDL consistently three to four times above ‘average’. He had tried various LDL lowering agents over the years. None of which had done anything much to lower LDL. Therefore, his average LDL level over a twenty-year period has been 486mg/dl (12.6mmol/l.

Despite this he has absolutely no signs of atherosclerotic plaque, in any artery, no symptoms of CVD and is – to all intents and purposes – CVD free. What of his relatives? If he has FH, so will many others in his family.

‘He has one sister three years his senior who also has FH and a history of high lipid levels. She also has no history of myocardial infarction, angina, or other symptoms of coronary artery disease. His mother had FH, although she died of pancreatic cancer at age 77. She and her three siblings were never treated for, and had no history of, cardiovascular disease. The patient reports that his father had one high cholesterol score (290s), but was never diagnosed with FH, had no history of cardiovascular disease and died in his 80s during surgery for hernia repair.’

What to make of this? Well, I know that the ‘experts’ in cardiology will simply ignore this finding. They prefer to use the ‘one swallow does not a summer make’ approach to cases like this. For myself I prefer the black swan approach to science. If your hypothesis is that a raised LDL causes CVD, then finding someone with extremely high LDL, and no CVD, refutes your hypothesis.

Unfortunately, but predictably, the authors of the paper have not questioned the LDL approach. Instead, they fully accept that LDL does cause CVD. So, this this man must represent ‘a paradox’. They have phrased it thus:

‘Further efforts are underway to interrogate why our patient has escaped the damaging consequences of familial hypercholesterolemia and could inform future efforts in drug discovery and therapy development.’

To rephrase their statement. We know that high LDL causes CVD. This man has extremely high LDL, with no CVD, so something must be protecting him. I have an alternative, and much simpler explanation: LDL does not cause CVD. My explanation has the advantage that it fits the facts of this case perfectly, with no need to start looking for any alternative explanation.

And just in case you believe this is a single outlier, something never seen before or since. Let me introduce you to the Simon Broome registry, set up in the UK many years ago to study what happens to individuals diagnosed with familial hypercholesterolaemia (FH). It is the longest, if not the largest, study on FH in the world.

It has mainly been used as one of the pillars in support of the cholesterol hypothesis. However, when you start to look closely at it – fascinating things emerge. One of the most interesting is that people with FH have a lower than expected overall mortality rate – in comparison to the ‘normal’ population. Or, to put this another way. If you have FH, you live longer than the average person.

Even if we look at death from heart disease (those with FH have never been found to have an increased rate of stroke) we find that in the older population, the rate of death from Coronary Heart Disease (CHD) was actually lower than the surrounding population in some age groups.

For instance, in the male population aged 60 – 79 (who were CHD free on entry to the study) the rate of death from heart attacks was lower than the surrounding population. Not significantly, but it certainly was not higher.

In fact, in the total male population aged 20 – 79 with FH, the rate of death from CHD was virtually identical to the surrounding population. Over a period of 13,717 years of observation, the expected number of fatal heart attacks was calculated to be 46. The actual observed number was 50.

In women, the expected number of heart attacks in the population aged 20 – 79 was 40, the actual number of observed fatal heart attacks was 40. Which means that FH was not found to be a risk factor for CHD in those enrolled in the study – who had no diagnosed heart disease prior to enrolment2.

Which represents, I suggest, another fully grown black swan. There you go. Two in one day.

1: https://www.cureus.com/articles/11752-a-72-year-old-patient-with-longstanding-untreated-familial-hypercholesterolemia-but-no-coronary-artery-calcification-a-case-report

2: https://academic.oup.com/eurheartj/article/29/21/2625/530400

Source: https://drmalcolmkendrick.org/2018/05/12/very-high-ldl-and-no-cardiovascular-disease-at-all/

#read more #see more #check it out #interesting #learn more

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