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Normally talking those will be perfect served acquiring a tablet computer kind; Clen tablet computer systems are rarely counterfeited as well as rather reasonable. Numerous frequently discovered in 20mcg as well as 40mcg type Clen tablet computer computers are fairly basic to handle as it is extremely simple to regulate the application with performance. Did we review they are cheap? It is not unusual to locate first-rate Clen in 40mcg tabs at a rate of $10 for FIFTY tablet computer computer systems. Provided, in a lot of cases those which purchase Dianabol, Deca-Durobolin as well as Clenbuterol are checking out require a reasonable little bit greater than 50 40mcg tabs nevertheless the expenditure to benefit proportion in-terms of dollars and also outcomes is a lot in your favor.
Outcomes are most successfully achieved if you abide by the recommended patterns which are set out above in the Piling Quick overview.
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The body building niche is huge and, being a man dominated sport, as you would expect, most CrazyBulk consumers are males. Nonetheless, women bodybuilding is preferred, so there is still a market for women (and also there are women pleasant products to be discovered on CrazyBulk). Although predominantly bodybuilding concentrated, CrazyBulk items such as those created to raise strength, energy as well as cardio efficiency could equally as effortlessly be efficiently targeted to basic toughness fitness instructors, professional athletes as well as anybody else aiming to get fit, strong as well as build muscle. People in right here ask about, which buy Dianabol, Deca-Durobolin as well as Clenbuterol typically get their item in both tablet computer system and also liquid kind. Regardless of the type, when you obtain Dianabol, Deca-Durobolin and also Clenbuterol in either manner it is to be taken orally as well as specifically likewise; one type is simply solid and the various other in aliquid state.
Assuming both items are genuine, dosed correctly and of a hygienic style there is truly no distinction in either item; in spite of kind, when you acquire Dianabol, Deca-Durobolin and also Clenbuterol in here inquire about. It will perform within the body similarly tablet computer system or otherwise. It holds true, many of the fluid kinds, far more so than the tablet kinds are definitely nothing except rubbish or unsteady at finest and also tough to dose accurately. Due to this a tablet computer acquisition is constantly a far better wager yet there are first class fluid items about, you simply should do a little research study to guarantee you locate the very best ones.
You can buy extremely typically many buy Dianabol, Deca-Durobolin and Clenbuterol in right here ask about as it is one of the most effective. So reliable those that take countless over-the-counter fat heaters will not get a kick out of or experience near the body fat burning results as those that shop Dianabol, Deca-Durobolin as well as Clenbuterol in below inquire about. No, this effective bronchodilator will absolutely not switch out sound diet plan programs as well as exercise ideas however in additional manner it could supply a much desired included side.
Why you should Get Dianabol, Deca-Durobolin and also Clenbuterol in below? Inquire about Where to Get Dianabol, Deca-Durobolin and Clenbuterol in right here ask about Check out any type of form of message board as well as there are all sort of stories and viewpoints in right here inquire about with concerning this bronchodilator; there are tales worrying merely just how much it assists the PCT process, how it develops fantastic harmony with an anabolic steroid pattern; the list continues. It is true, Dianabol, Deca-Durobolin and Clenbuterol Hydrochloride does possess a mild anabolic nature yet its hardly enough need to nutritional supplement with it.
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Where To Buy And Reviews Anavar Steroid In Sao Paulo Brazil. There are definitely only two good reasons any person would ever acquire Dianabol, Deca-Durobolin and Clenbuterol in right here ask about, for the treatment of persistent asthma as well as for metabolic enhancing results, i.e. physical body fat burning. True, you could possibly buy Dianabol, Deca-Durobolin as well as Clenbuterol in here ask about in an initiative to raise cardio efficiency and also this could be helpful for some yet by and large both after stated elements are the main concentration with physical body fat burning being the key focus of most anyone that finds themselves here.
Like all medications of any kind of kind of kind you need to have understanding, you should recognize exactly what you are doing this that you not just experience high quality outcomes nonetheless to make sure that you continue to be safe also; the good news is for you there are a number of guides below on steroid.com that could provide to this end. It corrects below nevertheless we want to discuss the kinds of Clen as it is commonly understood that you might definitely buy Of those in here inquire about which utilize Clen most will definitely locate it could come either approaches, as an oral tablet computer system or in a liquid choice you simply eat. The greatest tips you can obtain would be making specific that you comprehend how you can prepare.
Although this seems a little irrelevant, it is a capacity which is not to be taken also gently. Although a number of situate it a lot much easier to merely buy a take-away, if you intend your physique to react positively to the medicine consuming right is the first thing you need to do. Amongst the perks of food preparation by yourself is that you understand precisely simply exactly what you are taking in and also the quantity of calories you are taking in. This disregards the possibilities of over or under taking in as a result of misdirected areas marketed on a number of take-away food selections!
Warranty that you include huge quantities of fruits as well as vegetable in your weight-loss. Consume lots of citrus fruits which are high in vitamin C as well as great for your health and wellness. Bananas are additionally terrific when you are trying to shed fat as well as develop muscle mass. Green Veggies are very high in Iron which additionally fantastic for your body as well as keepings you conscious as well as sharp. This will definitely place you at a considerable perk as it will certainly enhance your concentration as well as maintain you urged. Make sure that you are additionally eating foods which are high in calcium as well as bountiful in vitamin D as this will aid to increase your bone sturdiness which is wonderful for when you are constructing muscular tissue mass as your physique will have the capacity to sustain itself much better. An additional terrific suggestion is to establish on your own tiny possible objectives. By setting your sights excessive you will definitely end up disappointing on your own and coming to be demotivated. By establishing little goals you will certainly take care of to record your progression effortlessly and also you will certainly continuing your own encouraged which as a result will certainly encourage you to proceed with the procedure.
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Dianabol, Deca-Durobolin and Clenbuterol Stacking is not an anabolic steroid but it does function very well in conjunction. Normally any anabolic steroid can be made use of nonetheless those that acquire Dianabol, Deca-Durobolin as well as Clenbuterol in here ask about will often doing this when anabolic steroids that market a leaner and also a lot more difficult figure remain in play. While Clen will definitely provide to this end there are various other products that function well with it; as an example, lots of people who get Dianabol, Deca-Durobolin as well as Clenbuterol in below inquire about often investment thyroid gland bodily hormones such as Cytomel (T3) to accompany it as well as many additionally supplement with Human Growth Bodily hormone. It holds true; a mix of Dianabol, Deca-Durobolin and also Clenbuterol, Cytomel as well as Human Growth Hormone coupleded with a solid anabolic steroid cycle will offer outcomes difficult to acquire otherwise.
You can acquire Dianabol, Deca-Durobolin and also Clenbuterol in here inquire about as well as definitely nothing else and also get a light anabolic bump and also ramping of the metabolic process yet if you choose this walloping it will be mild. It is necessary to note the influences will absolutely be much more obvious when an anabolic steroid pattern is at hand nevertheless while essential it is rarely one of the most essential point. Those which acquire Dianabol, Deca-Durobolin and Clenbuterol in here ask about yet fail to comply with audio diet programs concepts will absolutely not lose any physical body fat; you could actually take a huge quantity of Clen each day and also if you are taking in like a body fat porker then assume just exactly what, youre getting fat. When we shop. Dianabol, Deca-Durobolin and Clenbuterol there is genuinely merely one approach to watch it, as a supplement as well as the suggestion of a supplement is to consist of in the benefits, no Hydrochloride t establish them. Clen can be part of the equation, an useful tool to your fat burning needs; it is nevertheless not the reaction all alone.
Dianabol is amongst the most effective dental anabolic steroids on the market in Poltava Ukraine for the objective of quickly boosting both size as well as durability and as by its nature is a lot more effective compared to its usual coz Anadrol on a milligram for milligram basis. As toughness as well as measurement enhancing are its key part the majority of those who purchase Dianabol will doing this for a bulking cycle, as must come as not a surprise yet it can be utilized efficiently during a decreasing pattern also.
Dr. John Ziegler did not have any sort of hand in creating D-bol, yet he contributed in the circulation as well as very early usage of the steroid. He started by dealing with a vast array of his own medical people consisting of an appendectomy patient and shed sufferer. Dr. Ziegler attempted screening on himself and later transported to teaming up with athletes looking for a method to boost their effectiveness.
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If you're a performance enhancing professional athlete or possibly if you're merely preparing to start there's a superb possibility you'll buy Dianabol in Poltava Ukraine in the near future. The factors are simple; people in Poltava Ukraine purchase Dianabol as it is amongst one of the most very effective regarding its objective, it is really basic to control, it is usually really low-priced and also for years has actually been among one of the most extensively easily offered anabolic steroids of perpetuity; in-fact, the little 5mg pink Anabol tabs, amongst one of the most prominent brands of all time have been seen in fitness centers as generally as the weights themselves given that before the Golden Age of physical body structure.
Where To Buy And Reviews Anavar Steroid In Sao Paulo Brazil. In order to check the brand-new medicine and please a requested requirement, Dr. Ziegler worked with a triad of American weight lifters, considering that they were having troubles competing with the Russian weightlifting group. The experiment located combined results, yet in the long run Dr. Ziegler thought it to be a failing, considering that the only real outcome he positioned in the weightlifters was boosted horniness. Nonetheless, proof later on revealed the proper dose neither pattern were being utilized.
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While this steroid can be reliable in a cutting cycle, commonly most will certainly locate different other alternatives to be far more efficient after that limitation this steroid to off-season periods of use. Those that supplement with this effective C17-aa oral steroid typically report gains in size of as much as 20lbs in plain weeks, typically a lot much more; it should be born in mind, the person will certainly not multiply if sufficient nutrients are not ready. A common misconception is that you need to do is supplement with anabolic steroids along with you'll increase; this is merely unreal. If you wish to enable you must feed your growth along with while those that get Dianabol will identify it efficient it is not magic. The concept behind this steroid as is with all steroids is to take just what youre currently doing proper nevertheless to do it with a far better level of effectiveness.
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If this doesn't proved we're well and truly fucked, I don't know what does.
Sky News political editor Faisal Islam has been left speechless after claiming a Conservative pro-Brexit MP told him the Leave campaign 'didn't have a plan' for Brexit.
Yes, that's right. There is 'no plan' for Britain leaving the European Union.
The MP then apparently pointed toward the Houses of Parliament and said: "Number 10 should have had a plan".
It sounds like I'm making that up. That literally happened two hours ago.
So – and I've said this before – the person with the most thought through plan, as evidenced by the past 48 hours, is, astonishingly, Nicola Sturgeon, the first minister of Scotland.
Which is – let's be honest – worryingly true.
While Islam didn't specify exactly who he was speaking about in the clip, he said in a Tweet that it was a Conservative Leave MP and Boris Johnson supporter who claimed there was 'no plan' for Brexit.
So there we have it. The pound has hit a 30 year low, there is post-EU Referendum racism on the streets of Britain and the plan that has been prepared for life after Brexit? Well, there is none.


The good and the bad when it comes to taking the pill.
Here's the romantic way he won her back.
We've never seen her like this before.
If anyone knows how the girls are feeling, it's Sam.
Warning: Once you see it, you can't unsee it.
He's been dubbed the 'worst Bachelor ever'.
All while she rushes into labour.


As with many automation features suggested in the past, it'd remove the management aspect of the game and therefore probably wouldn't be added.
I think part of the bed shortage issue etc is hospital management. If I had a large terminal collapse with let's say 25 casualty's. 3 hospitals to transport them to I would do something like this.
That way it keeps all of my hospitals available for local medical calls.
If it was just a single button it would send all 25 to the nearest hospital filling it right up and then taking 25 hours to empty.
Also the automation options as we have said in the past are generally frowned upon by the dev for taking away from gameplay.


Higher education is a key factor for economic growth. However, Bakersfield ranks among the lowest in the nation for residents with higher degrees.
For this reason, CSUB is opening its Graduate Student Center, with the mission of increasing the number of students receiving graduate degrees and strengthening community engagement of CSUB's graduate programs. The media is invited to a ribbon cutting and dedication at 10 a.m. Thursday, Jan. 20, inside Dorothy Donahoe Hall.
The Center is funded by a five-year, $2.5 million Title V grant for Hispanic-Serving Institutions from the U.S. Department of Education. The grant, Promoting Post-baccalaureate Opportunities for Hispanic Americans (PPOHA), is designed to increase the number of Hispanic graduate students and master's degree recipients and to improve graduate students' educational experience.
The Center's programs and services will benefit all graduate students at CSUB, in addition to historically under-served Hispanics. The one-stop center, located in Dorothy Donahoe Hall C100/108, streamlines the admissions process by integrating graduate admissions with university and program admissions. The center also offers advising, graduate program support, workshops for graduate students and faculty, and community outreach. The center's support staff will be available during day and evening hours.
By helping students attain higher degrees, CSUB will help support regional economic development. Metro Bakersfield was recently ranked 196th out of 200 communities for "brainpower" by Portfolio.com, with only 4.5 percent of residents having a graduate or professional degree.
According to the U.S. Census Bureau, average earnings in 2008 totaled $83,144 for those with an advanced degree, compared with $58,613 for those with a bachelor's degree only, and $31,283 for those with no more than a high school diploma.
With a majority of CSUB alumni remaining within the region, higher wage earners with advanced degrees make a direct economic impact. According to a report from the CSU Chancellor's Office, nearly $676.4 million of the earnings by alumni from CSU Bakersfield are attributable to their CSU degrees, which creates an additional $996.5 million of industry activity throughout the state.
For further information about CSUB's Graduate Student Center, please call Stella Baeza, Graduate Studies Facilitator, at 661-654-2792.


A YOUNG MAN with very strong New Ross and district connections is leading the very first Irish team m the Information Olympics which are to be held in Argentina.
He is 18·years-old Walter O'Brien, whose father, Maurice, is a native of Cushinstown, and his mother, Anne, nee Ronan, hails from New Ross. They lived at Borohill House, Clonroche, until about five years ago and the families are now based near Callan in Co.Kilkenny.
The remarkable thing about Walter's achievement is that he is a self-taught computer expert who left for Sussex University two weeks ago to talk on 'Artificial Intelligence' which is all about getting computers to think like humans. He has also been to Queen's University where he was involved in a research project involving experts from England, Australia, America, etc.
He attended Courtnacuddy NS, Enniscorthy CBS and the CBS, Callan. He has competed against and has beaten Andrew Farrell, the child prodigy who was featured on the Late Late Show.
The three-man Irish team, which he leads in Argentina, is being sponsored by Cara Data Processing, while the Argentinian Government will pick up the tabs in Mendoza.


For many budding Gamestormers, one of the trickiest challenges isn't in running the games, but in sequencing them to get to a specific outcome for a meeting. This template should help you think through the process of organizing games to evaluate where a certain game path may take you. It's called Gameboarding because it's akin to Storyboarding – shuffling and reordering content until it creates a meaningful arc. Keep in mind that a good meeting is organized around a meta-structure of opening, exploring and closing, and also involves an awareness of the micro-structure of that same process embedded within each game. Ideally your session will be designed around this (often referred to as diverging, navigating and converging), while driving toward your primary meeting goal.


Capability to inject a single atom into the substrate, or irradiate it by a single ion at the exactly determined position, are challenges driven by the development of new – one may say - future technologies, in which the accelerator based ion beam technology play an important role.
The aim of the workshop is to present successful examples where focused ion beams or single ion irradiation play or could play a crucial role in emerging future technologies, including quantum computing and quantum sensing. Additionally, new irradiation approaches, or new techniques that could attract potential users will be also presented. Experts from other fields that may be potential users of ion beam technologies will be also invited. It is expected that the workshop could result in new collaborations and new project proposals, including those within the scope of European Union research funding possibilities.
More information on CONFERENCE WEB PAGE.


Though her early work consisted largely of poems about ghosts later, adlocked is a urban fantasy novel by American author Charlaine Harris , teenage angst, is the twelfth penultimate book in her The Southern Vampire Mysteries. Charlaine harris deadlocked pdf free. Charlaine Harris Schulz ( born November 25, 1951) is an American New York Times bestselling author who has been writing mysteries for thirty years. The book was released on.
She now lives in southern Arkansas with her husband and three children. She was born and raised in the Mississippi River Delta area of the United States.
Deadlocked is a urban fantasy novel by American author Charlaine Harris and is the twelfth and penultimate book in her The Southern Vampire Mysteries. The book was released on. Charlaine Harris Schulz ( born November 25, 1951) is an American New York Times bestselling author who has been writing mysteries for thirty years. She was born and raised in the Mississippi River Delta area of the United States.
She now lives in southern Arkansas with her husband and three children. Though her early work consisted largely of poems about ghosts and, later, teenage angst, she.


text:
By KS95 | September 7, 2022
Nicky Youre's "Sunroof" ends the summer in 'Billboard' Songs of the Summer Top 20, #1 at radio
Columbia Records/Thirty Knots Records
When Nicky Youre's "Sunroof" first blew up, he told ABC Audio he hoped it would be 2022's Song of the Summer. Well, he didn't achieve that title officially — Harry Styles got that — but he got pretty darn close.
"Sunroof" ended up at #15 on Billboard's official Song of the Summer 2022 chart, ahead of tracks from Justin Bieber, Drake and country superstar Morgan Wallen. But it's #1 on both Billboard's Pop Airplay chart and Billboard's Adult Pop Airplay chart … ahead of Harry.
While we were all blasting "Sunroof," what was Nicky listening to? What are his favorite summer songs?
"Off the dome, it's people like Tai Verdes, Quinn XCII [92] … I love blackbear," he tells ABC Audio. "I'm a big Justin Bieber fan, too, so I'm all about, like, the fun."
"I mean, blackbear's kinda on the darker side of things, but it's still fun music," he adds. "And ultimately, I just want to listen to stuff that's, like, easy to listen to, typically. Unless I'm feeling sad. Then I wanna get hit with the feels by a really sad song, y'know? So it just depends on my mood."
Stuff that's easy to listen to pretty much describes "Sunroof." Nicky says he's glad that's the song that put him on the map.
"I feel like it's, like, a good representation of my personality and what I'm all about with music," he tells ABC Audio. "So I'm really glad it was that song that was the one that went."
So what's next? Well, Dazy, the producer Nicky collaborated on Sunroof with, tells Variety, "We have one more song that we're really stoked about. It's done and pretty much ready to go, we just have to wait for the right time to release it."

redpajama_set_name: RedPajamaCommonCrawl


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The School of Business (SBS) aims to produce students who are confident and independent with marketable skills. Through the programmes offered, students have the opportunity to undergo industrial training through collaboration with local and international industrial partners. With the desire to adress the challenges of today's ever changing economy, SBS offers two main Level 5 Diploma programmes in Business Accounting & Finance, and Business Studies. The latter offers three choices of specialisations: Entrepreneurship, Marketing and Human Resource Management. At present, SBS is led by a Head of School, Assistant Head of School with more than20 lecturers who support the department.
The School offers programmes to students who are interested in attaining relevant business, management and entrepreneurial skills and knowledge and for those who aspire to establish their own businesses. Information Communication Technology (ICT) is used to enable students to learn more and faster at their own pace and time. A Learning Management System (LMS) also enables students to access learning resources both on and off campus with courses delivered through blended learning approaches. Programmes and modules are designed to provide students with the necessary skills and knowledge that are demanded of the business industry.
SBS holds the motto: Educate, Perform and Excel.
At the School of Business, we are committed to making Politeknik Brunei's Vision and Mission a reality by providing holistic education that is based on blended teaching and learning methods. Occasionally, speakers from different industries are invited to assist and deliver useful information that is relevant by sharing of their experiences and practices with our students.
Through discussion of local and international issues and with the application of classroom knowledge, our students embrace the challenge of solving problems in real life situation through practical projects and coursework.
In the School of Business, we strive to inculcate within our students the drive to achieve marketable skills that are highly valued in today's world. Our testimonies from our industries and local partners have shared reviews about our students.
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text:
Probiotics in the treatment of depression:
science or science fiction?
Timothy G. Dinan, Eamonn M. Quigley
The term probiotic is derived from the Greek meaning
' for life ' and the first formal description of a probiotic
was provided by the Nobel laureate Metchnikoff in 1908,
based on his observation that individuals who lived in a
certain region of Bulgaria had a longer lifespan than their
fellow citizens, a fact which he attributed to the regular
ingestion of a fermented milk product [1]. The current
accepted definotion of a probiotic is a live organism that,
when ingested in adequate amounts, exerts a health benefit
In recent years many products have appeared on
health food store and supermarket shelves which are
labelled probiotic. Due to a widespread lack of uniform
regulation extravagant claims for their effectiveness have
proliferated. Fortunately, from a consumer perspective,
times are changing and regulatory agencies around the
world have begun to cast a forensic and skeptical eye on
probiotics and their claims. What evidence, if any, is
there to indicate that probiotics might have psychotropic
actions or benefit in patients with depression?
Probiotics are a broad heterogeneous group of microbes
and the most commonly used are lactic acid bacteria and
non-pathogenic yeasts. Very few of the plethora of ' probiotic
' preparations marketed today fulfil the definotion
of a probiotic [2]. They may not contain live organisms
or have not been adequately tested to ensure that the
organisms will survive in the conditions (e.g. room temperature)
or for the length of time (days, weeks, or
months) that is claimed. They may not confer a health
benefit because either they have never been tested in humans or because what studies have been performed
have been grossly inadequate or even negative.
In contrast to the relative paucity of high-quality clinical
data, considerable information on the basic functions of
probiotics and their interactions with the host has been
generated from cutting edge basic science laboratories.
Indeed, a series of studies have recently been published
focusing on the impact of putative probiotics on the central
nervous system and behaviour.
Preclinical studies
Major depression is a stress-related disorder and over
the past two decades well-tolerated antidepressants have
emerged. However, not all patients respond to antidepressants
and some patients are averse to pharmacological
interventions, while access to cognitive behaviour therapy
is not always readily available. From a biological perspective
it is known that depressed patients frequently have
hypothalamic-pituitary-adrenal (HPA) alterations such as
elevated cortisol levels in plasma, elevated corticotropin
releasing hormone (CRH) levels in the cerebrospinal flui
and a failure to suppress cortisol in response to dexamethasone
challenge [3]. Antidepressants treatment is
accompanied by reversal of these abnormalities. That
microbes can inflsence the functioning of the HPA is
demonstrated by the fact that germ-free mice with a sterile
gastrointestinal tract have an overactive HPA in
response to stress. This hyper-response of the HPA is
reversed by mono-association with a single organism,
Bifi dobacterium infantis , which is a predominant bacterium
in the infant gut and a commonly used probiotic
organism [4]. Furthermore, in germ free animals the levels
of noradrenaline (NA) and 5-hydroxy-tryptamine
(5-HT) in the cortex and hippocampus are significantly
reduced [5]. Thus, preclinical data clearly show that commensal bacteria have the capability of altering not
only the HPA axis but key neurotransmitters thought to
be of relevance in the aetiology of depression.
Desbonnet et al . [6] assessed the potential benefits of
the probiotic Bifi dobacterium infantis in the rat maternal
separation (MS) model of depression, a paradigm that
has proven to be of value in the study of antidepressant
effects. MS adult rat offspring were chronically treated
with bifidobacter or the selective serotonin reuptake
inhibitor citalopram and subjected to the forced swim test
(FST) to assess motivational state. Cytokine concentrations
in stimulated whole blood samples, monoamine
levels in the brain, and central and peripheral HPA measures
were also analysed. MS reduced swim behaviour
and increased immobility in the FST, decreased NA content
in the brain, and enhanced peripheral interleukin
(IL)-6 release and amygdala corticotropin-releasing factor
mRNA levels. Probiotic treatment resulted in normalization
of the immune response, reversal of behavioural
deficits, and restoration of basal NA concentrations in the
brainstem. These findings point to an influential role for
bifidobacteria in neural function, and suggest that probiotics
may have broader therapeutic applications than previously
considered. Further support for this view is
provided by the series of studies by Lyte and his colleagues
[7 – 10]. They have shown that oral administration
of the pathogen Campylobacter jejuni , in subclinical
doses, which were too low to elicit overt immune activation,
resulted in anxiety-like behaviour in mice. They
also reported that areas of brainstem activation, most
notably the nucleus tractus solitarius and lateral parabrachial
nucleus, participate in neural information processing
that lead to autonomic, neuroendocrine and
behavioural responses. These experiments support the
view that the gut microbiota may be involved in the
modulation, not only of the central nervous system, but
also, and consequently, behaviour [11].
That patients with major depression have a pro-inflammatory
phenotype with increased levels of pro-inflammatory
cytokines is now generally accepted [12]. Elevations
in plasma IL-6 and tumour necrosis factor alpha (TNFalpha)
are those most consistently demonstrated [13]. It
is now clear from both animal and human studies that
certain probiotic bacteria have an anti-inflammatory
capacity with the ability to alter a pro-inflammatory phenotype
[14]. This has, however, yet to be shown in
patients with major depression but has been demonstrated
in patients with irritable bowel syndrome [14].
In a recent double-blind, placebo-controlled, randomized
parallel group study volunteers received either the
probiotic combination Lactobacillus helveticus R0052
and Bifi dobacterium longum or placebo for 30 days and
were assessed by the Hopkins Symptom Checklist
(HSCL-90), the Hospital Anxiety and Depression Scale
(HADS), the Perceived Stress Scale, the Coping Checklist
(CCL) and the measurement of 24 hour urinary free
cortisol levels [15]. Daily administration of probiotic
combination signifi cantly reduced psychological distress
in volunteers, as measured by the HSCL-90 scale, the
HADS and by the CCL. Furthermore, urinary free cortisol
levels were signifi cantly reduced by the probiotics.
This is the fi rst demonstration of a probiotic influencing
the HPA in humans.
Another study by Benton et al . [16] found that the consumption
of a probiotic-containing yoghurt improved
mood. A total of 132 physically healthy subjects with a
mean age 61.8 years, volunteered in response to local
media coverage; 124 completed the trial. For a 3 week
period, either a probiotic-containing milk drink or a placebo
was consumed daily. Mood and cognition were measured
at baseline and after 10 and 20 days of consumption.
When the third with the lowest baseline mood were considered,
they selectively responded by reporting themselves
as happy rather than depressed after taking the probiotic.
In a study of patients with chronic fatigue syndrome,
subjects were treated three times daily with Lactobacillus
casei strain Shirota (LcS) or a placebo with
identical taste and appearance [17]. Overall there was
a significant improvement in anxiety among those taking
the active LcS compared to the placebo, providing
further support for the view
Logan and Katzman [18] fi rst proposed the use of probiotics
as adjunct therapy in the management of depression.
Since then there has been an accumulation of data
from both clinical and preclinical studies supporting the
view that probiotics may have a role in the treatment of
depression. It is, however, certain that not all probiotics
are the same, and while some may have an impact on
neurotransmitters and behaviour, others will not [19].
After all, they each have a unique genome with varying
capacities to produce neuroactive substances. Certainly,
for some patients probiotics would be far more acceptable
than the current use of SSRIs and other antidepressants.
However, before any firm conclusions can be drawn, properly
powered studies comparing an appropriate probiotic
DHEA for Urogenital Atrophy and Sexual Function
Susan R. Davis, MBBS, FRACP, PhD
What is the current evidence on the use of intravaginal dehydroepiandrosterone (DHEA) in urogenital atrophy and sexual function?
Commentary from Susan R. Davis, MBBS, FRACP, PhD
Sex steroids are vital for the integrity of the urogenital tract (vagina, vulva, lower urinary tract, and supporting pelvic structures). These tissues are rich in estrogen and androgen receptors.[1] In addition, estrogen and testosterone enhance blood flow to the genital tract,[2] which is fundamental for genital sexual arousal and lubrication.[3]
;The fall in estrogen at menopause and the gradual decline in androgen levels with age[4] result in what is now described as genitourinary syndrome of menopause (GSM). This includes vulvovaginal atrophy (VVA) and an increase in vaginal pH.[3] At a cellular level, there is a reduction in healthy vaginal epithelial superficial cells and an increase in parabasal cells. The increase in vaginal pH changes the vaginal microflora. Lactobacilli disappear, and as a consequence there is increased vulnerability to vaginal infection. Symptoms of VVA include vaginal dryness, irritation, itching, infection, and dyspareunia.[5] This in turn leads to diminished sexual desire, arousal difficulties, diminished physical and emotional sexual satisfaction, and relationship issues.[6]
Most postmenopausal women will experience some GSM symptoms.[7] Symptoms of VVA can be effectively treated with either vaginal or systemic estrogen therapy.[8] Estrogenization will thicken and revascularize the vaginal epithelium, lower vaginal pH, and normalize vaginal flora. The number of vaginal epithelial superficial cells will increase.[8,9] Although data show that vaginal estrogen acts locally, thus minimizing systemic exposure to estrogen, some studies have shown blood estradiol levels increase with vaginal application.[10,11,12] A two- to fivefold increase in serum estradiol has been reported after one week of vaginal administration of a 25 µg estradiol vaginal tablet or 1g of 0.625 mg conjugated estrogen cream.[10] After 24 weeks of treatment, only 2% of women have estradiol levels outside the postmenopausal range.[13]
Researchers have looked for alternative approaches for GSM management. In postmenopausal women, adrenal dehydro-epiandrosterone (DHEA) is an important precursor for extra-gonadal biosynthesis of estrone (by aromatization) and testosterone (by 5-alpha reduction). Casson and colleagues first studied the effects of a vaginal DHEA 150 mg pessary versus placebo in five premenopausal women as a mode of hormone delivery and reported an increase in blood levels of DHEA with this approach.[14] The daily vaginal application of three different doses of DHEA cream (6.5 mg, 13 mg, and 23.5 mg) was studied for one week in postmenopausal women.[15] Labrie and colleagues reported a decrease in vaginal pH, an improvement in the vaginal cell maturation index, and restoration of DHEA levels to the range for premenopausal women at the highest dose.[15] The circulating levels of other sex steroids remained within the normal range for postmenopausal women.
A randomized controlled trial of the daily application of three different doses of vaginal DHEA ovules (3.25 mg, 6.5 mg, or 13 mg) was studied over 12 weeks in 218 postmenopausal women who met the entry criterion of dyspareunia. This single study has resulted in a number of publications to support the efficacy of this treatment for VVA.[16,17,18,19,20,21] In these various publications, the investigators have reported an improvement in vaginal cytology and a reduction in pH. An analysis restricted to the women who fulfilled investigational criteria for a low percentage of vaginal epithelial cells and vaginal pH greater than 5 reported an increase in superficial cells and a reduction in pH with an associated improvement in dyspareunia compared with placebo.[21] Sexual function was assessed by three questions in the Menopause Quality of Life Questionnaire (sexual desire, vaginal dryness during intercourse, or avoiding intimacy) and by the Abbreviated Sexual Function Questionnaire. At 12 weeks the total Menopause Quality of Life Questionnaire sexual domain score showed a significantly greater response for each treatment group versus placebo, with more mixed findings in the Abbreviated Sexual Function Question-naire.[17]
DHEA Benefits Include Helping To Relieve Vaginal Pain Caused By Menopausal Dryness, Atrophy
Jan 5, 2016 12:01 AM By Susan Scutti
A new DHEA vaginal suppository for treating vaginal dryness may be one step closer to government approval: study. Diana Robinson, CC by 2.0
New research suggests a DHEA vaginal suppository for treating vaginal dryness may be one step closer to government approval. The DHEA formulation could provide an effective alternative for women hoping to ease their symptoms of menopause — without resorting to estrogen.
During perimenopause, vaginal tissues begin to atrophy, the lining thins and secretes less and less fluid, and the pH becomes more alkaline, explain the researchers. Not only do these signs of age lead to discomfort during sex, they also increase a woman's susceptibility to infections and urinary problems. While hormonal treatments may help alleviate such symptoms, many women have a past history of cancer or higher genetic risk for reproductive cancers rendering such medicines unsafe.
As an alternatives to estrogen treatments, some women resort to non-hormonal lubricants. While these products may temporarily provide moisture and even ease sexual pains, they do not correct the physical problems producing the symptoms. By comparison, DHEA (dehydroepiandrosterone) is a precursor of estrogens and androgens and so can induce physical changes that protect the vagina, according to the researchers. That said, the DHEA product in this study is still considered "hormonal" by regulatory authorities, such as the Food and Drug Administration.
Safety Testing a New Product
For the study, a research team from EndoCeutics, a private bio-pharm company, recruited nearly 500 women to participate in a randomized, double-blind, placebo-controlled trial of its DHEA suppository product. The majority of the women, 84 percent, complained of moderate to severe vaginal dryness. The researchers divided the women, ranging in age from 40 to 80, into two groups: 325 women in the DHEA-treatment group and 157 in a placebo group. After a baseline gynecological test, the women used a daily suppository of either the DHEA or placebo, depending on their group, for 12 weeks.
Compared with the women using a placebo, the women who used the DHEA ovules experienced improvements. Their scores on a scale of 0 to 3 for pain during sex dropped 0.36 points more than the women using placebo and their scores improved by 0.27 points with regard to vaginal dryness. Importantly, the gynecologists who examined them saw 86 percent to 121 percent better improvements in vaginal secretions, integrity of the vaginal lining, lining thickness, and tissue color in the women who used DHEA, while their vaginal pH shifted 0.66 points toward acidity (a positive direction).
"The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6 percent of the participants," noted the researchers in their study.
Importantly, this therapy has not been tested in patient at risk or with a history of breast cancer.
"Although this medication is considered 'hormonal,' the mechanism appears to be primarily local with minimal side effects beyond vaginal discharge from the suppository," Dr. JoAnn V. Pinkerton, executive director of North American Menopause Society, stated in a press release.
Source: Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause. 2016.
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The hard facts on Viagra
Weekly dose: the hard facts on Viagra
May 11, 2016 12.34pm AEST
Nial Wheate
Nial Wheate is a Friend of The Conversation.
Senior Lecturer in Pharmaceutics, University of Sydney
Dr Wheate in the past has received funding from the ACT Cancer Council, Tenovus Scotland, Medical Research Scotland, Scottish Crucible and the Scottish Universities Life Sciences Alliance for research into platinum drugs. Dr Wheate is a named inventor on two international patents dealing with the drug delivery of anticancer drugs.
University of Sydney provides funding as a member of The Conversation AU.
We believe in the free flow of information. We use a Creative Commons Attribution NoDerivatives licence, so you can republish our articles for free, online or in print.
Viagra was discovered by accident when participants in a study looking at a treatment for high blood pressure reported an interesting side effect. Felix E Guerrero/Flickr, CC BY-SA
Viagra is one brand name of a drug that is used to treat erectile dysfunction (impotence): the inability to get, and maintain, an erection. It is also used in the treatment of high blood pressure specific to the heart and the arteries that feed the lungs. The generic name of the drug is sildenafil (pronounced sill-den-a-fill).
Like many great scientific discoveries, the benefits of Viagra in treating erectile dysfunction were discovered by accident. The pharmaceutical company Pfizer initially developed the drug in 1989 as a treatment for high blood pressure and angina.
Unfortunately, early clinical trials were not positive. To have the right effect the drug had to be taken three times a day and it gave some of the patients muscle aches. It was also found to interact with nitrates (the standard treatment for angina), which resulted in an unsafe drop in patients' blood pressure.
Luckily, some patients had reported the delayed side effect of erections. As a result, the focus on Viagra changed to its sexual applications.
After clinical testing, it was approved for use in Australia in 1998, having been approved in the US nine months earlier.
Viagra works by binding to an enzyme called phosphodiesterase. Viagra binding to the enzyme prevents it from converting the chemical cyclic guanosine monophosphate (abbreviated cGMP) into guanosine triphosphate (GTP).
The effect of a build-up in cGMP is the relaxing of artery walls. This makes the arteries bigger and thus allows more blood to flow into the penis.
However, the drug will not give patients an erection without sexual stimulation. When a man becomes aroused the brain sends a signal to the cells in the penis to release nitric oxide, which turns on the production of cGMP. Without the stimulation to produce nitric oxide, there is no cGMP build-up and no erection.
All forms of the drug are sold as solid oral tablets in doses between 25 and 100 milligrams. For the treatment of high blood pressure, the tablets also come in a 20 milligram dose.
The dose prescribed by the doctor takes into account a patient's age, underlying cause of their impotence, and their kidney function.
When used to treat erectile dysfunction, patients are directed to take the drug once per day, 30 minutes to one hour before their planned sexual activity. The effects of the drug will take longer to kick in if it is taken with food.
One in ten patients will experience the common side effects of Viagra. Side effects include the development of a rash, diarrhoea and an increased susceptibility to urinary tract infections.
A less common side effect is abnormal vision. This includes blurred vision, a sensitivity to light, and/or a blue-green tinge to the patient's vision called cyanopsia. Higher doses increase the chance of a patient experiencing abnormal vision.
Unusual alternative uses
Flowers stay more erect when dosed with viagra. Velodenz/Flickr, CC BY
Other than its approved medical uses, Viagra has also been shown to have alternative applications. For example, researchers have shown adding Viagra to the water of cut flowers makes them last longer.
When they gave just one milligram of Viagra to the flowers they were found to stand up straight for a week longer than flowers that were given ordinary water – a doubling in the flower's shelf life.
Counterfeit Viagra
Viagra is one of the most counterfeited medicines in the world. Because of its wide appeal many patients attempt to buy it without a prescription. Viagra can be bought from online auction sites, internet pharmacies and even bricks-and-mortar retail stores.
There are numerous risks in taking counterfeit Viagra. Fake tablets can contain no Viagra or too much Viagra. There have also been reports that counterfeit tablets have contained blue printer ink – to give them that genuine Viagra look – illegal drugs like amphetamines, and other unrelated drugs like the antibiotic metronidazole.
This is probably not authentic. Julian Fong/Flickr, CC BY
The best way to ensure you are not buying counterfeit Viagra is to have a trusted pharmacist fill your script in-store. For those patients who need to have their Viagra script filled over the internet, there are some ways to check whether the medicine you have been supplied is fake.
Look for the writing stamped into the tablets. Does it look crisp and sharp or does it have an out-of-focus look? Also, check their colour consistency; you are looking to see if there are regions that are a darker or lighter blue than the rest of the tablet.
Next, look to see if the tablets feel smooth. Rough or pitted tablets are a sign of fake medicines.
Viagra is supplied in packs of four. If your strip has more than four tablets, it's counterfeit.
And, finally, Viagra is supplied only as solid tablets. Your tablets are counterfeit if you have been supplied soft tablets, gel tablets or chewable tablets.
If you suspect you have been provided counterfeit tablets, take them to your local pharmacist for checking and disposal.
For the treatment of erectile dysfunction, Viagra comes in three doses (25, 50 and 100 milligrams) with four tablets per packet. The cost to the patient is the same regardless of the dose at $6.20 per packet.
The Australian Pharmaceutical Benefits Scheme subsidises the drug; the cost to the government is between $54 to $82 per packet depending on the brand. Patients can expect to pay more if they buy Viagra over the internet.
What's the point of sex? It's communication at a biological level
January 16, 2017 6.02am AEDT
Sarah Robertson
Professor and Director, Robinson Research Institute, University of Adelaide
Sarah Robertson receives funding from the National Health and Medical Research Council of Australia, and the Australian Research Council.
University of Adelaide provides funding as a member of The Conversation AU.
The act of penetrative sex has evolved over millions of years as a mechanism to deliver sperm to eggs and initiate pregnancy. But there's more to sex than just the meeting of two sets of genes. The 'What's the point of sex?' series examines biological, physical and social aspects of sex and gender.
Today's piece looks at how a woman's immune system responds to sexual intercourse and facilitates healthy pregnancy.
Most people think just one sperm is needed to fertilise a woman's egg and make a healthy pregnancy. This underpins a common view that all the other sperm – and all the other sex – are surplus to requirements, at least when it comes to conceiving a pregnancy.
However, biologists now believe sexual intercourse is not just a sperm delivery process, but also a kind of biological communication. Regardless of whether fertilisation occurs, sperm and other components of the ejaculated fluid trigger subtle changes in the immune system of women.
This has consequences for pregnancy should it happen later. More broadly, the importance of regular sexual activity also has implications for fertility planning, and for IVF and other forms of assisted reproduction, which generally do not take sexual practice or history into account.
Sperm swim in a soup of molecular messages
Evidence from animal research and clinical studies has led researchers to conclude seminal fluid – the fluid sperm are bathed in following ejaculation – plays an important role in fertility.
Seminal fluid contains small molecules that act as biological signals. Once deposited in the vagina and the cervix of a woman, these persuade the woman's immune system to adopt a profile that tolerates (that is, recognises and accepts) sperm proteins known as "transplantation antigens".
The tolerant profile matters if fertilisation takes place. Immune cells recognise the same transplantation antigens on the developing baby, and so support the process through which the embryo implants into the wall of the uterus and forms a healthy placenta and fetus.
So over time, repeated contact with the same male partner acts to stimulate and strengthen a tolerant immune response to his transplantation antigens. The immune system of a woman responds to her partner's seminal fluid to progressively build the chances of creating a healthy pregnancy over at least several months of regular sex.
Some forms of infertility and disorders of pregnancy are caused by immune rejection, when the process of tolerance is not adequately established.
Healthier pregnancy after months of sex
A condition known as preeclampsia provides useful insights into how exposure to seminal fluid influences the success of pregnancy. Preeclampsia is an inflammatory disorder of pregnancy that compromises growth of the fetus, and often causes prematurity in babies. It can be life-threatening for mothers if left untreated.
Preeclampsia is more common when there has been limited sexual contact with the father before pregnancy is conceived, and is associated with insufficient establishment of immune tolerance in the mother.
The length of time a couple have had a sexual relationship seems more important than the frequency of intercourse. In a study of first pregnancies in 2507 Australian women, around 5% developed preeclampsia. Affected women were more than twice as likely to have had a short sexual relationship (less than six months) compared to the women who had healthy pregnancies.
Women with less than three months sexual activity with the conceiving partner had a 13% chance of preeclampsia, more than double the average occurrence. Among the few women who conceived on the first sexual contact with the father, the chance of preeclampsia was 22%, three times higher than the average. Low birth weight babies were also more common in this group.
Sperm swim in a soup of molecules that trigger an immune response in women. from www.shutterstock.com
No relationship is observed between frequency of sexual activity during pregnancy and risk for preeclampsia, so it's the duration of exposure before conception that counts most.
Setting up a profile of immune tolerance that supports healthy pregnancy seems to be specific to the conceiving partner. Women who change partners return to a baseline state, and must rebuild immune tolerance with the new partner.
Women who use barrier methods such as condoms or cervical caps (which lower the exposure of the vagina and cervix to seminal fluid and sperm), and then conceive shortly after stopping contraception, have an elevated risk of preeclampsia.
In contrast, women using an intrauterine device before conception have been found to have a slightly lower risk of preeclampsia.
Sex during IVF can increase conception chances
The importance of sex in creating the right environment for healthy pregnancy is also observed in clinical studies in IVF and other methods of assisted reproduction. Fertility is improved when couples have intercourse in the period when an embryo is transferred to the uterus.
Combined data from more than 2000 patients across seven studies showed the occurrence of a detectable pregnancy increased by 24% after vaginal contact with seminal fluid near the time of egg collection or embryo transfer. A study of Australian and Spanish couples showed intercourse in the days just before or just after embryo transfer boosted pregnancy rates by 50%.
These studies focused on the early stages of pregnancy, with further research required to assess whether sexual intercourse influences rates of full term pregnancy after assisted reproduction.
Absence of exposure to seminal fluid may be one factor explaining why preeclampsia incidence is higher after use of donated eggs or donor sperm, where prior female contact with the donor transplantation antigens has not occurred. The elevated risk after using donor semen can be reduced if multiple prior insemination cycles take place with the same donor.
In couples who conceive using a modified version of IVF known as ICSI (intracytoplasmic sperm injection), preeclampsia incidence is also higher in women who experience minimal exposure to their partner's transplantation antigens due to very low sperm counts.
In some couples, an imbalance in seminal fluid composition or immune system factors may inhibit or slow down establishment of the tolerant immune profile in women. In other couples, there may be immunological incompatibility that impairs tolerance, regardless of time spent together.
Maybe some couples may just need a little longer having sex for pregnancy to occur.
Immune system acts as a gatekeeper in pregnancy
It is interesting to consider why the immune system is so closely involved in reproduction.
One theory is that females have evolved the ability to sense and respond to the signals in seminal fluid, in order to discern the quality or "fitness" of the male partner's genetics. Scientists are now seeking to define the key signals on the male and female sides that promote tolerance.
Also, since male smoking, being overweight and other factors may shape how a woman responds to intercourse in a biological sense, it helps explains why dad's health is just as important as that of the mother in preparing for pregnancy.
Is vulvovaginal atrophy due to a lack of both estrogens and androgens?
Menopause. 2016 Nov 21. [Epub ahead of print]
Labrie F1, Martel C, Pelletier G.
11Laval University, Quebec City, Quebec, Canada 2Endoceutics Inc, Quebec City, Quebec, Canada.
The aim of this study was to review the preclinical data showing the role of both estrogens and androgens in the physiology of the vagina, and, most likely, in vulvovaginal atrophy of menopause.
Mass spectrometry-based assays (validated according to the FDA guidelines) for the measurement of sex steroids, their precursors, and metabolites were used. In addition to fixation of the vagina for morphological examination, histomorphometry, immunocytochemistry, immunofluorescence, and quantitative reverse transcription polymerase chain reaction were performed.
The vaginal epithelium of the animals receiving dehydroepiandrosterone (DHEA) was made of large multilayered columnar mucous cells showing distended cytoplasmic vacuoles representative of an androgenic effect. DHEA also stimulates collagen fiber compactness of the lamina propria (second layer)-an effect essentially due to an androgenic effect, whereas stimulation by DHEA of the muscularis in the third vaginal layer is approximately 70% due to the androgenic conversion of DHEA. Stimulation of the surface area of the nerve endings, on the contrary, is exclusively androgenic. Vaginal weight stimulation by DHEA is about 50% androgenic and 50% estrogenic.
Practically all studies on the influence of steroid hormones in the vagina have focused on luminal epithelial cells. Since all estrogens and androgens in postmenopausal women are made intracellularly and derive from the conversion of circulating DHEA, it is of interest to observe from these preclinical data that DHEA exerts both estrogenic and androgenic activity in the three layers of the vagina, the stimulatory effect on nerve density being 100% androgenic. Taking vaginal weight as a global parameter, the stimulatory effect of DHEA in the rat vagina is about equally estrogenic and androgenic, thus illustrating the importance of androgens in vaginal morphology and function, and the likely importance of androgens in vulvovaginal atrophy of menopause.
The use of high-dose estrogens for the treatment of breast cancer.
I know, I know, everyone is scared of oestrogen. I have over the years tried to point out that oestrogen is actually women's friend, as it does so many marvelous things for women. However, the scare mongering over the use of oestrogen has scared many women off using it. Even in oestrogen receptor positive breast cancer, oestrogen is used to treat breast cancer. I will be publishing more articles on this over the next week. The word apoptosis means "death", so when they talk about oestrogen causing apoptosis of breast cancer cells, it means they destroy the cells.
See comment in PubMed Commons below
Maturitas. 2017 Jan;95:11-23. doi: 10.1016/j.maturitas.2016.10.010. Epub 2016 Oct 18.
The use of high–dose estrogens for the treatment of breast cancer.
Coelingh Bennink HJ1, Verhoeven C2, Dutman AE1, Thijssen J3.
Pantarhei Oncology BV, Zeist, The Netherlands.
Pantarhei Oncology BV, Zeist, The Netherlands. Electronic address: cv@pantarheibio.com.
Department of Endocrinology, University Medical Center Utrecht, The Netherlands.
Estrogens are known to stimulate the growth of breast cancer but they are also an effective treatment for this disease (this has been termed the 'estrogen paradox'). The fact that estrogens can be an effective treatment for breast cancer is something that has almost been forgotten, whereas the fear for estrogens remains. This paper reviews the use of estrogens for the treatment of breast cancer and identifies possible applications. The data summarised in this review demonstrate that high–dose estrogens are effective for the treatment of advanced breast cancer, both as first-line treatment as well as for treatment after occurrence of endocrine resistance to TAM and AIs. Essential for efficacy is an extended period of estrogen deprivation before the tumour is subject to estrogen treatment (the gap hypothesis). Research on the mechanism of action has shown that apoptosis induced by estrogens is regulated via the estrogen receptor and growth factor signalling pathways. High–dose estrogens have a negative safety image, especially in terms of side-effects and increased rates of cardiovascular disease, but the safety data reviewed in this paper do not give rise to major concerns. Taking into account their side-effect profile together with their observed clinical efficacy, high–dose estrogens should be considered a valuable alternative to chemotherapy in selected patients.
Cureus. 2017 Jul 6;9(7):e1434. doi: 10.7759/cureus.1434.
Estradiol as a Targeted, Late-Line Therapy in Metastatic Breast Cancer with Estrogen Receptor Amplification.
Kota K1, Brufsky A2, Oesterreich S3, Lee A3.
Internal Medicine, UPMC Presbyterian.
Division of Hematology/Oncology, Magee Women's Hospital of UPMC.
Pharmacology and Chemical Biology, University Of Pittsburgh.
Estradiol is a major regulator of growth for the subset of breast cancers that express the estrogen receptor (ER, ESR1). Strategies to block ER action, via reduction of estradiol or direct inhibition of ER, have shown major success in the prevention and treatment of breast cancer. However, most ER-positive (ER+) metastatic breast cancers (MBC) eventually become resistant to these interventions. Interestingly, high dose estrogen can induce apoptosis in breast cancer cell lines, and high-dose estrogen has been used for over 50 years as therapy for ER+ breast cancer. The mechanism for growth control of MBC by high dose estrogen is unclear. We present a patient with metastatic breast cancer whose tumor was found to have amplification of ESR1 by tumor genome sequencing. This patient was treated with high dose estradiol and subsequently experienced a sustained partial response, which was predicted by prior experiments with patient-derived xenograft animal models containing breast cancers with ER amplification.
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Why you should avoid hospitals in January
Mistakes happen in hospitals – no-one is perfect. I have witnessed many errors in treatment for myself or my family over the years. Luckily, my medical knowledge has allowed me to correct the mistake before too much damage was done. What if I had been a normal patient/father? I would not have known about the error. Most mistakes were of incorrect dosage, or the wrong medication. I strongly advise all of you to check everything – medicines, doses, procedures and ask questions of your medical personnel, especially in hospitals.
January 15, 2018 11.35am AEDT
Stephen Duckett and Greg Moran
Stephen Duckett
Stephen Duckett is a Friend of The Conversation.
Director, Health Program, Grattan Institute
Greg Moran
Associate, Grattan Institute
Grattan Institute began with contributions to its endowment of $15 million from each of the Federal and Victorian Governments, and $4 million from BHP Billiton. In order to safeguard its independence, Grattan Institute's board controls this endowment. The funds are invested and Grattan uses the income to pursue its activities.
Greg Moran does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.
January is the quietest month in Australia. But for hospitals, which provide care 24/7/365, January is a time of big transition. And for patients, that means January is when things are more likely to go wrong.
More than 3,000 newly graduated doctors will enter the next phase of their training in January. New nurses and allied health professionals, such as physiotherapists and hospital pharmacists, also join the workforce in January.
These new staff fill the posts vacated by people one year ahead of them in the pipeline. Last year's first-year-out doctor goes into his second year of training, and his predecessor goes into her third-year role or leaves the hospital to join a new workplace.
These new minds and hands, and the massive reshuffles of existing staff, disrupt hospitals. Old informal networks break down as new relationships are forged, and the less-experienced staff learn the hospital's processes and expectations.
Read more: Reducing medical errors, one patient at a time
Not surprisingly, this staff disruption has an impact on patient care. Around the world, overblown descriptions of the changeover period as the "killing season" and of doctors' first day in the UK as "Black Wednesday" have become part of medical folklore.
More sober studies of the "July Effect" (so named in the northern hemisphere) have indeed found evidence of worse patient outcomes during the changeover period.
The graph below shows the trend in complications in Australian hospitals over the past few years. It reveals a small but clear "January Effect". On average, at least one complication occurs in just under 11% of hospital admissions in Australia. But each January, this rate ticks up by more than half a percentage point.
What goes wrong?
New staff might be less adept at monitoring patients, leading to the patient becoming malnourished. Or the new staff may not have acquired sufficient technical skills leading to an accidental puncture or laceration during a procedure.
Other hospital complications include pressure sores from not moving enough, infections from hygiene breaches, and being given the wrong dose or type of drug.
In January 2015, about 74,000 hospital patients in Australia had a complication of care, about 3,000 more than would have been expected if there were no January Effect. That is 3,000 people suffering complications that might not have arisen had they received care at "normal" times of the year.
What hospitals can do
Although the effect is clear, the causes – and therefore, solutions – are not. Is it the effect of the new doctors and other staff who are inadequately prepared for their new responsibilities? Or is it team disruption? Or is it that senior staff take their leave over January, resulting in weaker supervision just when it is needed most? Probably all of the above.
To the extent the problem is diminished supervision, start dates for new staff could be pushed back a month or so. Perhaps senior staff leave could be more evenly spread across the year.
Read more – Infections, complications and safety breaches: why patients need better data on how hospitals compare
If the problem is poorly prepared junior staff, then a longer and better induction might be the answer. Typically newly graduated doctors now have a one-week introduction, this could be extended or restructured to include more time to be introduced to the specific practices of units they will be joining.
If the problem is disrupted teamwork, the solution might involve better handover and induction processes, either as part of the formal induction period, or as a structured experience when they join their new unit.
Most likely, all facets will need to be improved.
What patients and their advocates can do
The January Effect underlines the fallibility of the people and systems that deliver our hospital care. Australia's hospital system is staffed by motivated and highly trained people working in well-developed systems, often using state-of-the-art technologies and medicines.
But people can make mistakes, particularly when they are new to a task. Systems can break down. Patients in Australia can take comfort in the safety and quality of hospital care, but they should not assume it is perfect.
Read more: Blaming individual doctors for medical errors doesn't help anyone
The burden of fixing health system problems should never rest on the shoulders of those with least power – patients and their families and carers. But patients do have a role. Alert and active patients and their families and carers can help identify and prevent errors – and this role becomes slightly more important in January.
Patients often know when they are about to be given the wrong medication, or when their regular medication has been stopped, or when the care they are about to get has not been fully discussed with them so might be wrong. They can speak up and prevent the problem – but too often they feel put down, disempowered and dismissed.
So the simple message for patients is this: if you see something that doesn't look right, speak up, and speak up again.
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What supplements do scientists use, and why?
I take a range of supplements daily. They include 12 gms fish oil, Turmeric with black pepper and ginger, Aged Kyolic garlic, Magnesium, CoQ 10 and low dose aspirin – I classify that as a supplement as it comes from the willow bark.
January 11, 2018 2.16pm SAST • Updated January 11, 2018 6.28pm SAST
Simon Bishop, Graeme Close, Haleh Moravej, Justin Roberts, Neil Williams, and Tim Spector
Lecturer in Public Health and Primary Care, Bangor University
Graeme Close
Professor of Human Physiology, Liverpool John Moores University
Senior Lecturer in Nutritional Sciences, Manchester Metropolitan University
Senior Lecturer, Anglia Ruskin University
Neil Williams
Lecturer in Exercise Physiology and Nutrition, Nottingham Trent University
Tim Spector
Professor of Genetic Epidemiology, King's College London
Graeme Close consults to Gatorade Sport Science Institute (GSSI) and Healthspan Elite. He has received funding from The MRC, BBSRC, Aliment Nutrition, GSK and GSSI.
Tim Spector receives funding from The MRC, Wellcome Trust, CDRF, NIHR, EU Horizon Grants, and is author of "The Diet Myth : the real science behind what we eat – Orion 2016"
Haleh Moravej, Justin Roberts, Neil Williams, and Simon Bishop do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.
Supplements are a multi-billion dollar industry. But, unlike pharmaceutical companies, manufacturers of these products don't have to prove that their products are effective, only that they are safe – and that's for new supplements only.
We wanted to know which supplements are worth our attention (and money) so we asked six scientists – experts in everything from public health to exercise physiology – to name a supplement they take each day and why they take it. Here is what they said.
Simon Bishop, lecturer in public health and primary care, Bangor University
Turmeric is more familiar as an ingredient in South Asian cooking, adding an earthy warmth and fragrance to curried dishes, but, in recent years, it has also garnered attention for its potential health benefits. I have been taking ground turmeric root as a dietary supplement for around two years, but I have been interested in its use in Ayurvedic medicine for far longer.
Turmeric is used as a traditional remedy in many parts of Asia to reduce inflammation and help wounds heal. Now, mounting evidence suggests that curcumin, a substance in turmeric, may also help to protect against a range of diseases, including rheumatoid arthritis, cardiovascular disease, dementia and some cancers.
The evidence underpinning these claims of health-giving properties is not conclusive, but it is compelling enough for me to continue to take turmeric each morning, along with my first cup of coffee – another habit that may help me live a bit longer.
Turmeric may protect against arthritis, heart disease and some cancers. Trum Ronnarong/Shutterstock.com
Graeme Close, professor of human physiology, Liverpool John Moores University
Vitamin D is a peculiar vitamin in that it is synthesised in our bodies with the aid of sunlight, so people who live in cold countries, or who spend a lot of time indoors, are at risk of a deficiency. People with darker skin tone are also more at risk of vitamin D deficiency as melanin slows down skin production of vitamin D. It is estimated that about a billion people are deficient in the vitamin.
Most people are aware that we need enough vitamin D to maintain healthy bones, but, over the past few years, scientists have become increasingly aware of other important roles of vitamin D. We now believe vitamin D deficiencies can result in a less efficient immune system, impaired muscle function and regeneration, and even depression.
Vitamin D is one of the cheapest supplements and is a really simple deficiency to correct. I used to test myself for deficiencies, but now – because I live in the UK where sunlight is scarce between October and April, and it doesn't contain enough UVB radiation during these cold months – I supplement with a dose of 50 micrograms, daily, throughout the winter. I also advise the elite athletes that I provide nutrition support to, to do the same.
Justin Roberts, senior lecturer in sport and exercise nutrition, Anglia Ruskin University
Having diverse beneficial gut bacteria is important for your physical and mental health. However, the balance of bacterial species can be disrupted by poor diet, being physically inactive and being under constant stress. One way to support the health of the gut is to consume dietary probiotics (live bacteria and yeasts), such as yogurt, kefir and kombucha.
I first came across probiotics after years of triathlon training, often experiencing gastrointestinal symptoms – such as nausea and stomach cramps – after training and races. I was also more susceptible to colds. After researching the area, I was surprised at how many people experience similar gastrointestinal problems after exercise. Now I have found that taking a probiotic regularly lessens my symptoms after training and benefits my general health.
A recent study we conducted showed that taking a probiotic in the evening with food, over 12 weeks of exercise training, reduced gastrointestinal problems in novice triathletes.
There is also a wealth of research supporting the use of probiotics for general health benefits, including improving intestinal health, enhancing the immune response and reducing serum cholesterol.
Neil Williams, lecturer in exercise physiology and nutrition, Nottingham Trent University
Prebiotics are non-digestible carbohydrates that act as a "fertiliser" to increase the growth and activity of beneficial bacteria in the gut. This is turn can have positive effects on inflammation and immune function, metabolic syndrome, increase mineral absorption, reduce traveller's diarrhoea and improve gut health.
I first came across prebiotics in my research to target the gut microbiota in athletes suffering from exercise-induced asthma. Previous research had shown asthma patients to have altered gut microbiota, and feeding prebiotics to mice had been shown to improve their allergic asthma. Taking this as our launching point, we showed that taking prebiotics for three weeks could reduce the severity of exercise-induced asthma in adults by 40%. Participants in our study also noted improvements in eczema and allergic symptoms.
I add prebiotic powder to my coffee every morning. I have found that it reduces my hayfever symptoms in the summer and my likelihood of getting colds in the winter.
Haleh Moravej, senior lecturer in nutritional sciences, Manchester Metropolitan University
I started taking omega 3 after attending a Nutrition Society winter conference in 2016. The scientific evidence that omega 3 could improve my brain function, prevent mood disorders and help to prevent Alzheimer's disease was overwhelming. After analysing my diet it was obvious that I wasn't getting enough omega 3 fatty acids. A healthy adult should get a minimum of 250-500mg, daily.
Omega 3 is a form of fatty acid. It comes in many forms, two of which are very important for brain development and mental health: EPA and DHA. These types are primarily found in fish. Another type of omega 3 – ALA (alpha-linolenic acid) – is found in plant-based foods, such as nuts and seeds, including walnuts and flax seeds. Due to my busy schedule as a lecturer, during term time my diet is not as varied and enriched with omega 3 fatty acids as I would like, forcing me to choose a supplement. I take one 1,200mg capsule, daily.
Nothing but real food
Tim Spector, professor of genetic epidemiology, King's College London
I used to take supplements, but six years ago I changed my mind. After researching my book I realised that the clinical studies, when properly carried out and independent of the manufacturers, clearly showed they didn't work, and in many cases could be harmful. Studies of multivitamins show regular users are more likely to die of cancer or heart disease, for example. The only exception is supplements for preventing blindness due to macular degeneration, where randomised trials have been generally positive for a minor effect with a mixture of antioxidants.
Why take supplements when you can get all you need from a healthy diet? margouillat photo/Shutterstock.com
In many cases, there is some experimental evidence these chemicals in supplements work naturally in the body or as foods, but no good evidence that when given in concentrated form as tablets they have any benefit. Recent evidence shows that high doses of some supplements can even be harmful – a case in point being calcium and vitamin D. Rather than taking expensive and ineffective synthetic products, we should get all the nutrients, microbes and vitamins we need from eating a range of real foods, as evolution and nature intended.
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HRT in BRAC positive women
Interesting research that shows taking HRT in BRAC positive women does n0t appear to increase the risk of getting breast cancer.
Menopause. 2014 Jul;21(7):763-8. doi: 10.1097/GME.0000000000000126.
Hormone therapy in oophorectomized BRCA1/2 mutation carriers.
Marchetti C1, Iadarola R, Palaia I, di Donato V, Perniola G, Muzii L, Panici PB.
From the Department of Gynecological and Obstetrical Sciences and Urological Sciences, Sapienza University of Rome, Rome, Italy.
BRCA1/2 mutation carriers have greatly elevated lifetime risks of breast, ovarian, and fallopian tube cancers. Bilateral prophylactic salpingo-oophorectomy is recommended to prevent cancer in these women. As it is often performed before natural menopause, it may be accompanied by menopausal symptoms, impaired quality of life, and increased cardiovascular risk.
In this review, we describe the indications, timing, and implications of salpingo-oophorectomy for BRCA-positive women, with a special focus on the risks and benefits of hormone therapy (HT). Furthermore, retrospective and prospective trials of HT in BRCA mutation carriers undergoing prophylactic salpingo-oophorectomy are debated.
Hormonal deprivation after prophylactic salpingo-oophorectomy may negatively impact health and quality of life; most women experience menopausal symptoms shortly after surgical operation. Literature data suggest that HT generally reduces vasomotor symptoms related to surgical menopause, improving sexual functioning without affecting survival.
Despite the limitations of retrospective and prospective observational studies, short-term HT seems to improve quality of life and does not seem to have an adverse effect on oncologic outcomes in BRCA1 and BRCA2 mutation carriers without a personal history of breast cancer. Therefore, randomized and larger trials are urgently needed.
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Cimicifuga foetida extract in menopausal women
This is a very interesting study, as it gives women another option for helping the menopausal symptoms. This could also be useful for women who cannot take HRT for whatever reason, eg breast cancer.
Bugbane, also called Rattletop, any of about 15 species of tall perennial herb constituting the genus Cimicifuga of the buttercup family (Ranunculaceae) native to North Temperate woodlands. They are said to put bugs to flight by the rustling of their dried seed heads.
In North America the American bugbane, or summer cohosh (C. americana), about 120 cm (4 feet) tall, and the black cohosh, or black snakeroot (C. racemosa; see photograph), about 180 cm (5.91 feet) tall, have roots that have been used medicinally. C. foetida, native to Europe and Siberia, is used medicinally by the Chinese. These species are sometimes grown in the shady woodland garden for their whitish branched flower stalks that rise strikingly above the large, divided leaves.
Climacteric. 2017 Dec 4:1-6. doi: 10.1080/13697137.2017.1406913. [Epub ahead of print]
Efficacy and safety evaluation of Cimicifuga foetida extract in menopausal women.
Gao L1,2, Zheng T1, Xue W1, Wang Y1, Deng Y1, Zuo H3, Sun A1.
a Department of Obstetrics and Gynecology , Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing , China.
b Department of Obstetrics and Gynecology , Jiaxing Maternity and Child Health Care Hospital , Jiaxing , China.
c Department of Obstetrics and Gynecology , The Second Hospital of Hebei Medical University , Hebei , China.
The aim of this study was to evaluate the efficacy and safety of long-term treatment with Cimicifuga foetida extract in menopausal women.
A prospective, randomized, controlled clinical trial was conducted. A total of 96 early postmenopausal women were randomly assigned to three groups: group A received 1 mg estradiol valerate daily plus 4 mg medroxyprogesterone acetate on days 19-30; group B received 1 mg estradiol valerate daily plus 100 mg micronized progesterone on days 19-30; group C received 100 mg C. foetida extract daily. The efficacy was evaluated. Safety parameters were recorded.
A total of 81 patients completed the treatment and follow-up visit. The modified Kupperman Menopausal Index scores decreased after 3 months in all groups. No significant changes were observed in the liver, renal function and components of metabolic syndrome in group C (p > 0.05). There were no significant differences in the incidences of metabolic syndrome among the three groups (p > 0.05). After 24 months, the endometrial thickness increased significantly in group B (p = 0.014), but not in the C. foetida extract group (p > 0.05).
C. foetida extract is safe and effective for the treatment of menopausal symptoms in postmenopausal women.
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text:
Koshair
Revision as of 14:41, 10 September 2013 by Mordechaig (talk | contribs) (orchot shabbat on bows)
The Melacha of Koshair is the binding two pliable items by intertwining them such as through a firm knot or twining threads into rope. [1]
A knot that's forbidden on a Torah level is one that is both (1) professional and (2) is meant to be permanent. [2]
Many Rishonim hold that it is rabbinically forbidden to tie a knot which is either professional or meant to last for more than 24 hours. Some Sephardim hold that a non-professional knot is only rabbinically forbidden if it meant to last a week. Some Rishonim hold that a knot which is permanent even if it's not professional is Biblical prohibited.[3]
A knot which is both non-professional and meant to be undone within 24 hours may be tied. [4] Some Sephardic authorities permit a non-professional knot which is meant to last less than 7 days. [5]
Even if you personally intend to leave it less than 24 hours, if it's a knot sometimes left permanently by people it's forbidden Rabbinically to prevent confusion between temporary and permanent knots. [6]
Any knot which is forbidden to tie is also forbidden to tighten. [7]
For example, one may not tighten the double knot of the tzitzit or talit if it became loose. [8]
Any knot that's permitted to tie is permitted to untie. [9]
A bow-knot, slipknot, or a single-knot isn't a true Kesher-bind and is permissible even if it does remain in place for a while. [10] For example: a ribbon on a gift, a single bind on a shopping bag or garbage liner.
It is permitted to tie a slip knot or bow without a underlying knot even if it is tight and meant never to be undone. [11]
After tying a bow knot (a bow on top of a single knot), as is common when tying one's shoes, one may not tie a second bow on top of the bow knot. [12] Others permit tying this knot since it can still be untied with a single hand by pulling on the end of the string. [13]
According to Ashkenazim, it is permissible to tie one's shoelaces with a bow on top of a single knot (initial winding) only if it is meant to be untied within 24 hours. According to Sephardim, it is permissible as long as it is meant to be untied within 7 days. [14] However, if one doesn't usually untie it within 24 hours (and manages to slip one's foot in and out) it would be forbidden to tie one's shoes on Shabbat. [15]According to Sephardim it is permissible even if it isn't meant to be untied within 24 hours, yet it's preferable to make sure to untie it within 7 days. [16]
Someone doing the wrapping of an Ashkenaz Sefer Torah (Gelilah) and has to tie a sash around the Torah, it's preferable to just wrap the sash around the Torah and tuck in the end, however, if that's not possible then some are lenient to tie a bow on top of a single knot [17] while others are strict unless one is planning on untying it within 24 hours. [18]
Many authorities hold that it is permissible to tie a necktie on Shabbat if one usually unties it within 24 hours. However, if one doesn't usually untie it within 24 hours, some say that if one intends to untie it within 24 hours it is permitted, while others write that one should tie it from before Shabbat and put it on and take it off by just tightening and loosening the side which goes around the neck, however, one shouldn't untie it on Shabbat. [19]
It is forbidden to tie a single knot with one string onto itself. [20]
In situations where it's common to tie a double knot such as the last knot of a tzitzit fringe one may tie a single knot. [21]
It is permitted to tie a single knot in two strands of string even if it is tight and meant never to be undone. [22]
It is permitted to tie a single knot and then tuck in the ends of the string so that it doesn't come out only if it is menat to be undone within 24 hours. [23]
One may not add a second knot on top of a preexisting single knot,[24] nor may one add a third knot onto a double knot in order to tighten it. [25]
According to Ashkenazim, a tight double knot is considered like a professional knot and may not be tied. The Sephardic custom, however, is to be lenient if one intends to untie it within 7 days, yet, one who is strict will be blessed. [26]
It is permitted to tie a loose double knot if it's usually not meant to last 24 hours and this time specifically it's also not meant to last 24 hours. [27] For example, it's permissible to tie a double knot for a belt (gartel) or sash (tichel) if it's going to be untied in 24 hours since it's not meant to be tight. [28]
If unintentionally one pulled the bow-knot of the shoelaces and it became a double knot, one may untie it. [29]
One can untie a double knot that is made on a candy bag given out at shul for a simcha. [30]
One may tie a bandage on a wound with a loose double knot if it is meant to be untied within 24 hours. If it is meant to last for more than 24 hours but less than 7 days, one should use a adhesive bandage or a bow knot, however, if that isn't possible then it's permissible. [31]
One may tie a head covering with a loose double knot as long as one usually unties it everyday. However, if one usually removes it within untying the knot then it's forbidden to tie it even if this time one's intent is to untie within 24 hours. [32]
It is permitted to wrap a string around an object and then tuck the ends of the string in even if it is meant to be left permanently. [33]
Some authorities forbid using wire twist ties to close bags unless one plans to undo it within 24 hours. [34] However, others permit. [35] It is praiseworthy to avoid using them if they will remain undone for more than 24 hours. [36]
Some poskim permit using plastic cables ties since it is not a knot, but simply tightening. [37]
Socks or gloves that are tied together should be detached before Shabbat, but if one forgot one should untie it but ripe it so as to destroy the string. [38]
One can take out the pins put into shirts in packaging to keep it from wrinkling. [39]
It's totally permitted to thread new laces into shoes to replace old laces but it's not permitted if the shoe was never laced. [40]
↑ Mishna Brurah(317:34) quoting the Rambam, Shemirat Shabbat KeHilchata 51:52
According to Rashi, (Gemara Shabbat 112a), tying a knot that lasts forever is forbidden Deoritta, tying a knot that is untied after some time is forbidden Derabbanan, and tying a knot that is untied all the time is permitted. (For a precise explanation of Rashi see Bet Yosef 317:1 and Taz 317:1.) The Rosh 15:1 agrees. The Rif 41b, however, explains that a professional knot which is meant to last forever is forbidden Deoritta, a non-professional knot which is meant to last is forbidden Derabbanan, and a non-professional knot which is not meant to last is permitted. The Rambam 10:2 adds that a professional knot which is not meant to last is forbidden Derabbanan. S"A 317:1 and Yalkut Yosef 317:1-4 rule like the Rif, while the Rama and Mishna Brurah 317:5 and 14 are concerned both for Rashi and the Rif. Pri Megadim M"Z 317:3 and Mishna Brurah 317:5 writes that according to the Rambam even if it lasts a long time it's permitted as long as it is not meant to last forever.
The Bet Yosef 317:1 explains based on the Tur that a knot that lasts for less than a week is considered to be untied every day. Yalkut Yosef (vol 2 p. 555) agrees. Rama 317:1, however, quotes the Maharam MiRotenburg's who says that a knot that lasts for more than a day is forbidden. Pri Megadim (E"A 317:2) and Mishna Brurah 317:6 clarify that one day means 24 hours. Sh"t Yabea Omer 8:39:8 agrees that one day means 24 hours for this halacha, unlike the Tal Orot who says that it goes by the halachic day. Taz 317:1, Eliyah Rabba 317:2 Aruch HaShulchan 317:8, and Kaf HaChaim 317:14 rule like the Maharam.
↑ Magan Avraham (317:20), Kol Sinai (Koshair #3)
↑ Shemirat Shabbat KeHilchata 15:50 (in new editions 15:53), Kesot HaShulchan (Siman 123, at the end of note 4), Sh"t Az Nidabru 3:22, Sh"t Bear Moshe 6:3
↑ Rama 317:1, Rambam Hilchot Shabbat 10:7, Chazon Ovadia Shabbat volume 5: page 47.
↑ Shulchan Aruch (317:5) and implied by Rama (317:1). Kitzur S"A 80:45 and Yalkut Yosef (317:11) agree.
↑ Shulchan Aruch (317:5), Biur Halacha 317:5, Yalkut Yosef (317:11, Shabbat, vol 2, pg 562), The Shabbos Home (Rabbi Simcha Cohen, vol 1, chap 13, pg 207)
Rambam 10:5, Tur, and S"A 317:5 rule like Chachamim on Shabbat 113a who hold that tying a bow is permitted. Bet Yosef 317:5 quotes the Mordechai, who forbids tying a bow on top of a single knot. However, Darkei Moshe 317:3 quotes the Agur who says that the minhag is lenient to tie a bow on top of a single knot.
Magen Avraham 317:15, Taz 317:7, Eliyah Rabba 317:13, Mishna Brurah 317:29, and Kaf HaChaim 317:59 rule like the Agur but explain that it must be untied within 24 hours so that it is not considered a permanent knot. The Aruch HaShulchan 317:25, however, rules like the Mordechai. Kitzur S"A 80:45, Shemirat Shabbat KeHilchata 15:53 (in new edition 15:56), and the Shabbos Home (Rabbi Simcha Cohen, vol 1, chap 13, pg 207) concur with the Mishna Brurah.
Rabbi Mordechai Willig ("Hilchos Shabbat 5761 Kosher#1" min 90-4) says that even according to those who consider a tie to be a knot, it is permitted to make a tie if one has intent to undo it within 24 hours. This is even true for a person who usually leaves their tie tied. Although the Beiur Halacha D"H HaKosher writes that one's personal intent to undo it within 24 hours is ineffective when the way of the world is to leave a knot tied, Rabbi Willig explained that this case is not similar because some do untie their ties everyday. The 39 Melachos (footnote #41) has the same idea.
↑ Rama (317:1) quoting the Hagahot Alfasi, Kitzur S"A 80:45, Shemirat Shabbat KeHilchata (in the new edition 15:52)
Shiltei Giborim 41b writes that a double knot might be a professional knot because it is a strong knot. Thus, Rama 317:1 forbids tying a double knot even if it is not meant to last. Many Ashkenazic authorities, including Kitzur S"A 80:45, Mishna Brurah 317:14, Shemirat Shabbat KeHilchata 15:52 and The 39 Melachos (vol 3, p. 792) agree, while the Aruch HaShulchan 317:10 disagrees.
↑ Shemirat Shabbat Kahilchata 15:63 in name of Rav Shlomo Zalman Aurbach, Az Nidabru 1:58.
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A. Mitchell Palmer was a Democratic politician from Pennsylvania who served as Congressman, Alien Property Custodian and Attorney General between 1908 and 1921. This collection consists of material largely relating to Palmer's political career, from 1912 until his retirement in 1921. Researchers will find material created during Palmer's life time as well as material collected, after his death, by family, including photographs, political cartoons, material relating to his unsuccessful 1920 run for president, and an address given by Palmer at Swarthmore College.
Lichtenberg family Palmer, A. Mitchell (Alexander Mitchell), 1872-1936 Democratic National Convention. Palmer, A. Mitchell (Alexander Mitchell), 1872-1936 United States. Department of Justice. Office of the Attorney General.