Date:
January 24, 2017

Source:
University of California – San Diego

Summary:
Molecular biologists have unlocked the code that initiates transcription and regulates the activity of more than half of all human genes, an achievement that should provide scientists with a better understanding of how human genes are turned on and off.

 

Each tiny human cell contains about six feet of DNA, a double-helical molecular chain containing several billion chemical nucleotides—adenine (A), cytosine (C), guanine (G) and thymine (T)—arranged in a specific sequence, or code, that when transcribed guide the cell into producing specific proteins.
Credit: Image courtesy of University of California – San Diego

 

 

Molecular biologists at UC San Diego have unlocked the code that initiates transcription and regulates the activity of more than half of all human genes, an achievement that should provide scientists with a better understanding of how human genes are turned on and off.

The discovery of this critical DNA sequence code — what molecular biologists term the “human Initiator” — is detailed in a paper in the February 10 print issue of the journal Genes & Development.

“There are many sequence signals that control gene activity in human cells and the Initiator is the most commonly occurring sequence at the start sites of genes,” says James T. Kadonaga, a molecular biology professor at UC San Diego who headed the team of researchers. “The solution of the human Initiator code will enable us to explore new frontiers in gene regulation. In the future, it will be possible to use the code to identify other regulatory signals and, in this way, gain a more complete understanding of how human genes are turned on and off.”

Each tiny human cell contains about six feet of DNA, a double-helical molecular chain containing several billion chemical nucleotides — adenosine (A), cytosine (C), guanine (G) and tyrosine (T) — arranged in a specific sequence, or code, that when transcribed guide the cell into producing specific proteins.

“In these six feet of DNA, there are tens of thousands of genes, which are segments of DNA that direct specific functions, such as the production of a hormone or an enzyme,” explains Kadonaga. “It is essential for the cell to control the activity of each of its tens of thousands of genes, because the improper control of gene activity can lead to adverse outcomes such as cell death or the formation of a cancer cell.”

That’s where the human Initiator comes in.

First observed by Pierre Chambon and his colleagues in Strasbourg, France in 1980, the human Initiator and its role in gene activation were articulated in 1989 by two MIT biologists, Stephen Smale and David Baltimore at MIT, who revealed in the 1990s, the approximate sequence code of the Initiator.

Since then, however, other scientists had proposed a number of different sequences for the human Initiator, but none of them were found to be consistently associated with the start sites of human genes. As a result, the true Initiator sequence code remained a mystery until now.

Kadonaga and his team employed emerging genomic techniques and devised novel computational strategies to unlock the DNA sequence code for the human Initiator. They also discovered that this sequence is located precisely at the start site of more than half of all human genes, underlining the importance of the human Initiator in the human genome.


Story Source:

Materials provided by University of California – San Diego. Original written by Kim McDonald. Note: Content may be edited for style and length.


Journal Reference:

  1. Long Vo ngoc, California Jack Cassidy, Cassidy Yunjing Huang, Sascha H.C. Duttke, James T. Kadonaga. The human initiator is a distinct and abundant element that is precisely positioned in focused core promoters. Genes & Development, 2017; DOI: 10.1101/gad.293837.116

 

Source: University of California – San Diego. “Biologists unlock code regulating most human genes.” ScienceDaily. ScienceDaily, 24 January 2017. <www.sciencedaily.com/releases/2017/01/170124140749.htm>.

Date:
January 23, 2017

Source:
BMJ

Summary:
The world remains ‘grossly underprepared’ for outbreaks of infectious disease, which are likely to become more frequent in the coming decades, warn a team of international experts.

 

Virus and bacteria cells (stock image).
Credit: © Jezper / Fotolia

 

 

The world remains “grossly underprepared” for outbreaks of infectious disease, which are likely to become more frequent in the coming decades, warn a team of international experts in The BMJ.

They reviewed reports on the recent Ebola virus outbreak in West Africa and say better preparedness and a faster, more coordinated response could have prevented most of the 11,000 deaths directly attributed to Ebola and also the broader economic, social, and health crises that ensued.

In August 2014, the World Health Organization (WHO) declared the Ebola outbreak in West Africa a Public Health Emergency of International Concern (PHEIC), and the world scrambled to respond.

In the aftermath, a number of reports were published reviewing what went wrong and how we should better manage infectious disease outbreaks. However, the main priorities emerging from these reports and the extent to which action has been taken on the proposed reforms is unclear.

So a research team, led by Suerie Moon at the Graduate Institute of International and Development Studies in Geneva, synthesized seven major post-Ebola reports and laid out the key problems and recommendations they highlighted.

They also assessed progress to date and identified the biggest gaps between recommendations and action in each area of reform.

They found that, while the reports differed in scope and emphasis, their diagnosis of the key problems and recommendations for action converged in three critical areas: strengthening compliance with the International Health Regulations (IHR); improving outbreak-related research and knowledge sharing; and reforming the World Health Organization (WHO) and broader humanitarian response system.

They found significant efforts beginning to address these issues, but that progress has been mixed with many critical issues largely unaddressed.

For example, they point out that investments in country capacity building have been inadequate and difficult to track, arrangements for fair and timely sharing of patient samples remain weak, and reform efforts at WHO have focused on operational issues but have neglected to address deeper institutional shortcomings.

As the WHO Executive Board gathers this week to shortlist candidates in the running for the 2017 WHO Director-General election, the authors point out that “spearheading institutional reforms is likely to fall to the next director general.”

“We found remarkable consensus on what went wrong with the Ebola response and what we need to do to address the deficiencies. Yet not nearly enough has been done,” write the authors.

“Ebola, and more recently Zika and yellow fever, have demonstrated that we do not yet have a reliable or robust global system for preventing, detecting, and responding to disease outbreaks,” they add.

And they urge the global community “to mobilize greater resources and put in place monitoring and accountability mechanisms to ensure we are better prepared for the next pandemic.”

“We will not be ready for the next outbreak without deeper and more comprehensive change,” they conclude.


Story Source:

Materials provided by BMJ. Note: Content may be edited for style and length.


Journal Reference:

  1. Suerie Moon, Jennifer Leigh, Liana Woskie, Francesco Checchi, Victor Dzau, Mosoka Fallah, Gabrielle Fitzgerald, Laurie Garrett, Lawrence Gostin, David L Heymann, Rebecca Katz, Ilona Kickbusch, J Stephen Morrison, Peter Piot, Peter Sands, Devi Sridhar, Ashish K Jha. Post-Ebola reforms: ample analysis, inadequate action. BMJ, 2017; j280 DOI: 10.1136/bmj.j280

 

Source: BMJ. “World still ‘grossly underprepared’ for infectious disease outbreaks.” ScienceDaily. ScienceDaily, 23 January 2017. <www.sciencedaily.com/releases/2017/01/170123125527.htm>.

Ongoing and Completed eSource Programs at Target Health and ICH E6(R2)

 

Target e*CTR® (eClinical Trial Record) is Target Health’s patented eSource solution fully integrated with Target e*CRF®. A de novo 510(k) was cleared in December 2015 that used direct data entry at the time of the office visit, and an NDA was submitted to FDA with 7 studies which all used Target e*CTR. There were no FDA inspection findings in any of these programs. Ongoing studies include a large pivotal trial in Autism, a phase 2 study in dermatology and a device study. A new study in psychiatry will start in Q2 2017 as well as several other programs. Recently, a phase 2 study in neurology was completed with 900 subjects at 40 clinical sites.  Completed programs include ADHD, urology, and phase 1 studies.

 

As part of the ICH E6(R2), sections were modified to address electronic records and associated roles and responsibilities. Target Health Inc. congratulates our colleagues at ICH who clarified the acceptance of electronic records as original records in lieu of a requirement to have paper source records.

 

The following are some highlights of the revisions as they relate to electronic records. Also refer to a paper recently authored by Mitchel and Helfgott, published on 4 January 2017 in Applied Clinical Trials entitled, “Regulatory Considerations when Designing and Running 21st Century Paperless Clinical Trials

 

 

Glossary: Certified Copy

A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure, as the original. (section 1.6.3)

 

Section 5. Sponsor

Record Access: The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection. (Section 5.15.1)

 

6.4 Trial Design

The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design, should include: The identification of any data to be recorded directly on the CRFs (i.e., no prior written or electronic record of data), and to be considered to be source data. (section 6.4.9)

 

8. Essential Documents for the Conduct of a Clinical Trial (Addendum)

 

The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document identification, version history, search, and retrieval.

 

The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not have exclusive control of those data.

 

When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the requirements for certified copies.

 

The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

QUIZ

Filed Under News | Leave a Comment

Birth Control

A package of birth control pills Source: Wikipedia Commons

 

 

Birth control, also known as contraception and fertility control, is a method or device used to prevent 1) ___. Birth control has been used since ancient times, but effective and safe methods of birth control only became available in the 20th century. Planning, making available, and using birth control is called family planning. Some cultures limit or discourage access to birth control because they consider it to be morally, religiously, or politically undesirable.

 

The most effective methods of birth control are sterilization by means of vasectomy in 2) ___ and tubal ligation in females, intrauterine devices (IUDs), and implantable birth control. This is followed by a number of hormone based methods including oral pills, patches, vaginal rings, and injections. Less effective methods include physical barriers such as condoms, diaphragms and birth control sponges and fertility awareness methods. The least effective methods are spermicides and withdrawal by the male before ejaculation. Sterilization, while highly effective, is not usually reversible; all other methods are reversible, most immediately upon stopping them. Safe practices, such as with the use of male or female condoms, can also help prevent sexually transmitted infections. Other methods of birth control do not protect against ST 3) ___. Emergency 4) ___ control can prevent pregnancy if taken within the 72 to 120 hours after unprotected relations. In teenagers, pregnancies are at greater risk of poor outcomes. Comprehensive education and access to birth control decreases the rate of unwanted pregnancies in this age group. While all forms of birth control can generally be used by young people, long-acting reversible birth control such as implants, IUDs, or rings are more successful in reducing rates of 5) ___ pregnancy.

 

After the delivery of a child, a woman who is not exclusively 6) ___ may become pregnant again after as few as four to six weeks. Some methods of birth control can be started immediately following the birth, while others require a delay of up to six months. In women who are breastfeeding, progestin-only methods are preferred over combined oral birth control pills. In women who have reached menopause, it is recommended that birth control be continued for one year after the last period.

 

About 222 million women who want to avoid pregnancy in developing countries are not using a modern birth control method. Birth control use in developing countries has decreased the number of 7) ___ during or around the time of pregnancy by 40% (about 270,000 deaths prevented in 2008) and could prevent 70% if the full demand for birth control were met. By lengthening the time between pregnancies, birth control can improve adult women’s delivery outcomes and the survival of their children. In the developing world women’s earnings, assets, weight, and their children’s schooling and health all improve with greater access to birth control. Birth control increases economic growth because of fewer dependent 8) ___, more women participating in the workforce, and less use of scarce resources.

 

ANSWERS: 1) pregnancy; 2) males; 3) diseases; 4) birth; 5) teenage; 6) breastfeeding; 7) deaths; 8) children

 

Ancient Methods of Birth Control

Ancient silver coin from Cyrene depicting a stalk of silphium

Sources: Wikipedia Commons

 

The Egyptian Ebers Papyrus from 1550 BCE and the Kahun Papyrus from 1850 BCE have within them some of the earliest documented descriptions of birth control: the use of honey, acacia leaves and lint to be placed in the vagina to block sperm. It is believed that in Ancient Greece silphium was used as birth control which, due to its effectiveness and thus desirability, was harvested into extinction. In medieval Europe, any effort to halt pregnancy was deemed immoral by the Catholic Church, although it is believed that women of the time still used a number of birth control measures, such as coitus interruptus and inserting lily root and rue into the vagina. Women in the Middle Ages were also encouraged to tie weasel testicles around their thighs during sex to prevent pregnancy. The oldest condoms discovered to date were recovered in the ruins of Dudley Castle in England, and are dated back to 1640. They were made of animal gut, and were most likely used to prevent the spread of sexually transmitted diseases during the English Civil War. Casanova, living in 18th century Italy, described the use of a lambskin covering to prevent pregnancy; however, condoms only became widely available in the 20th century.

 

A CycleBeads, used for estimating fertility based on days since last menstruation. Credit: By Dellex – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5608730

 

 

Birth Control Movement

 

And the villain still pursues her“, a satirical Victorian era postcard. Source: Wikipedia Commons

 

 

The birth control movement developed during the 19th and early 20th centuries. The Malthusian League, based on the ideas of Thomas Malthus, was established in 1877 in the United Kingdom to educate the public about the importance of family planning and to advocate for getting rid of penalties for promoting birth control. It was founded during the “Knowlton trial“ of Annie Besant and Charles Bradlaugh, who were prosecuted for publishing on various methods of birth control. In the United States, Margaret Sanger and Otto Bobsein popularized the phrase “birth control“ in 1914. Sanger was mainly active in the United States but had gained an international reputation by the 1930s. At the time, under the Comstock Law, distribution of birth control information was illegal. She jumped bail in 1914 after her arrest for distributing birth control information and left the United States for the United Kingdom to return in 1915. Sanger established a short-lived birth-control clinic based in the Brownville section of Brooklyn, New York in 1916, which was shut down after eleven days and resulted in her arrest. The publicity surrounding the arrest, trial, and appeal sparked birth control activism across the United States.

 

The first permanent birth-control clinic was established in Britain in 1921 by Marie Stopes working with the Malthusian League. The clinic, run by midwives and supported by visiting doctors, offered women’s birth-control advice and taught them the use of a cervical cap. Her clinic made contraception acceptable during the 1920s by presenting it in scientific terms. In 1921, Sanger founded the American Birth Control League, which later became the Planned Parenthood Federation of America. In 1924 the Society for the Provision of Birth Control Clinics was founded to campaign for municipal clinics; this led to the opening of a second clinic in Greengate, Salford in 1926. Throughout the 1920s, Stopes and other feminist pioneers, including Dora Russell and Stella Browne, played a major role in breaking down taboos. In April 1930 the Birth Control Conference assembled 700 delegates and was successful in bringing birth control and abortion into the political sphere. Three months later, the Ministry of Health, in the United Kingdom, allowed local authorities to give birth-control advice in welfare centers. In 1936 the U.S. court ruled in U.S. v. One Package that medically prescribing contraception to save a person’s life or well-being was not illegal under the Comstock Law. Following this decision, the American Medical Association Committee on Contraception revoked its 1936 statement condemning birth control. A national survey in 1937 showed 71% of the adult population supported the use of contraception. By 1938 347 birth control clinics were running in the United States despite their advertisement still being illegal. First Lady Eleanor Roosevelt publicly supported birth control and family planning. In 1966, President Lyndon B. Johnson started endorsing public funding for family planning services, and the Federal Government began subsidizing birth control services for low-income families. The Affordable Care Act, passed into law on March 23, 2010 under President Barack Obama, requires all plans in the Health Insurance Marketplace to cover contraceptive methods. These include barrier methods, hormonal methods, implanted devices, emergency contraceptives, and sterilization procedures.

 

In 1909, Richard Richter developed the first intrauterine device made from silkworm gut, which was further developed and marketed in Germany by Ernst Grafenberg in the late 1920s. In 1951, a chemist, named Carl Djerassi from Mexico City made the hormones in progesterone pill using Mexican yams. Djerassi had chemically created the pill but was not equipped to distribute them to patients. Meanwhile, Gregory Pincus and John Rock, with help from the Planned Parenthood Federation of America, developed the first birth control pills in the 1950s, such as mestranol/noretynodrel, which became publicly available in the 1960s in the US under the name Enovid. Medical abortion became an alternative to surgical abortion with the availability of prostaglandin analogs in the 1970s and mifepristone in the 1980s.

 

2017 marks the 57th anniversary of the birth control pill, which many considered to have empowered women and sparked the sexual revolution. However, for centuries, women have had some control over reproduction, although perhaps, not as effective as what’s available today.

 

Records exist of women in ancient Rome and Greece relying on dances and amulets to prevent pregnancy, and we can assume that those practices probably didn’t work.

 

Citric Acid

 

Credit: Wikipedia

 

 

Citric acid is said to have spermicidal properties, and women used to soak sponges in lemon juice before inserting them vaginally. Mentioned in the Talmud, this was a preferred method of birth control in ancient Jewish communities. The sponge itself would act as a pessary, a physical barrier between the sperm and the cervix. The great womanizer Casanova was said to have inserted the rind of half a lemon into his lovers as a primitive cervical cap or diaphragm, the residual lemon juice serving to annihilate the sperm. Lemon- and lime-juice douches following coitus were also recommended as a form of birth control, but this method was likely less effective, since sperm can enter the cervix – and hence out of reach of any douching – within minutes of ejaculation. Incidentally, some alternative medicine practitioners today suggest that megadoses of vitamin C (6 to 10 g a day) could induce an abortion in women under 4 weeks of pregnancy, but there’s no evidence that citrus fruits were used in this way in ancient times.

 

Queen Anne’s Lace

 

Queen Anne’s Lace (most beautiful wild flower). Credit: Wikipedia

 

 

Queen Anne’s Lace is also known as wild carrot, and its seeds have long been used as a contraceptive. Hippocrates described this use over two millennia ago. The seeds block progesterone synthesis, disrupting implantation and are most effective as emergency contraception within eight hours of exposure to sperm, a sort of “morning after“ form of birth control. Taking Queen Anne’s Lace led to no or mild side effects (like a bit of constipation), and women who stopped taking it could conceive and rear a healthy child. The only danger, it seemed, was confusing the plant with similar-looking but potentially deadly poison hemlock and water hemlock.

 

Pennyroyal

 

Pennyroyal Credit: Wikipedia Commons

 

Pennyroyal is a plant in the mint genus and has a fragrance similar to that of spearmint. The ancient Greeks and Romans used it as a cooking herb and a flavoring ingredient in wine. They also drank pennyroyal tea to induce menstruation and abortion. 1st-century physician Dioscorides records this use of pennyroyal in his massive five-volume encyclopedia on herbal medicine. Too much of the tea could be highly toxic, however, leading to multiple organ failure.

 

Blue Cohosh

 

Blue cohosh found on the grounds of the University of Michigan.

Credit: Wikipedia Commons

 

Blue cohosh, traditionally used for birth control by Native Americans. It contains at least two abortifacient substances: one mimics oxytocin, a hormone produced during childbirth that stimulates the uterus to contract, and a substance unique to blue cohosh, caulosaponin, also results in uterine contractions. Midwives today may use blue cohosh in the last month of pregnancy to tone the uterus in preparation for labor. The completely unrelated but similarly named black cohosh also has estrogenic and abortifacient properties and was often combined with blue cohosh to terminate a pregnancy.

 

Dong Quai or Chinese Angelica

 

Dong quai, also known as Chinese angelica, has long been known for its powerful effects on a woman’s cycle. Women drank a tonic brewed with dong quai roots to help regulate irregular menstruation, alleviate menstrual cramps and help the body regenerate after menstruation. Taken during early pregnancy, however, dong quai had the effect of causing uterine contractions and inducing abortion. European and American species of angelica have similar properties but were not as widely used.

 

Common Rue

 

The Tacuinum Sanitatis, a medieval handbook on wellness, lists the following 5 properties of rue:

  • Nature: Warm and dry in the third degree.
  • Optimum: That which is grown near a fig tree.
  • Usefulness: It sharpens the eyesight and dissipates flatulence.
  • Dangers: It augments the sperm and dampens the desire for coitus.
  • Neutralization of the Dangers: With foods that multiply the sperm.

 

The refined oil of rue is an emmenagogue and was cited by the Roman historian Pliny the Elder and the gynecologist Soranus as a potent abortifacient (inducing abortion). Rue, a blue-green herb with feathery leaves, is also grown as an ornamental plant and is favored by gardeners for its hardiness. It is rather bitter but can be used in small amounts as a flavoring ingredient in cooking. Soranus, a gynecologist from 2nd-century Greece, described its use as a potent abortifacient, and women in Latin America have traditionally eaten rue in salads as a contraceptive and drunk rue tea as emergency contraception or to induce abortion. Ingested regularly, rue decreases blood flow to the endometrium, essentially making the lining of the uterus non-nutritive to a fertilized egg.

 

Cotton

 

Cotton Shrub; Credit: Wikipedia Commons

 

The earliest evidence of cotton use has been found at sites where cotton threads were preserved in copper beads; these finds have been dated to Neolithic (between 6000 and 5000 BCE). Cotton cultivation in the region is dated to the Indus Valley Civilization.In the ancient medical manuscript the Ebers Papyrus (1550 BCE), women were advised to grind dates, acacia tree bark, and honey together into a paste, apply this mixture to seed wool, and insert the seed wool vaginally for use as a pessary. Granted, it was what was in the cotton rather than the cotton itself that promoted its effectiveness as birth control – acacia ferments into lactic acid, a well-known spermicide – but the seed wool did serve as a physical barrier between ejaculate and cervix. Interestingly, though, women during the times of American slavery would chew on the bark of cotton root to prevent pregnancy. Cotton root bark contains substances that interfere with the corpus luteum, which is the hole left in the ovary when ovulation occurs. The corpus luteum secretes progesterone to prepare the uterus for implantation of a fertilized egg. By impeding the corpus luteum’s actions, cotton root bark halts progesterone production, without which a pregnancy can’t continue.

 

 

Papaya

 

Papaya tree and fruit, from Koehler’s Medicinal-Plants (1887). Source: Wikipedia Commons

 

 

In South Asia and Southeast Asia, unripe papaya was used to prevent or terminate pregnancy. Once papaya is ripe, though, it loses the phytochemicals that interfere with progesterone and thus its contraceptive and abortifacient properties. The seeds of the papaya could actually serve as an effective male contraceptive. Papaya seeds, taken daily, could cut a man’s sperm count to zero and was safe for long-term use. Best of all, the sterility was reversible: if the man stopped taking the seeds, his sperm count would return to normal.

 

Silphium

 

Silphium on ancient Banner. Source: Italian Wikipedia, Wikipedia Commons

 

 

Silphium was a member of the fennel family that grew on the shores of Cyrenaica (in present-day Libya). It was so important to the Cyrenean economy that it graced that ancient city’s coins. Silphium had a host of uses in cooking and in medicine, and Pliny the Elder recorded the herb’s use as a contraceptive. It was reportedly effective for contraception when taken once a month as a tincture. It could also be used as emergency birth control, either orally or vaginally, as an abortifacient. By the second century CE, the plant had gone extinct, likely because of over harvesting.

 

Mercury

 

Credit: Wikipedia Commons

 

Civilizations the world over, from the ancient Assyrians and Egyptians to the Greeks, were fascinated by mercury and were convinced that it had medicinal value and special curative properties, using it to treat everything from skin rashes to syphilis. In ancient China, women were advised to drink hot mercury to prevent pregnancy. It was effective at convincing a woman’s body that she wasn’t fit to carry a child, leading to miscarriage, so, it did work as a contraceptive. However, mercury is enormously toxic, causing kidney and lung failure, as well as brain damage and death. Sources: Iva Cheung; Wikipedia

 

Gene Complex Linked To Premenstrual Mood Disorder

 

By the late 1990s, investigators at the NIMH demonstrated that women who regularly experience mood disorder symptoms just prior to their periods were abnormally sensitive to normal changes in sex hormones, even though their hormone levels were normal. But the cause remained a mystery. Subsequently it was found that in women with PMDD, experimentally turning off estrogen and progesterone eliminated PMDD symptoms, while experimentally adding back the hormones that triggered the re-emergence of symptoms. This confirmed that there was a biologically-based behavioral sensitivity to the hormones that might be reflected in cellular molecular differences.

 

According to an article in the journal Molecular Psychiatry (3 January 2017), molecular mechanisms have now been discovered that may underlie a woman’s susceptibility to disabling irritability, sadness, and anxiety in the days leading up to her menstrual period. Such premenstrual dysphoric disorder (PMDD) affects 2 to 5% of women of reproductive age, whereas less severe premenstrual syndrome (PMS) is much more common. The authors stated that this dysregulated expression in a suspect gene complex adds to evidence that PMDD is a disorder of cellular response to estrogen and progesterone, and that learning more about the role of this gene complex holds hope for improved treatment of such prevalent reproductive endocrine-related mood disorders.

 

Following up on clues — including the fact that PMS is 56% heritable — the authors studied the genetic control of gene expression in cultured white blood cell lines from women with PMDD and controls. These cells express many of the same genes expressed in brain cells — potentially providing a window into genetically-influenced differences in molecular responses to sex hormones. An analysis of all gene transcription in the cultured cell lines turned up a large gene complex in which gene expression differed conspicuously in cells from patients compared to controls. The gene complex, identified as ESC/E(Z) (Extra Sex Combs/Enhancer of Zeste) gene complex, regulates epigenetic mechanisms that govern the transcription of genes into proteins in response to the environment — including sex hormones and stressors. Results showed that more than half of the ESC/E(Z) genes were over-expressed in PMDD patients’ cells, compared to cells from controls. But paradoxically, protein expression of four key genes was decreased in cells from women with PMDD. In addition, progesterone boosted expression of several of these genes in controls, while estrogen decreased expression in cell lines derived from PMDD patients. This suggested dysregulated cellular response to the hormones in PMDD. According to the authors, for the first time, there is now cellular evidence of abnormal signaling in cells derived from women with PMDD, and there is now a plausible biological cause for their abnormal behavioral sensitivity to estrogen and progesterone. Going forward, using cutting edge “disease in a dish“ technologies, the authors are now following up the leads discovered in blood cell lines in neurons induced from stem cells derived from the blood of PMDD patients in the hopes of gaining a more direct window into the ESC/E(Z) complex’s role in the brain.

 

Transmission of Extensively Drug-Resistant Tuberculosis in South Africa

 

Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions.

 

As a result, a prospective study, published in the New England Journal of Medicine (2017; 376:243-253), was performed involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. For the study, interviews and medical-record reviews were used to elicit information on the participants’ history of tuberculosis and HIV infection, hospitalizations, and social networks. In addition, Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment-length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. Clinical and genotypic case definitions were used to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). In addition, social-network analysis was used to identify community and hospital locations of transmission.

 

Results showed that of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%).

 

According to the authors, the majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission.

 

FDA Approves Trulance for Chronic Idiopathic Constipation

 

According to the National Institutes of Health, an estimated 42 million people are affected by constipation. Chronic Idiopathic Constipation (CIC) is a diagnosis given to those who experience persistent constipation and for whom there is no structural or biochemical explanation.

 

The FDA has approved Trulance (plecanatide) for the treatment of CIC in adult patients. Trulance, taken orally once daily, works locally in the upper GI tract to stimulate secretion of intestinal fluid and support regular bowel function.

 

The safety and efficacy of Trulance were established in two 12-week, placebo-controlled trials including 1,775 adult participants. Participants were randomly assigned to receive a placebo or Trulance, once daily. Participants in the trials were required to have been diagnosed with constipation at least six months prior to the study onset and to have less than three defecations per week in the previous three months, as well as other symptoms associated with constipation. Participants receiving Trulance were more likely to experience improvement in the frequency of complete spontaneous bowel movements than those receiving placebo, and also had improvements in stool frequency and consistency and straining.

 

Trulance should not be used in children less than six years of age due to the risk of serious dehydration and should be avoided in patients six years of age to 18 years of age. The safety and effectiveness of Trulance have not been established in patients less than 18 years of age and Trulance should not be used in patients with known or suspected mechanical gastrointestinal obstruction. The most common and serious side effects of Trulance was diarrhea. Patients may experience severe diarrhea. If severe diarrhea occurs, patients should stop taking Trulance and contact their health care provider.

 

Trulance is manufactured by New York, New York-based Synergy Pharmaceuticals Inc.

 

Warm Curry Cauliflower Salad with Avocado-Cilantro-Lime Dressing

It’s not every day that we rave about a salad; however, this warm curry creation is worth trying. It’s extremely easy to make, so no time wasted. Marinating overnight, does a lot of the work for you. Give it a try; you won’t be disappointed. Add some warm bread and/or rolls, a chilled glass of wine and enjoy with whomever you share this salad. One evening, along with this warm salad, and chilled wine, we had hummus and a new kind of sourdough flat cracker (11 calories each). We were satisfied and happy.  Oh, and Happy New Year everybody! ©Joyce Hays, Target Health Inc.

 

Ingredients

 

1 large cauliflower head, washed, dried, chopped into bite size pieces

1 fresh lime, juiced

Zest of 1 lime

10 fresh garlic cloves, sliced

1 cup cilantro, finely chopped

1 teaspoon curry (more if you want spicier)

Pinch salt

Pinch black pepper

Pinch chili flakes

1 cup cheddar cheese, grated

2 avocados, diced

2 stalks scallions, chopped up to half the white section. Save some for garnish

 

Just the right herbs and spices, not many, and amazingly?. You have a tasty warm salad to start your meal, or fine alone for lunch or low calorie dinner. Warm crunchy bread or rolls dipped in extra virgin olive oil, a chilled white wine and you’re all set. Joyce Hays, Target Health Inc.

 

Directions

 

1. Preheat oven to 425 degrees.

2. Get all your chopping, squeezing, cutting, slicing done, except for the avocados. Cut them the next day, just before serving the warm salad.

 

Chopping cilantro, scallions, and slicing garlic on same board and at same time. ©Joyce Hays, Target Health Inc.

 

 

3. In a large mixing bowl, add cauliflower, lime juice, lime zest, garlic, cilantro, cumin, chili flakes, salt and pepper and 1 chopped scallion. Mix to combine, cover and let it marinate overnight.

 

Getting ready to cover the cauliflower with marinade overnight. ©Joyce Hays, Target Health Inc.

 

 

4. Transfer cauliflower into a very lightly oiled (extra virgin olive oil) baking dish, (or no oil at all) using a slotted spoon. Keep as much of the marinade in the bowl (the garlic and cilantro, etc.) as you can.

 

Cauliflower, having marinated overnight, has been transferred into a baking dish. Naturally, some of the herbs and spices are sticking, but most remain in the bowl. ©Joyce Hays, Target Health Inc.

 

Cauliflower is going into oven (first without the cheese) to bake for 15 minutes. ©Joyce Hays, Target Health Inc.

 

 

5. Bake the cauliflower for 15 minutes. Remove from the oven. Add the grated cheddar cheese stir with cauliflower and bake for another 5 minutes or until the cheese has melted.

 

After baking for 15 minutes, baking dish removed, grated cheddar cheese added and stirred a bit; dish goes back into oven until cheese melts. ©Joyce Hays, Target Health Inc.

 

 

6. While cauliflower is baking, check the bowl and taste any marinade that’s left, to determine if you want to add something more. Consider adding a little more fresh lime juice or more curry, pepper, or chili flakes, etc.

7. When cheese has melted, remove baking dish.

 

Here’s what the cauliflower looks like after the cheese has melted. Set aside while you finalize the dressing. ©Joyce Hays, Target Health Inc.

 

 

8. Now, to the bowl with dressing, add a little more well chopped cilantro. Cut into cubes the two ripe avocados and add to bowl. Stir the dressing well, so that all ingredients are well combined.

9. To the baking dish with warm cauliflower, scrape all of the dressing out of the bowl and over the cauliflower. Toss everything together. Garnish with extra chopped scallion. Serve warm immediately.

 

Cheese melted, baking dish out of oven. Here the dressing with added avocados, has been added to the warm cauliflower. Next, the salad will be tossed and served. ©Joyce Hays, Target Health Inc.

 

Tossed, ready to serve; filling the room with a soft yet spicy scent. ©Joyce Hays, Target Health Inc.

 

Salad for two. By now, we really love it. This is the fourth time this week, we’ve had this particular warm salad. Each time a slight tweak, and each time it got better and better. The trick seemed to be to get the right balance of lime juice and curry. ©Joyce Hays, Target Health Inc.

 

Warm, healthy and delicious! ©Joyce Hays, Target Health Inc.

 

This was the perfect chilled wine, that we sipped with our warm cauliflower salad.

Let us know if you tried it. ©Joyce Hays, Target Health Inc.

 

 

From Our Table to Yors !

 

Bon Appetit!

 

Scientists provide first evidence that carbamates can upset circadian rhythms

Date:
January 19, 2017

Source:
University at Buffalo

Summary:
Synthetic chemicals commonly found in insecticides and garden products bind to the receptors that govern our biological clocks researchers have found.

 

This computer-generated image demonstrates how melatonin (in yellow) and carbaryl, (in light turquoise), a commonly used insecticide, bind directly to the same binding region on the human melatonin receptor.
Credit: Raj Rajnarayanan, UB

 

 

Synthetic chemicals commonly found in insecticides and garden products bind to the receptors that govern our biological clocks, University at Buffalo researchers have found. The research suggests that exposure to these insecticides adversely affects melatonin receptor signaling, creating a higher risk for metabolic diseases such as diabetes.

Published online on Dec. 27 in Chemical Research in Toxicology, the research combined a big data approach, using computer modeling on millions of chemicals, with standard wet-laboratory experiments. It was funded by a grant from the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

Disruptions in human circadian rhythms are known to put people at higher risk for diabetes and other metabolic diseases but the mechanism involved is not well-understood.

“This is the first report demonstrating how environmental chemicals found in household products interact with human melatonin receptors,” said Margarita L. Dubocovich, PhD, senior author on the paper and SUNY Distinguished Professor in the Department of Pharmacology and Toxicology and senior associate dean for diversity and inclusion in the Jacobs School of Medicine and Biomedical Sciences at UB.

“No one was thinking that the melatonin system was affected by these compounds, but that’s what our research shows,” she said.

The current research focuses on two chemicals, carbaryl, the third most widely used insecticide in the U.S. but which is illegal in several countries, and carbofuran, the most toxic carbamate insecticide, which has been banned for applications on food crops for human consumption since 2009. It is still used in many countries, including Mexico and traces persist in food, plants and wildlife.

“We found that both insecticides are structurally similar to melatonin and that both showed affinity for the melatonin, MT2 receptors, that can potentially affect glucose homeostasis and insulin secretion,” said Marina Popevska-Gorevski, co-author, now a scientist with Boehringer Ingelheim Pharmaceuticals, who worked in Dubocovich’s lab while earning her master’s degree at UB. “That means that exposure to them could put people at higher risk for diabetes and also affect sleeping patterns.”

The results suggest that there is a need to assess environmental chemicals for their ability to disrupt circadian activity, something which is not currently being considered by federal regulators. The UB researchers are developing a rapid bioassay that might be able to assess environmental chemicals for this kind of activity.

The work is part of a larger effort by Dubocovich and her colleagues at UB to develop their Chem2Risk pipeline, combining UB’s expertise in computational biology and melatonin receptor pharmacology.

“Our approach seamlessly integrates the screening of environmental chemicals through computer simulation, in vitro and in vivo techniques to gauge the risk these chemicals present for various disease end points,” explained Raj Rajnarayanan, PhD, lead author and assistant professor of pharmacology and toxicology at UB.

The UB database contains about four million chemicals reported to have some level of toxicity. “From those, we identified hundreds of thousands of compounds that had readily available chemical structures so that we could study them,” Rajnarayanan explained. After grouping the chemicals in clusters according to their similarity, they found several with functional groups similar to melatonin.

Using predictive computational modeling and in vitro experiments with cells that express human melatonin receptors, they found that carbamates selectively interact with a melatonin receptor. That interaction can disrupt melatonin signaling and alter important regulatory processes in the body.

“By directly interacting with melatonin receptors in the brain and peripheral tissues, environmental chemicals, such as carbaryl, may disrupt key physiological processes leading to misaligned circadian rhythms, sleep patterns, and altered metabolic functions increasing the risk for chronic diseases such as diabetes and metabolic disorders,” said Dubocovich.

For example, she explained, there is a fine balance between the release of insulin and glucose in the pancreas at very specific times of day, but if that balance becomes disrupted over a long period of time, there is a higher risk of developing diabetes.

Dubocovich is an internationally renowned authority on the brain hormone melatonin and how melatonin receptors are regulated. Her work has significantly boosted the scientific understanding of how melatonin impacts circadian rhythms and human health in general, including sleep disorders, metabolic disease and drug addiction.

Popovska-Gorevski presented preliminary findings on this work at the 2014 Experimental Biology meeting in San Diego, receiving a Best Abstract Award from the Toxicology Division of the American Society for Pharmaceutical and Experimental Therapeutics and a Best Poster Award from the Upstate New York Pharmacology Society.


Story Source:

Materials provided by University at Buffalo. Note: Content may be edited for style and length.


Journal Reference:

  1. Marina Popovska-Gorevski, Margarita L. Dubocovich, Rajendram V. Rajnarayanan. Carbamate Insecticides Target Human Melatonin Receptors. Chemical Research in Toxicology, 2017; DOI: 10.1021/acs.chemrestox.6b00301

 

Source: University at Buffalo. “Insecticides mimic melatonin, creating higher risk for diabetes: Scientists provide first evidence that carbamates can upset circadian rhythms.” ScienceDaily. ScienceDaily, 19 January 2017. <www.sciencedaily.com/releases/2017/01/170119120213.htm>.

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