Target Health – Champions of the Paperless Clinical Trial™

 

A good time was had by all at DIA this year. We were able to demo both the current version of Target e*CRF® a one log-in, web based, paperless clinical trial solution built by Target Health Inc., aka, the “Champions of the Paperless Clinical Trial.™

 

Starting with Target e*ICF™ and all the way to patient lock, no need to travel outside the website. Not only does the site use one website for signing of Target e*ICF™, data entry and randomization, but study monitors can create and sign monitoring reports, perform central monitoring, track IMP from depot to the study site, and access standard and RBM reports etc. Medical monitors can perform SAE management including initial and follow-up 3500A and CIOMS reports, And yes, a lot more.

 

In addition to the United States, we now have EMA and Australia marketing approvals for products which used our paperless clinical trial solution, which also includes direct data entry (BYOD) at the time of patient encounter.

 

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. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

To unsubscribe from the On Target mailing list, click on the following link: unsubscribeontarget@targethealth.com.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

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Tears

Anatomy of lacrimation, showing a) Lacrimal gland b) Superior lacrimal punctum c) Superior lacrimal canal d) Lacrimal sac e) Inferior lacrimal punctum f) Inferior lacrimal canal g) Nasolacrimal canal

 

Graphic credit: Erin Silversmith, The labels in Portuguese were replaced with letters, for internationalization purposes. If a version with labels in a certain language is deemed necessary, it should be uploaded with the language suffix i.e. Tear system xx.svg where xx is the language code. User: FML uploaded to Commons as Image: Sistema lacrimal.gif and Image:Sistema lacrimal.svg., CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=1045167

 

 

Tearing, lacrimation, or lachrymation (from Latin lacrima, meaning ?tear’) is the secretion of tears, which often serves to clean and lubricate the 1) ___ in response to an irritation of the eyes. Tears formed through crying are associated with strong internal emotions, such as sorrow, elation, love, awe, and pleasure. Laughing or yawning may also lead to the production of tears. In humans, the tear film coating the eye, known as the precorneal film, has three distinct layers, from the most outer surface:

 

Lipid layer: Oils from the Meibomian glands (or tarsal glands) coats the aqueous layer, provides a hydrophobic barrier that envelops tears and prevents their spilling onto the cheek. These glands are found among the tarsal plates. Thus, the tear fluid deposits between the eye proper and oil barriers of the lids.

Aqueous layer: Electrolytes, 60 metabolites including amino 2) ___, purines and derivatives, quaternary amines (acetylcholine, glycerolphosphocholine, phosphocholine), and tricarboxylic acids (citric acid)-and other substances such as proteins (e.g., antibodies, lipocalin, lactoferrin, lysozyme, and lacritin)      The lacrimal gland promotes spreading of the tear film, the control of infectious agents and osmotic regulation.

Mucous layer: Mucins from the conjunctival goblet cells coat the cornea, provides a hydrophilic layer and allows for even distribution of the tear film.

 

Having a thin tear film may prevent one’s ability to wear contact lenses, as the amount of oxygen needed is higher than normal, and contact lenses stop oxygen from entering the eye. Eyes with thin tear film will dry out while wearing contact lenses. Special eye drops are available for contact lens wearers. Certain types of contact 3) ___ are designed to let more oxygen through to the eye.

 

The lacrimal glands secrete lacrimal fluid, which flows through the main excretory ducts into the space between the eyeball and lids. When the eyes blink, the lacrimal fluid is spread across the surface of the eye. Lacrimal fluid gathers in the lacrimal lake, and is drawn into the puncta by capillary action, then flows through the lacrimal canaliculi at the inner corner of the eyelids entering the lacrimal sac, then on to the nasolacrimal duct, and finally into the nasal cavity. An excess of tears, as with strong emotion, can thus cause the 4) ___ to run.

 

There are three very basic types of tears:

 

Basal tears: In healthy mammalian eyes, the cornea is continually kept wet and nourished by basal tears. They lubricate the eye and help to keep it clear of dust. Tear fluid contains water, mucin, lipids, lysozyme, lactoferrin, lipocalin, lacritin, immunoglobulins, glucose, urea, sodium, and potassium. Some of the substances in lacrimal fluid (such as lysozyme) fight against bacterial infection as a part of the immune system. Lysozyme does this by dissolving a layer in the outer coating, called peptidoglycan, of certain bacteria. It is a typical body fluid with a salt content similar to blood plasma. Usually, in a 24-hour period, 0.75 to 1.1 grams of tears are secreted; this rate slows with 5) ___. In addition, the basal tears are composed of antioxidants such as ascorbate, urate, cysteine, glutathione, and tyrosine. Ascorbate and urate constitute half of the tears.

 

Reflex tears: The second type of tears results from irritation of the eye by foreign particles, or from the presence of irritant substances such as onion vapors, perfumes and other fragrances, tear gas, or pepper spray in the eye’s environment, including the cornea, conjunctiva, or nasal mucosa, which trigger TRP channels in the ophthalmic nerve. It can also occur with bright light and hot or peppery stimuli to the tongue and mouth. It is also linked with vomiting, coughing and yawning. These reflex tears attempt to wash out irritants that may have come into contact with the eye.

 

Psychic tears: Crying or weeping (psychic tears) are the 3rd category. In general, these tears are referred to as crying or weeping, is increased tearing due to strong emotional stress, pleasure, anger, suffering, mourning, or physical pain.

 

Tears are not restricted to negative emotions, as many people cry when extremely happy such as during times of intense humor and laughter. In humans, emotional tears can be accompanied by reddening of the face and sobbing – cough-like, convulsive breathing, sometimes involving spasms of the whole upper body. Tears brought about by emotions have a different chemical make-up than those for lubrication; emotional tears contain more of the protein-based hormones prolactin, adrenocorticotropic hormone, and Leu-enkephalin (a natural painkiller) than basal or reflex tears. The limbic system is involved in production of basic emotional drives, such as anger, fear, etc. The limbic system, to be specific, the hypothalamus, also has a degree of control over the autonomic system. The parasympathetic branch of the autonomic nervous 6) ___ controls the lacrimal glands via the neurotransmitter acetylcholine through both the nicotinic and muscarinic receptors. When these receptors are activated, the lacrimal gland is stimulated to produce tears.

 

The trigeminal V1 (fifth cranial) nerve bears the sensory pathway of the tear reflexes. When the trigeminal nerve is cut, tears from reflexes will stop, but not emotional tears. Likewise, application of cocaine to the surface of the eye, due to its paralyzing effect on the sensory nerve endings, inhibits the reflex even under exposure to strong tear gases. The motor pathway is autonomic (involuntary), and, in general, uses the pathway of the facial (seventh) nerve in the parasympathetic division. In parasympathetic imitators (such as acetylcholine), more tears are produced, and an anticholinergic drug like atropine inhibits tear production. A newborn infant has insufficient development of nervous control, so the baby “cries without weeping.“ If the lacrimal gland malfunctions or is damaged (e.g. by surgery) but does not cause any severe drying of the cornea, it is not a serious matter, for the accessory glands are enough for general secretion. In reflex situations, copious tears are produced mainly in emergencies.

 

“Crocodile tears syndrome“, also known as Bogorad’s syndrome, is an uncommon consequence of nerve regeneration subsequent to Bell’s palsy or other damage to the facial nerve in which efferent fibers from the superior salivary nucleus become improperly connected to nerve axons projecting to the lacrimal glands, causing one to shed tears (lacrimate) during salivation while smelling foods or eating. It is presumed that one would also salivate while crying due to the inverse improper connection of the lacrimal nucleus to the salivary glands, but this would be less noticeable.

 

Keratoconjunctivitis sicca, known as dry eye, is a very common disorder of the tear film. However, sufferers can experience watering of the eyes, which is in fact a response to irritation caused by the original tear film deficiency. Lack of Meibomian gland secretion can mean the tears are not enveloped in a hydrophobic film coat, leading to tears spilling onto the face.

 

Familial dysautonomia is a genetic condition that can be associated with a lack of overflow tears (alacrima) during emotional crying.

 

Obstruction of the punctum, nasolacrimal canal, or nasolacrimal duct can cause even normal levels of basal tear to overflow onto the face (epiphora), giving the appearance of constant psychic tearing. This can have significant social consequences.

 

In nearly all cultures, crying is associated with tears trickling down the cheeks and accompanied by characteristic sobbing sounds. Emotional triggers are most often sadness and grief; but crying can also be triggered by anger, happiness, fear, laughter or humor, frustration, remorse, or other strong, intense emotions. In many cultures, crying is associated with babies and children. Some cultures consider crying to be undignified and infantile, casting aspersions on those who cry publicly, except if it is due to the 7) ___ of a close friend or relative. In most cultures, it is more socially acceptable for women and children to cry than men. In some Latin regions, crying among men is acceptable. Some modern therapy movements such as Re-evaluation Counseling teach that crying is beneficial to health and mental well-being, encouraging it positively. An insincere display of grief or dishonest remorse is sometimes called crocodile tears in reference to an Ancient Greek anecdote that crocodiles would pretend to weep while luring or devouring their prey. In addition, in medical terms, someone is said to have crocodile tears syndrome as an uncommon consequence of recovery from Bell’s palsy, in which faulty regeneration of the facial nerve causes sufferers to shed tears while eating.

 

On a study conducted by the Weizmann Institute of Science in Rehovot, Israel, emotional tears from women have been found to reduce sexual arousal in men. Also, emotional tears are made up of a different chemical component than those evoked by eye irritants and can relay chemical messages to others. The change in sex drive could be attributed to a drop in testosterone provoked by the tear chemicals, reducing aggression. In the animal world, it has been found that some blind mole rats rub tears all over their bodies as a strategy to keep aggressive mole rats away.  Emotional tears are composed of more protein-based hormones, such as prolactin, adrenocorticotropic, and leucine enkephalin (a natural pain killer), which is suggested to be the mechanism behind the experience of crying from emotion making an individual feel better. Emotional tears, unlike basal or reflex tears, contain stress 8) ___, which the body is able to physically push out through the process of crying. Crying triggers the body to release feel-good endorphins (the same ones you get from exercise or laughing.

 

Crying and Survival

 

The parent-infant bond is central to the human condition, contributes to risks for mood and anxiety disorders, and provides the potential for resiliency and protection against the development of psychopathology. Animal models of parenting provide compelling evidence that biological mechanisms may be studied in humans. This has led to brain imaging and endocrine system studies of human parents using baby stimuli (crying) and concerted psychological and behavioral measures. Certain brain circuits and related hormonal systems, including subcortical regions for motivation (striatum, amygdala, hypothalamus and hippocampus) and cortical regions for social cognition (anterior cingulate, insula, medial frontal and orbitofrontal cortices), appear to be involved. These 9) ___ circuits work with a range of endocrine systems to manage stress and motivate appropriate parental caring behavior with a flexibility appropriate to the environment. Work in this field links evolving models of parental brain performance with resilience, risk and treatment toward mother-infant mental health. Parenting is critical for an infant’s survival and development across mammalian species. Despite increased levels of stress as a result of physiological, emotional and economical demands (crying) from the baby, parents typically find themselves highly motivated to take care of their infants’ needs and also find the interactions with infants rewarding. Recent human and animal brain research has used infant (crying) stimuli to examine psychological and biological aspects of maternal motivations and behaviors. Using the example of selected maternal brain and endocrine responses to the hunger cry of an infant, it has been discovered that the modulatory roles of dopamine (DA), oxytocin (OT), cortisol (CORT) and endogenous opioids (EO), all play an important role. A baby’s cry triggers the 10) ___ (stress) levels (other hormonal levels are involved, as well) of the parents, which in turn, motivates them to do what they can to calm and satisfy a baby needs.

 

Keep in mind that our bodies aim for biobehavioral parental and infant responses that will modulate a neuroendocrine homeostasis.

 

Sources: nih.govpubmed.gov; Wikipedia

 

Fig. 1: Graphic credit: Object name is NIHMS-659808-f0001.jpg

 

An integrated neuroendocrine model of parenting. From Figure 1 above, left to right in time, the baby stimulus, behavioral response, brain activity and associated hormonal shifts of dopamine, endogenous opioids. No strict timeline for events is given. During baby-cry, dopamine may be the first to rise to assist with arousal, motivation and decision-making circuits, including striatum and amygdala. Oxytocin also rises relatively quickly with hypothalamus brain activity to support milk let-down and promote parenting behaviors. Cortisol (CORT) increases with a slower time course to support stress responses and prepare the mother for demanding behavior depending on the reason for baby-cry and other circumstances. Assuming a simple hunger cry, CORT will start to drop first, with oxytocin next after it has performed lactation-supporting anxiety-reducing functions. Finally, the parent-infant interaction requires regulatory cortical regions of anterior cingulate, medial frontal and orbitofrontal cortices that are modulated by opioids to mediate satisfaction and reinforce caring behavior. This may be paired with a proposed second rise in dopamine to mediate reinforcement, learning and any extended play or other dyadic interactions. Abnormalities in these neuroendocrine systems, such as in mood, anxiety or substance abuse disorders, contribute to the impaired orchestration of these parental neuroendocrine systems. DA, dopamine; EO, endogenous opioids; mPFC, medial prefrontal cortex; OFC, orbitofrontal cortex; OT, oxytocin.

 

ANSWERS: 1) eyes; 2) Acids; 3) lenses; 4) nose; 5) age; 6) system; 7) death; 8) hormones; 9) brain; 10) cortisol

 

Tears

The Crying Boy, by Italian painter, Giovanni Bragolin

Source: Fair use, https://en.wikipedia.org/w/index.php?curid=53447130

 

The original Angel of Grief in Rome, a 1894 sculpture by William Wetmore Story which serves as the grave stone of the artist and his wife Emelyn at the Protestant Cemetery, Rome. Photo credit: LuciusCommons, Public domain. I, the copyright holder of this work, release this work into the public domain. This applies worldwide. I grant anyone the right to use this work for any purpose, without any conditions, unless such conditions are required by law.

 

Angel of Grief or the Weeping Angel is an 1894 sculpture by William Wetmore Story for the grave of his wife Emelyn Story at the Protestant Cemetery in Rome. Its full title bestowed by the creator was The Angel of Grief Weeping Over the Dismantled Altar of Life. This was Story’s last major work prior to his death, which happened one year after his wife. The statue’s creation was documented in an 1896 issue of Cosmopolitan Magazine: according to this account, his wife’s death so devastated Story that he lost interest in sculpture but was inspired to create the monument by his children, who recommended it as a means of memorializing the woman. Unlike the typical angelic grave art, “this dramatic life-size winged figure speaks more of the pain of those left behind“ by appearing “collapsed, weeping and draped over the tomb.“ The term is now used to describe multiple grave stones throughout the world erected in the style of the Story stone. A feature in The Guardian called the design “one of the most copied images in the world“. Story himself wrote that “It represents the angel of Grief, in utter abandonment, throwing herself with drooping wings and hidden face over a funeral altar. It represents what I feel. It represents Prostration. Yet to do it helps me.“

 

Humans are the only living creature that weeps.

In Hippocratic and medieval medicine, tears were associated with the bodily humors, and crying was seen as purgation of excess humors from the brain. William James thought of emotions as reflexes prior to rational thought, believing that the physiological response, as if to stress or irritation, is a precondition to cognitively becoming aware of emotions such as fear or anger. This connection between weeping and excretion was common in Europe in 1586, when the English clergyman and physician Timothie Bright wrote an influential Treatise of Melancholie, whose many readers probably included Shakespeare, which described tears as a ?kinde of excrement not much unlike’ urine. In a poem called ?A Lady Who P-st at the Tragedy of Cato’, Alexander Pope lampooned Joseph Addison’s celebrated play, Cato: A Tragedy (1712) by describing a woman who responds to the drama with copious urine rather than the expected tears:

 

While maudlin Whigs deplor’d their Cato’s Fate,

Still with dry Eyes the Tory Celia sate,

But while her Pride forbids her Tears to flow,

The gushing Waters find a Vent below:

Tho’ secret, yet with copious Grief she mourns,

Like twenty River-Gods with all their Urns.

Let others screw their Hypocritick Face,

She shews her Grief in a sincerer Place;

There Nature reigns, and Passion void of Art,

For that Road leads directly to the Heart.

 

This old idea has been reinforced by modern science in the last century and a half. In recent decades, the most widely quoted theorist of tears has been the American biochemist William H Frey II who, since the 1980s, has been arguing that the metaphor of weeping as excretion should be taken quite literally. In an interview with The New York Times in 1982, Frey claimed that crying is ?an exocrine process’ which, ?like exhaling, urinating, defecating and sweating’ releases toxic substances from the body – in this case, so-called ?stress hormones’.

 

An anonymous British pamphlet from 1755, Man: A Paper for Ennobling the Species, proposed a number of ideas for human improvement, and among them was the idea that something called “moral weeping“ would help:

 

We may properly distinguish weeping into two general kinds, genuine and counterfeit; or into physical crying and moral weeping. Physical crying, while there are no real corresponding ideas in the mind, nor any genuine sentimental feeling of the heart to produce it, depends upon the mechanism of the body: but moral weeping proceeds from, and is always attended with, such real sentiments of the mind, and feeling of the heart, as do honour to human nature; which false crying always debases.

 

In his “Confessions,“ St. Augustine implored God to explain “why weeping is sweet to the miserable.“ Religious traditions honor the gift of tears and have found ways to ritualize it. During the Passover Seder, when Jews remember their escape from Egypt, they bring salt water to their lips to symbolize the tears of bondage. In ancient times, when a person died, mourners put their tears in bottles and sometimes even wore them around their necks. Over the ages, the weeping of tears has been a sign of the mystical experiences of saints and repentant sinners. These transcendent moments go beyond what the mind can comprehend; tears are a response of the heart. The question had never been asked in quite that way. Charles Darwin, in “The Expression of the Emotions in Man and Animals“ (1872), speculated that we weep in times of mental distress because of an accidental mechanical relationship between the act of squalling and the production of tears. When an infant wails, Darwin argued, it causes such an engorgement of blood vessels and general pressure around the eye that the lachrymal glands are affected “by reflex action.“ Several millennia’s worth of babies later, “it has come to pass that suffering readily causes the secretion of tears, without being necessarily accompanied by any other action.“ Though Darwin was aware that emotional weeping produces a sense of solace, he believed the tears themselves to be “an incidental result; purposeless.“ Darwin noted that tears could not be neatly associated with any single kind of mental state. They can be secreted ?in sufficient abundance to roll down the cheeks’, he wrote, ?under the most opposite emotions, and under no emotion at all’. A tear on its own means nothing. A tear shed in a particular mental, social, and narrative context, can mean anything. ?Tears, idle tears,’ wrote the English poet, Alfred Tennyson, ?I know not what they mean.’ Yet he, and we, continue to feel compelled to interpret them, to try to distil their meaning. The intellectual climate was not conducive to further inquiry. Crying was, at least in part, a social behavior; and according to prevailing notions of cultural relativism then in vogue, it was therefore a matter of social conditioning. “One weeps,“ wrote French sociologist Emile Durkheim in 1915, “not simply because he is sad but because he is forced to weep. It is a ritual attitude he is forced to adopt out of respect for custom.“

 

There have been many attempts to differentiate between the two distinct types of crying: positive and negative. Different perspectives have been broken down into three dimensions to examine the emotions being felt and also to grasp the contrast between the two types. Spatial perspective explains sad crying as reaching out to be “there“, such as at home or with a person who may have just died. In contrast, joyful crying is acknowledging being “here.“ It emphasized the intense awareness of one’s location, such as at a relative’s wedding. Temporal perspective explains crying slightly differently. In temporal perspective, sorrowful crying is due to looking to the past with regret or to the future with dread. This illustrated crying as a result of losing someone and regretting not spending more time with them or being nervous about an upcoming event. Crying as a result of happiness would then be a response to a moment as if it is eternal; the person is frozen in a blissful, immortalized present. The last dimension is known as the public-private perspective. This describes two types of crying as ways to imply details about the self as known privately or one’s public identity. For example, crying due to a loss is a message to the outside world that pleads for help with coping with internal sufferings. Or, as Arthur Schopenhauer suggested, sorrowful crying is a method of self-pity or self-regard, a way one comforts oneself. Joyful crying, in contrast, is in recognition of beauty, glory, or wonderfulness.

 

Anthropologist Ashley Montagu found such explanations inadequate. As for Darwin’s squeeze-reflex theory, he wrote in 1959, the same evolutionary outcome “might have occurred in any number of other species possessing the necessary lacrimal and orbicular muscles. How, then, has it come about that weeping occurs in man alone?“ Montagu noted that “as is well known, human infants do not usually cry with tears until they are about six weeks of age. Weeping, then, would appear to be both phylogenetically and ontogenetically a late development in the human species“ — that is, it came about as late in our evolution as a species as it does in each individual’s growth. (Though well before laughter, which arrives at about five months.) That timing suggested that weeping was somehow an adaptive trait. Working from Darwin’s own notion of natural selection, Montagu then postulated an evolutionary argument: We cry now because our ancient forebears tended to live longer the more abundantly they wept. Babies breathe heavily when they cry, Montagu argued, and consequently “even a short session of tearless crying in a young infant is likely to dry out the mucous membranes of the nose and throat, rendering the child vulnerable to the invasion of harmful bacteria and, probably, viruses.“

 

Tears, however, contain an enzyme called lysozyme (discovered by Alexander Fleming in 1922), which within five or 10 minutes will destroy the cell walls of as much as 95% of those bacteria. And thanks to an intricate plumbing scheme, the liquid drains directly onto the imperiled membranes: From the glands under the upper eyelid, down into the canal at the inside corner of the eye, and thence into the nasolacrimal duct which empties into the nasal cavity. Thus, Montagu argued, those primordial infants who were least able to produce tears would have been the most prone to infection and early death, and therefore the least likely to pass on their genetic characteristics-leaving “the perpetuation of the species increasingly to those who could weep.“ Biochemist, William H. Frey PhD, who is director of the Dry Eye and Tear Research Center at the St. Paul-Ramsey Medical Center, first began studying tears in the 1980s. When he came across Montagu’s explanation, he wondered: If emotional weeping serves such an essential life-sustaining purpose, then “why hasn’t nature provided this protection during the first critical days and weeks of life?“ In addition, how would one explain the fact that humans frequently cry without an increase in breathing rate? Or that tears customarily precede gasping or sobbing? Frey had been intrigued by stress researcher Hans Selye’s notion of homeostasis — the process whereby the body attempts to maintain an internal biochemical equilibrium in the face of disruptive stimuli and hostile shocks. Might not tears serve this purpose by purging certain chemicals produced by emotional stress? In 1959, psychiatrist, Thomas Szasz MD postulated that weeping represented an unconscious regression to the prenatal state in which the body is bathed in amniotic fluid. Weeping, then, was a regressive fantasy of return to the saline wetness of the womb.

 

Emotional tears were chemically different, containing 21% more protein, among other substances. Since then, research has concentrated on three of them: Leucine-enkephalin, a brain chemical of the family called endorphines, which are thought to affect pain sensations; a pituitary hormone known as ACTH; and another pituitary hormone, prolactin, which stimulates milk production in mammals. Tears may also serve a therapeutic role, though researchers say the supposedly cathartic role of “a good cry“ has been overstated. Thirty years ago, biochemist Frey found that emotional tears carried more protein than non-emotional tears (say, from chopping an onion). The implication was that when you cry for emotional reasons, you are involved in a healing process.

 

The inability to cry:

Psychologists have also gleaned new insights into people who can’t produce tears at all – either emotional or the basal tears that keep eyes lubricated. Some say that ophthalmologists have typically treated ?dry eye’ as a medical issue, completely missing the fact that emotional communication is impaired when you lack tears. Patients with Sjogren’s syndrome, for example, have great difficulty producing tears. A study found that 22% of patients with the syndrome had significantly more difficulty identifying their own feelings than control participants did.

.

Sources: http://www.apa.orgwww.washingtonpost.comhttps://aeon.com;

www.Nih.gov; Wikipedia

 

For our readers:

 

For your listening pleasure, a work of pure brilliance:

 

An artist, beyond genius, enabling the mysteries of the universe to become manifest in glorious music, and through us, the listeners, complete a circuit, still not explained by neuroscience.

 

W.A. Mozart: Requim, Lacrimosa

Full Requiem Mozart REQUIEM KV 626 conducted by Leonard Bernstein in Salzburg, Germany

David Garrett, violin version – Lacrimosa

Mozart, Lacrimosa, Organ

NIH Research Shows How Eye Loss Occurs in Blind Cavefish

 

The “blind cavefish“ Astyanax mexicanus, is a tropical freshwater fish native to Mexico. A few million years ago, some of these fish presumably got trapped in dark caves and gave rise to completely different varieties, or “morphs,“ that lack eyes and have several other unique physical, behavioral and physiological changes. Despite their dramatic differences, surface and cave morphs share similar genomes and can interbreed. Cave morphs begin eye development early but fail to maintain this program, undergoing eye degeneration within a few days of development. Previous research has not revealed any obvious mutations in genes important for their eye development.

 

According to a study published online in Nature Ecology & Evolution (28 May 2018) an NIH sponsored research study showed how eye loss occurs in the blind cavefish. Results showed that loss of eye tissue in the blind cavefish, which occurs within a few days of their development, happens through epigenetic silencing of eye-related genes. Epigenetic regulation is a process where genes are turned off or on, typically in a reversible or temporary manner. This mechanism differs from genetic mutations, which are permanent changes in the DNA code. The study team found more DNA methylation of eye development genes and subsequently, less activity of these genes in the cavefish. DNA methylation is an epigenetic process in which DNA is modified with tags called methyl groups. These tags, which are added by proteins called DNA methyltransferases, silence genes by making the DNA inaccessible.

 

According to the authors, many of the cavefish genes identified in the study are also linked to human eye disorders, suggesting these genes are conserved across evolution and may be similarly regulated in people. The study showed that the epigenetic-based silencing of a large set of genes limits the eye development of the cavefish and that 26 of these genes are also expressed in human eyes, and 19 are linked to human eye disorders. The authors found that cavefish have higher levels of a DNA methyltransferase, called DNMT3B, in their developing eyes. When the study team mutated DNMT3B in another type of fish with eyes, zebrafish, they discovered that the mutant zebrafish have more active eye genes and larger eyes. The results suggest that a genetic change resulting in elevated DNMT3B levels occurred during the evolution of cavefish, leading to epigenetic suppression of eye development genes.

 

According to the authors, the results from this study may yield potential clues to understanding eye disease and blindness in people.

 

NIH Testing Ebola Treatment in Early-Stage Trial

 

Ebola virus disease is a serious and often fatal illness that can cause fever, headache, muscle pain, weakness, fatigue, diarrhea, vomiting, stomach pain and hemorrhage (severe bleeding). It was first discovered in humans in 1976 in the Democratic Republic of the Congo (DRC) and has caused periodic cases and outbreaks in several African countries since then. The largest outbreak, which occurred in West Africa from 2014 to 2016, caused more than 28,600 infections and more than 11,300 deaths, according to the World Health Organization. In May 2018, the DRC reported an Ebola outbreak, located in Equateur Province in the northwest of the country. As of May 20, health officials have reported 51 probable or confirmed cases and 27 deaths. There are currently no licensed treatments available for Ebola virus disease, although multiple experimental therapies are being developed.

 

A first-in-human trial evaluating an experimental treatment for Ebola virus disease has begun at the National Institutes of Health Clinical Center in Bethesda, Maryland. The Phase 1 clinical trial is examining the safety and tolerability of a single monoclonal antibody called mAb114. Investigators aim to enroll between 18 and 30 healthy volunteers aged 18 to 60. The trial will not expose participants to Ebola virus. According to the authors, it is hoped that the trial will establish the safety of this experimental treatment for Ebola virus disease — an important first step in a larger evaluation process.

 

MAb114 is a monoclonal antibody — a protein that binds to a single target on a pathogen — isolated from a human survivor of the 1995 Ebola outbreak in Kikwit, a city in the DRC. The research team discovered that the survivor retained antibodies against Ebola 11 years after infection. The authors then isolated the antibodies and tested the most favorable ones in the laboratory and non-human primate studies, and selected mAb114 as the most promising. Professor Jean-Jacques Muyembe, one of the scientists involved in the original detection of the Ebola virus in 1976, played a key role in discovering mAb114.

 

For the basic research, it was shown that the monoclonal antibody binds to the hard-to-reach core of the Ebola virus surface protein and blocks the protein’s interaction with its receptor on human cells. A single dose of mAb114was also shown to protect non-human primates days after lethal Ebola virus infection. The antibody was developed in partnership with the U.S. Army Medical Research Institute of Infectious Diseases and the Defense Advanced Research Projects Agency, and was manufactured for clinical studies by the company MedImmune based in Gaithersburg, Maryland.

 

For the study, the first three participants will receive a 5 milligram (mg)/kilogram (kg) intravenous infusion of mAb114 for 30 minutes. The study monitoring team will evaluate safety data to determine if the remaining participants can receive higher doses (25 mg/kg and 50 mg/kg). Participants will have blood taken before and after the infusion and will bring a diary card home to record their temperature and any symptoms for three days. Participants will visit the clinic approximately 14 times over six months to have their blood drawn to see if mAb114 is detectable and to be checked for any health changes. Investigators expect that the trial, called VRC 608, will be fully enrolled by July 2018. For more information about the trial, please visit ClinicalTrials.gov and search identifier NCT03478891.

 

FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy

 

Dravet syndrome is a rare genetic condition that appears during the first year of life with frequent fever-related seizures (febrile seizures). Later, other types of seizures typically arise, including myoclonic seizures (involuntary muscle spasms). Additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with Dravet syndrome typically experience poor development of language and motor skills, hyperactivity and difficulty relating to others.

 

Lennox-Gastaut syndrome begins in childhood. It is characterized by multiple types of seizures. People with Lennox-Gastaut syndrome begin having frequent seizures in early childhood, usually between ages 3 and 5. More than three-quarters of affected individuals have tonic seizures, which cause the muscles to contract uncontrollably. Almost all children with Lennox-Gastaut syndrome develop learning problems and intellectual disability. Many also have delayed development of motor skills such as sitting and crawling. Most people with Lennox-Gastaut syndrome require help with usual activities of daily living.

 

The FDA has approved Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. It is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome.

 

CBD is a chemical component of the Cannabis sativa plant, more commonly known as marijuana. However, CBD does not cause intoxication or euphoria (the “high“) that comes from tetrahydrocannabinol (THC). It is THC (and not CBD) that is the primary psychoactive component of marijuana.

 

According to FDA, this approval serves as a reminder that advancing sound development programs that properly evaluate active ingredients contained in marijuana can lead to important medical therapies, and that the FDA is committed to this kind of careful scientific R&D development. FDA added that because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes.

 

Epidiolex’s effectiveness was studied in three randomized, double-blind, placebo-controlled clinical trials involving 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. Results showed that Epidiolex, taken along with other medications, was shown to be effective in reducing the frequency of seizures when compared with placebo. The most common side effects that occurred in Epidiolex-treated patients in the clinical trials were: sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections.

 

Epidiolex must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. As is true for all drugs that treat epilepsy, the most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks. Epidiolex also caused liver injury, generally mild, but raising the possibility of rare, but more severe injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine.

 

Under the Controlled Substances Act (CSA), CBD is currently a Schedule I substance because it is a chemical component of the cannabis plant. In support of this application, the company conducted nonclinical and clinical studies to assess the abuse potential of CBD. The FDA prepares and transmits, through the U.S. Department of Health and Human Services, a medical and scientific analysis of substances subject to scheduling, like CBD, and provides recommendations to the Drug Enforcement Administration (DEA) regarding controls under the CSA. DEA is required to make a scheduling determination.

 

The FDA granted Priority Review designation for this application. Fast-Track designation was granted for Dravet syndrome. Orphan Drug designation was granted for both the Dravet syndrome and Lennox-Gastaut syndrome indications.

 

The FDA granted approval of Epidiolex to GW Research Ltd.

Creamy Stuffed Portobellos

I divided the stuffing in half. One half got an egg yolk (this photo) and the other half got turkey sausage. Those with egg, got a cilantro leaf on top. Jules gives this version the highest score.  I love both. ©Joyce Hays, Target Health Inc.

 

This photo is the stuffed portobello with chopped turkey sausage as one of the stuffing ingredients. ©Joyce Hays, Target Health Inc.

 

Don’t know if you’ve noticed, but where I want to get a certain depth of flavor (umami), I substitute anchovy fillets, for salt. There is never (so far) the least little hint of fishy taste. Not only is the flavor enhanced, but anchovies have a lot of Omega3, found in fish. Here is a healthy delivery system for Omega3. ©Joyce Hays, Target Health Inc.

 

Ingredients

1 pound Italian Sausage, casing removed

1 Onion, minced

2 scallions, chopped

3 anchovy fillets + 3 fresh cloves garlic: mash in mortar & pestle

10 fresh garlic cloves, chopped (not pressed)

2 heaping Tablespoons fresh parsley, chopped

2 heaping Tablespoons fresh thyme, chopped

1 heaping Tablespoon dried oregano

1 teaspoon curry

1 teaspoon turmeric

1 pinch black pepper

12 Large White Button Mushrooms, stems removed and finely chopped, then remove the gills, by scraping with a teaspoon or smaller, from inside the mushroom cap

1 Tablespoon extra virgin Olive Oil

1 container Tofutti

1/4 cup gruyere cheese, grated by hand

1/4 cup buffalo mozzarella, grated or shredded by hand

1/4 cup fresh parmesan grated by hand

1/4 cup sharp cheddar, grated by hand

1 jalapeno, seeds removed, chopped well

 

As you can see in the photo, the Portobello stems have been removed and chopped and the inside of the caps have been scraped out. ©Joyce Hays, Target Health Inc.

 

Directions

1. Preheat your oven to 400 degrees.

2. Put Tofutti on counter and let it reach room temperature

3. In a mortar & pestle, grind the anchovies with 3 garlic cloves

 

This little bowl is about the size of my mortar & pestle set. The anchovies and garlic were simply mashed with a fork. This combo has become the little secret for many of my recipes. Keep in mind, not only does it add flavor depth, but it also substitutes for salt and contributes Omega3, each time it’s used. ©Joyce Hays, Target Health Inc.

 

4. Do all the chopping, slicing, grating, scraping

 

Chopping everything at once. ©Joyce Hays, Target Health Inc.

 

Grating all of the cheeses. Don’t buy pre-grated packaged cheese, marked fresh; they all have a certain amount of preservatives. ©Joyce Hays, Target Health Inc.

 

5. In a small bowl, put all 4 cheeses, mix together well and set aside.

 

Combining all the cheeses in a bowl. ©Joyce Hays, Target Health Inc.

 

6. Chop the sausage.

 

Chopping the turkey sausage. Use your favorite sausage. ©Joyce Hays, Target Health Inc.

 

7. In a large (oven proof) skillet, with handles on both sides, cook the sausage on medium-high heat. When the sausage is nearly cooked through, add the diced mushroom stems, garlic, jalapeno, scallions and onion and continue to cook until they soften a bit.

 

Cook the mushroom/herb mixture with the sausage you select (or none at all). Consider adding eggs instead, at this point. ©Joyce Hays, Target Health Inc.

 

8. Next, to the pan, add all herbs (fresh and dried), all spices and seasoning and stir until all ingredients are well combined. Cook for 1 or 2 more minutes.

9. Transfer the mixture from the pan to a large bowl. Add the Tofutti and stir it into the mixture, while it’s still warm.

 

Just added Tofutti. ©Joyce Hays, Target Health Inc.

 

10. Don’t wash out the pan, but with a spatula, scrape all little bits into the bowl.

 

Here, half the mixture, without sausage, got egg yolks, combined well with the rest and used to stuff two of the portobellos. Jules requested no sausage in his portobellos. ©Joyce Hays, Target Health Inc.

 

11. Next, stuff each mushroom with the mixture, as high as it will go without falling over or crumbling. Put the stuffed mushrooms back into the bowl.

12. Just before you pop the pan back into the oven with the stuffed mushrooms, take fingers filled with the grated cheeses and put on top of each stuffed mushroom. Bake for 15 to 20 minutes.

 

Going into the oven now. ©Joyce Hays, Target Health Inc.

 

Serve nice and warm, with a vegetarian entr?e like spinach pie, serve with pasta, chicken, fish, seafood or serve as an appetizer.

 

Delicious Sunday brunch. ©Joyce Hays, Target Health Inc.

 

Because of the richness of the stuffed Portobellos, this shiraz went well. We love this vineyard run by the same family for two or three generations. ©Joyce Hays, Target Health Inc.

 

Have a great week everyone!

Bon Appetit!