Researchers advance understanding of autism

March 14, 2018

University of Houston

Researchers link autism spectrum disorders to defects in a nuclear receptor inside the brain.


Two University of Houston scientists are reporting that defects in a portion of the brain’s hippocampus, called the dentate gyrus, is regulated by the nuclear receptor LXRβ (Liver X receptor Beta). The dentate gyrus, or DG, is responsible for emotion and memory and is known to be involved in autism spectrum disorders (ASD).


Margaret Warner, professor of biology and biochemistry, and Jan-Åke Gustafsson, professor of biology, biochemistry and founding director of the UH Center of Nuclear Receptors and Cell Signaling, describe the work in the Proceedings of the National Academy of Sciences.

For four decades they have worked together, making discovery after discovery about the role of nuclear receptors in brain functions, and they show no sign of slowing down.

Tracking down the culprit

Neurogenesis, or the regulation of growth of the dentate gyrus, occurs prenatally and postnatally.

“Our findings suggest early changes in DG neurogenesis ultimately provide an aberrant template upon which to build the circuitry that is involved in normal social function,” said Warner.

Their studies propose that defects in the neurogenesis of the DG seem to be involved in the etiology of autism spectrum disorders and their associated behaviors. Specifically, defects in the nuclear receptor LXRβ has emerged as the possible culprit of defects in the DG.

Why this gray matter matters

In the world of physiology (how the organisms in our bodies communicate and keep us alive), nuclear receptors rule the day. They are a class of proteins within cells that control hormones and regulate metabolism. One of these proteins, LXRβ, may be the one that holds the key to the genesis of autism. Warner and Gustafsson established this the only way they could — by taking LXRβ out of the equation.

“Knocking out LXRβ led to autistic behavior and reduced cognitive flexibility,” said Warner. “In this paper we share our findings that that deletion of the LXRβ causes hypoplasia or underdevelopment in the DG and autistic-like behaviors, including abnormal social interaction and repetitive behavior.”

They went on to report: “The behavioral studies confirmed that ablation of LXRβ caused behavior disorders relevant to major ASD symptoms. Social interaction deficits, as key phenotypic traits of ASD, were evident…”

Gustafsson said the findings are the path forward in autism research.

“The Liver X receptor Beta is important in the dentate gyrus and in autism and more studies on the receptor are going to help us cure or treat autism,” he said.

He should know. He’s the scientist who discovered LXRβ in 1996.

“Until 1996 we did not know that this receptor even existed and it is so important in brain function,” said Warner.

Story Source:

Materials provided by University of Houston. Original written by Laurie Fickman. Note: Content may be edited for style and length.

Journal Reference:

  1. Yulong Cai, Xiaotong Tang, Xi Chen, Xin Li, Ying Wang, Xiaohang Bao, Lian Wang, Dayu Sun, Jinghui Zhao, Yan Xing, Margaret Warner, Haiwei Xu, Jan-Åke Gustafsson, Xiaotang Fan. Liver X receptor β regulates the development of the dentate gyrus and autistic-like behavior in the mouseProceedings of the National Academy of Sciences, 2018; 201800184 DOI: 10.1073/pnas.1800184115


Source: University of Houston. “Researchers link defects in a nuclear receptor in the brain to autism spectrum disorders: Researchers advance understanding of autism.” ScienceDaily. ScienceDaily, 14 March 2018. <>.

Warming Arctic’s connection to US weather is ‘no coincidence’

March 13, 2018

Rutgers University

Scientists have linked the frequency of extreme winter weather in the United States to Arctic temperatures.


Winter snowstorm.
Credit: © onepony / Fotolia



Scientists from Rutgers University-New Brunswick and Atmospheric and Environmental Research (AER) have linked the frequency of extreme winter weather in the United States to Arctic temperatures.

Their research was published today in Nature Communications.

“Basically, this confirms the story I’ve been telling for a couple of years now,” said study co-author Jennifer Francis, research professor of marine and coastal sciences in Rutgers’ School of Environmental and Biological Sciences. “Warm temperatures in the Arctic cause the jet stream to take these wild swings, and when it swings farther south, that causes cold air to reach farther south. These swings tend to hang around for awhile, so the weather we have in the eastern United States, whether it’s cold or warm, tends to stay with us longer.”

The research is timely given the extreme winter of 2017-2018, including record warm Arctic and low sea ice, record-breaking polar vortex disruption, record-breaking cold and disruptive snowfalls in the United States and Europe, severe “bomb cyclones” and costly nor’easters, said Judah Cohen, director of seasonal forecasting at AER and lead author of the study.

In their study, Cohen, Francis and AER’s Karl Pfeiffer found that severe winter weather is two to four times more likely in the eastern United States when the Arctic is abnormally warm than when the Arctic is abnormally cold. Their findings also show that winters are colder in the northern latitudes of Europe and Asia when the Arctic is warm.

Paradoxically, the study shows that severe winter weather in the western United States is more likely when the Arctic is colder than normal.

The researchers found that when Arctic warming occurred near the surface, the connection to severe winter weather was weak. When the warming extended into the stratosphere, however, disruptions of the stratospheric polar vortex were likely. These disruptions usually cause severe winter weather in mid- to late winter and affect large metropolitan centers of the northeastern United States.

“Five of the past six winters have brought persistent cold to the eastern U.S. and warm, dry conditions to the West, while the Arctic has been off-the-charts warm,” Francis said. “Our study suggests that this is no coincidence. Exactly how much the Arctic contributed to the severity or persistence of the pattern is still hard to pin down, but it’s becoming very difficult to believe they are unrelated.”

Story Source:

Materials provided by Rutgers University. Original written by Ken Branson. Note: Content may be edited for style and length.

Journal Reference:

  1. Judah Cohen, Karl Pfeiffer, Jennifer A. Francis. Warm Arctic episodes linked with increased frequency of extreme winter weather in the United StatesNature Communications, 2018; 9 (1) DOI: 10.1038/s41467-018-02992-9


Source: Rutgers University. “Warm Arctic means colder, snowier winters in northeastern US, study says: Warming Arctic’s connection to US weather is ‘no coincidence’.” ScienceDaily. ScienceDaily, 13 March 2018. <>.

March 8, 2018

Arizona State University

Scientists have, for the first time, observed one of the more intriguing properties predicted by water theoreticians — that, on sufficient super-cooling and under specific conditions it will suddenly change from one liquid to a different one.


Frost. (stock image)
Credit: © Mandrixta / Fotolia



Water, always important, always controversial, always fascinating, remains surprising. For a substance that is ubiquitous on Earth, three quarters of our planet is covered with it, researchers can still be surprised by some of its properties, according to Arizona State University chemist C. Austen Angell.

Angell, a Regents Professor in ASU’s School of Molecular Sciences, has spent a good portion of his distinguished career tracking down some of water’s more curious physical properties. In a new piece of research just published in Science (March 9), Angell and colleagues from the University of Amsterdam have, for the first time, observed one of the more intriguing properties predicted by water theoreticians — that, on sufficient super-cooling and under specific conditions it will suddenly change from one liquid to a different one. The new liquid is still water but now it is of lower density and with a different arrangement of the hydrogen bonded molecules with stronger bonding that makes it a more viscous liquid.

“It has nothing to do with ‘poly-water,'” Angell adds recalling a scientific fiasco of many decades ago. The new phenomenon is a liquid-liquid phase transition, and until now it had only been seen in computer simulations of water models.

The problem with observing this phenomenon directly in real water is that, shortly before the theory says it should happen, the real water suddenly crystallizes to ice. This has been called the “crystallization curtain” and it held up progress in understanding water physics and water in biology for decades.

“The domain between this crystallization temperature and the much lower temperature at which glassy water (formed by deposition of water molecules from the vapor) crystallizes during heating has been known as a ‘no-man’s land,'” Angell said. “We found a way to pull aside the ‘crystallization curtain’ just enough to see what happens behind — or more correctly, below — it,” Angell said.

Phase transitions of water are important to understand for a multitude of applications. For example, the well-known and destructive heaving of concrete roads and footpaths in winter is due to the phase transition from water to ice under the concrete. The phase transition between liquid states, described in the current work, has much in common with the transition to ice but it occurs at a much lower temperature, about -90 C (-130 F), and only under super-cooled conditions so it is likely to remain mostly a scientific curiosity for the foreseeable future.

Angell explained that a couple of years ago he and his research associate Zuofeng Zhao, were studying the thermal behavior of a special type of “ideal” aqueous solution they had been using to explore the folding and unfolding of globular proteins. They wanted to observe these solutions’ ability to supercool and then vitrify. Seeking the limit to the glassy domain, they added extra water to enhance the probability of ice crystallization and found that instead of finally evolving heat as ice crystallized (leaving a residual unfrozen solution) as is normally found when cooling saline solutions, it actually gave off heat to form a new liquid phase.

The new liquid was much more viscous, maybe even glassy. Furthermore, by reversing the direction of the temperature change, Angell and Zhao found that they could transform the new phase back into the original solution before any ice would start to crystallize.

“This observation, published in Angewandte Chemie, raised considerable interest but there was no structural information to explain what was happening,” Angell said. That changed when Angell visited the University of Amsterdam two summers ago, and met Sander Woutersen, a specialist in infrared spectroscopy who became very interested in the structural aspects of the phenomenon.

In the Science paper, the team with Woutersen, his student Michiel Hilbers and his computational colleague Bernd Ensing has now shown that the structures involved in the liquid-liquid transition have the same spectroscopic signatures — and the same hydrogen bonding patterns — as are seen in the two known glassy forms of ice produced by laborious alternative processes (high- and low-density amorphous solid phases of water).

“The liquid-liquid transition we had found was now seen to be the ‘living analog’ of the change between two glassy states of pure water that had been reported in 1994, using pure pressure as the driving force,” Angell explained.

The results would seem to “provide direct evidence for the existence of a liquid-liquid transition behind the ‘crystallization curtain’ in pure water,” Woutersen said, adding that the findings offer a general explanation for the thermodynamic anomalies of liquid water, and a validation for the “second critical point theory” put forward by Gene Stanley’s group to explain those anomalies.

“This behavior is almost unique among the myriad of known molecular liquids,” Angell added. “Only a few other substances are thought to exhibit it, but none have been proven to date.”

Story Source:

Materials provided by Arizona State UniversityNote: Content may be edited for style and length.

Journal Reference:

  1. Sander Woutersen, Bernd Ensing, Michiel Hilbers, Zuofeng Zhao, C. Austen Angell. A liquid-liquid transition in supercooled aqueous solution related to the HDA-LDA transitionScience, 2018; 359 (6380): 1127 DOI: 10.1126/science.aao7049


Source: Arizona State University. “Water’s mysterious phase transitions.” ScienceDaily. ScienceDaily, 8 March 2018. <>.

Target Health Inc. – What We Do and How We Do It


Several times a year we get asked by current and potential clients: Exactly what services do we provide. Our answer is that basically we are a Pharmaceutical or Medical Device Company without our own products, but with the staff, software and skills to take your unique product to the market. Our experienced staff are home grown, as well as coming to us from companies like Pfizer, Microsoft, Wyeth, Amgen, Teva, Boehringer Ingelheim, Quintiles and more.


TARGET HEALTH INC. is a New York City based full service eCRO with staff dedicated to all aspects of Drug and Device Development including: Strategic Planning, Regulatory Affairs, Toxicology, Clinical Research, Biostatistics, Data Management and Medical Writing.  In addition, we have developed innovative web-based software tools that support the paperless clinical trial thus providing our clients with a significant productivity edge.


Why Do Companies Work With Target Health?


1. Drug/Device Development is Our Business

2. In Business since 1993

3. Extensive Experience with FDA

4. Track Record of NDA, PMA, BLA, 1510(k) and Other Regulatory Approvals

5. Broad Clinical Backgrounds

6. Experienced Management Team

7. >50% of Employees 5+ Years at the Company

8. Champions of the Paperless Clinical Trial

9. We Are Not Just a Technology Company

10. EDC (Target e*CRF®) since 1999

11. Always Meet Deadlines

12. Repeat Business From Our Clients

13. We Measure Our Success By Your Success


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.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor



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End-of-Life Care in the 21st Century

Exterior of an inpatient hospice unit, connected with a hospital

Photo credit: Wikipedia Commons


End-of-life care (or EoLC) refers to health care, not only of a person in the final hours or days of their 1) ___, but more broadly care of all those with a terminal condition that has become advanced, progressive, and incurable. End-of-life care requires a range of decisions, including questions of palliative care, patients’ right to self-determination (of treatment, life), medical experimentation, the ethics and efficacy of extraordinary or hazardous medical interventions, and the ethics and efficacy even of continued routine medical interventions. In addition, end-of-life often touches upon rationing and the allocation of resources in hospitals and national medical systems. Such decisions are informed both by technical, medical considerations, economic factors as well as bioethics. In addition, end-of-life treatments are subject to considerations of patient autonomy. “Ultimately, it is still up to patients and their families to determine when to pursue aggressive treatment or withdraw life 2) ___.“ In most advanced countries, medical spending on those in the last twelve months of life makes up roughly 10% of total aggregate medical spending, and spending on those in the last three years of life can account for up to 25%.



In 2012, Statistics Canada’s General Social Survey on Caregiving and care receiving found that 13% of Canadians (3.7 million) aged 15 and older reported that at some point in their lives they had provided end-of-life or palliative care to a family member or friend. For those in their 50s and 60s, the percentage was higher, with about 20% reporting having provided palliative care to a family member or friend. 3) ___ were also more likely to have provided palliative care over their lifetimes, with 16% of women reporting having done so, compared with 10% of men. These caregivers helped terminally ill family members or friends with personal or medical care, food preparation, managing finances or providing transportation to and from medical appointments.


United Kingdom

End of life care has been identified by the UK Department of Health as an area where quality of care has previously been “very variable,“ and which has not had a high profile in the NHS and social care. To address this, a national end of 4) ___ care program was established in 2004 to identify and propagate best practice, and a national strategy document published in 2008.The Scottish Government has also published a national strategy. In 2006 just over half a million people died in England, about 99% of them adults over the age of 18, and almost two-thirds adults over the age of 75. About three-quarters of deaths could be considered “predictable“ and followed a period of chronic illness – for example heart disease, cancer, stroke, or dementia. In all, 58% of deaths occurred in an NHS hospital, 18% at home, 17% in residential care homes (most commonly people over the age of 85), and about 4% in hospices. However, a majority of people would prefer to die at 5) ___ or in a hospice, and according to one survey less than 5% would rather die in hospital. A key aim of the strategy therefore is to reduce the needs for dying patients to have to go to hospital and/or to have to stay there; and to improve provision for support and palliative care in the community to make this possible. One study estimated that 40% of the patients who had died in hospital had not had medical needs that required them to be there. In 2015 and 2010, the UK ranked highest globally in a study of end-of-life care. The 2015 study said: “Its ranking is due to comprehensive national policies, the extensive integration of palliative care into the National Health Service, a strong hospice movement, and deep community engagement on the issue.“ The studies were carried out by the Economist Intelligence Unit and commissioned by the Lien Foundation, a Singaporean philanthropic organization.


United States

Spending on those patients in the last twelve months accounts for 8.5% of total aggregate medical spending in the United States. When considering only those aged 65 and older, estimates show that about 27% of Medicare’s annual $327 billion budget ($88 billion) in 2006 goes to care for patients in their final year of life. For those over 65, between 1992-1996, spending on those in their last year of life represented 22% of all medical spending, 18% of all non-Medicare spending, and 25% of all Medicaid spending for the poor. These percentages appears to be falling over time, as in 2008, 16.8% of all medical spending on the over 65s went on those in their last year of life.


Non-medical care and support – Family and loved ones


Many times, family members are uncertain what they can do when a person is dying. Many gentle, familiar daily tasks, such as combing hair, putting lotion on delicate skin, and holding hands, are comforting and provide a meaningful method of communicating love to a dying person. Family members may be suffering emotionally due to the impending death. Their own fear of death may affect their behavior. They may feel guilty about past events in their relationship with the dying person or feel that they have been neglectful. These common emotions can result in tension, fights between family members over decisions, worsened care, and sometimes a long-absent family member swoops in while a patient is dying to demand inappropriately aggressive care. Family members may also be coping with unrelated problems, such as physical or 6) ___ illness, emotional and relationship issues, or legal difficulties. These problems can limit their ability to be involved, civil, helpful, or present.


Pastoral/Spiritual care is of particular significance in end of life care. ‘In palliative care, responsibility for spiritual care is shared by the whole team, with leadership given by specialist practitioners such as pastoral care workers. The palliative care approach to spiritual care may, however, be transferred to other contexts and to individual practice. Fragmented, dysfunctional, or grieving families are often unable to make timely decisions that respect the patient’s wishes and values. This can result in over-treatment, under-treatment, and other problems. For example, family members may differ over whether life extension or life quality is the main goal of treatment. Family members may also be unable to grasp the inevitability of 7) ___ and the risks and effects of medical and non-medical interventions. They may demand common treatments, such as antibiotics for pneumonia, or drugs to reduce high blood pressure without wondering whether that person might prefer dying quickly of pneumonia or a heart attack to a long-drawn-out decline in a skilled care facility. Some treatments, such as pureed foods for a person who has trouble swallowing or IV fluids for a person who is actively dying, seem harmless, but can significantly prolong the process of dying.


The U.S. Government National Cancer Institute advises that the presence of some of the following signs may indicate that death is approaching:


1. Drowsiness, increased sleep, and/or unresponsiveness (caused by changes in the patient’s metabolism).

2. Confusion about time, place, and/or identity of loved ones; restlessness; visions of people and places that are not present; pulling at bed linens or clothing (caused in part by changes in the patient’s metabolism).

3. Decreased socialization and withdrawal (caused by decreased oxygen to the brain, decreased blood flow, and mental preparation for dying).

4. Decreased need for food and fluids, and loss of appetite (caused by the body’s need to conserve energy and its decreasing ability to use food and fluids properly).

5. Loss of 8) ___ or bowel control (caused by the relaxing of muscles in the pelvic area).

6. Darkened urine or decreased amount of urine (caused by slowing of kidney function and/or decreased fluid intake).

7. Skin becoming cool to the touch, particularly the hands and feet; skin may become bluish in color, especially on the underside of the body (caused by decreased circulation to the extremities).

8. Rattling or gurgling sounds while breathing, which may be loud (death rattle); breathing that is irregular and shallow; decreased number of breaths per minute; breathing that alternates between rapid and slow (caused by congestion from decreased fluid consumption, a buildup of waste products in the body, and/or a decrease in circulation to the organs).

9. Turning of the head toward a light source (caused by decreasing vision).

10. Increased difficulty controlling pain (caused by progression of the disease).

11. Involuntary movements (called myoclonus), increased heart rate, hypertension followed by hypotension, and loss of reflexes in the legs and arms are additional signs that the end of life is near.


Disease Symptom Management


The following are some of the most common potential problems that can arise in the last days and hours of a patient’s life:


1. Pain -Suffering from uncontrolled pain is a significant fear of those at end of life. Pain is typically controlled using 9) ___ or, in the United Kingdom, diamorphine or other opioids.

2. Agitation: Delirium, terminal anguish, restlessness (e.g. thrashing, plucking, or twitching). Typically controlled using midazolam, or other benzodiazepines. Haloperidol is commonly used as well. Disease symptoms may also sometimes be alleviated by rehydration, which may reduce the effects of some toxic drug metabolites.

3. Respiratory Tract Secretions: Saliva and other fluids can accumulate in the oropharynx and upper airways when patients become too weak to clear their throats, leading to a characteristic gurgling or rattle-like sound (“death rattle“). While apparently not painful for the patient, the association of the diseases symptom with impending death can create fear and uncertainty for those at the bedside. The secretions may be controlled using drugs such as scopolamine (hyoscine), glycopyrronium, or atropine. Rattle may not be controllable if caused by deeper fluid accumulation in the bronchi or the lungs, such as occurs with pneumonia or some tumors.

4. Nausea and vomiting: Typically controlled using haloperidol, cyclizine; or other anti-emetics; Dyspnea (breathlessness), typically controlled using morphine or, in the United Kingdom, diamorphine.


Typical care plans, such as those based on the Liverpool Care Pathway for dying patients, pre-authorize staff to address such disease symptoms as soon as they are needed, without needing to take time to seek further authorization. Subcutaneous injections are one preferred means of delivery when it has become difficult for patients to swallow or to take pills orally; and if repeated medication is needed, a syringe driver (called an infusion pump in the US) is often likely to be used, to deliver a steady low dose of medication. Another means of medication delivery, available for use when the oral route is compromised, is a specialized catheter designed to provide comfortable and discreet administration of ongoing medications via the rectal route. The catheter was developed to make rectal access more practical and provide a way to deliver and retain liquid formulations in the distal rectum so that health practitioners can leverage the established benefits of rectal administration. Its small flexible silicone shaft allows the device to be placed safely and remain comfortably in the rectum for repeated administration of medications or liquids. The catheter has a small lumen, allowing for small flush volumes to get medication to the rectum. Small volumes of medications (under 15ml) improve comfort by not stimulating the defecation response of the rectum, and can increase the overall absorption of a given dose by decreasing pooling of medication and migration of medication into more proximal areas of the rectum where absorption can be less effective.


Other disease symptoms that may occur, and can be mitigated to some extent, include cough, fatigue, fever, and in some cases bleeding.


A study was conducted by Jessica Schmit from the University of Florida in 2016 about the level of comfort, medical residents have with certain end-of-life care. Through this study it was found that residents received an inadequate amount of formal education on comfort-care and end-of-life care. In Schmit’s study it was found that 61.9% of residents reported that their end of life conversations were “mostly unsupervised“ or “never supervised“, giving them very little guidance about how to do better in the future. Nurses also play an extremely important role in comfort care at the end of life. Nurses are able to explain in practical terms what is happening to the patient after the doctor has left. Nurses also work to advocate for the patients, as they spend a lot of time with them and typically know a great deal more about the patient’s wishes, symptoms, and previous medical history. Nurses, doctors, and hospice workers are critical in helping both the patient and the 10) ___ move through the death process, as well as the grief that follows after.


ANSWERS: 1) lives; 2) support; 3) Women; 4) life; 5) home; 6) mental; 7) death; 8) bladder; 9) morphine; 10) family


Britain’s Charles II’s Medical Treatment Led to His Suffering and Death

Charles is of thin build and has chest-length curly black hair

Graphic credit: John Michael Wright – National Portrait Gallery: NPG 531, While Commons policy accepts the use of this media, See Commons: Licensing for more information., Public Domain,



Charles II (29 May 1630-6 February 1685) was king of England, Scotland and Ireland. He was king of Scotland from 1649 until his deposition in 1651, and king of England, Scotland and Ireland from the restoration of the monarchy in 1660 until his death. Charles II was one of the most popular and beloved kings of England, known as the Merry Monarch, in reference to both the liveliness and hedonism of his court and the general relief at the return to normality after over a decade of rule by Cromwell and the Puritans. Charles’s wife, Catherine of Braganza, bore no live children, but Charles acknowledged at least twelve illegitimate children by various mistresses. He was succeeded by his brother James.


Charles II’s father, Charles I, was executed at Whitehall on 30 January 1649, at the climax of the English Civil War. Although the Parliament of Scotland proclaimed Charles II King on 5 February 1649, England entered the period known as the English Interregnum or the English Commonwealth, and the country was a de facto republic, led by Oliver Cromwell. Cromwell defeated Charles II at the Battle of Worcester on 3 September 1651, and Charles fled to mainland Europe. Cromwell became virtual dictator of England, Scotland and Ireland, and Charles spent the next nine years in exile in France, the Dutch Republic and the Spanish Netherlands. A political crisis that followed the death of Cromwell in 1658 resulted in the restoration of the monarchy, and Charles was invited to return to Britain. On 29 May 1660, his 30th birthday, he was received in London to public acclaim. After 1660, all legal documents were dated as if he had succeeded his father as king in 1649.


Charles’s English parliament enacted laws known as the Clarendon Code, designed to shore up the position of the re-established Church of England. Charles acquiesced to the Clarendon Code even though he favored a policy of religious tolerance. The major foreign policy issue of his early reign was the Second Anglo-Dutch War. In 1670, he entered into the Treaty of Dover, an alliance with his first cousin King Louis XIV of France. Louis agreed to aid him in the Third Anglo-Dutch War and pay him a pension, and Charles secretly promised to convert to Catholicism at an unspecified future date. Charles attempted to introduce religious freedom for Catholics and Protestant dissenters with his 1672 Royal Declaration of Indulgence, but the English Parliament forced him to withdraw it. In 1679, Titus Oates’s revelations of a supposed “Popish Plot“ sparked the Exclusion Crisis when it was revealed that Charles’s brother and heir (James, Duke of York) was a Catholic. The crisis saw the birth of the pro-exclusion Whig and anti-exclusion Tory parties. Charles sided with the Tories, and, following the discovery of the Rye House Plot to murder Charles and James in 1683, some Whig leaders were executed or forced into exile. Charles dissolved the English Parliament in 1681 and ruled alone until his death on 6 February 1685. Ironically, he was received into the Roman Catholic Church on his deathbed.


He died in his bed, surrounded by his spaniels, friends, and family, in the early hours of 6 February 1685. His death was torture, due to a complete lack of medical knowledge. Hence, in Charles II case, the torturers/killers were his doctors. It was not the intention of the doctors to cause the death of the king. But through their total medical ignorance, their actions, led the already ailing Charles, a speedier and agonizing death. Because the daily accounts of Charles II demise are so detailed and vivid, we include the next few passages as a stark contrast to the 21st century hospice and palliative care we are now accustomed to.


DAY 1: On the morning of 2nd February 1685, things seemed to be going normally for Charles. As he was preparing to shave, he suddenly cried out to pain, fell to the floor and suffered from a series of fits. Six royal physicians rushed into the Royal Bedchamber to help Charles. Their good intentions, however, paved the path to Charles’ undoubtedly excruciating end. Once the seizure had passed, the first thing that the doctors did was bleed him of 16 ounces of blood. Next, they applied heated cups to the king’s skin, to form blisters. This treatment, which is still practiced in parts of the world today, was believed to ?stimulate’ his system, and once the blister was lanced, the disease would go away with its contents. After the cupping procedure was completed, Charles’ doctors drained him of 8 more ounces of blood. After this second bleeding session was completed, they gave the king a drug to induce vomiting, an enema to purify his bowels, and a purgative to clean out his intestines. The doctors believed that the bad consequences of the disease was not only in the blood, but also in the bowels. The next treatment was to force-feed a syrup, containing blackthorn and rock salt, followed by shaving his head and blistered his scalp, which caused the king to wake from a nap. None of the physicians understood the healing nature of sleep. They administered yet another enema to the ailing king, put an irritant powder up his nostrils, blistered his skin again with cupping, and applied cow-slip flowers to his stomach. At the end of the day they applied pigeon droppings to his feet. The torturous treatment of the first day, lasted for 12 hours. After the ?care’ was done, the king was put to bed.


DAY 2: When the king awoke, he seemed greatly improved. This should have been a sign that something had worked, however, as soon as Charles II woke, his doctors began to bleed the king again, this time, opening both of Charles’ jugular veins bleeding out 10 ounces. At this point, the king had lost 34 ounces of blood. The physicians then proceeded to feed him a potion containing black cherries, peony, lavender, sugar, and crushed pearls. After he ingested the liquid, he slept through the day and night soundly.


DAY 3: When Charles awoke on the third morning, he suffered another seizure. His doctors bled him again, after feeding him first sienna pods in spring water, and white wine with nutmeg; next a force-fed drink made of ?40 drops of extract of human skull’, taken from a man who met a very violent demise, as well as a gallstone (the Bezoar Stone) from an East Indian goat. The physicians proudly announced that the king was going to survive.


DAY 4: The king was near death on this day. Seeing his pitiful state of health, the doctors applied the hot cups to his skin again to form blisters, gave him another enema and emetic, and was bled yet again. He was then given Jesuit’s Powder; a quinine remedy, laced with opium and wine. Perhaps this potion helped as a pain killer and a soporific.


DAY 5: Dr. Scarborough, one of the royal doctors, wrote on the morning of 5th February 1685: “Alas! After an ill-fated night, His Serene Majesty’s strength seemed exhausted to such a degree that the whole assembly of physicians became despondent and lost hope.“ On this day, in an attempt to revive the king, he was bled until the doctors gave up this technique and turned to creating a new stronger potion. The physicians gathered an antidote containing ?extracts of all the herbs and animals of the Kingdom’ by scouring the palace grounds. These ingredients were then mixed with ammonia and poured down his throat.


DAY 6: 6th February 1685 was the final day for the popular monarch. The scene around his deathbed was one that still draws some emotion 300 years or more later. Charles, although incredibly weak and in great pain, wished to see each of his surviving children and mistresses for one last time. At one point, the king asked for the curtains of his room to be drawn back, so that he could view the sun over the Thames for one last time. As he took in the view, he said: “I have suffered much more than you can imagine. You must pardon me, gentlemen, for being a most unconscionable time a-dying.“ He converted to Catholicism shortly before he died. At 11:15 am, on 6th February 1685, at the age of 54 years, King Charles II died.


It’s said that Charles was suffering from a variety of ailments at this time; uremia, malaria, mercury poisoning, chronic nephritis, and quite possibly some form of an STD. We know that he was ill, but the exact illness was not known. Could today’s physicians have kept the king alive? We’ll never know; however, we do know that his death would have been peaceful and would have lacked all the suffering Charles II endured.


Can Monoclonal Antibodies Be Crucial to Fighting Emerging Infectious Diseases?


According to an article published online in the New England Journal of Medicine (7 March 2018), monoclonal antibodies (mAbs) — preparations of a specific type of antibody designed to bind to a single target, not only have shown promise in the fight against cancer and autoimmune diseases, they may also play a critical role in future battles against emerging infectious disease outbreaks.


Although mAbs were originally described in the 1970s, their value has become more widely recognized as processes have been developed to improve approaches to identify, select, optimize and manufacture them. These advances have allowed for improved safety and efficacy, and substantial efficiencies in identifying promising candidates. For example, mAbs now can be identified directly from individuals previously infected by or vaccinated against a specific pathogen. Moreover, modifications can be made to extend the life of a mAb and further improve its safety.


Because mAbs with optimized targeting and other characteristics can be developed, their activity can be precisely tailored to serve specific treatment and prevention purposes. For example, during the 2014-2016 Ebola outbreak, a small clinical trial <> of the drug ZMapp, which contains three different mAbs, appeared to show a drop in mortality among infected volunteers who received the experimental therapeutic. Additionally, research in laboratory animals suggests that mAbs may play a role in protecting pregnant women in Zika-endemic areas and their fetuses from infection. Further, promising preclinical studies suggest that mAbs aimed at specific targets on the influenza virus could treat influenza disease and interrupt influenza transmission when used prophylactically in uninfected individuals.


The authors, however, caution that mAb-based therapies may be costly to develop and deploy, thus should be used judiciously. However, the authors are optimistic that development efforts will increase, as prices will likely fall in the future, and target optimization may offer effectiveness with smaller amounts of antibody. In addition, other novel approaches such as delivering antibodies through DNA or mRNA constructs, may be further developed. By prioritizing research for mAbs against infectious diseases, the authors assert, global health leaders can improve preparedness for treating and preventing emerging and re-emerging infectious diseases.


Brain’s Internal Clock Continually Takes its Temperature


The circadian clock is a fundamental process found in nearly every living organism that coordinates sleep behavior with changes in the environment. The link between the light/dark cycle and the onset of sleep is well recognized; however, changes in temperature also appear to affect sleep patterns in humans.


According to a study published in Nature (21 February  2018), circuits in the brain act as an internal clock to tell us it is time to sleep and to control how long we then stay asleep. The new study in flies suggests a part of that clock constantly monitors changes in external temperature and integrates that information into the neural network controlling sleep. By using a special fluorescent protein that changes from green to red when neurons fire, the authors watched the activity of different parts of the fly brain’s circadian clock while they increased or decreased the surrounding temperature. To the surprise of the authors, an area in the fly brain’s circadian clock called the DN1p increased its activity when cooled and became less active when heated.


As we all know when travelling, the circadian clock can be “reset“ over time in response to new day/light cycles. Since the clocks of flies can be retrained to new cycles of either light or temperature, the authors next looked at whether the DN1p is involved in resetting the clock to a new heating/cooling cycle. Because DN1p neurons are thought to be sleep-promoting, the authors blocked their activity or eliminated them genetically. Both affected the flies’ ability to retrain their sleep cycle in response to changes in temperature, highlighting the importance of the DN1p for the control of sleep behavior. According to the authors, because flies’ bodies are translucent and their clock neurons can respond to light directly, the next question asked was whether temperature worked in the same way or required external organs.


In flies, temperature could be sensed directly by neurons in the brain or via nerve impulses from sensory organs in the body. To distinguish between the two, the authors genetically manipulated or physically removed the sensory organs and found that the DN1p neurons no longer responded to changes in temperature. This meant that the clock interprets temperature signals from the body rather than sensing temperature changes directly.


The circadian clock of larger animals and humans is also sensitive to changes in temperature, and because of their larger size, would require input from external sensory organs. The fact that, despite its small size, the fly clock also relies on temperature sensors outside the brain suggests that the findings of this study could have broad implications in the control of sleep in humans.


FDA Has Approved the Smallest Mechanical Heart Valve in the World


Heart valve disease occurs if one or more of the four heart valves, which direct the flow of blood through the heart, fail to function properly. In pediatric patients, a malfunctioning heart valve is often the result of a congenital heart defect at birth. Each year, more than 35,000 babies in the U.S. are born with congenital heart defects, some of which will require heart valve surgery and, potentially, replacement heart valve surgery.


The FDA has expanded the approval of a heart valve to include a size small enough to be used in newborn pediatric patients to treat heart defects. Specifically, the agency approved the Masters Series Mechanical Heart Valve with Hemodynamic Plus (HP) Sewing Cuff to include the 15-mm valve size, making it the smallest mechanical heart valve approved in the world. Prior to this approval, there have been limited replacement heart valve options available because of the patients’ small size. The Masters Series 15-mm HP valve represents an important treatment option for these patients.


The Master Series Mechanical Heart Valve is a rotatable, bileaflet (two-leaflet) valve designed for implantation in the aortic or mitral position. The bileaflet design consists of two semi-circular discs that open and close in response to blood pressure changes during the heartbeat, similar to a patient’s own valve. The Masters Series Mechanical Heart Valve was first approved in 1995 for patients with a diseased, damaged or malfunctioning aortic or mitral heart valve. The device is also approved for use in replacing previously implanted aortic or mitral prosthetic heart valves. The approval expands the range of valve sizes available, providing smaller patients another treatment option.


The FDA evaluated clinical data from a single-arm study of 20 pediatric patients with serious heart failure ranging in age from 1.5 weeks to 27 months at the time of mitral valve implant. The data showed that one year after the implant procedure, the probability of survival was 69.3% and the probability of not experiencing a valve-related adverse event was 66.8%. Serious valve-related adverse events observed during the study through one-year follow-up included blood clots in the device and bleeding in the brain. Anticoagulation (blood thinning) therapy may be necessary after the procedure, to prevent clotting on the device, which can increase the risk of bleeding. As a caution, the Master Series Mechanical Heart Valve should not be used by patients unable to tolerate anticoagulation therapy.


The FDA granted approval of the Master Series Heart Valve to St. Jude Medical.


Cauliflower Gratin with South Asian Spices

I spent a fair amount of time, experimenting with this recipe. I was in a cheesy mood but didn’t want to include pasta. I’m learning about and loving Middle Eastern and South Asian spices. I know that goat cheese and yogurt are used a lot but wasn’t sure how good these spices would be with typical Western cheeses. Hence, the need to experiment a lot. ©Joyce Hays, Target Health Inc.


This experiment had less cheddar, but just as good. ©Joyce Hays, Target Health Inc.



1 onion, chopped

2 scallions, chopped

2 shallots, chopped

15 fresh garlic cloves, sliced

1 jalapeno, seeds removed, well chopped

1 heaping teaspoon curry powder

1 teaspoon turmeric

1 teaspoon cardamom

1 cup fresh cilantro, chopped

1 teaspoon black mustard seeds, toasted

2 heads cauliflower, steam for 5 minutes, then break into bite size pieces

3 Tablespoons unsalted butter

1/2 cup almond or chickpea flour

1 cup almond milk, warmed

2 cups freshly grated mozzarella cheese

3 cups shredded extra-sharp cheddar cheese

1 cup grated muenster

2 cups ricotta

1 pinch black pepper

1/4 teaspoon freshly ground nutmeg

1-1/2 cups panko bread crumbs. Mix separately, the panko with the parmesan. Set aside.

1/2 cup grated Parmesan cheese

1 Tablespoons butter, melted, then add to Panko topping


Wonderful fresh ingredients. The seasonings are on a long shelf in the above left corner, conveniently located next to the stove. ©Joyce Hays, Target Health Inc.



1. Chop, slice, cut everything that needs this initial preparation.


Chopping everything on the same cutting board. ©Joyce Hays, Target Health Inc.


2. Preheat oven to 350o

3. Oil a very large baking dish

4. Sautee in olive oil, the onion, scallion, shallots, jalapeno, garlic. When onion and garlic are soft, add all other spices and seasoning and stir together well.


Cooking all the chopped veggies. ©Joyce Hays, Target Health Inc.


5. Toast the mustard seeds, then add them to the onion mixture.


In photo above, the mustard seeds are toasting. I love using toasted mustards seeds; they pack a huge amount of flavor in any recipe. ©Joyce Hays, Target Health Inc.


Adding seasoning, spices, seeds, etc. ©Joyce Hays, Target Health Inc.


Adding all chopped herbs to the pot – stir, cook and blend. ©Joyce Hays, Target Health Inc.


Add the grated cheese. Stir it in well. ©Joyce Hays, Target Health Inc.


Here the roux with added ricotta is ready to scrape into the large skillet. ©Joyce Hays, Target Health Inc.


6. Steam the cauliflower for 5 minutes or less. It needs to stay crisp. Drain; return to pot. When completely drained, pat with paper towel and put into the large oiled baking dish


Cauliflower was steamed and is now draining in the sink. ©Joyce Hays, Target Health Inc.


7. In a saucepan, melt 3 Tablespoons butter over medium heat. Stir in flour until smooth and make your roux; whisk in the warmed milk. Bring to a boil, stirring constantly; cook and stir 2-3 minutes or until thickened. Now, lower heat and stir in the ricotta very well.

8. Stir into the saucepan everything from the onion mixture. Make sure to mix very well into all of the milky ingredients.

9. Stir in muenster and cheddar cheeses.

10. Finally, pour all of the cheesy mixture over the cauliflower and toss well so that the vegetables are all covered with the cheesy mixture.


The above photo is just before sprinkling the mixture of panko, melted butter and parmesan, all over the top of the casserole. Then it goes into the oven. ©Joyce Hays, Target Health Inc.


11. In a separate bowl, toss bread crumbs with Parmesan cheese and melted butter; sprinkle over top of casserole.

12. Bake, uncovered, 30-40 minutes or until bubbly and top is golden brown.


One version with lots of cheddar cheese. ©Joyce Hays, Target Health Inc.


Above is another version. I cut down on the cheese and added precooked slices of turkey sausage. Yummy! ©Joyce Hays, Target Health Inc.


Same recipe but I left all cheddar out. Very delicious. I added the spot of broccoli, just to get some color when serving, and also with the photo in mind. This version was served with baked halibut. ©Joyce Hays, Target Health Inc.


This recipe goes extremely well with fish and seafood. Here it’s served with velvety wild salmon, and a ginger/garlic topping. ©Joyce Hays, Target Health Inc.


A dinner guest brought this chardonnay, The Vice. During the following week, we chilled then sampled it. We could not believe how delicious it was. We rarely order chardonnay. It’s usually too dry and tastes like it’s been stored in slate; we know that many like it for that very reason. But, back to The Vice: we liked it so much we wanted to order more. I tried my two, go-to wine stores in Manhattan, but they didn’t carry it. I knew our guest had bought it in the Sutton Place area, so used Google Maps to track a wine store and found Ambassador Wines. They had 4 bottles left and delivered them that day. You will not believe the price! I asked how anyone could make a profit and charge so little. I put in an order for 2 more cases, which arrived about two weeks later. The person who answers the phone at Ambassador Wine is knowledgeable. He agreed with my theory that this smooth wine was one of the sleepers that restaurants favor, for their assortment of house wines, served by the glass. Le Volte is another low cost tasty red Tuscan blend, used by many restaurants as their house wine-by-the-glass. ©Joyce Hays, Target Health Inc.


The Big Apple always loved Edward Albee, who passed away just a few years ago. This year NYC is honoring the great playwright, with two revivals: Three Tall Women, on B’way and At Home At The Zoo, off-B’way at Signature Theater, where we are patrons. We’re seeing the B’way production later this Spring. Saturday we saw the off-B’way production and loved it. The acting is superb. If you like Theater of the Absurd, you shouldn’t miss either of these Albee revivals.


We discovered a new seafood restaurant connected to the W Hotel on B’way and 47th Street, Blue Fin. The food was excellent, service was very good, casual dress— not fancy; we would go again.


Have a great week everyone!


From Our Table to Yours

Bon Appetit!


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