How Well Do You Know Your Spleen?
The spleen is an organ found in virtually all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood 1) ___. It is possible to remove the spleen without jeopardizing life. The spleen plays important roles in regard to red blood cells (also referred to as erythrocytes) and the immune system. It removes old red blood cells and holds a reserve of blood, which can be valuable in case of hemorrhagic shock, and also recycles iron. As a part of the mononuclear phagocyte system, it metabolizes hemoglobin removed from senescent erythrocytes. The globin portion of hemoglobin is degraded to its constitutive amino 2) ___, and the heme portion is metabolized to bilirubin, which is removed in the liver. The spleen synthesizes antibodies in its white pulp and removes antibody-coated bacteria and antibody-coated 3) ___ cells by way of blood and lymph node circulation.
A study using mice found that the spleen contains, in its reserve, half of the body’s monocytes within the red pulp. These monocytes, upon moving to injured tissue (such as the heart), turn into dendritic cells and macrophages while promoting tissue healing. The spleen is a center of activity of the mononuclear phagocyte system and can be considered analogous to a large lymph node, as its absence causes a predisposition to certain infections.
In humans, the spleen is brownish in color and is located in the left upper quadrant of the 4) ___, and is approximately 7 centimeters (2.8 in) to 14 centimeters (5.5 in) in length. It usually weighs between 150 grams (5.3 oz.) and 200 grams (7.1 oz.). An easy way to remember the anatomy of the spleen is the 1x3x5x7x9x11 rule. The spleen is 1″ by 3″ by 5″, weighs approximately 7 oz, and lies between the 9th and 11th ribs on the left hand side.
Visceral surface of the spleen
The diaphragmatic surface of the spleen (or phrenic surface) is convex, smooth, and is directed upward, backward, and to the left, except at its upper end, where it is directed slightly to the middle. It is in relation with the under surface of the diaphragm, which separates it from the ninth, tenth, and eleventh 5) ___ of the left side, and the intervening lower border of the left lung and pleura. The visceral surface of the spleen is divided by a ridge into two regions: an anterior or gastric and a posterior or renal. The gastric surface (facies gastrica) is directed forward, upward, and toward the middle, is broad and concave, and is in contact with the posterior wall of the stomach. Below this it is in contact with the tail of the pancreas. Near to its mid-border is a long fissure, termed the hilum. This is pierced by several irregular openings, for the entrance and exit of vessels and nerves. The renal surface (facies renalis) is directed medialward and downward. It is somewhat flattened, considerably narrower than the gastric surface, and is in relation with the upper part of the anterior surface of the left 6) ___and occasionally with the left suprarenal gland.
Like the thymus, the spleen possesses only efferent lymphatic vessels. The spleen is part of the 7) ___ system. Both the short gastric arteries and the splenic artery supply it with blood. The germinal centers are supplied by arterioles called penicilliary radicles. The spleen is unique in respect to its development within the gut. While most of the gut viscera are endodermally derived (with the exception of the neural-crest derived suprarenal gland), the spleen is derived from mesenchymal tissue. Specifically, the spleen forms within, and from, the dorsal mesentery. However, it still shares the same blood supply – the celiac trunk – as the foregut organs. Mesenchyme is a type of tissue characterized by loosely associated cells that lack polarity and are surrounded by a large extracellular matrix. Mesenchymal cells are able to develop into the tissues of the lymphatic and circulatory systems, as well as connective 8) ___ throughout the body, such as bone and cartilage. Endoderm is one of the three primary germ 9) ___ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer), with the endoderm as the innermost layer.
Other functions of the spleen are less prominent, especially in the healthy adult:
- Production of opsonins, properdin, and tuftsin.
- Creation of red blood cells. While the bone marrow is the primary site of the matopoiesis in the adult, the spleen has important hematopoietic functions up until the fifth month of gestation. After birth, erythropoietic functions cease, except in some hematologic disorders. As a major lymphoid organ and a central player in the reticuloendothelial system, the spleen retains the ability to produce lymphocytes and, as such, remains an hematopoietic organ.
- Storage of red blood cells, lymphocytes and other formed elements. In horses, roughly 30% of the red blood cells are stored there. The red blood cells can be released when needed. In humans, up to a cup (236.5 ml) of red blood cells can be held in the spleen and released in cases of hypovolemia. It can store platelets in case of an emergency and also clears old platelets from the circulation. Up to a quarter of lymphocytes can be stored in the spleen at any one time.
Enlarged spleen can signify disorders which include splenomegaly, where the spleen is enlarged for various reasons, such as cancer, specifically blood-based leukemias, and asplenia, where the spleen is not present or functions abnormally. Traumas, such as a motor vehicle accident, can cause rupture of the spleen, which is a situation requiring immediate medical attention. Asplenia refers to a non-functioning spleen, which may be congenital or due to surgical removal. These may cause:
- modest increases in circulating white blood cells and platelets,
- diminished responsiveness to some vaccines,
- increased susceptibility to 10) ___ by bacteria and protozoa; in particular, there is an increased risk of sepsis from polysaccharide encapsulated bacteria. Encapsulated bacteria inhibit binding of complement or prevent complement assembled on the capsule from interacting with macrophage receptors. Natural antibodies are required for phagocytosis, which are immunoglobulins that facilitate phagocytosis either directly or by complement deposition on the capsule. They are produced by IgM memory B cells in the marginal zone of the spleen. Splenectomy greatly diminishes the frequency of memory B cells.
A 28-year follow-up of 740 World War II veterans who had their spleens removed (splenectomy), on the battlefield, showed a significant increase in the usual death rate from pneumonia (6 rather than the expected 1.3) and an increase in the death rate from ischemic heart disease (4.1 rather than the expected 3) but not from other conditions.
The word spleen comes from the Ancient Greek, and is the idiomatic equivalent of the heart in English, i.e. to be good-spleened means to be good-hearted or compassionate. In English the word spleen was customary during the period of the 18th century. Authors like Richard Blackmore or George Cheyne employed it to characterize the hypochondriacal and hysterical affections. William Shakespeare, in Julius Caesar uses the spleen to describe Cassius’ irritable nature.
Must I observe you? must I stand and crouch
Under your testy humour? By the gods
You shall digest the venom of your spleen,
Though it do split you; for, from this day forth,
I’ll use you for my mirth, yea, for my laughter,
When you are waspish.
In French, splenetique refers to a state of pensive sadness or melancholy. It has been popularized by the poet Charles Baudelaire (1821-1867) but was already used before in particular to the Romantic literature (19th century). The word for the organ is rate. The connection between spleen (the organ) and melancholy (the temperament) comes from the humoral medicine of the ancient Greeks. One of the humors (body fluid) was the black bile, secreted by the spleen organ and associated with melancholy. In contrast, the Talmud (tractate Berachoth 61b) refers to the spleen as the organ of laughter while possibly suggesting a link with the humoral view of the organ. In eighteenth- and nineteenth-century England, women in bad humor were said to be afflicted by the spleen, or the vapors of the spleen. In modern English, to vent one’s spleen means to vent one’s anger, e.g. by shouting, and can be applied to both males and females. Similarly, the English term splenetic is used to describe a person in a foul mood.
ANSWERS: 1) filter; 2) acids; 3) blood; 4) abdomen; 5) ribs; 6) kidney; 7) lymphatic; 8) tissues; 9) cell; 10) infection
Captain Meriwether Lewis and Captain William Clarke: Medical Practices of Early 1800s Expeditions
In April 1803, The United States, under President Thomas Jefferson, purchased 828,000 square miles (2,144,510 square km) of land from France. This land acquisition is commonly known as the Louisiana Purchase. The U.S. paid 50 million francs ($11,250,000) plus cancellation of debts worth 18 million francs ($3,750,000), a total sum of 15 million dollars (around 4 cents per acre), for the Louisiana territory ($236 million in 2013 dollars, less than 42 cents per acre). The lands included in the Louisiana Purchase were those west of the Mississippi River but they were largely unexplored and therefore completely unknown to both the U.S. and France at the time. Because of this, shortly after the purchase of the land President Jefferson requested that Congress approve $2,500 for an exploratory expedition west.
The Purchase (white area) was one of several territorial additions to the U.S.
Once Congress approved the funds for the expedition, President Jefferson chose Captain Meriwether Lewis as its leader. Lewis was chosen mainly because he already had some knowledge of the west and was an experienced Army officer. After making further arrangements for the expedition, Lewis decided he wanted a co-captain and selected another Army officer, William Clark. The goals of this expedition, as outlined by President Jefferson, were to study the Native American tribes living in the area as well as the plants, animals, geology and terrain of the region. The expedition was also to be a diplomatic one and aid in transferring power over the lands and the people living on them from the French and Spanish to the United States. In addition, President Jefferson wanted the expedition to find a direct waterway to the West Coast and the Pacific Ocean so westward expansion and commerce would be easier to achieve in the coming years.
The Lewis and Clark expedition officially began on May 21, 1804 when they and the 33 other men making up the Corps of Discovery departed from their camp near St. Louis, Missouri. The first portion of the expedition followed the route of the Missouri River during which, they passed through places such as present-day Kansas City, Missouri and Omaha, Nebraska. On August 20, 1804, the Corps experienced its first and only casualty when Sergeant Charles Floyd died of appendicitis. He was the first U.S. soldier to die west of the Mississippi River. The expedition returned to St. Louis on September 23, 1806. President Jefferson knew that no doctors would accompany the expedition and that there were no hospitals to be found once the crew left the St. Louis area. He therefore sent Capt. Meriwether Lewis to Philadelphia to spend three months learning not just the scientific subjects of biology, botany, zoology and map making, but how to take care of his expeditions health needs. Dr. Benjamin Rush was Lewis’ contact with the American Philosophical Society. Dr. Rush was considered to be one of the leading physicians and thinkers of his time. Dr. Rush had signed the Declaration of Independence as a Pennsylvania delegate in 1776, was instrumental in stopping a yellow fever outbreak in Philadelphia in 1793, and with John Adams was thought to have authored several of the so-called Federalist Papers in support of the US Constitution as it was being ratified by the states after the Constitutional Convention.
When the Lewis and Clark expedition left St. Louis in May of 1804 the captains knew that they would face many challenges; not the least of which would be the many illnesses and injuries that plagued them all the way to the Pacific and back! Lewis’s crash course in medicine would be put to good use as he faced cases of: heatstroke, frostbite, hypothermia, a dislocated shoulder, strained back, various cuts and bruises (from cacti, an axe, etc.), diarrhea/dysentery, syphilis, boils, a gunshot wound, fleas, lice, and other pests. There were also less clear cut ailments like ague (fever and chills), intestinal disorders, and stomach complaints. Such disorders might have been caused by bugs (fleas, ticks, mosquitoes) parasites in the food and water of the expedition, malaria, or other viral infections. In the Journals of Lewis and Clark, the reader finds instances in which both explorers make reference to illness, and medical treatment. Clark served as camp doctor right along with Lewis. Even though Clark had not had the advantage of formal training, he would have shared Lewis’s frontier upbringing and military background, so was quite proficient at ministering to the medical needs of his men. It is obvious that Dr. Rush had an impact on the young captains. On July 7, 1804, Clark wrote that one man verry Sick, Struck with the Sun. He was referring to Robert Frazer, who according to Dr. David Peck, was probably suffering from heatstroke or heat exhaustion. The logical treatment for either ailment would have been shade, rest, and the consumption of liquids to re-hydrate the soldier. Clark wrote that Capt. Lewis bled him & gave Niter which has revived him much. In this case, Dr. Peck notes that bloodletting probably worsened Frazer’s condition, leading to even further dehydration and exhaustion. Though Frazer survived, it was probably NOT due to Lewis’s treatment! Clark used bloodletting on at least two other occasions that are noted in the journals. On January 26, 1805 one of the men was diagnosed with pleurisy (an infection of the lungs and or chest cavity), and Clark wrote that he treated this man with a Bleed. Clark also used the lancet on Sacagawea (Sioux guide) after she became ill in June of 1805. On the 10th of that month, he noted that our Indian woman verry sick and recorded that he blead her. Though we do not know what afflicted Sacagawea, Clark showed great concern for the young Indian mother, and tried several different treatments before affecting a cure.
In September of 1805 (September 23 to October 1st), Clark wrote that the men were suffering from Lax & heaviness at the stomach and a running of the bowels. His journal over several days is practically a hospital daybook. He related that Capt. Lewis scarcely able to ride on a jentle horse – Several men So unwell that they were Compelled to lie on the Side of the road – 3 parts of the Party sick – Capt. Lewis very sick and finally that he himself was a little unwell. Clark attacked the illness, probably dysentery caused by a change in diet, with Rush’s pills. Was it appropriate to give men disabled by dysentery a powerful purgative? Such treatment gave them even worse diarrhea and caused greater intestinal irritation, and dehydration, but was the accepted medical treatment of the day. There are countless examples of the Captain’s using purgatives in the journals; it was definitely the treatment of choice on the expedition!
On several occasions in the journals we see both the influence of the captains’ military background and Dr. Rush’s training. This was evident in the treatment of syphilis. Syphilis was considered a routine disease in the military in the early 19th century, and Lewis and Clark were well prepared to treat the disorder. It is obvious in reading the journals that the men had sexual contact with native women. Clark noted on October 12th of 1804 that the Sioux had a curious custom, as did the Arikara, which was to give handsom squars to those whome they wish to Show some acknowledgements to. He goes on to note that the party had got clare [clear] of the Sioux without taking their squars. But by October 15, 1804 Clark noted that the party had arrived at the Camp of the Arikara, and that Their womin [were] verry fond of caressing our men &c. By March of 1805 he noted that the men were Generally helthy except Venerials Complaints which is very Common amongst the natives and the men Catch it from them. On January 7th 1806, Lewis described the incidence of venereal disorders which he observed amongst the natives of the Columbia River Valley. On that same day, he made a note that one of his men, Goodrich, has recovered from the Louis Veneri [syphilis] which he contracted from an amourous contact with a Chinnook damsel. Lewis cured Goodrich, with the uce of mercury and tried to determine if the natives had any simples or cures for the disease but determined that they did not. He also noted that both gonorrhea and syphilis existed amongst the native tribes west of the Rockies, but that the incidence of these diseases had declined when compared to the natives of the Plains. In July of 1806, Lewis reported that two of the men, Goodrich and McNeal were both very unwell with the pox which they contracted last winter with the Chinnook women and determined to make use of an interval of rest [so that] they can use the mercury freely. The use of calomel or mercury to treat syphilis was extremely common in the early 19th century; But the administration of mercury to cure a nasty problem was a very sharp double-edged sword. Mercury is toxic to the spirochete that causes syphilis, but it can also be toxic to the patient. The medicine could be given in one of two forms, orally (usually by pill – calomel) or via a salve (usually applied under the arm). The topical application tended to work more slowly, but was safer as the mercury was absorbed slowly into the system. With either application, side effects of the mercury could cut nearly as deep as the syphilitic bacteria. It was generally known that treatment should end when the patient began to salivate excessively. Today we know that salivation is the first sign of mercury poisoning. In addition to salivation, patients often experienced mouth sores and bad breath. Their teeth often became loose or fell out, and their mouths turned brown. In severe cases a patient might suffer inflammation to the mouth, throat, and intestines, causing pain, nausea, vomiting and diarrhea. If exposure to the mercury continued, and the poisoning became chronic, the patient would experience a red body rash, sweating, loss of appetite, increased heart rate, and might suffer kidney failure and death. Though Lewis’s treatment of his men in this case could have been lethal, there was little alternative. At least with mercury there was a chance that the disease could be stopped before it advanced to the second stage or beyond. Why didn’t the captains ask their men to abstain from encounters, or use some sort of contraceptive device to lessen their risk of infection? Lewis and Clark did ask the men to abstain for a time at Fort Clatsop on the Pacific Coast, but their reasons were related to commerce not the prevention of disease.
Lewis and Clark would be forced to deal with many medical problems on their expedition. While the training that Lewis received from Dr. Rush was evident in his use of bloodletting and purgatives, we can also see the influence of his mother’s herbal arts, and his military discipline and training. The Corps of Discovery would travel over 8,000 miles from 1804 to 1806, and only suffered one death. Sgt. Charles Floyd would become ill on August 19th(1804). Clark noted that Serjeant Floyd is taken verry bad all at once with a Biliose Chorlick we attempt to relieve him without success yet. Floyd grew worse over night and was dead within days. Most historians agree that Floyd was probably suffering from appendicitis, which would have proved fatal even had he been attended by Dr. Rush himself. It is amazing that the Corps which consisted of 33 men (and Sacagawea) was able to travel so far, with so few fatalities. But, as Dr. E. G. Chuinard stated in his book Only One Man Died, the generally non-scientific basis of medical practice at the time permitted to care for their men as well as a graduate physician of the day might have done. Throughout the journals, the men of the expedition exhibit only confidence in their captains. Even in the case of Sgt. Floyd’s death there is no hint of criticism. Patrick Gass wrote, Floyd died, notwithstanding every possible effort [that] was made by the commanding officers, and other persons, to save his life.
Though many of the treatments used by Lewis and Clark offered little potential for real healing, and may have done more harm than good, the men would have received nothing better in a 19th century hospital. Medical technology simply had not reached a professional state by 1804. Doctors, like Benjamin Rush followed inaccurate theories, guessed at the cause of disease, and used treatments that were as likely to kill as to heal. As physicians, Lewis and Clark both performed admirably. They showed care and concern for the men under their command and even for the Indians they met. They used all the information available to them at the time to keep the Corps safe and healthy. The practical skills of most doctors of the day were not much better than those possessed by Meriwether Lewis, and as an amateur, Lewis was probably more conservative in his treatments than a trained physician, whose unfounded confidence in his medical abilities would likely have made him more aggressive. Lewis and Clarks’ conservative treatments probably helped to insure the health of their party. The expedition they led was an absolute success. The captains not only opened the west, they brought every man but one home with them, safe and sound!
Dr. Benjamin Rush advised Lewis on rules to promote the good health of his men. He also compiled a list of medical supplies that would be needed for the trip. It was under the guidance of Dr. Rush that Lewis learned the scientific medicine that was practiced throughout the twenty-eight month journey into the unknown. Medical practices had not changed much in over two hundred years by the time of the early 1800s. Most of the scientific treatments of the period were useless and some were even harmful. Yet at that time, they were considered state of art. It is often said that the members of the Corps of Discovery survived in spite of their medical treatments.
Dr. Rush had prepared a list of medical supplies for the expedition: total cost $90.69. Among the items purchased in St. Louis were:
Peruvian bark (quinine-3500 doses)
Glauber salts (sodium sulfide)
Niter (potassium nitrate/saltpeter)
Tartar emetic (1100 doses)
Chief among the medicines was 50 dozen Dr. Rush’s patented pills (also known as ?Thunderclappers’). The pills were composed of calomel (a mixture of six parts mercury to one part chlorine), and jalap (eds note: jalapeno is a form of jalap). Each portion of the concoction was a purgative of explosive power the combination was awesome. Dr. Rush suggested that if one pill didn’t do the trick, you could take two or three. In their early journals, references to health care are frequent. Capt. William Clark recorded that:
I have a bad cold with a sore throat. June 3, 1804.
On June 16th, Clark observes the Mosquitoes and Ticks are noumerous & bad.
On June 17th, Clark writes the party is much aflicted by boils and several have deassentary which I contribute to the water (which is muddy).
On July 4th (near present day Atchison, Kansas), Sgt. Ordway wrote: Fields got bit by a snake, which was quickly doctored by bark by Cap. Lewis. A poultice of bark and gunpowder was sufficient to cure the wound.
Also on July 4th, Pvt. Whitehouse noted: The day mighty hot when we went to toe the Sand, (s)calded our (feet) some fled from the rope had to put on our mockisons.
On July 7th, near St. Michael’s Meadow (present day St. Joseph, Missouri), Clark wrote: one man verry sick, struck with the Sun. Capt. Lewis bled him and gave Niter which has revived him much.
July 8th saw five men sick today with a violent head ake &c.
By July 10th Clark had written our men all getting well but much fatigued.
And, so it goes: The men were chased by bears, teased by prairie dogs, fell off river bluffs, suffered mild frostbite, and acquired a variety of other ills and complaints along the way. Lewis nearly died on the return trip when he was accidentally shot in the hip (buttocks) by Pierre Cruzatte during an elk hunt. He writes on October 18, 1806: with the assistance of Sgt. Gass I took off my cloaths and dressed my wounds myself as well as I could, introducing tents of patent lint in the ball holes, the wound blead considerably but I was hapy to find that it had touched neither bone nor artery my wounds being so situated that I could not move without infinite pain as it was painful to me to be removed I slept on board the perogue; the pain I experienced excited a high fever and I had a very uncomfortable night.
Ceremony at Place d’Armes, New Orleans marking transfer of Louisiana to the United States, 10 March 1804, as depicted by Thure de Thulstrup.
Sources: Wikipedia; http://lewis-clark.org/content/content-article.asp?ArticleID=2561; https://pharmacy.wisc.edu/sites/default/files/content/american-institute-history-pharmacy/resources-teaching/AC8.pdf
Fatal Anaphylaxis in the United States – Pharma Take Note
Anaphylaxis is a life-threatening type of allergic reaction.
Anaphylaxis-related deaths in the United States have not been well characterized in recent years. As a result, a study published online in the Journal of Allergy and Clinical Immunology (14 September 2014), sought to define epidemiologic features and time trends of fatal anaphylaxis in the United States from 1999 to 2010.
For the study, anaphylaxis-related deaths were identified by using the 10th clinical modification of the International Classification of Diseases system diagnostic codes on death certificates from the US National Mortality Database. Rates were calculated by using census population estimates.
Results showed that there were a total of 2,458 anaphylaxis-related deaths in the United States from 1999 to 2010, with medications being the most common cause (58.8%), followed by unspecified (19.3%), venom (15.2%), and food (6.7%). There was a significant increase in fatal drug-induced anaphylaxis over 12 years: from 0.27 per million in 1999 to 2001 to 0.51 per million in 2008 to 2010 (P <0.001). Fatal anaphylaxis caused by medications, food, and unspecified allergens was significantly associated with African American race and older age (P <0.001). Fatal anaphylaxis to venom was significantly associated with white race, older age, and male gender. The rates of fatal anaphylaxis to foods in male African American subjects increased from 0.06 per million in 1999 to 2001 to 0.21 per million in 2008 to 2010 (P <0.001). The rates of unspecified fatal anaphylaxis decreased over time from 0.30 per million in 1999 to 2001 to 0.09 per million in 2008 to 2010 (P <0.001).
According to the authors, there are strong and disparate associations between race and specific classes of anaphylaxis-related mortality in the United States and that the increase in medication-related deaths caused by anaphylaxis likely relates to increased medication and radiocontrast imaging agents used to enhance diagnosis, and coding changes.
Benzodiazepine Use and Risk of Alzheimer’s Disease
According to an article published online in the British Medical Journal (09 September 2014), a case-control study was performed from data derived from the Quebec health insurance program database (RAMQ), in order to investigate the relation between the risk of Alzheimer’s disease (AD) and exposure to benzodiazepines started at least five years before.
Study participants included 1,796 people with a first diagnosis of AD and followed up for at least six years before were matched with 7,184 controls on gender, age group, and duration of follow-up. Both groups were randomly sampled from older people (age >66) living in the community in 2000-09.
The main outcome measure was the association between AD and benzodiazepine use started at least five years before diagnosis, considering both the dose-response relation and prodromes (anxiety, depression, insomnia) possibly linked with treatment. Ever exposure to benzodiazepines was first considered and then categorized according to the cumulative dose expressed as prescribed daily doses (1-90, 91-180, >180) and the drug elimination half-life.
Results showed that during the study period, 894 people with AD (49.8%) and 2,873 controls (40.0%) had ever used benzodiazepines, with treatment still active at the date of the diagnosis of dementia in 64.8% of cases and 60.6% of controls. The proportion of cumulative exposures of six or fewer months (that is, <180 prescribed daily doses (PDDs)) did not substantially differ between the groups. Conversely, long term use (that is, >180 PDDs or cumulative exposure over six months) was markedly more common among people with AD (32.9%) than controls (21.8%). The excess of benzodiazepine use in cases concerned products with both short (32.6% v 27.8%) and long half life (17.2% v 12.2%).
A history of myocardial infarction (MI) was less common among people with AD than controls (3.4% v 4.6%). The opposite was found for stroke (7.0% v 5.8%), hypercholesterolaemia (20.9% v 16.5%), and anxiety (21.4% v 15.1%). No difference was observed for the other covariates.
According to the authors, benzodiazepine use is associated with an increased risk of AD and the stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. The authors added that unwarranted long term use of these drugs should be considered as a public health concern.
Regulatory Science Collaborations Support Emergency Preparedness
FDA’s Medical Countermeasures Initiative (MCMi) is working with federal agencies (through the Public Health Emergency Medical Countermeasures Enterprise), product developers, healthcare professionals, and researchers, among other partners, to help translate cutting-edge science and technology into safe, effective medical countermeasures. Through these collaborations, MCMi supports research to help develop solutions to complex regulatory science challenges.
These data are critical to help FDA evaluate the safety and effectiveness of medical countermeasures -products that can save lives – during public health emergencies. But collecting data in the midst of an emergency is exceptionally challenging. Working with the Biomedical Advanced Research and Development Authority (BARDA), FDA is teaming with critical care physicians nationwide to help address these challenges. Under a contract awarded last month, FDA and BARDA will work with the U.S. Critical Illness and Injury Trials Group (USCIITG) to gather important information about medical countermeasures used during public health emergencies. Physicians will help address challenges with collecting and sharing data rapidly in emergencies, including streamlining electronic case reporting for clinical trials and rapidly disseminating key findings to FDA and other stakeholders to support clinical decision-making.
During this four-year project, USCIITG will also develop and pre-position a simple influenza treatment protocol in 10 hospitals throughout the U.S. during the 2015-2016 influenza season. The project will help doctors more easily use an investigational treatment protocol for patients with severe influenza, and test the data collection and reporting system during peak times. The goal is to help streamline the process during future influenza seasons and emergencies. When it is not ethical or feasible to test the effectiveness of products in humans – such as countermeasures for potential bioterror agents – products may be approved under the Animal Rule. The animal rule allows for drugs to be approved based solely on animal studies when clinical trials in humans is not feasible (e.g. drugs to treat bioterrorism attacks; cipro to treat anthrax). When products are approved under the Animal Rule, FDA requires additional studies, called phase 4 clinical trials, to confirm safety and effectiveness. In addition to the MCMi work, BARDA is funding USCIITG to investigate conducting phase 4 clinical studies during public health emergencies. USCIITG partners will train on these protocols, have them reviewed through their Institutional Review Boards (a requirement for all human studies), and create plans for enactment. USCIITG will then conduct an annual exercise to test these plans, a unique approach to broader science preparedness.
MCMi has also recently awarded regulatory science contracts to support other aspects of emergency preparedness, including two projects to investigate decontamination and reuse of respirators in public health emergencies (awarded to Battelle and Applied Research Associates, Inc.), and an award to support appropriate public use of medical countermeasures through effective emergency communication.
Our work involves big challenges. Through regulatory science, and through new and expanding collaborations, we continue to address these challenges to better prepare our nation to use medical countermeasures in emergencies.
Want to help? FDA is currently accepting submissions for additional research to support medical countermeasure preparedness. If you have an idea for a new medical countermeasure regulatory science collaboration, please contact FDA.
October Pumpkin Delice
1 cup pumpkin puree
1 teaspoon ground cinnamon
1 1/2 cups Cool Whip
1/2 cup dark brown sugar substitute or brown Splenda
1 1/4 cups mascarpone
Chocolate bits (you choose)
Gather all the ingredients together, before you start anything else. ©Joyce Hays, Target Health Inc.
- In a mixing bowl, combine the pumpkin puree with the ground cinnamon.
- In another bowl, add the cool whip, brown Splenda and mascarpone.
- Stir until all the ingredients are combined, but don’t stir a lot or the stiffness of the cool whip will disappear.
- Now, carefully fold the pumpkin puree into the cool whip mixture using a rubber spatula.
- Fold until everything is somewhat mixed, but leave separate streaks of the orange pumpkin mixture, and the white-ish cool whip mixture
Use individual clear glass dessert dishes. In the bottom of each individual dish, mix one teaspoon of wheat germ and a few chocolate bits.
If you want to improvise here, at the bottom of the dessert dish, add anything you want or have left-over. For example, crumble up a favorite cookie, or a small piece of pound cake. For my blueberry dessert, in the bottom of the dessert dish, I crumble up half of a weight watchers blueberry muffin; then I pour over that, the blueberry puree concoction. For the next batch of pumpkin puree desserts, I’m thinking of adding 1 or 2 teaspoons of Amaretto in bottom of glass dish, then mix in the 1 teaspoon of wheat germ, then add the pumpkin parfait. Or to the bottom add 1 Tablespoon glazed chestnuts with or without the Amaretto. Or part of a baked apple etc. etc etc.
- Now add the streaked pumpkin mixture into the dessert dishes.
- Sprinkle the top of each dish with a few wheat germ crumbs and/or a few chocolate chips
- Refrigerate for at least one hour, and up to 24 hours, before serving
Here we are again, toward the end of the week already. In between new contracts, contracts in progress, new hires, legal stuff (meeting with one of our two favorite lawyers), constant reading to keep up, HR issues, investments, company maintenance, company expansion, writing the newsletter, and on and on, I got some time for a few new recipes. Some lamb meatballs with pine nuts tucked into the center; a shrimp avocado mango salad and this Pumpkin Delice is my latest. This dessert is quick and easy to make. My only issue with it is that, it’s not too sweet. If you like not too sweet you’ll like this. I think the next time I make this, I’ll add candied chestnuts to the recipe. Chestnuts are a Fall favorite and so is pumpkin; I think this addition of glazed chestnuts would add greatly to the flavor. I would fold in 1 cup candied chestnuts, as the last ingredient to fold into the pumpkin, mascarpone, cool whip mixture.
My dear husband, critic and guinea pig, agrees. He liked this dessert but thought it could use an additional, he didn’t say what, but I can easily fill in the blank. You wouldn’t believe what we had for dinner before the pumpkin dessert, so I won’t say. I will say that twice a week, we’re going to dine on a low-cal veggie puree soup, as the main dish, with white wine and a low fat, low calorie dessert. We’re trying to stay in shape, is why.
Having said that, on Saturday we’re seeing a new B’way play with dinner at an excellent French restaurant. Because the restaurants in Manhattan are so good, we’ve got to cut down somewhere. We’ve chosen the veggie soup dinner diet for Tuesday and Thursday nights, as the way to cut down.
Hope your week and weekend went well. Here’s to happiness and success for the coming week!
We had Cloudy Bay (New Zealand) Sauvignon Blanc, well chilled with the dinner ending with Pumpkin Delice. ©Joyce Hays, Target Health Inc.
From Our Table to Yours!
The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry for 2014 to Eric Betzig of Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA; Stefan W. Hell of Max Planck Institute for Biophysical Chemistry, Göttingen, and German Cancer Research Center, Heidelberg, Germany; and William E. Moerner of Stanford University, Stanford, CA, USA, “for the development of super-resolved fluorescence microscopy.”
Surpassing the limitations of the light microscope
For a long time optical microscopy was held back by a presumed limitation: that it would never obtain a better resolution than half the wavelength of light. Helped by fluorescent molecules the Nobel Laureates in Chemistry 2014 ingeniously circumvented this limitation. Their ground-breaking work has brought optical microscopy into the nanodimension.
In what has become known as nanoscopy, scientists visualize the pathways of individual molecules inside living cells. They can see how molecules create synapses between nerve cells in the brain; they can track proteins involved in Parkinson’s, Alzheimer’s and Huntington’s diseases as they aggregate; they follow individual proteins in fertilized eggs as these divide into embryos.
It was all but obvious that scientists should ever be able to study living cells in the tiniest molecular detail. In 1873, the microscopist Ernst Abbe stipulated a physical limit for the maximum resolution of traditional optical microscopy: it could never become better than 0.2 micrometres. Eric Betzig, Stefan W. Hell and William E. Moerner are awarded the Nobel Prize in Chemistry 2014 for having bypassed this limit. Due to their achievements the optical microscope can now peer into the nanoworld.
Two separate principles are rewarded. One enables the method stimulated emission depletion (STED) microscopy, developed by Stefan Hell in 2000. Two laser beams are utilized; one stimulates fluorescent molecules to glow, another cancels out all fluorescence except for that in a nanometre-sized volume. Scanning over the sample, nanometre for nanometre, yields an image with a resolution better than Abbe’s stipulated limit.
Eric Betzig and William Moerner, working separately, laid the foundation for the second method, single-molecule microscopy. The method relies upon the possibility to turn the fluorescence of individual molecules on and off. Scientists image the same area multiple times, letting just a few interspersed molecules glow each time. Superimposing these images yields a dense super-image resolved at the nanolevel. In 2006 Eric Betzig utilized this method for the first time.
Today, nanoscopy is used world-wide and new knowledge of greatest benefit to humankind is produced on a daily basis.
Nobel Foundation. “2014 Nobel Prize in Chemistry: Super-resolved fluorescence microscopy.” ScienceDaily. ScienceDaily, 8 October 2014. <www.sciencedaily.com/releases/2014/10/141008085419.htm>.
Sea ice surrounding Antarctica reached a new record high extent this year, covering more of the southern oceans than it has since scientists began a long-term satellite record to map sea ice extent in the late 1970s. The upward trend in the Antarctic, however, is only about a third of the magnitude of the rapid loss of sea ice in the Arctic Ocean.
The new Antarctic sea ice record reflects the diversity and complexity of Earth’s environments, said NASA researchers. Claire Parkinson, a senior scientist at NASA’s Goddard Space Flight Center, has referred to changes in sea ice coverage as a microcosm of global climate change. Just as the temperatures in some regions of the planet are colder than average, even in our warming world, Antarctic sea ice has been increasing and bucking the overall trend of ice loss.
“The planet as a whole is doing what was expected in terms of warming. Sea ice as a whole is decreasing as expected, but just like with global warming, not every location with sea ice will have a downward trend in ice extent,” Parkinson said.
Since the late 1970s, the Arctic has lost an average of 20,800 square miles (53,900 square kilometers) of ice a year; the Antarctic has gained an average of 7,300 square miles (18,900 sq km). On Sept. 19 this year, for the first time ever since 1979, Antarctic sea ice extent exceeded 7.72 million square miles (20 million square kilometers), according to the National Snow and Ice Data Center. The ice extent stayed above this benchmark extent for several days. The average maximum extent between 1981 and 2010 was 7.23 million square miles (18.72 million square kilometers).
The single-day maximum extent this year was reached on Sept. 20, according to NSIDC data, when the sea ice covered 7.78 million square miles (20.14 million square kilometers). This year’s five-day average maximum was reached on Sept. 22, when sea ice covered 7.76 million square miles (20.11 million square kilometers), according to NSIDC.
A warming climate changes weather patterns, said Walt Meier, a research scientist at Goddard. Sometimes those weather patterns will bring cooler air to some areas. And in the Antarctic, where sea ice circles the continent and covers such a large area, it doesn’t take that much additional ice extent to set a new record.
“Part of it is just the geography and geometry. With no northern barrier around the whole perimeter of the ice, the ice can easily expand if conditions are favorable,” he said.
Researchers are investigating a number of other possible explanations as well. One clue, Parkinson said, could be found around the Antarctic Peninsula — a finger of land stretching up toward South America. There, the temperatures are warming, and in the Bellingshausen Sea just to the west of the peninsula the sea ice is shrinking. Beyond the Bellingshausen Sea and past the Amundsen Sea, lies the Ross Sea — where much of the sea ice growth is occurring.
That suggests that a low-pressure system centered in the Amundsen Sea could be intensifying or becoming more frequent in the area, she said — changing the wind patterns and circulating warm air over the peninsula, while sweeping cold air from the Antarctic continent over the Ross Sea. This, and other wind and lower atmospheric pattern changes, could be influenced by the ozone hole higher up in the atmosphere — a possibility that has received scientific attention in the past several years, Parkinson said.
“The winds really play a big role,” Meier said. They whip around the continent, constantly pushing the thin ice. And if they change direction or get stronger in a more northward direction, he said, they push the ice further and grow the extent. When researchers measure ice extent, they look for areas of ocean where at least 15 percent is covered by sea ice.
While scientists have observed some stronger-than-normal pressure systems — which increase winds — over the last month or so, that element alone is probably not the reason for this year’s record extent, Meier said. To better understand this year and the overall increase in Antarctic sea ice, scientists are looking at other possibilities as well.
Melting ice on the edges of the Antarctic continent could be leading to more fresh, just-above-freezing water, which makes refreezing into sea ice easier, Parkinson said. Or changes in water circulation patterns, bringing colder waters up to the surface around the landmass, could help grow more ice.
Snowfall could be a factor as well, Meier said. Snow landing on thin ice can actually push the thin ice below the water, which then allows cold ocean water to seep up through the ice and flood the snow — leading to a slushy mixture that freezes in the cold atmosphere and adds to the thickness of the ice. This new, thicker ice would be more resilient to melting.
“There hasn’t been one explanation yet that I’d say has become a consensus, where people say, ‘We’ve nailed it, this is why it’s happening,'” Parkinson said. “Our models are improving, but they’re far from perfect. One by one, scientists are figuring out that particular variables are more important than we thought years ago, and one by one those variables are getting incorporated into the models.”
For Antarctica, key variables include the atmospheric and oceanic conditions, as well as the effects of an icy land surface, changing atmospheric chemistry, the ozone hole, months of darkness and more.
“Its really not surprising to people in the climate field that not every location on the face of Earth is acting as expected — it would be amazing if everything did,” Parkinson said. “The Antarctic sea ice is one of those areas where things have not gone entirely as expected. So it’s natural for scientists to ask, ‘OK, this isn’t what we expected, now how can we explain it?'”
NASA/Goddard Space Flight Center. “Antarctic sea ice reaches new record maximum.” ScienceDaily. ScienceDaily, 8 October 2014. <www.sciencedaily.com/releases/2014/10/141008122102.htm>.
In a ground-breaking research project at the University of Gothenburg, seven Swedish women have had embryos reintroduced after receiving wombs from living donors. Now the first transplanted woman has delivered a baby — a healthy and normally developed boy. The world-unique birth was acknowledged in The Lancet on 5 October.
The uterus transplantation research project at the University of Gothenburg started in 1999 and has been evaluated in over 40 scientific articles. The goal of the Gothenburg project is to enable women who were born without a womb or who have lost their wombs in cancer surgery to give birth to their own children.
Nine women in the project have received a womb from live donors — in most cases the recipient’s mother but also other family members and close friends. The transplanted uterus was removed in two cases, in one case due to a serious infection and in the other due to blood clots in the transplanted blood vessels.
The seven remaining women have in 2014 tried to become pregnant through a process where their own embryos, produced through IVF, are reintroduced to the transplanted uterus.
First child from a transplanted uterus
The first early pregnancy was confirmed in the spring after a successful first pregnancy attempt in a woman in her mid-30s, a little over a year after her transplantation.
In early September, the woman successfully delivered a baby by caesarean section, making her the first woman in the world to deliver a child from a transplanted uterus. Her uterus was donated by a 61-year-old unrelated woman.
The caesarean section had to be performed earlier than planned: the woman developed preeclampsia in week 32 of her pregnancy and the CTG indicated that the baby was under stress. A caesarean section was performed in accordance with normal clinical routines so as not to risk the health of the mother and child.
According to Professor Mats Brännström, who performed the caesarean section, the perfectly healthy newborn boy is developing normally. The baby weighed 1,775 grams (3 lbs 14.6 oz) at birth, which is normal size considering the gestational age at delivery.
‘The baby screamed right away and has not required any other care than normal clinical observation at the neonatal unit. The mother and child are both doing well and have returned home. The new parents are of course very happy and thankful,’ says Professor Mats Brännström, who is leading the research project.
‘The reason for the woman’s preeclampsia is unknown, but it may be due to her immunosuppressive treatment combined with the fact that she is missing one kidney. The age of the donated womb may also be a factor. Also, preeclampsia is generally more common among women who have become pregnant through IVF treatment.’
Mild rejection episodes
The woman has had three mild rejection episodes since the transplant, one of which occurred during the pregnancy. The rejection episodes, which are often seen also in other types of transplants, could be stopped with immunosuppressive treatment.
The research team followed the pregnancy closely, carefully monitoring the growth and development of the foetus with a special focus on the blood supply to the uterus and umbilical cord.
‘There were concerns that the blood supply may be compromised since we had reattached the blood vessels to the womb. But we did not notice anything unusual concerning the function of the uterus and the foetus, and the pregnancy followed all normal curves,’ says Brännström.
The successful delivery is considered a major step forward.
‘It gives us scientific evidence that the concept of uterus transplantation can be used to treat uterine factor infertility, which up to now has remained the last untreatable form of female infertility. It also shows that transplants with a live donor are possible, including if the donor is past menopause,’ says Brännström.
Several research teams around the world have been awaiting the results of the Gothenburg study in order to launch similar observational studies. The pregnancy attempts are ongoing with the other six women in the project.
- Mats Brännström, Liza Johannesson, Hans Bokström, Niclas Kvarnström, Johan Mölne, Pernilla Dahm-Kähler, Anders Enskog, Milan Milenkovic, Jana Ekberg, Cesar Diaz-Garcia, Markus Gäbel, Ash Hanafy, Henrik Hagberg, Michael Olausson, Lars Nilsson. Livebirth after uterus transplantation. The Lancet, 2014; DOI:10.1016/S0140-6736(14)61728-1
University of Gothenburg. “World’s first child born after uterus transplantation.” ScienceDaily. ScienceDaily, 7 October 2014. <www.sciencedaily.com/releases/2014/10/141007092110.htm>.
The cold waters of Earth’s deep ocean have not warmed measurably since 2005, according to a new NASA study, leaving unsolved the mystery of why global warming appears to have slowed in recent years.
Scientists at NASA’s Jet Propulsion Laboratory in Pasadena, California, analyzed satellite and direct ocean temperature data from 2005 to 2013 and found the ocean abyss below 1.24 miles (1,995 meters) has not warmed measurably. Study coauthor Josh Willis of JPL said these findings do not throw suspicion on climate change itself.
“The sea level is still rising,” Willis noted. “We’re just trying to understand the nitty-gritty details.”
In the 21st century, greenhouse gases have continued to accumulate in the atmosphere, just as they did in the 20th century, but global average surface air temperatures have stopped rising in tandem with the gases. The temperature of the top half of the world’s ocean — above the 1.24-mile mark — is still climbing, but not fast enough to account for the stalled air temperatures.
Many processes on land, air and sea have been invoked to explain what is happening to the “missing” heat. One of the most prominent ideas is that the bottom half of the ocean is taking up the slack, but supporting evidence is slim. This latest study is the first to test the idea using satellite observations, as well as direct temperature measurements of the upper ocean. Scientists have been taking the temperature of the top half of the ocean directly since 2005, using a network of 3,000 floating temperature probes called the Argo array.
“The deep parts of the ocean are harder to measure,” said JPL’s William Llovel, lead author of the study, published Sunday, Oct. 5 in the journal Nature Climate Change. “The combination of satellite and direct temperature data gives us a glimpse of how much sea level rise is due to deep warming. The answer is — not much.”
The study took advantage of the fact that water expands as it gets warmer. The sea level is rising because of this expansion and water added by glacier and ice sheet melt.
To arrive at their conclusion, the JPL scientists did a straightforward subtraction calculation, using data for 2005 to 2013 from the Argo buoys, NASA’s Jason-1 and Jason-2 satellites, and the agency’s Gravity Recovery and Climate Experiment (GRACE) satellites. From the total amount of sea level rise, they subtracted the amount of rise from the expansion in the upper ocean, and the amount of rise that came from added meltwater. The remainder represented the amount of sea level rise caused by warming in the deep ocean.
The remainder was essentially zero. Deep ocean warming contributed virtually nothing to sea level rise during this period.
Coauthor Felix Landerer of JPL noted that during the same period, warming in the top half of the ocean continued unabated, an unequivocal sign that our planet is heating up. Some recent studies reporting deep-ocean warming were, in fact, referring to the warming in the upper half of the ocean but below the topmost layer, which ends about 0.4 mile (700 meters) down.
Landerer also is a coauthor of another paper in the same Nature Climate Changejournal issue on ocean warming in the Southern Hemisphere from 1970 to 2005. Before Argo floats were deployed, temperature measurements in the Southern Ocean were spotty, at best. Using satellite measurements and climate simulations of sea level changes around the world, the new study found the global ocean absorbed far more heat in those 35 years than previously thought — a whopping 24 to 58 percent more than early estimates.
Both papers result from the work of the newly formed NASA Sea Level Change Team, an interdisciplinary group tasked with using NASA satellite data to improve the accuracy and scale of current and future estimates of sea level change. The Southern Hemisphere paper was led by three scientists at Lawrence Livermore National Laboratory in Livermore, California.
NASA monitors Earth’s vital signs from land, air and space with a fleet of satellites and ambitious airborne and ground-based observation campaigns. NASA develops new ways to observe and study Earth’s interconnected natural systems with long-term data records and computer analysis tools to better see how our planet is changing. The agency shares this unique knowledge with the global community and works with institutions in the United States and around the world that contribute to understanding and protecting our home planet.
For more information about NASA’s Earth science activities in 2014, visit:http://www.nasa.gov/earthrightnow
For more information on ocean surface topography from space, visit:http://sealevel.jpl.nasa.gov
More information on NASA’s GRACE satellites is available at: http://grace.jpl.nasa.gov
For more information on the Argo array, visit: http://www.argo.ucsd.edu/index.html
The above story is based on materials provided by NASA/Jet Propulsion Laboratory. The original article was written by Carol Rasmussen, NASA Earth Science News Team. Note: Materials may be edited for content and length.
- W. Llovel, J. K. Willis, F. W. Landerer, I. Fukumori. Deep-ocean contribution to sea level and energy budget not detectable over the past decade. Nature Climate Change, 2014; DOI: 10.1038/nclimate2387
- Paul J. Durack, Peter J. Gleckler, Felix W. Landerer, Karl E. Taylor. Quantifying underestimates of long-term upper-ocean warming. Nature Climate Change, 2014; DOI: 10.1038/nclimate2389
NASA/Jet Propulsion Laboratory. “Earth’s ocean abyss has not warmed, NASA study finds.” ScienceDaily. ScienceDaily, 6 October 2014. <www.sciencedaily.com/releases/2014/10/141006101043.htm>.