Date:
September 29, 2014

 

Source:
Weizmann Institute of Science

 

Summary:
Evidence of a unique ‘signature’ that may be the ‘missing link’ between cognitive decline and aging has been found by researchers. The scientists believe that this discovery may lead, in the future, to treatments that can slow or reverse cognitive decline in older people.

 

 

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Immunofluorescence microscope image of the choroid plexus. Epithelial cells are in green and chemokine proteins (CXCL10) are in red.
Credit: Image courtesy of Weizmann Institute of Science

 

How the brain ages is still largely an open question — in part because this organ is mostly insulated from direct contact with other systems in the body, including the blood and immune systems. In research that was recently published in Science, Weizmann Institute researchers Prof. Michal Schwartz of the Neurobiology Department and Dr. Ido Amit of Immunology Department found evidence of a unique “signature” that may be the “missing link” between cognitive decline and aging. The scientists believe that this discovery may lead, in the future, to treatments that can slow or reverse cognitive decline in older people.

Until a decade ago, scientific dogma held that the blood-brain barrier prevents the blood-borne immune cells from attacking and destroying brain tissue. Yet in a long series of studies, Schwartz’s group had shown that the immune system actually plays an important role both in healing the brain after injury and in maintaining the brain’s normal functioning. They have found that this brain-immune interaction occurs across a barrier that is actually a unique interface within the brain’s territory.

This interface, known as the choroid plexus, is found in each of the brain’s four ventricles, and it separates the blood from the cerebrospinal fluid. Schwartz: “The choroid plexus acts as a ‘remote control’ for the immune system to affect brain activity. Biochemical ‘danger’ signals released from the brain are sensed through this interface; in turn, blood-borne immune cells assist by communicating with the choroid plexus.This cross-talk is important for preserving cognitive abilities and promoting the generation of new brain cells.”

This finding led Schwartz and her group to suggest that cognitive decline over the years may be connected not only to one’s “chronological age” but also to one’s “immunological age,” that is, changes in immune function over time might contribute to changes in brain function — not necessarily in step with the count of one’s years.

To test this theory, Schwartz and research students Kuti Baruch and Aleksandra Deczkowska teamed up with Amit and his research group in the Immunology Department. The researchers used next-generation sequencing technology to map changes in gene expression in 11 different organs, including the choroid plexus, in both young and aged mice, to identify and compare pathways involved in the aging process.

That is how they identified a strikingly unique “signature of aging” that exists solely in the choroid plexus — not in the other organs. They discovered that one of the main elements of this signature was interferon beta — a protein that the body normally produces to fight viral infection. This protein appears to have a negative effect on the brain: When the researchers injected an antibody that blocks interferon beta activity into the cerebrospinal fluid of the older mice, their cognitive abilities were restored, as was their ability to form new brain cells. The scientists were also able to identify this unique signature in elderly human brains. The scientists hope that this finding may, in the future, help prevent or reverse cognitive decline in old age, by finding ways to rejuvenate the “immunological age” of the brain.


Story Source:

The above story is based on materials provided by Weizmann Institute of Science.Note: Materials may be edited for content and length.


Journal Reference:

  1. K. Baruch, A. Deczkowska, E. David, J. M. Castellano, O. Miller, A. Kertser, T. Berkutzki, Z. Barnett-Itzhaki, D. Bezalel, T. Wyss-Coray, I. Amit, M. Schwartz.Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science, 2014; DOI: 10.1126/science.1252945

 

Weizmann Institute of Science. “Signature of aging in brain: Researchers suggest that the brain’s ‘immunological age’ is what counts.” ScienceDaily. ScienceDaily, 29 September 2014. <www.sciencedaily.com/releases/2014/09/140929093856.htm>.

Meeting with Congress

According to an article published in CenterWatch Weekly (22 Sept. 2014), by Ronald Rosenberg, entitled  “Bipartisan 21st Century Cures Initiative Prepares to Draft Legislation to Accelerate Biomedical R&D, Lower Cost,“ a bipartisan initiative by two U.S. Representatives is about to be drafted into proposed legislation designed to promote novel ways to encourage and accelerate biopharmaceutical innovation. The program, entitled “21st Century Cures: A Call to Action“ is an initiative that seeks broad industry, government, academic and patient advocacy support and input. Rep. Diana DeGette (D-Colo.) and Rep. Fred Upton (R-Mich.). chair of the House Energy and Commerce Committee, are holding Congressional hearings and a series of regional roundtables with industry, patient advocacy and government leaders.

 

Rep. DeGette presented at the Disruptive Innovations to Advance Clinical Trials conference in Boston, sponsored by The Conference Forum, run by our good friend and colleague Valerie Bowling. Dr. Mitchel, President of Target Health, was fortunate to be invited to a breakfast with Rep. DeGette together with representatives from Pfizer, Eli Lilly, Novartis, Roche/Genentech and a patient advocate from the Parkinson’s Disease Foundation. A lot of ideas were shared on how to assure the leadership of the US in basic biomedical research and how to accelerate novel drugs, biologics and devices to the market.

 

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Here we are hard at work!!!

 

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Back Row (L-R): J. Kim (Eli Lilly); J. Mitchel (Target Health); J. Kasher (Eli Lilly); J. Van Dam (Novartis); C. Lipset (Pfizer)
Front Row (l-R); K. Stem (Genentech); Rep. D. DeGette (Colorado.); V. Bowling (TCF); L. Morgan (Parkinson’s Disease Foundation)

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

Deep Vein Thrombosis

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Deep vein thrombosis, or deep venous thrombosis, (DVT) is the formation of a blood clot (thrombus) in a deep vein, predominantly in the1) ___. Non-specific signs may include pain, swelling, redness, warmness, and engorged superficial veins. Pulmonary embolism, a potentially life-threatening complication, is caused by the detachment (embolization) of a clot that travels to the lungs. Together, DVT and pulmonary embolism constitute a single disease process known as venous thromboembolism. Post-thrombotic syndrome, another complication, significantly contributes to the health-care cost of DVT.

 

Prevention options for at-risk individuals include early and frequent walking, calf exercises, anticoagulants, aspirin, graduated compression stockings, and intermittent pneumatic compression. In 1856, German pathologist Rudolf Virchow postulated the interplay of three processes resulting in venous thrombosis, now known as Virchow’s triad: a decreased blood flow rate (venous stasis), increased tendency to clot (hypercoagulability), and changes to the blood vessel wall. DVT formation typically begins inside the valves of the calf 2) ___, where the blood is relatively oxygen deprived, which activates certain biochemical pathways. Several medical conditions increase the risk for DVT, including cancer, trauma, and antiphospholipid syndrome. Other risk factors include older age, surgery, immobilization (as with bed rest, orthopedic casts, and sitting on long flights), combined oral contraceptives, pregnancy, the postnatal period, and genetic factors such as a non-O blood type. The frequency of occurrence (incidence) increases dramatically from childhood to old 3) ___. In adulthood, about 1 in 1000 adults develops DVT annually.

 

Individuals suspected of having DVT may be assessed using a clinical prediction rule such as the Wells score. A D-dimer test may also be used to assist with excluding the diagnosis (because of its high sensitivity) or to signal a need for further testing. Diagnosis is most commonly done with ultrasound of the suspected veins. Anticoagulation is the standard 4) ___; typical medications include a low-molecular-weight heparin and a vitamin K antagonist. Wearing graduated compression stockings appears to reduce the risk of post-thrombotic syndrome. Common signs and symptoms of DVT include pain or tenderness, swelling, warmth, redness or discoloration, and distention of surface veins, although about half of those with the condition have no symptoms. Signs and symptoms alone are not sufficiently sensitive or specific to make a diagnosis, but when considered in conjunction with known 5) ___ factors can help determine the likelihood of DVT. In most suspected cases, DVT is ruled out after evaluation, and symptoms are more often due to other causes, such as cellulitis, Baker’s cyst, musculoskeletal injury, or lymphedema. Other differential diagnoses include hematoma, tumors, venous or arterial aneurysms, and connective tissue disorders. A severe and uncommon form of DVT, phlegmasia cerulea dolens, may develop in association with a life-threatening illness. It is characterized by an acute and almost total venous occlusion of the entire extremity outflow, including the iliac and femoral veins. The leg is usually painful, cyanosed 6) ___ (from lack of oxygen), and edematous (filled with fluid), which may result in venous gangrene.

 

 

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The incision for a completed knee replacement surgery, a procedure that can predispose people to a DVT

 

The three factors of Virchow’s triad are: venous stasis, hypercoagulability stasis, and changes in the endothelial blood vessel lining (such as physical damage or endothelial activation) – contribute to DVT and are used to explain its formation. Other related causes include activation of immune system components, the state of microparticles in the blood, the concentration of oxygen, and possible platelet activation. Various risk factors contribute to DVT, though many at high risk never develop it. Acquired risk factors include the strong risk factor of older age, which alters blood composition to favor clotting. Other important acquired risk factors include major surgery and trauma, both of which may increase the risk because of tissue factor from outside the vascular system entering the blood. In orthopedic surgery, venous stasis may be temporarily provoked by a cessation of blood flow as part of the procedure. Cancer can grow in and around veins, causing venous stasis, and can also stimulate increased levels of tissue factor. Pregnancy causes blood to favor clotting, and in the postpartum, placental tearing releases substances that favor 7) ___. Oral contraceptives and hormonal replacement therapy increase the risk through a variety of mechanisms, including altered blood coagulation protein levels and reduced fibrinolysis.

 

The disease term venous thromboembolism (VTE) includes the development of either DVT or pulmonary embolism (PE). Genetic factors that increase the risk of VTE include deficiencies of three proteins that normally prevent blood from clotting – protein C, protein S, and antithrombin – in addition to non-O blood type and mutations in the factor V and prothrombin genes. Having a non-O blood type approximately doubles VTE risk. Non-O blood type is common in all races, making it an important risk factor. Individuals without O blood type have higher blood levels of von Willebrand factor and factor VIII than those with O blood type, increasing the likelihood of clotting. Some risk factors influence the location of DVT within the body. In isolated distal DVT, the profile of risk factors appears distinct from proximal DVT. Transient factors, such as surgery and immobilization, appear to dominate whereas thrombophilias and age do not seem to increase risk. In upper-extremity DVT, the most important risk factor is having a central venous catheter, and thoracic outlet syndrome also increases risk.

 

DVT often develops in the calf veins and “grows“ in the direction of venous flow, towards the 8) ___. When DVT does not grow, it can be cleared naturally and dissolved into the blood (fibrinolysis). Veins in the calf or thigh are most commonly affected, including the femoral vein, the popliteal vein, and the iliofemoral vein (as with May-Thurner syndrome). Extensive lower-extremity DVT can reach into the iliac vein of the pelvis or the inferior vena cava. Occasionally the veins of the arm are affected. The mechanism behind arterial thrombosis, such as with heart attacks, is more established than the steps that cause venous thrombosis. With arterial thrombosis, blood vessel wall damage is required, as it initiates coagulation, but clotting in the veins mostly occurs without any such damage.

 

The beginning of venous thrombosis is thought to be caused by tissue factor, which leads to conversion of prothrombin to thrombin, followed by fibrin deposition. Red blood cells and fibrin are the main components of venous thrombi, and the fibrin appears to attach to the blood vessel wall lining (endothelium), a surface that normally acts to prevent clotting. Platelets and white blood cells are also components. Platelets are not as prominent in venous clots as they are in arterial ones, but they may play a role.  Inflammation is associated with VTE, and white blood cells play a role in the formation and resolution of venous clots. Often, DVT begins in the valves of veins.  The blood flow pattern in the valves can cause low oxygen concentrations in the blood (hypoxemia) of a valve sinus. Hypoxemia, which is worsened by venous stasis, activates pathways – ones that include hypoxia-inducible factor-1 and early-growth-response protein 1.

 

DVT diagnosis requires the use of imaging devices such as ultrasound. Clinical assessments, which predict DVT likelihood, can help determine if a D-dimer test is useful. In those not highly likely to have DVT, a normal D-dimer result can rule out a diagnosis. Acute DVT is characterized by pain and swelling and is usually occlusive, which means that it obstructs 9) ___ flow, whereas non-occlusive DVT is less symptomatic. The label of chronic has been applied to symptomatic DVT that persists longer than 10 or 14 days. DVT that has no symptoms, but is found only by screening, is labeled asymptomatic or incidental. DVT in the legs is proximal (or iliofemoral) when above the knee and distal (or calf) when below the knee.  DVT below the popliteal vein, a proximal vein behind the knee, is classified as distal and has limited clinical significance compared to proximal DVT. An initial episode of DVT is called incident and any subsequent DVT is termed recurrent.  Bilateral DVT refers to clots in both legs while unilateral means that only a single leg is affected. For a suspected first leg DVT in a low-probability situation, the American College of Chest Physicians (ACCP) recommends testing either D-dimer levels with moderate or high sensitivity or compression ultrasound of the proximal veins. Depending upon the risk for DVT, different preventative measures are used. Walking and calf exercises reduce venous stasis because leg muscle contractions compress the veins and pump blood up towards the heart.

 

In 2011, three large randomized controlled trials – the Norwegian CaVent trial, the North American ATTRACT trial, and the Dutch CAVA trial – were initiated to study the effectiveness and safety of catheter-directed thrombolysis.  In 2012, two studies found a clinical benefit in taking 10) ___to prevent recurrent VTE.

 

ANSWERS: 1) legs; 2) veins; 3) age; 4) treatment; 5) risk; 6) blue; 7) clotting; 8) heart; 9) blood; 10) aspirin

 

Deep Vein Thrombosis

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The femoral vein (in the thigh), the iliac veins (in the pelvis), and the inferior vena cava (in the abdomen) are places of potential DVT extension.

 

In the 18th Century, the increased incidence of deep vein thrombosis (DVT) in women after childbirth was noticed, and in the late 1700s, a public health recommendation was issued to encourage women to breast feed as a means to prevent this phenomenon. DVT was called “milk leg“, as it was thought to result from milk building up in the leg.

 

Rudolf Virchow MD (1821-1902), German physician and pathologist, is known for elucidating the mechanism of pulmonary thrombo embolism, coining the term embolism and thrombosis. In 1856, he published what is referred to as Virchow’s triad, the three major causes of thrombosis. The triad provides the theoretical framework for the current explanation of venous thrombosis, although it was focused on the effect of a foreign body in the venous system and the conditions required for clot propagation. Virchow noted that blood clots in the pulmonary artery originate first from venous thrombi, stating: “The detachment of larger or smaller fragments from the end of the softening thrombus which are carried along by the current of blood and driven into remote vessels. This gives rise to the very frequent process on which I have bestowed the name of Embolia“. Having made these initial discoveries based on autopsies, he proceeded to put forward a scientific hypothesis; that pulmonary thrombi are transported from the veins of the leg and that the blood has the ability to carry such an object. He then proceeded to prove this hypothesis through well-designed experiments, repeated numerous times to consolidate evidence, and with meticulously detailed methodology. This work rebuked a claim made by the eminent French pathologist Jean Cruveilhier that phlebitis led to clot development and therefore coagulation was the main consequence of venous inflammation. This was a view held by many before Virchow’s work.

 

Related to this research, Virchow described the factors contributing to venous thrombosis, Virchow’s triad.

 

Virchow’s triad

 

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Virchow’s triad or the triad of Virchow describes the three broad categories of factors that are thought to contribute to thrombosis.

 

  1. Hypercoagulability
  2. Hemodynamic changes (stasis, turbulence)
  3. Endothelial injury/dysfunction

 

Although named after Virchow, the elements comprising Virchow’s triad were neither proposed by Virchow, nor did he ever suggest a triad to describe the pathogenesis of venous thrombosis. In fact, it was decades following Virchow’s death before a consensus was reached proposing that thrombosis is the result of alterations in blood flow, vascular endothelial injury, or alterations in the constitution of the blood. Still, the modern understanding of the factors leading to embolism is similar to the description provided by Virchow. Its nebulous origins notwithstanding, Virchow’s triad remains a useful concept for clinicians and pathologists alike in understanding the contributors to thrombosis.

 

The triad consists of three components:

 

Virchow’s Modern Notes
Phenomena of interrupted blood-flow Stasis The first category, alterations in normal blood flow, refers to several situations. These include venous stasis, mitral stenosis, prolonged immobility (as on a long plane or car ride, bed bound during hospitalization) and varicose veins. The equivalence of Virchow’s version and the modern version has been disputed.
Phenomena associated with irritation of the vessel and its vicinity Endothelial injury or vessel wall injury The second category, injuries and/or trauma to endothelium includes vessel piercings and damages arising from shear stress or hypertension. This category is ruled by surface phenomena and contact with procoagulant surfaces, such as bacteria, shards of foreign materials, biomaterials of implants or medical devices, membranes of activated platelets, and membranes of monocytes in chronic inflammation.
Phenomena of blood-coagulation Hypercoagulability The last category, alterations in the constitution of blood, has numerous possible risk factors such as hyperviscosity, deficiency of antithrombin III, protein C or S deficiency, Leiden V factor, nephrotic syndrome, changes after severe trauma or burn, disseminated cancer, late pregnancy and delivery, race, advanced age, cigarette smoking, hormonal contraceptives, and obesity. All of these risk factors can cause the situation called hypercoagulability (excessively easy clotting of blood).

 

Multiple pharmacological therapies for DVT were introduced in the 20th century: oral anticoagulants in the 1940s, subcutaneous LDUH in 1962, and subcutaneous LMWH in 1982. Diagnoses were commonly performed by impedance plethysmography in the 1970s and 1980s. Today, the most used diagnostic tool is the Doppler ultrasound techniques, with their increased sensitivity and specificity, performed by a radiologist.

 

ONCOLOGY

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NIH Exceptional Responders to Cancer Therapy Study

 

In treating patients with cancer, unexpected and prolonged remissions following standard therapy can be observed; the reasons why certain patients experience these remissions have been unclear. If molecular markers could be developed that predict positive responses to certain therapies, even in a small subset of patients, it might be possible to more effectively choose treatment programs for individual patients.

 

According to the NIH, the Exceptional Responders Initiative (ERI), a study to investigate the molecular factors of tumors associated with exceptional treatment responses of cancer patients to drug therapies, was launched by the National Cancer Institute (NCI). In this program, the NCI will attempt to identify the molecular features of tumors that predict whether or not a particular drug or class of drugs will be beneficial. Investigators will examine tumor specimens from patients in clinical trials who achieved an exceptional response relative to other trial participants, or other patients who achieved an exceptional and unexpected response to a non-investigational therapy.

 

This initiative was initially considered two years ago when, through the use of advanced DNA sequencing methods, the molecular basis for the prolonged remission of bladder cancer in a patient following treatment with a molecularly targeted drug in a clinical trial was determined. Based on this single and perhaps profound observation, it was proposed that it was a good idea to understand the mechanism of drug response for a relatively small number of patients in early phase clinical trials who benefit dramatically from therapy. In the past, trials in which up to only 10% of patients had significant and prolonged responses were considered unsuccessful, as it was not possible to understand why some patients benefitted from treatment and others did not.

 

In the ERI, some of the tissue and clinical data from exceptional responders will be obtained from NCI-supported trials as well as potentially other clinical trials. The remaining samples and data will come from standard therapy settings, such as community practice, where there are reliable outcome data, and from pharmaceutical industry trials or other sources. Consequently, letters of solicitation are being sent to cancer centers and others clinicians nationwide to ask them to assist in this effort. DNA and RNA from tissue samples will be isolated at the Biospecimen Core Resource at Nationwide Children’s Hospital, Columbus, Ohio, and those isolates will then be shipped to a DNA sequencing and analysis center at Baylor University, Houston.

 

Ultimately, this information could be used to identify patients who may potentially respond to agents with the same or similar mechanism of action. It may be difficult to determine if abnormalities found in exceptional responders are functionally significant and whether the abnormalities actually drive tumor growth. Additionally, relevant mutations may be present in less than 5% of tumors, making them difficult to identify. The study will also examine the feasibility of conducting a larger exceptional responder study (especially given what is expected to be a limited amount of tissue that can be collected over the study period of three to four years). The output of this initiative might include a list of plausible mutations, possible mutations, or simply all the mutations found in the exceptional responder cases. In addition, it is hoped that other investigators will seek to build on the data generated by this study by testing hypotheses on specimens from a trial that used a particular drug, or by comparing their own dataset with the shared data. Placing the full genomic annotation of 100 cases of exceptional responders in the public domain should aid all clinicians and researchers looking for patterns in drug response.

 

Link Among Alzheimer’s Disease, Down Syndrome and Atherosclerosis

 

We read an article in Scientific American on Trisomy 21 in patients with Alzheimer’s disease (AD). While the reports are a few years old, they are so intriguing that we wanted to share the following from the University of South Florida (14 January 2010).

 

Nearly 20 years ago Huntington Potter proposed the idea that Down syndrome and Alzheimer’s were the same disease. Now, Down syndrome, artery-clogging cardiovascular disease, and possibly even diabetes, appear to share a common disease mechanism with AD. Two papers – one in Molecular Biology of the Cell and the other in PLoS ONE – implicate the Alzheimer’s-associated protein beta amyloid (amyloid protein), which damages the microtubule transport system responsible for moving chromosomes, proteins and other cargo around inside cells. Both studies were done in mice and human cell cultures modeling AD. Together, the laboratory discoveries suggest that protecting the microtubule network from this amyloid damage might be an effective way to prevent or even reverse AD and associated disorders.

 

The first paper, published online (23 Dec. 2009) in Molecular Biology of the Cell (MBC), provides the mechanism behind previous work by Dr. Potter’s laboratory showing that all AD patients harbor some cells with three copies of chromosome 21, known as trisomy 21, instead of the usual two. Trisomy 21 is a characteristic shared by all the cells in people with the birth defect Down syndrome. This earlier work demonstrated that AD could be considered a late onset form of Down syndrome. By age 30 to 40, all people with Down syndrome develop the same brain pathology seen in AD, including a nerve-killing buildup of sticky amyloid protein clumps. This contributes to accelerated nerve cell loss and dementia. The study reported in MBC showed that the Alzheimer’s-associated amyloid protein is the culprit that interferes with the microtubule transport system inside cells. The microtubules are responsible for segregating newly duplicated chromosomes as cells divide. When the microtubule network is disrupted, chromosomes can be incorrectly transported as cells divide and the result is new cells with the wrong number of chromosomes and an abnormal assortment of genes. For example, Down syndrome cells contain three copies of the beta amyloid gene on chromosome 21 – leading to more accumulation of the “bad“ amyloid protein over a lifetime. According to the authors, AD probably is caused in part from the continuous development of new trisomy 21 nerve cells, which amplify the disease process by producing extra beta amyloid.

 

The second paper, published (31 Dec. 2009) in the online journal PLoS ONE, describes another consequence of the damaged microtubule network caused by the amyloid protein. As a background, many AD patients also commonly develop vascular diseases and diabetes. Whether this coincidence is bad luck or due to shared disease processes is not yet determined. Research teams have investigated the role that low-density lipoprotein (LDL), the bad cholesterol that causes atherosclerosis, cardiovascular disease and stroke, may play in the development of AD with mixed results. In contrast, the study focused on the amyloid protein’s potential effects on LDL metabolism. The receptor needed to detect and use LDL is among the proteins transported by the microtubules. As previously reported in the MBC paper, the second study found that the amyloid protein inflicts damage to the microtubule network. As a consequence, the receptor needed to pull LDL circulating throughout the bloodstream into the body’s cells has trouble getting to the cell surface to retrieve this bad cholesterol. This interference with LDL metabolism may allow bad cholesterol to build up in into plaques that choke off blood supply to the brain and heart in people with Alzheimer’s. Similarly, other key proteins – including insulin receptors and receptors for brain signaling molecules – are also likely locked inside cells when the transport system is damaged by amyloid or other factors. As the insulin receptors are needed to get blood sugar inside the cell where it can be used for energy and the nerve cell signaling receptors help promote memory and learning, if these receptors are unable to function properly, it may lead to diabetes and problems with learning and memory.

 

Glucose Monitoring System for Use in Hospital Critical Care Units

 

Blood glucose monitoring systems, also called blood glucose meters, are handheld devices that measure the amount of sugar (glucose) in blood by analyzing a small drop of blood that is placed on a test strip. After inserting the test strip into the device, the system displays a glucose level reading. Blood glucose measurements are used in the management of many patients in the hospital, including patients requiring insulin to manage blood sugar, and in the assessment of blood glucose levels in newborn babies.

 

The FDA has cleared a new indication for the Nova StatStrip Glucose Hospital Meter System, extending its use to critically ill patients who have been hospitalized. This is the first blood glucose monitoring system (BGMS) cleared by FDA for use in these patients. The Nova StatStrip Glucose Hospital Meter System is the first FDA clearance of a device specifically indicated for use in all types of hospital patients, including critically ill patients. Users of BGMS with manufacturer instructions that do not provide for use with critically ill hospital patients would be subject to the high complexity testing requirements under the Clinical Laboratory Improvement Amendments (CLIA) if such systems were to be used in the critically ill hospital population. Those requirements include the validation of how well the BGMS worked in that patient population.

 

The FDA determined that the Nova StatStrip Glucose Hospital Meter System is simple to use and has a low risk for false results, and granted with the clearance “waived“ test system status under CLIA. This waived status will allow a broad variety of health care professionals, such as nurses and technicians, to perform the test at the point-of-care, such as at a patient’s bedside, instead of requiring that the test be performed in a hospital lab (or other lab) that meets the CLIA requirements for high complexity testing.  The CLIA waiver will also allow hospital labs to safely provide blood glucose monitoring to their critically ill patients without having to meet the significant CLIA requirements for high complexity testing.

 

The FDA originally cleared the Nova StatStrip Glucose Hospital Meter System in April of 2006 for use in hospitals as an aid in monitoring the effectiveness of a diabetes control program, but not for use with critically ill patients. The device manufacturer submitted a new premarket submission to the FDA seeking clearance of the device with this new indication. The current clearance is for indications that include using arterial or venous whole blood from patients in all areas of a hospital with various conditions, including: trauma, cancer, sepsis and infection; cardiac, kidney, neurological, obstetric, gynecological, gastroenterological, endocrine, and lung issues; and people recovering from general or cardiothoracic surgery. Data supporting this clearance included a study of more than 1,650 patients with a range of medical conditions, taking various medications, and being treated in a variety of hospital departments, such as cardiac, emergency intensive care, and surgical. Results showed agreement in blood glucose results compared to a comparator laboratory glucose analyzer in all patients types tested.

 

The Nova StatStrip Glucose Hospital Meter System is manufactured by Nova Biomedical in Waltham, Massachusetts.

 

Fennel Salad with Figs, Feta, Grapes & Walnuts

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My most severe critic and dear husband, said that this salad was a great success! He loves fennel with fruit, especially fresh figs! ©Joyce Hays, Target Health Inc.

 

 

Ingredients

1 cup walnut halves, chopped coarsely

Pinch Salt (optional)

Best-quality olive oil

2 Tablespoons minced shallots

2 garlic cloves, juiced

1/2 teaspoon chopped tarragon

1/4 teaspoon chopped rosemary

4 Tablespoons sherry vinegar

7 Tablespoons best-quality olive oil

Pinch black pepper

8 ripe figs

20 red seedless grapes, cut in half

1 head radicchio (use a few inside leaves)

1 large head fennel

6 to 8 ounces fresh feta

Cream sherry used to warm up the figs and grapes

 

Directions

 

  1. In a small bowl, add 1 and ? teaspoons olive oil and 3 teaspoons cream sherry, stir and toss the walnuts in this bowl. Let them sit for a few minutes. Then, toast the walnuts in a pan, stirring constantly until nuts are done and not burnt. Set aside.
  1. In a medium bowl, whisk together the shallots, garlic, tarragon, rosemary, sherry vinegar and 7 Tablespoons olive oil. Season with pinch salt and pinch black pepper, or to taste. This is the home made vinaigrette dressing for the salad.
  1. Wash, dry, trim the hard top off and halve the figs lengthwise.
  1. Remove any wilted outer leaves from the radicchio and use a few of the center leaves, just to add color to the salad and a bit of bitterness to set off the sweetness of the fresh fruit, and cream sherry. Pile the leaves on top of each other, roll them up in a tube shape and cut thin ribbons. Set aside
  1. Trim the top off the fennel, and slice it with a mandolin, into paper-thin strips, discarding the core.
  1. Use the pan you toasted the walnuts in. Brush the figs and grapes, with the vinaigrette and place the fruit in the pan, figs with cut-side down, over medium flame. After about 30 seconds, turn the figs (with the grapes) and cook for another 30 seconds.
  1. Into a salad bowl, add the fennel, radicchio, grapes and figs. Toss lightly.
  1. Now, to the salad add, the feta and walnuts. Toss again.
  1. Now, slowly drizzle the remaining vinaigrette over the salad and give it one last light toss

Serve immediately, while the figs and grapes are still warm.

 

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Remember a few weeks ago, I mentioned that we discovered a new “Cab” at db Bistro in Manhattan?  And I tried to order it right away, but because it’s gotten so popular, all that was left were “splits” so ordered a case?  Well, here it is, smooth as silk to start, then it grabs your throat, and you love it because it fires up, with heat all the way down.   Ah, you’re gonna want what we’re having!

 

We had a minimalist Sunday supper, with the Fennel Fig salad as the vegetable accompanying some fresh salmon, quickly cooked, medium rare, in an olive-oiled pan, with some dill and this wine (photo above), which every sip, we savored.

 

Then, believe it or not, we each had (portion control) a weight watchers ice cream sandwich for dessert.

 

Saw an opera that we’d never seen before, Macbeth, at the MetOpera. It was lugubrious beyond words, with dark morose sets, that belied the beautiful music of Verdi. The voice of Lady Macbeth was sung to perfection by Anna Netrebko, whose powerful, gorgeous voice we’ve heard many times at the MetOpera, where she made her debut in 2002. She has dual citizenship in Russia and Austria (she speaks no German) but lives in Manhattan. If you’ve never heard her sing, you’ve missed one of the great sopranos. I still prefer another Manhattan soprano, Renee Fleming, but loved Netrebko in Macbeth, this weekend. The audience went wild with many curtain calls.  This was our first opera this season; good to be back at the MetOpera.  We left feeling high on life!

 

Here are some examples of a great soprano voice

 

Anna Netrebko sings Lady Macbeth’s aria from Act I of Verdi’s “Macbeth.” Production: Adrian Noble

Anna Netrebko sings “La luce langue, il faro spegnesi” from Act II of Giuseppe Verdi’s MACBETH

Final scene, Act II, Macbeth

Anna Netrebko, “O Mio Babbino Caro” Puccini

Anna Netrebko, “Casta Diva“, Norma, Bellini

We had a good week, hope you did too.

 

 

From Our Table to Yours!

 

Bon Appetit!

 

Date:
September 25, 2014

 

Source:
Howard Hughes Medical Institute (HHMI)

 

Summary:
The brain can temporarily disconnect information about past experience from decision-making circuits, thereby triggering random behavior, a study has demonstrated. The new studies look at how the brain generates strategic and random behavior, and how it switches between the two modes.

 

 

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Janelia scientists are learning how the brain switches between random and strategic modes.
Credit: Image courtesy of Howard Hughes Medical Institute (HHMI)

 

 

Many of the choices we make are informed by experiences we’ve had in the past. But occasionally we’re better off abandoning those lessons and exploring a new situation unfettered by past experiences. Scientists at the Howard Hughes Medical Institute’s Janelia Research Campus have shown that the brain can temporarily disconnect information about past experience from decision-making circuits, thereby triggering random behavior.

In the study, rats playing a game for a food reward usually acted strategically, but switched to random behavior when they confronted a particularly unpredictable and hard-to-beat competitor. The animals sometimes got stuck in a random-behavior mode, but the researchers, led by Janelia lab head Alla Karpova and postdoctoral fellow Gowan Tervo, found that they could restore normal behavior by manipulating activity in a specific region of the brain. Because the behavior of animals stuck in this random mode bears some resemblance to that of patients affected by a psychological condition called learned helplessness, the findingsmay help explain that condition and suggest strategies for treating it. Karpova, Tervo and their colleagues published their findings in the September 25, 2014, issue of the journal Cell.

The brain excels at integrating information from past experiences to guide decision-making in new situations. But in certain circumstances, random behavior may be preferable. An animal might have the best chance of avoiding a predator if it moves unpredictably, for example. And in a new environment, unrestricted exploration might make more sense than relying on an internal model developed elsewhere. So scientists have long speculated that the brain may have a way to switch off the influence of past experiences so that behavior can proceed randomly, Karpova says. But others disagreed. “They argue that it’s inefficient, and that it would be at odds with what some people call one of the most central operating principles of the brain — to use our past experience and knowledge to optimize behavioral choices,” she notes.

Karpova and her colleagues wanted to see if they could create a situation that would force animals to switch into this random mode of behavior. “We tried to create a setting that would push the need to create behavioral variability and unpredictability to its extreme,” she says. They did this by placing rats in a competitive setting in which a computer-simulated competitor determined which of two holes in a wall would provide a sugary reward. The virtual competitor, whose sophistication was varied by the experimenters, analyzed the rats’ behavior to predict their future choices.

“We thought if we came up with very sophisticated competitors, then the animals would eventually be unable to figure out how to outcompete them, and be forced to either give up or switch into this [random] mode, if such a mode exists,” Karpova says. And that’s exactly what happened: When faced with a weak competitor, the animals made strategic choices based on the outcomes of previous trials. But when a sophisticated competitor made strong predictions, the rats ignored past experience and made random selections in search of a reward.

Now that they had evidence that the brain could generate both strategic and random behavior, Karpova and her colleagues wanted to know how it switched between modes. Since that switch determines whether or not an animal’s internal model of the world influences its behavior, the scientists suspected it might involve a brain region called the anterior cingulate cortex, where that internal model is likely encoded.

They found that they could cause animals to switch between random and strategic behavior by manipulating the level of a stress hormone called norepinephrine in the anterior cingulate cortex. Increasing norepinephrine in the region activated random behavior and suppressed the strategic mode. Inhibiting release of the hormone had the opposite effect.

Karpova’s team observed that animals in their experiments sometimes continued to behave randomly, even when such behavior was no longer advantageous. “If all they’ve experienced is this really sophisticated competitor for several sessions that thwarts their attempts at strategic, model-based counter-prediction, they go into this [random mode], and they can get stuck in it for quite some time after that competitor is gone,” she says. This, she says, resembles the condition of learned helplessness, in which strategic decision-making is impaired following an experience in which a person finds they are unable to control their environment.

The scientists could release the animals from this “stuck” state by suppressing the release of norepinephrine in the anterior cingulate cortex. “Just by manipulating a single neuromodulatory input into one brain area, you can dramatically enhance the strategic mode. The effect is strong enough to rescue animals out of the random mode and successfully transform them into strategic decision makers,” Karpova says. “We think this might shed light on what has gone wrong in conditions such as learned helplessness, and possibly how we can help alleviate them.”

Karpova says that now that her team has uncovered a mechanism that switches the brain between random and strategic behavior, she would like to understand how those behaviors are controlled in more natural settings. “We normally try to use all of our knowledge to think strategically, but sometimes we still need to explore,” she says. In most cases, that probably means brief bouts of random behavior during times when we are uncertain that past experience is relevant, followed by a return to more strategic behavior — a more subtle balance that Karpova intends to investigate at the level of changes in activity in individual neural circuits.


Story Source:

The above story is based on materials provided by Howard Hughes Medical Institute (HHMI). Note: Materials may be edited for content and length.

Journal Reference:

  1. Dougal G.R. Tervo, Mikhail Proskurin, Maxim Manakov, Mayank Kabra, Alison Vollmer, Kristin Branson, Alla Y. Karpova. Behavioral Variability through Stochastic Choice and Its Gating by Anterior Cingulate Cortex. Cell, 2014; 159 (1): 21 DOI: 10.1016/j.cell.2014.08.037

 

Howard Hughes Medical Institute (HHMI). “Strategic or random? How the brain chooses.” ScienceDaily. ScienceDaily, 25 September 2014. <www.sciencedaily.com/releases/2014/09/140925130514.htm>.

Date:
September 24, 2014

 

Source:
University of Missouri-Columbia

 

Summary:
A molecule used as a communication system by bacteria can be manipulated to prevent cancer cells from spreading, a study has demonstrated. “During an infection, bacteria release molecules which allow them to ‘talk’ to each other,” said the lead author of the study. “Depending on the type of molecule released, the signal will tell other bacteria to multiply, escape the immune system or even stop spreading.”

 

 

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Bacteria molecule kills cancer cells: Cancer cells on the left are pre-molecule treatment. The cells on the right are after the treatment and are dead.
Credit: Image courtesy of University of Missouri-Columbia

 

 

Cancer, while always dangerous, truly becomes life-threatening when cancer cells begin to spread to different areas throughout the body. Now, researchers at the University of Missouri have discovered that a molecule used as a communication system by bacteria can be manipulated to prevent cancer cells from spreading. Senthil Kumar, an assistant research professor and assistant director of the Comparative Oncology and Epigenetics Laboratory at the MU College of Veterinary Medicine, says this communication system can be used to “tell” cancer cells how to act, or even to die on command.

“During an infection, bacteria release molecules which allow them to ‘talk’ to each other,” said Kumar, the lead author of the study. “Depending on the type of molecule released, the signal will tell other bacteria to multiply, escape the immune system or even stop spreading. We found that if we introduce the ‘stop spreading’ bacteria molecule to cancer cells, those cells will not only stop spreading; they will begin to die as well.”

In the study published in PLOS ONE, Kumar, and co-author Jeffrey Bryan, an associate professor in the MU College of Veterinary Medicine, treated human pancreatic cancer cells grown in culture with bacterial communication molecules, known as ODDHSL. After the treatment, the pancreatic cancer cells stopped multiplying, failed to migrate and began to die.

“We used pancreatic cancer cells, because those are the most robust, aggressive and hard-to-kill cancer cells that can occur in the human body,” Kumar said. “To show that this molecule can not only stop the cancer cells from spreading, but actually cause them to die, is very exciting. Because this treatment shows promise in such an aggressive cancer like pancreatic cancer, we believe it could be used on other types of cancer cells and our lab is in the process of testing this treatment in other types of cancer.”

Kumar says the next step in his research is to find a more efficient way to introduce the molecules to the cancer cells before animal and human testing can take place.

“Our biggest challenge right now is to find a way to introduce these molecules in an effective way,” Kumar said. “At this time, we only are able to treat cancer cells with this molecule in a laboratory setting. We are now working on a better method which will allow us to treat animals with cancer to see if this therapy is truly effective. The early-stage results of this research are promising. If additional studies, including animal studies, are successful then the next step would be translating this application into clinics.”


Story Source:

The above story is based on materials provided by University of Missouri-Columbia.Note: Materials may be edited for content and length.


Journal Reference:

  1. Ashwath S. Kumar, Jeffrey N. Bryan, Senthil R. Kumar. Bacterial Quorum Sensing Molecule N-3-Oxo-Dodecanoyl-L-Homoserine Lactone Causes Direct Cytotoxicity and Reduced Cell Motility in Human Pancreatic Carcinoma Cells.PLoS ONE, 2014; 9 (9): e106480 DOI: 10.1371/journal.pone.0106480

 

University of Missouri-Columbia. “Bacterial ‘communication system’ could be used to stop, kill cancer cells, study finds.” ScienceDaily. ScienceDaily, 24 September 2014. <www.sciencedaily.com/releases/2014/09/140924145016.htm>.

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