Wednesday, August 23, 2017

Melting Permafrost in Alaska

It is my fervent hope that the total solar eclipse that has received so much attention is a reminder of our real relationship with this our remarkable planet and its place in the cosmos. For we need to pay close attention to the degree to which our behavior is changing the planet. The following may help illustrate this (from the New York Times) - Alaska's Melting Permafrost

Wednesday, August 16, 2017

The Biochemistry of Nitric Oxide and its Application to Medicine

Nitric oxide (see illustration below) is a highly reactive compound.  Nitrogen (N2) (see illustration below constitutes 78 % of the ambient air; whereas, the concentration of NO in the lower atmosphere has been determined to be within the range of .4 to 71 parts per billion (ppb).


Atmospheric Nitrogen

 
NO was discovered to play an important role in human metabolism.  Within the human body, the enzyme responsible for its production is nitrogen oxide synthase (NOS) (see diagram below) and exists in a number of forms (isoenzymes) – one residing within epithelial cells (eNOS) and another residing within neuronal cells (nNOS).  Once NO is produced, it functions as a chemical messenger that influences a wide variety of cellular processes.  The general scheme of its metabolism is represented below.
Enzymatic Synthesis of NO

NO Metaobolism

Within the human body, NO provides protection against cardiovascular diseases on account of its roles in the regulation of blood pressure.  In addition, NO inhibits the aggregation of platelets and leukocyte (white blood cell) adhesion and thereby diminishes the likelihood of blood clots.  It appears that areduced availability of NO plays a role in the onset of cardiovascular disease.


For all the reasons cited above, NO seems to be vitally important in the maintenance of the continued health of the human cardiovascular system.  The following diagram demonstrates the various stages of NO metabolism in which particular drugs can increase the bio-availability of NO.  This approach to the manufacture and use of particular drugs that can target NO metabolism is of special interest in the practice of medicine.

Bio-availability of  NO Enhanced by the Application of Particular Drugs

Friday, July 14, 2017

Vaccine Development for the Lassa Virus

The Lassa virus is the causative agent for Lassa fever that is serious ailment sometimes leading to death.  This disease is a so-called “hemorrhagic disease.”  Lassa fever is prevalent in West Africa   Currently there is no vaccine available for this disease.

According to the Center for Disease Control and Prevention (CDC): “Signs and symptoms of Lassa fever typically occur 1-3 weeks after the patient comes into contact with the virus. For the majority of Lassa fever virus infections (approximately 80%), symptoms are mild and are undiagnosed. Mild symptoms include slight fever, general malaise and weakness, and headache. In 20% of infected individuals, however, disease may progress to more serious symptoms including hemorrhaging (in gums, eyes, or nose, as examples), respiratory distress, repeated vomiting, facial swelling, pain in the chest, back, and abdomen, and shock. Neurological problems have also been described, including hearing loss, tremors, and encephalitis. Death may occur within two weeks after symptom onset due to multi-organ failure.

The most common complication of Lassa fever is deafness. Various degrees of deafness occur in approximately one-third of infections, and in many cases hearing loss is permanent. As far as is known, severity of the disease does not affect this complication: deafness may develop in mild as well as in severe cases.

Approximately 15%-20% of patients hospitalized for Lassa fever die from the illness. However, only 1% of all Lassa virus infections result in death. The death rates for women in the third trimester of pregnancy are particularly high. Spontaneous abortion is a serious complication of infection with an estimated 95% mortality in fetuses of infected pregnant mothers.
Because the symptoms of Lassa fever are so varied and nonspecific, clinical diagnosis is often difficult. Lassa fever is also associated with occasional epidemics, during which the case-fatality rate can reach 50% in hospitalized patients.”

The Lassa virus is a member of the class of single-stranded RNA viruses within the arenavirus family (see image below).  It possesses a rather simple structure with only one glycoprotein on its surface – GPC.  The function of this protein is to preferentially bind to its host cell target that are primarily the epithelial cells that line the blood capillaries.



Dr Kathryn M. Hastie from and her colleagues from the Scripps Research Institute in La Jolla, California were interested in studying the binding of neutralizing antibodies obtained from a human survivor of Lassa fever with GPC in order to gain some insight in regards to the structure of GPC and the virus’ manner of entry into the host cell.  Elucidating this mechanism would provide significant insight into the development of an effective vaccine against this horrific disease.

GPC in its configuration on the virus particle (virion) exists as a trimer each containing a receptor bind subunit (GP1) and a transmembrane subunit (GP2).  Once binding via GPC is successful and the viral RNA successfully gains entry into the host cell, it commandeers the host’s cellular machinery within the cytoplasm leading to the production of infectious virions – a process that leads to cell death and release of the viral progeny that go on to infect neighboring cells.
   

In order to elucidate the structure and organization of GPC on the viral surface, the research team studied, “more than 100 antibodies from human survivors of Lassa fever.”  This investigation lead to the discovery that the majority of antibody responses targeted the entire GPC assembly rather than individual subunits.  High resolution images of the antibody-GPC complex were derived from X-Ray crystallography.  These data provide information essential for the development of an effective vaccine for this virus.

Wednesday, April 12, 2017

Melting Ice in Antartica

Another example of why Climate Change is a cause for our deepest concern. It certainly deserves our undivided attention. Any government on this planet that attempts to deny this reality is deeply suspect in my judgment.

Tuesday, March 14, 2017

Strategy for the Preferential Elimination of Cancer Cells

The cell surface of mammalian cells is populated with a wide array of proteins that are involved in many aspects of cell-cell communication that is absolutely essential for life. When a normal tissue cell is transformed into a cancerous cell, it often exhibits proteins on the surface that indicate that it has become aberrant – no longer subject to the usual controls that inhibit unrestrained growth.

These “marker” proteins are frequently used to identify cancerous cells and therapeutic strategies are being studied to exploit the presence of these proteins to preferentially kill tumor cells. However, in some types of cancer no unique markers are identifiable.

In order to circumvent this obstacle, Zhiyu Wang from the University of Illinois recently reported on a methodology to positively identify cancer cells that relies on a different approach. Their research strategy can be described in the following way.

 They incubated tumor cultured cells with a class of compounds called sugar azides (structure shown below). The compound DBCO (structure shown below) binds preferentially to sugar azide on the cell surface. In order to ensure that the sugar azide appears only on cancer cells, the researchers modified the sugar azide with protective group that could only be removed with an intracellular tumor-specific enzyme. Once the DBCO-sugar azide complex is on the cell surface, it can be exploited to deliver cancer treating drugs or agents that can used to provide important imaging information.


Azide Sugars


DBCO

This methodology has been successfully employed against colon cancer tumors and metastatic breast cancer in the mouse animal model.

Tuesday, February 21, 2017

The Metabolic Syndrome

The metabolic syndrome refers to that constellation of risk factors that increase the likelihood of such potentially life-threatening conditions as coronary heart disease (CHD), stroke and diabetes.  It is now estimated that some forty-seven million individuals currently suffer from metabolic syndrome within the United States.  The size of this at-risk population is a cause for concern from a public health perspective.  On account of the fact that this population is growing strongly suggest that there are environmental factors involved and that need to be explored.

The five conditions enumerated below are referred to as metabolic risk factors and they are -
  • ·         “A large waistline. This also is called abdominal obesity.  Excess fat in the stomach area is a greater risk factor for heart disease than excess fat in other parts of the body, such as on the hips.
  • ·         A high triglyceride level (or you're on medicine to treat high triglycerides). Triglycerides are a type of fat found in the blood.
  • ·         A low HDL cholesterol level (or you're on medicine to treat low HDL cholesterol). HDL sometimes is called "good" cholesterol. This is because it helps remove cholesterol from your arteries. A low HDL cholesterol level raises your risk for heart disease.
  • ·         High blood pressure (or you're on medicine to treat high blood pressure). Blood pressure is the force of blood pushing against the walls of your arteries as your heart pumps blood. If this pressure rises and stays high over time, it can damage your heart and lead to plaque buildup.
  • ·         High fasting blood sugar (or you're on medicine to treat high blood sugar). Mildly high blood sugar may be an early sign of diabetes.”

The projected risk for heart disease, diabetes, and stroke increases with the number of metabolic risk factors presented. The risk of having metabolic syndrome is also closely linked to obesity and a lack of physical activity.


Insulin resistance is a definitive risk factor for the metabolic syndrome and is strongly associated with Type II Diabetes.  Insulin is the small protein hormone produced by specialized cells of the pancreas (Islets of Langerhans).  Insulin (see image below) is produced in response to the presence of elevated glucose in the blood – usually following a meal – and is responsible for regulating glucose levels in the blood.  Insulin resistance refers to that condition in which the body fails to use this hormone properly.

    Structure of Human Insulin

Tuesday, January 17, 2017

Human Pancreatic Cancer and CD155 Expression

The cell surface transmembrane glycoprotein CD 155 is expressed in many different human tissue cells. This protein has also been shown to be expressed in pancreatic cells in patients suffering from pancreatic cancer. CD 155 is also referred to as a poliovirus receptor (PVR) on account of the fact that it has been implicated in infection with poliovirus in the primate animal model. Current evidence suggests that its function within normal cells is associated with maintaining cohesion between epithelial cells.

S. Nishiwada and his colleagues from the Department of Surgery, Nara Medical University in Kashihara Nara, Japapn have put considerable effort into the study of the role CD 155 expression in human pancreatic cancer within a clinical setting.

In their study of 134 patients with pancreatic cancer, they found that those patients that demonstrated high levels of CD 155 expression also showed a poorer postoperative prognosis than those with low expression of this protein. In addition, they have found an inverse relationship between the expression of CD 155 and the body’s ability to dispatch tumor-infiltrating lymphocytes to the site of the tumor in order to destroy cancerous cells. Furthermore, expression of CD 155 positively correlated with increased growth of the malignancy and angiogenesis – growth of new blood vessels towards the growing tumor. Both of these effects enhances tumor growth. As would be expected, suppression of CD 155 expression, inhibited cell division within pancreatic cancer cells.

Given these important findings, CD 155 may prove to be an important target in pancreatic cancer therapy.