HT Staff

Drop of blood

Credit: Максим Кукушкин

Researchers have developed an optical device that requires only a few drops of blood and a few minutes to measure coagulation parameters that can guide blood transfusions and anticoagulant therapy.

The team described their device in Biomedical Optics Express.

“Currently, the most comprehensive measures of coagulation are a battery of lab tests that are expensive and can take hours to perform,” said study author Seemantini Nadkarni, PhD, of Massachusetts General Hospital in Boston.

She noted that other systems have been developed that provide clotting measurements at the point of care, but the systems can be big and expensive or have other limitations, such as requiring significant amounts of blood or only measuring clotting time.

“Our goal is to provide as much information as a lab test, but to provide it quickly and cheaply at a patient’s bedside,” Dr Nadkarni said.

To reach this goal, she and her colleagues turned to an optical technique they pioneered called laser speckle rheology. The technique involves shining a laser into a sample and monitoring the patterns of light that bounce back.

The researchers had previously used the technique to measure the mechanical properties of a range of different tissue types and found that it was extremely sensitive to the coagulation of blood.

When light hits a blood sample, blood cells and platelets scatter the light. In unclotted blood, these light-scattering particles move easily about, making the pattern of scattered light, a speckle pattern, fluctuate rapidly.

“It’s almost like looking at a starry night sky, with twinkling stars,” Dr Nadkarni said. “But as the blood starts to coagulate, blood cells and platelets come together within a fibrin network to form a clot. The motion is restricted as the sample gets stiffer, and the ‘twinkling’ of the speckle pattern is reduced significantly.”

Dr Nadkarni and her colleagues used a miniature high-speed camera to record the fluctuating speckle pattern and then correlated the intensity of changes in the pattern with 2 blood sample measurements: clotting time and fibrinogen concentration.

The team noted that physicians could use the measurements to make decisions about how much blood to give a bleeding patient and what type of blood product is needed most.

“The timely detection of clotting defects followed by the appropriate blood product transfusion is critical in managing bleeding patients,” Dr Nadkarni said. “If you transfuse too much, there could be further coagulation defects that occur, but if you don’t transfuse enough, bleeding continues.”

On the other end of the spectrum, the device could help patients on anticoagulant therapy. Having a small device that can analyze their blood in a doctor’s office or at home could reduce the cost and inconvenience of blood tests, while increasing the safety of anticoagulation treatment, Dr Nadkarni said.

At present, her team’s device is about the size of a tissue box and is connected to a computer. The researchers are working to further miniaturize the system and aim to perform clinical studies with a  version smaller than a cell phone within the next year.

Drop of blood

Credit: Максим Кукушкин

Researchers have developed an optical device that requires only a few drops of blood and a few minutes to measure coagulation parameters that can guide blood transfusions and anticoagulant therapy.

The team described their device in Biomedical Optics Express.

“Currently, the most comprehensive measures of coagulation are a battery of lab tests that are expensive and can take hours to perform,” said study author Seemantini Nadkarni, PhD, of Massachusetts General Hospital in Boston.

She noted that other systems have been developed that provide clotting measurements at the point of care, but the systems can be big and expensive or have other limitations, such as requiring significant amounts of blood or only measuring clotting time.

“Our goal is to provide as much information as a lab test, but to provide it quickly and cheaply at a patient’s bedside,” Dr Nadkarni said.

To reach this goal, she and her colleagues turned to an optical technique they pioneered called laser speckle rheology. The technique involves shining a laser into a sample and monitoring the patterns of light that bounce back.

The researchers had previously used the technique to measure the mechanical properties of a range of different tissue types and found that it was extremely sensitive to the coagulation of blood.

When light hits a blood sample, blood cells and platelets scatter the light. In unclotted blood, these light-scattering particles move easily about, making the pattern of scattered light, a speckle pattern, fluctuate rapidly.

“It’s almost like looking at a starry night sky, with twinkling stars,” Dr Nadkarni said. “But as the blood starts to coagulate, blood cells and platelets come together within a fibrin network to form a clot. The motion is restricted as the sample gets stiffer, and the ‘twinkling’ of the speckle pattern is reduced significantly.”

Dr Nadkarni and her colleagues used a miniature high-speed camera to record the fluctuating speckle pattern and then correlated the intensity of changes in the pattern with 2 blood sample measurements: clotting time and fibrinogen concentration.

The team noted that physicians could use the measurements to make decisions about how much blood to give a bleeding patient and what type of blood product is needed most.

“The timely detection of clotting defects followed by the appropriate blood product transfusion is critical in managing bleeding patients,” Dr Nadkarni said. “If you transfuse too much, there could be further coagulation defects that occur, but if you don’t transfuse enough, bleeding continues.”

On the other end of the spectrum, the device could help patients on anticoagulant therapy. Having a small device that can analyze their blood in a doctor’s office or at home could reduce the cost and inconvenience of blood tests, while increasing the safety of anticoagulation treatment, Dr Nadkarni said.

At present, her team’s device is about the size of a tissue box and is connected to a computer. The researchers are working to further miniaturize the system and aim to perform clinical studies with a  version smaller than a cell phone within the next year.

Drop of blood

Credit: Максим Кукушкин

Researchers have developed an optical device that requires only a few drops of blood and a few minutes to measure coagulation parameters that can guide blood transfusions and anticoagulant therapy.

The team described their device in Biomedical Optics Express.

“Currently, the most comprehensive measures of coagulation are a battery of lab tests that are expensive and can take hours to perform,” said study author Seemantini Nadkarni, PhD, of Massachusetts General Hospital in Boston.

She noted that other systems have been developed that provide clotting measurements at the point of care, but the systems can be big and expensive or have other limitations, such as requiring significant amounts of blood or only measuring clotting time.

“Our goal is to provide as much information as a lab test, but to provide it quickly and cheaply at a patient’s bedside,” Dr Nadkarni said.

To reach this goal, she and her colleagues turned to an optical technique they pioneered called laser speckle rheology. The technique involves shining a laser into a sample and monitoring the patterns of light that bounce back.

The researchers had previously used the technique to measure the mechanical properties of a range of different tissue types and found that it was extremely sensitive to the coagulation of blood.

When light hits a blood sample, blood cells and platelets scatter the light. In unclotted blood, these light-scattering particles move easily about, making the pattern of scattered light, a speckle pattern, fluctuate rapidly.

“It’s almost like looking at a starry night sky, with twinkling stars,” Dr Nadkarni said. “But as the blood starts to coagulate, blood cells and platelets come together within a fibrin network to form a clot. The motion is restricted as the sample gets stiffer, and the ‘twinkling’ of the speckle pattern is reduced significantly.”

Dr Nadkarni and her colleagues used a miniature high-speed camera to record the fluctuating speckle pattern and then correlated the intensity of changes in the pattern with 2 blood sample measurements: clotting time and fibrinogen concentration.

The team noted that physicians could use the measurements to make decisions about how much blood to give a bleeding patient and what type of blood product is needed most.

“The timely detection of clotting defects followed by the appropriate blood product transfusion is critical in managing bleeding patients,” Dr Nadkarni said. “If you transfuse too much, there could be further coagulation defects that occur, but if you don’t transfuse enough, bleeding continues.”

On the other end of the spectrum, the device could help patients on anticoagulant therapy. Having a small device that can analyze their blood in a doctor’s office or at home could reduce the cost and inconvenience of blood tests, while increasing the safety of anticoagulation treatment, Dr Nadkarni said.

At present, her team’s device is about the size of a tissue box and is connected to a computer. The researchers are working to further miniaturize the system and aim to perform clinical studies with a  version smaller than a cell phone within the next year.

Man loading a pump to

spray insecticide

Credit: Morgana Wingard

A single genetic mutation can cause resistance to the main insecticides used to combat malaria, according to a study published in Genome Biology.

Researchers identified a mutation in the gene GSTe2 that allows mosquitoes to break down the insecticide DDT into non-toxic substances.

The mutation also makes mosquitoes resistant to pyrethroids, an insecticide class used in mosquito nets.

“We found a population of mosquitoes fully resistant to DDT but also to pyrethroids,” said study author Charles Wondji, PhD, of the Liverpool School of Tropical Medicine in the UK.

“So we wanted to elucidate the molecular basis of that resistance in the population and design a field-applicable diagnostic assay for its monitoring.”

To that end, the researchers did a genome-wide comparison on mosquitoes that were fully susceptible to insecticides and Anopheles funestus mosquitoes from the Republic of Benin in Africa, which were resistant to DDT and the pyrethroid permethrin.

The team found the GSTe2 gene was upregulated in the resistant mosquitoes. And a single mutation (L119F) changed a non-resistant version of the gene to an insecticide-resistant version.

The researchers then designed a DNA-based diagnostic test for this metabolic resistance and confirmed that this mutation was found in mosquitoes from other areas of the world with DDT resistance, but it was completely absent in regions without resistance.

X-ray crystallography of the protein coded by the gene illustrated exactly how the mutation conferred resistance—by opening up the active site where DDT molecules bind to the protein so that more can be broken down. In other words, the mosquito can survive by breaking down the poison into non-toxic substances.

The researchers also introduced the gene into Drosophila melanogaster and found the flies became resistant to DDT and pyrethroids, whereas control flies did not. The team said this confirms that a single mutation is enough to make insects resistant to both DDT and pyrethroids.

“For the first time, we have been able to identify a molecular marker for metabolic resistance in a mosquito population and to design a DNA-based diagnostic assay,” Dr Wondji said.

“Such tools will allow control programs to detect and track resistance at an early stage in the field, which is an essential requirement to successfully tackle the growing problem of insecticide resistance in vector control. This significant progress opens the door for us to do this with other forms of resistance as well and in other vector species.”

Man loading a pump to

spray insecticide

Credit: Morgana Wingard

A single genetic mutation can cause resistance to the main insecticides used to combat malaria, according to a study published in Genome Biology.

Researchers identified a mutation in the gene GSTe2 that allows mosquitoes to break down the insecticide DDT into non-toxic substances.

The mutation also makes mosquitoes resistant to pyrethroids, an insecticide class used in mosquito nets.

“We found a population of mosquitoes fully resistant to DDT but also to pyrethroids,” said study author Charles Wondji, PhD, of the Liverpool School of Tropical Medicine in the UK.

“So we wanted to elucidate the molecular basis of that resistance in the population and design a field-applicable diagnostic assay for its monitoring.”

To that end, the researchers did a genome-wide comparison on mosquitoes that were fully susceptible to insecticides and Anopheles funestus mosquitoes from the Republic of Benin in Africa, which were resistant to DDT and the pyrethroid permethrin.

The team found the GSTe2 gene was upregulated in the resistant mosquitoes. And a single mutation (L119F) changed a non-resistant version of the gene to an insecticide-resistant version.

The researchers then designed a DNA-based diagnostic test for this metabolic resistance and confirmed that this mutation was found in mosquitoes from other areas of the world with DDT resistance, but it was completely absent in regions without resistance.

X-ray crystallography of the protein coded by the gene illustrated exactly how the mutation conferred resistance—by opening up the active site where DDT molecules bind to the protein so that more can be broken down. In other words, the mosquito can survive by breaking down the poison into non-toxic substances.

The researchers also introduced the gene into Drosophila melanogaster and found the flies became resistant to DDT and pyrethroids, whereas control flies did not. The team said this confirms that a single mutation is enough to make insects resistant to both DDT and pyrethroids.

“For the first time, we have been able to identify a molecular marker for metabolic resistance in a mosquito population and to design a DNA-based diagnostic assay,” Dr Wondji said.

“Such tools will allow control programs to detect and track resistance at an early stage in the field, which is an essential requirement to successfully tackle the growing problem of insecticide resistance in vector control. This significant progress opens the door for us to do this with other forms of resistance as well and in other vector species.”

Man loading a pump to

spray insecticide

Credit: Morgana Wingard

A single genetic mutation can cause resistance to the main insecticides used to combat malaria, according to a study published in Genome Biology.

Researchers identified a mutation in the gene GSTe2 that allows mosquitoes to break down the insecticide DDT into non-toxic substances.

The mutation also makes mosquitoes resistant to pyrethroids, an insecticide class used in mosquito nets.

“We found a population of mosquitoes fully resistant to DDT but also to pyrethroids,” said study author Charles Wondji, PhD, of the Liverpool School of Tropical Medicine in the UK.

“So we wanted to elucidate the molecular basis of that resistance in the population and design a field-applicable diagnostic assay for its monitoring.”

To that end, the researchers did a genome-wide comparison on mosquitoes that were fully susceptible to insecticides and Anopheles funestus mosquitoes from the Republic of Benin in Africa, which were resistant to DDT and the pyrethroid permethrin.

The team found the GSTe2 gene was upregulated in the resistant mosquitoes. And a single mutation (L119F) changed a non-resistant version of the gene to an insecticide-resistant version.

The researchers then designed a DNA-based diagnostic test for this metabolic resistance and confirmed that this mutation was found in mosquitoes from other areas of the world with DDT resistance, but it was completely absent in regions without resistance.

X-ray crystallography of the protein coded by the gene illustrated exactly how the mutation conferred resistance—by opening up the active site where DDT molecules bind to the protein so that more can be broken down. In other words, the mosquito can survive by breaking down the poison into non-toxic substances.

The researchers also introduced the gene into Drosophila melanogaster and found the flies became resistant to DDT and pyrethroids, whereas control flies did not. The team said this confirms that a single mutation is enough to make insects resistant to both DDT and pyrethroids.

“For the first time, we have been able to identify a molecular marker for metabolic resistance in a mosquito population and to design a DNA-based diagnostic assay,” Dr Wondji said.

“Such tools will allow control programs to detect and track resistance at an early stage in the field, which is an essential requirement to successfully tackle the growing problem of insecticide resistance in vector control. This significant progress opens the door for us to do this with other forms of resistance as well and in other vector species.”

Bone marrow aspirate

showing multiple myeloma

Blacks may be twice as likely as whites to develop multiple myeloma (MM) because they are more likely to have monoclonal gammopathy of undetermined significance (MGUS), according to research published in Leukemia.

In a US-wide study, researchers found that MGUS is more common in blacks than in whites or Hispanics.

And the type of MGUS seen in the black population is more apt to have features associated with a higher risk of progression to full-blown MM.

The study also revealed different rates of MGUS in different parts of the country, which suggests there may be an environmental component to the racial disparities.

“We have known for a long time that there is a marked racial disparity in multiple myeloma, but the big question has been why that disparity exists,” said study author Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“We suspected it may be genetic or it may be environmental. We also thought that the predisposing factor is more common, or it may be that the predisposing factor progresses to cancer much more quickly. We found that the answer is all of the above.”

A number of studies have investigated the prevalence of MGUS in various populations. The most prominent took place in the predominantly white community of Olmsted County, Minnesota. There, researchers estimated that MGUS occurred in approximately 3.2% of individuals aged 50 and older.

In the current study, Dr Rajkumar and his colleagues set out to determine the prevalence of MGUS in blacks and Hispanics, as well as whites in other parts of the country. They analyzed stored serum samples of 12,482 people older than 50 years of age taken from the National Health and Nutritional Examination Survey.

By examining the M protein present in each sample, the researchers assessed both the prevalence of MGUS and its likelihood for progression. They found that the prevalence of MGUS was significantly higher in blacks (3.7%) compared with whites (2.3%) or Hispanics (1.8%), as were features that posed a higher risk of progression to MM.

The researchers were surprised that the prevalence of MGUS in whites in their national sample was significantly lower than the rates previously reported for Olmsted County. However, when they broke down the national numbers into geographic regions, they found that people living in Northern and Midwestern states have a higher incidence of MGUS than those living in Southern and Western states.

“We would have missed this geographic difference if we hadn’t looked at the whole country,” Dr Rajkumar said. “This is the largest study of its kind and the first to look at MGUS in a sample of the entire US population.”

Dr Rajkumar and his colleagues are now investigating the underlying causes of these geographic variations to see if they can identify the genetic and environmental factors contributing to the risk of MGUS. They are also repeating their experiments in samples from individuals under age 50 in an effort to pinpoint when the risk of MGUS and, ultimately, MM begins.

Bone marrow aspirate

showing multiple myeloma

Blacks may be twice as likely as whites to develop multiple myeloma (MM) because they are more likely to have monoclonal gammopathy of undetermined significance (MGUS), according to research published in Leukemia.

In a US-wide study, researchers found that MGUS is more common in blacks than in whites or Hispanics.

And the type of MGUS seen in the black population is more apt to have features associated with a higher risk of progression to full-blown MM.

The study also revealed different rates of MGUS in different parts of the country, which suggests there may be an environmental component to the racial disparities.

“We have known for a long time that there is a marked racial disparity in multiple myeloma, but the big question has been why that disparity exists,” said study author Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“We suspected it may be genetic or it may be environmental. We also thought that the predisposing factor is more common, or it may be that the predisposing factor progresses to cancer much more quickly. We found that the answer is all of the above.”

A number of studies have investigated the prevalence of MGUS in various populations. The most prominent took place in the predominantly white community of Olmsted County, Minnesota. There, researchers estimated that MGUS occurred in approximately 3.2% of individuals aged 50 and older.

In the current study, Dr Rajkumar and his colleagues set out to determine the prevalence of MGUS in blacks and Hispanics, as well as whites in other parts of the country. They analyzed stored serum samples of 12,482 people older than 50 years of age taken from the National Health and Nutritional Examination Survey.

By examining the M protein present in each sample, the researchers assessed both the prevalence of MGUS and its likelihood for progression. They found that the prevalence of MGUS was significantly higher in blacks (3.7%) compared with whites (2.3%) or Hispanics (1.8%), as were features that posed a higher risk of progression to MM.

The researchers were surprised that the prevalence of MGUS in whites in their national sample was significantly lower than the rates previously reported for Olmsted County. However, when they broke down the national numbers into geographic regions, they found that people living in Northern and Midwestern states have a higher incidence of MGUS than those living in Southern and Western states.

“We would have missed this geographic difference if we hadn’t looked at the whole country,” Dr Rajkumar said. “This is the largest study of its kind and the first to look at MGUS in a sample of the entire US population.”

Dr Rajkumar and his colleagues are now investigating the underlying causes of these geographic variations to see if they can identify the genetic and environmental factors contributing to the risk of MGUS. They are also repeating their experiments in samples from individuals under age 50 in an effort to pinpoint when the risk of MGUS and, ultimately, MM begins.

Bone marrow aspirate

showing multiple myeloma

Blacks may be twice as likely as whites to develop multiple myeloma (MM) because they are more likely to have monoclonal gammopathy of undetermined significance (MGUS), according to research published in Leukemia.

In a US-wide study, researchers found that MGUS is more common in blacks than in whites or Hispanics.

And the type of MGUS seen in the black population is more apt to have features associated with a higher risk of progression to full-blown MM.

The study also revealed different rates of MGUS in different parts of the country, which suggests there may be an environmental component to the racial disparities.

“We have known for a long time that there is a marked racial disparity in multiple myeloma, but the big question has been why that disparity exists,” said study author Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“We suspected it may be genetic or it may be environmental. We also thought that the predisposing factor is more common, or it may be that the predisposing factor progresses to cancer much more quickly. We found that the answer is all of the above.”

A number of studies have investigated the prevalence of MGUS in various populations. The most prominent took place in the predominantly white community of Olmsted County, Minnesota. There, researchers estimated that MGUS occurred in approximately 3.2% of individuals aged 50 and older.

In the current study, Dr Rajkumar and his colleagues set out to determine the prevalence of MGUS in blacks and Hispanics, as well as whites in other parts of the country. They analyzed stored serum samples of 12,482 people older than 50 years of age taken from the National Health and Nutritional Examination Survey.

By examining the M protein present in each sample, the researchers assessed both the prevalence of MGUS and its likelihood for progression. They found that the prevalence of MGUS was significantly higher in blacks (3.7%) compared with whites (2.3%) or Hispanics (1.8%), as were features that posed a higher risk of progression to MM.

The researchers were surprised that the prevalence of MGUS in whites in their national sample was significantly lower than the rates previously reported for Olmsted County. However, when they broke down the national numbers into geographic regions, they found that people living in Northern and Midwestern states have a higher incidence of MGUS than those living in Southern and Western states.

“We would have missed this geographic difference if we hadn’t looked at the whole country,” Dr Rajkumar said. “This is the largest study of its kind and the first to look at MGUS in a sample of the entire US population.”

Dr Rajkumar and his colleagues are now investigating the underlying causes of these geographic variations to see if they can identify the genetic and environmental factors contributing to the risk of MGUS. They are also repeating their experiments in samples from individuals under age 50 in an effort to pinpoint when the risk of MGUS and, ultimately, MM begins.

Thrombus

Credit: Kevin MacKenzie

Updated guidelines from the American Academy of Neurology provide a comparison of oral anticoagulants as stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF).

The guidelines suggest that newer anticoagulants, such as dabigatran, rivaroxaban, and apixaban, are at least as effective, if not more effective, than warfarin at preventing stroke in patients with NVAF. But bleeding risks vary.

Clopidogrel plus aspirin appears to be less effective than warfarin and its derivatives but more effective than aspirin alone.

Apixaban also appears to be more effective than aspirin, with a similar bleeding risk.  And triflusal plus acenocoumarol is likely more effective than acenocoumarol alone.

“Of course, doctors will need to consider the individual patient’s situation in making a decision whether or not to use anticoagulants and which one to use, as the risks and benefits can vary for each person,”  said guideline author Antonio Culebras, MD, of SUNY Upstate Medical University in Syracuse, New York.

Comparing therapies

The authors noted that several new anticoagulants have been developed since the American Academy of Neurology’s last published guidelines on this topic, in 1998.

For the current guidelines, the authors evaluated the results of 6 studies comparing antithrombotics to warfarin and its derivatives, as well as 2 studies comparing antithrombotics to aspirin.

One study suggested that dabigatran is probably more effective than warfarin for reducing the risk of stroke or systemic embolism. Hemorrhage risks were similar with the 2 drugs. But intracranial hemorrhage was less frequent with dabigatran, and gastrointestinal bleeding was higher with dabigatran.

Another study indicated that rivaroxaban is likely as effective as warfarin for preventing cerebral and systemic embolism. Patients who received rivaroxaban had an increased risk of gastrointestinal bleeding but a decreased risk of intracranial hemorrhage and fatal bleeding.

Apixaban seemed to be more effective than warfarin in patients with NVAF who were at moderate risk of embolism. However, this superiority appeared to be the result of a decreased risk in bleeding and reduced mortality. Apixaban was no more effective than warfarin in reducing the risk of cerebral and systemic embolism.

Yet another study suggested that vitamin K antagonists (VKAs) are likely more effective than clopidogrel plus aspirin as stroke prevention in NVAF patients. However, intracranial bleeding was more common with VKAs.

In NVAF patients at moderate risk of stroke, treatment with triflusal plus acenocoumarol and moderate-intensity anticoagulation (INR target 1.25–2.0) appeared to be more effective than treatment with acenocoumarol alone and conventional-intensity anticoagulation (INR target 2.0–3.0).

Low-dose aspirin plus dose-adjusted VKA (fluindione) appeared to increase the risk of hemorrhagic complications compared to VKA therapy alone. However, there was not enough evidence to determine whether aspirin plus VKA decreases the risk of ischemic stroke or other thromboembolic events.

Apixaban appeared to be more effective than aspirin for decreasing the risk of stroke or systemic embolism in patients with NVAF who have a moderate risk of embolism and are not candidates for warfarin treatment. And the bleeding risks were similar with apixaban and aspirin.

In patients with NVAF who were ineligible for VKA therapy, clopidogrel plus aspirin reduced the risk of major vascular events, especially stroke, when compared to aspirin alone. However, the combination also increased the risk of major hemorrhage, including intracranial bleeding.

Recommendations

The authors noted that determining stroke risk in NVAF patients is difficult. So they recommend that clinicians weigh the risks and benefits of stroke prophylaxis in each patient. The authors also recommend informing patients about the potential risk of stroke and taking the patient’s preferences into account.

Clinicians should routinely offer anticoagulant therapy to patients with NVAF and a history of transient ischemic attack or stroke. On the other hand, anticoagulants might not be necessary in NVAF patients who lack additional risk factors for stroke.

Clinicians should use a risk-stratification scheme to help them identify patients at a higher risk for stroke and those with no clinically significant risk. However, anticoagulation thresholds are not necessarily  definitive indicators of the need for anticoagulant therapy.

When choosing among anticoagulants, clinicians should consider the individual patient’s needs and take into account the aforementioned efficacy and safety data.

For more details, see the guidelines in Neurology.

Thrombus

Credit: Kevin MacKenzie

Updated guidelines from the American Academy of Neurology provide a comparison of oral anticoagulants as stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF).

The guidelines suggest that newer anticoagulants, such as dabigatran, rivaroxaban, and apixaban, are at least as effective, if not more effective, than warfarin at preventing stroke in patients with NVAF. But bleeding risks vary.

Clopidogrel plus aspirin appears to be less effective than warfarin and its derivatives but more effective than aspirin alone.

Apixaban also appears to be more effective than aspirin, with a similar bleeding risk.  And triflusal plus acenocoumarol is likely more effective than acenocoumarol alone.

“Of course, doctors will need to consider the individual patient’s situation in making a decision whether or not to use anticoagulants and which one to use, as the risks and benefits can vary for each person,”  said guideline author Antonio Culebras, MD, of SUNY Upstate Medical University in Syracuse, New York.

Comparing therapies

The authors noted that several new anticoagulants have been developed since the American Academy of Neurology’s last published guidelines on this topic, in 1998.

For the current guidelines, the authors evaluated the results of 6 studies comparing antithrombotics to warfarin and its derivatives, as well as 2 studies comparing antithrombotics to aspirin.

One study suggested that dabigatran is probably more effective than warfarin for reducing the risk of stroke or systemic embolism. Hemorrhage risks were similar with the 2 drugs. But intracranial hemorrhage was less frequent with dabigatran, and gastrointestinal bleeding was higher with dabigatran.

Another study indicated that rivaroxaban is likely as effective as warfarin for preventing cerebral and systemic embolism. Patients who received rivaroxaban had an increased risk of gastrointestinal bleeding but a decreased risk of intracranial hemorrhage and fatal bleeding.

Apixaban seemed to be more effective than warfarin in patients with NVAF who were at moderate risk of embolism. However, this superiority appeared to be the result of a decreased risk in bleeding and reduced mortality. Apixaban was no more effective than warfarin in reducing the risk of cerebral and systemic embolism.

Yet another study suggested that vitamin K antagonists (VKAs) are likely more effective than clopidogrel plus aspirin as stroke prevention in NVAF patients. However, intracranial bleeding was more common with VKAs.

In NVAF patients at moderate risk of stroke, treatment with triflusal plus acenocoumarol and moderate-intensity anticoagulation (INR target 1.25–2.0) appeared to be more effective than treatment with acenocoumarol alone and conventional-intensity anticoagulation (INR target 2.0–3.0).

Low-dose aspirin plus dose-adjusted VKA (fluindione) appeared to increase the risk of hemorrhagic complications compared to VKA therapy alone. However, there was not enough evidence to determine whether aspirin plus VKA decreases the risk of ischemic stroke or other thromboembolic events.

Apixaban appeared to be more effective than aspirin for decreasing the risk of stroke or systemic embolism in patients with NVAF who have a moderate risk of embolism and are not candidates for warfarin treatment. And the bleeding risks were similar with apixaban and aspirin.

In patients with NVAF who were ineligible for VKA therapy, clopidogrel plus aspirin reduced the risk of major vascular events, especially stroke, when compared to aspirin alone. However, the combination also increased the risk of major hemorrhage, including intracranial bleeding.

Recommendations

The authors noted that determining stroke risk in NVAF patients is difficult. So they recommend that clinicians weigh the risks and benefits of stroke prophylaxis in each patient. The authors also recommend informing patients about the potential risk of stroke and taking the patient’s preferences into account.

Clinicians should routinely offer anticoagulant therapy to patients with NVAF and a history of transient ischemic attack or stroke. On the other hand, anticoagulants might not be necessary in NVAF patients who lack additional risk factors for stroke.

Clinicians should use a risk-stratification scheme to help them identify patients at a higher risk for stroke and those with no clinically significant risk. However, anticoagulation thresholds are not necessarily  definitive indicators of the need for anticoagulant therapy.

When choosing among anticoagulants, clinicians should consider the individual patient’s needs and take into account the aforementioned efficacy and safety data.

For more details, see the guidelines in Neurology.

Thrombus

Credit: Kevin MacKenzie

Updated guidelines from the American Academy of Neurology provide a comparison of oral anticoagulants as stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF).

The guidelines suggest that newer anticoagulants, such as dabigatran, rivaroxaban, and apixaban, are at least as effective, if not more effective, than warfarin at preventing stroke in patients with NVAF. But bleeding risks vary.

Clopidogrel plus aspirin appears to be less effective than warfarin and its derivatives but more effective than aspirin alone.

Apixaban also appears to be more effective than aspirin, with a similar bleeding risk.  And triflusal plus acenocoumarol is likely more effective than acenocoumarol alone.

“Of course, doctors will need to consider the individual patient’s situation in making a decision whether or not to use anticoagulants and which one to use, as the risks and benefits can vary for each person,”  said guideline author Antonio Culebras, MD, of SUNY Upstate Medical University in Syracuse, New York.

Comparing therapies

The authors noted that several new anticoagulants have been developed since the American Academy of Neurology’s last published guidelines on this topic, in 1998.

For the current guidelines, the authors evaluated the results of 6 studies comparing antithrombotics to warfarin and its derivatives, as well as 2 studies comparing antithrombotics to aspirin.

One study suggested that dabigatran is probably more effective than warfarin for reducing the risk of stroke or systemic embolism. Hemorrhage risks were similar with the 2 drugs. But intracranial hemorrhage was less frequent with dabigatran, and gastrointestinal bleeding was higher with dabigatran.

Another study indicated that rivaroxaban is likely as effective as warfarin for preventing cerebral and systemic embolism. Patients who received rivaroxaban had an increased risk of gastrointestinal bleeding but a decreased risk of intracranial hemorrhage and fatal bleeding.

Apixaban seemed to be more effective than warfarin in patients with NVAF who were at moderate risk of embolism. However, this superiority appeared to be the result of a decreased risk in bleeding and reduced mortality. Apixaban was no more effective than warfarin in reducing the risk of cerebral and systemic embolism.

Yet another study suggested that vitamin K antagonists (VKAs) are likely more effective than clopidogrel plus aspirin as stroke prevention in NVAF patients. However, intracranial bleeding was more common with VKAs.

In NVAF patients at moderate risk of stroke, treatment with triflusal plus acenocoumarol and moderate-intensity anticoagulation (INR target 1.25–2.0) appeared to be more effective than treatment with acenocoumarol alone and conventional-intensity anticoagulation (INR target 2.0–3.0).

Low-dose aspirin plus dose-adjusted VKA (fluindione) appeared to increase the risk of hemorrhagic complications compared to VKA therapy alone. However, there was not enough evidence to determine whether aspirin plus VKA decreases the risk of ischemic stroke or other thromboembolic events.

Apixaban appeared to be more effective than aspirin for decreasing the risk of stroke or systemic embolism in patients with NVAF who have a moderate risk of embolism and are not candidates for warfarin treatment. And the bleeding risks were similar with apixaban and aspirin.

In patients with NVAF who were ineligible for VKA therapy, clopidogrel plus aspirin reduced the risk of major vascular events, especially stroke, when compared to aspirin alone. However, the combination also increased the risk of major hemorrhage, including intracranial bleeding.

Recommendations

The authors noted that determining stroke risk in NVAF patients is difficult. So they recommend that clinicians weigh the risks and benefits of stroke prophylaxis in each patient. The authors also recommend informing patients about the potential risk of stroke and taking the patient’s preferences into account.

Clinicians should routinely offer anticoagulant therapy to patients with NVAF and a history of transient ischemic attack or stroke. On the other hand, anticoagulants might not be necessary in NVAF patients who lack additional risk factors for stroke.

Clinicians should use a risk-stratification scheme to help them identify patients at a higher risk for stroke and those with no clinically significant risk. However, anticoagulation thresholds are not necessarily  definitive indicators of the need for anticoagulant therapy.

When choosing among anticoagulants, clinicians should consider the individual patient’s needs and take into account the aforementioned efficacy and safety data.

For more details, see the guidelines in Neurology.

Red blood cell culture showing

Staphylococcus infection

Credit: Bill Branson

A computerized safety checklist that pulls information from patients’ electronic medical records can reduce the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in Pediatrics.

The study was conducted among children admitted to the pediatric intensive care unit at Lucile Packard Children’s Hospital Stanford in California.

Researchers found the safety checklist increased overall staff compliance with best practices for CLABSI prevention and resulted in a 3-fold reduction in CLABSI incidence.

The automated checklist, and a dashboard-style interface used to interact with it, was designed to help caregivers follow national guidelines for CLABSI prevention. The system combed through data in a patient’s electronic medical record and pushed alerts to physicians and nurses when a patient’s central line was due for care.

The dashboard interface displayed real-time alerts on a large LCD screen in the nurses’ station. Alerts—shown as red, yellow, or green dots beside patients’ names—were generated if, for example, the dressing on a patient’s central line was due to be changed, or if it was time for caregivers to re-evaluate whether medications given in the central line could be switched to oral formulations instead.

“The information was visible and easy to digest,” said study author Deborah Franzon, MD. “We improved compliance with best-care practices and pulled information that otherwise would have been difficult to look for. It reduced busy work and made it possible for the healthcare team to perform their jobs more efficiently and effectively.”

The system was implemented on May 1, 2011, but the researchers considered the rollout period to extend to August 31, 2011. So this period was not included in the analysis.

The team compared data on CLABSI rates, compliance with bundle elements, and staff perceptions/knowledge before the intervention began—from June 1, 2009, to April 30, 2011—and after the system was fully implemented—September 1, 2011, to December 31, 2012.

CLABSI rates decreased from 2.6 per 1000 line-days before the intervention to 0.7 per 1000 line-days afterward (P=0.02). There were a total of 19 CLABSIs per 7322 line-days pre-intervention and 7 CLABSIs per 6155 line-days post-intervention.

The researchers estimated that the intervention saved approximately $260,000 per year in healthcare costs. Treating a single CLABSI costs approximately $39,000.

The team also found that daily documentation of line necessity increased from 30% before the intervention to 73% after (P<0.001). Compliance with dressing changes increased from 87% to 90% (P=0.003).

Compliance with cap changes increased from 87% to 93% (P<0.001). And compliance with port needle changes increased from 69% to 95% (P<0.001). However, compliance with insertion bundle documentation decreased from 67% to 62% (P=0.001).

After the system was implemented, there was a significant increase in staff perception that the medical team addressed central line necessity during rounds (P=0.02). But there was no significant difference in communication among team members (P=0.73) or knowledge regarding the components of the maintenance bundle (P=0.39).

Nevertheless, the researchers concluded that their system promotes compliance with best practices for CLABSI prevention, thereby reducing the risk of harm to patients.

The team hopes to use the system in other ways, such as monitoring the recovery of children who have received organ transplants.

“[The system] lets physicians focus on taking care of the patient while automating some of the background safety checks,” said study author Natalie Pageler, MD. “The nice thing about this tool is that it’s integrated into the electronic medical record, which we use every single day.”

Red blood cell culture showing

Staphylococcus infection

Credit: Bill Branson

A computerized safety checklist that pulls information from patients’ electronic medical records can reduce the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in Pediatrics.

The study was conducted among children admitted to the pediatric intensive care unit at Lucile Packard Children’s Hospital Stanford in California.

Researchers found the safety checklist increased overall staff compliance with best practices for CLABSI prevention and resulted in a 3-fold reduction in CLABSI incidence.

The automated checklist, and a dashboard-style interface used to interact with it, was designed to help caregivers follow national guidelines for CLABSI prevention. The system combed through data in a patient’s electronic medical record and pushed alerts to physicians and nurses when a patient’s central line was due for care.

The dashboard interface displayed real-time alerts on a large LCD screen in the nurses’ station. Alerts—shown as red, yellow, or green dots beside patients’ names—were generated if, for example, the dressing on a patient’s central line was due to be changed, or if it was time for caregivers to re-evaluate whether medications given in the central line could be switched to oral formulations instead.

“The information was visible and easy to digest,” said study author Deborah Franzon, MD. “We improved compliance with best-care practices and pulled information that otherwise would have been difficult to look for. It reduced busy work and made it possible for the healthcare team to perform their jobs more efficiently and effectively.”

The system was implemented on May 1, 2011, but the researchers considered the rollout period to extend to August 31, 2011. So this period was not included in the analysis.

The team compared data on CLABSI rates, compliance with bundle elements, and staff perceptions/knowledge before the intervention began—from June 1, 2009, to April 30, 2011—and after the system was fully implemented—September 1, 2011, to December 31, 2012.

CLABSI rates decreased from 2.6 per 1000 line-days before the intervention to 0.7 per 1000 line-days afterward (P=0.02). There were a total of 19 CLABSIs per 7322 line-days pre-intervention and 7 CLABSIs per 6155 line-days post-intervention.

The researchers estimated that the intervention saved approximately $260,000 per year in healthcare costs. Treating a single CLABSI costs approximately $39,000.

The team also found that daily documentation of line necessity increased from 30% before the intervention to 73% after (P<0.001). Compliance with dressing changes increased from 87% to 90% (P=0.003).

Compliance with cap changes increased from 87% to 93% (P<0.001). And compliance with port needle changes increased from 69% to 95% (P<0.001). However, compliance with insertion bundle documentation decreased from 67% to 62% (P=0.001).

After the system was implemented, there was a significant increase in staff perception that the medical team addressed central line necessity during rounds (P=0.02). But there was no significant difference in communication among team members (P=0.73) or knowledge regarding the components of the maintenance bundle (P=0.39).

Nevertheless, the researchers concluded that their system promotes compliance with best practices for CLABSI prevention, thereby reducing the risk of harm to patients.

The team hopes to use the system in other ways, such as monitoring the recovery of children who have received organ transplants.

“[The system] lets physicians focus on taking care of the patient while automating some of the background safety checks,” said study author Natalie Pageler, MD. “The nice thing about this tool is that it’s integrated into the electronic medical record, which we use every single day.”

Red blood cell culture showing

Staphylococcus infection

Credit: Bill Branson

A computerized safety checklist that pulls information from patients’ electronic medical records can reduce the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in Pediatrics.

The study was conducted among children admitted to the pediatric intensive care unit at Lucile Packard Children’s Hospital Stanford in California.

Researchers found the safety checklist increased overall staff compliance with best practices for CLABSI prevention and resulted in a 3-fold reduction in CLABSI incidence.

The automated checklist, and a dashboard-style interface used to interact with it, was designed to help caregivers follow national guidelines for CLABSI prevention. The system combed through data in a patient’s electronic medical record and pushed alerts to physicians and nurses when a patient’s central line was due for care.

The dashboard interface displayed real-time alerts on a large LCD screen in the nurses’ station. Alerts—shown as red, yellow, or green dots beside patients’ names—were generated if, for example, the dressing on a patient’s central line was due to be changed, or if it was time for caregivers to re-evaluate whether medications given in the central line could be switched to oral formulations instead.

“The information was visible and easy to digest,” said study author Deborah Franzon, MD. “We improved compliance with best-care practices and pulled information that otherwise would have been difficult to look for. It reduced busy work and made it possible for the healthcare team to perform their jobs more efficiently and effectively.”

The system was implemented on May 1, 2011, but the researchers considered the rollout period to extend to August 31, 2011. So this period was not included in the analysis.

The team compared data on CLABSI rates, compliance with bundle elements, and staff perceptions/knowledge before the intervention began—from June 1, 2009, to April 30, 2011—and after the system was fully implemented—September 1, 2011, to December 31, 2012.

CLABSI rates decreased from 2.6 per 1000 line-days before the intervention to 0.7 per 1000 line-days afterward (P=0.02). There were a total of 19 CLABSIs per 7322 line-days pre-intervention and 7 CLABSIs per 6155 line-days post-intervention.

The researchers estimated that the intervention saved approximately $260,000 per year in healthcare costs. Treating a single CLABSI costs approximately $39,000.

The team also found that daily documentation of line necessity increased from 30% before the intervention to 73% after (P<0.001). Compliance with dressing changes increased from 87% to 90% (P=0.003).

Compliance with cap changes increased from 87% to 93% (P<0.001). And compliance with port needle changes increased from 69% to 95% (P<0.001). However, compliance with insertion bundle documentation decreased from 67% to 62% (P=0.001).

After the system was implemented, there was a significant increase in staff perception that the medical team addressed central line necessity during rounds (P=0.02). But there was no significant difference in communication among team members (P=0.73) or knowledge regarding the components of the maintenance bundle (P=0.39).

Nevertheless, the researchers concluded that their system promotes compliance with best practices for CLABSI prevention, thereby reducing the risk of harm to patients.

The team hopes to use the system in other ways, such as monitoring the recovery of children who have received organ transplants.

“[The system] lets physicians focus on taking care of the patient while automating some of the background safety checks,” said study author Natalie Pageler, MD. “The nice thing about this tool is that it’s integrated into the electronic medical record, which we use every single day.”

Blood for transfusion

Credit: UAB Hospital

In a large study, patients who received red blood cell (RBC) transfusions after percutaneous coronary intervention (PCI) had a higher risk of in-hospital heart attack, stroke, and death than their non-transfused peers.

The retrospective study included data on nearly 2 million patients who underwent a PCI at hospitals across the US.

The research revealed considerable variation in transfusion practices for this patient population, although the overall rate of transfusion was low.

This makes sense, as giving RBC transfusions to patients with coronary artery disease is controversial, according to the study authors.

They said there is a growing body of evidence suggesting that transfusion in the setting of acute coronary syndromes (ACS) and in hospitalized patients with a history of coronary artery disease may be associated with an increased risk of heart attack and death.

Furthermore, current guideline statements are cautious about recommending transfusion in hospitalized patients with a history of coronary artery disease and make no recommendation on transfusion in the setting of ACS, citing an absence of definitive evidence.

With this in mind, Matthew W. Sherwood, MD, of Duke Clinical Research Institute in Durham, North Carolina, and his colleagues examined transfusion practice patterns and outcomes in 1,967,218 patients (2,258,711 visits) who underwent PCI from July 2009 to March 2013 at 1431 US hospitals.

The team reported their findings in JAMA.

Overall, 2.1% of patients had a transfusion. However, transfusion practices varied among the hospitals. The unadjusted transfusion rates ranged from 0% to 13%. Overall, 96.3% of hospitals transfused less than 5% of patients, and 3.7% of hospitals transfused 5% of patients or more.

Risk-standardized rates of transfusion by hospital ranged from 0.3% to 9.3%. The risk was adjusted for factors such as age, sex, body mass index, ACS presentation, PCI status, history of congestive heart failure, etc.

Compared to no transfusion, receiving an RBC transfusion was associated with a greater risk of heart attack (4.5% vs 1.8%), stroke (2.0% vs 0.2%), and in-hospital death (12.5% vs 1.2%), irrespective of bleeding complications.

Patients were more likely to receive a transfusion if they were older, female, and had hypertension, diabetes, advanced renal dysfunction, and prior heart attack or heart failure.

The researchers speculated that the variation in transfusion practice patterns observed in this study may be related to several factors, including previously held beliefs about the benefit of transfusion and recently published data indicating the lack of benefit and potential hazard associated with transfusion.

The team said these data highlight the need for randomized trials of transfusion strategies to guide practice in patients undergoing PCI. And until these trials provide more definitive answers, clinicians should try to reduce the risk of bleeding and, therefore, the need for transfusion in patients undergoing PCI.

Blood for transfusion

Credit: UAB Hospital

In a large study, patients who received red blood cell (RBC) transfusions after percutaneous coronary intervention (PCI) had a higher risk of in-hospital heart attack, stroke, and death than their non-transfused peers.

The retrospective study included data on nearly 2 million patients who underwent a PCI at hospitals across the US.

The research revealed considerable variation in transfusion practices for this patient population, although the overall rate of transfusion was low.

This makes sense, as giving RBC transfusions to patients with coronary artery disease is controversial, according to the study authors.

They said there is a growing body of evidence suggesting that transfusion in the setting of acute coronary syndromes (ACS) and in hospitalized patients with a history of coronary artery disease may be associated with an increased risk of heart attack and death.

Furthermore, current guideline statements are cautious about recommending transfusion in hospitalized patients with a history of coronary artery disease and make no recommendation on transfusion in the setting of ACS, citing an absence of definitive evidence.

With this in mind, Matthew W. Sherwood, MD, of Duke Clinical Research Institute in Durham, North Carolina, and his colleagues examined transfusion practice patterns and outcomes in 1,967,218 patients (2,258,711 visits) who underwent PCI from July 2009 to March 2013 at 1431 US hospitals.

The team reported their findings in JAMA.

Overall, 2.1% of patients had a transfusion. However, transfusion practices varied among the hospitals. The unadjusted transfusion rates ranged from 0% to 13%. Overall, 96.3% of hospitals transfused less than 5% of patients, and 3.7% of hospitals transfused 5% of patients or more.

Risk-standardized rates of transfusion by hospital ranged from 0.3% to 9.3%. The risk was adjusted for factors such as age, sex, body mass index, ACS presentation, PCI status, history of congestive heart failure, etc.

Compared to no transfusion, receiving an RBC transfusion was associated with a greater risk of heart attack (4.5% vs 1.8%), stroke (2.0% vs 0.2%), and in-hospital death (12.5% vs 1.2%), irrespective of bleeding complications.

Patients were more likely to receive a transfusion if they were older, female, and had hypertension, diabetes, advanced renal dysfunction, and prior heart attack or heart failure.

The researchers speculated that the variation in transfusion practice patterns observed in this study may be related to several factors, including previously held beliefs about the benefit of transfusion and recently published data indicating the lack of benefit and potential hazard associated with transfusion.

The team said these data highlight the need for randomized trials of transfusion strategies to guide practice in patients undergoing PCI. And until these trials provide more definitive answers, clinicians should try to reduce the risk of bleeding and, therefore, the need for transfusion in patients undergoing PCI.

Blood for transfusion

Credit: UAB Hospital

In a large study, patients who received red blood cell (RBC) transfusions after percutaneous coronary intervention (PCI) had a higher risk of in-hospital heart attack, stroke, and death than their non-transfused peers.

The retrospective study included data on nearly 2 million patients who underwent a PCI at hospitals across the US.

The research revealed considerable variation in transfusion practices for this patient population, although the overall rate of transfusion was low.

This makes sense, as giving RBC transfusions to patients with coronary artery disease is controversial, according to the study authors.

They said there is a growing body of evidence suggesting that transfusion in the setting of acute coronary syndromes (ACS) and in hospitalized patients with a history of coronary artery disease may be associated with an increased risk of heart attack and death.

Furthermore, current guideline statements are cautious about recommending transfusion in hospitalized patients with a history of coronary artery disease and make no recommendation on transfusion in the setting of ACS, citing an absence of definitive evidence.

With this in mind, Matthew W. Sherwood, MD, of Duke Clinical Research Institute in Durham, North Carolina, and his colleagues examined transfusion practice patterns and outcomes in 1,967,218 patients (2,258,711 visits) who underwent PCI from July 2009 to March 2013 at 1431 US hospitals.

The team reported their findings in JAMA.

Overall, 2.1% of patients had a transfusion. However, transfusion practices varied among the hospitals. The unadjusted transfusion rates ranged from 0% to 13%. Overall, 96.3% of hospitals transfused less than 5% of patients, and 3.7% of hospitals transfused 5% of patients or more.

Risk-standardized rates of transfusion by hospital ranged from 0.3% to 9.3%. The risk was adjusted for factors such as age, sex, body mass index, ACS presentation, PCI status, history of congestive heart failure, etc.

Compared to no transfusion, receiving an RBC transfusion was associated with a greater risk of heart attack (4.5% vs 1.8%), stroke (2.0% vs 0.2%), and in-hospital death (12.5% vs 1.2%), irrespective of bleeding complications.

Patients were more likely to receive a transfusion if they were older, female, and had hypertension, diabetes, advanced renal dysfunction, and prior heart attack or heart failure.

The researchers speculated that the variation in transfusion practice patterns observed in this study may be related to several factors, including previously held beliefs about the benefit of transfusion and recently published data indicating the lack of benefit and potential hazard associated with transfusion.

The team said these data highlight the need for randomized trials of transfusion strategies to guide practice in patients undergoing PCI. And until these trials provide more definitive answers, clinicians should try to reduce the risk of bleeding and, therefore, the need for transfusion in patients undergoing PCI.

ALL in the bone marrow

Inhibiting two biosynthesis pathways can override treatment resistance in acute lymphoblastic leukemia (ALL), preclinical research suggests.

Researchers found that inhibiting only one pathway did not effectively kill ALL cells. The cells simply used another pathway to replicate their DNA and continue dividing.

But inhibiting both pathways induced apoptosis in human leukemia cells and reduced tumor burden in mouse models of T- and B-cell ALL.

“This new, dual-targeting approach shows that we can overcome the redundancy in DNA synthesis in ALL cells and identifies a potential target for metabolic intervention in ALL, and possibly in other hematological cancers,” said study author Caius Radu, MD, of the University of California, Los Angeles.

He and his colleagues described this approach in The Journal of Experimental Medicine.

The research began with the knowledge that deoxyribonucleotide triphosphates, including deoxycytidine triphosphate (dCTP), are required for DNA replication, which is necessary for cell division. And dCTP can be produced by the de novo pathway or the nucleoside salvage pathway.

Dr Radu and his colleagues discovered that inhibiting the de novo pathway with the compound thymidine caused leukemia cells to switch to the nucleoside salvage pathway for dCTP production.

However, inhibiting both the de novo and nucleoside salvage pathways prevented dCTP production and proved lethal for leukemia cells.

A number of experiments elicited these results. In one, the researchers knocked down the deoxycytidine kinase (dCK) in human T-ALL cells to inhibit the nucleoside salvage pathway. Then, they administered thymidine to inhibit the de novo pathway. This resulted in dCTP depletion, stalled DNA replication, replication stress, DNA damage, and apoptosis.

The researchers also used the small-molecule inhibitor DI-39 to target dCK. They found that co-administration of DI-39 and thymidine induced replication stress and apoptosis in several leukemia cell lines: CEM, Jurkat, MOLT-4, NALM-6 and RS4;116.

The team then tested DI-39 and thymidine in mice bearing CEM tumors. They found the combination reduced tumor growth in mice bearing established, subcutaneous CEM xenografts and in mice with systemic T-ALL.

In the systemic T-ALL model, treatment with thymidine alone resulted in a 7-fold reduction in tumor burden compared to vehicle control or DI-39 alone. But when thymidine and DI-39 were administered together, mice saw a 100-fold reduction in tumor burden compared to thymidine alone.

The thymidine-DI-39 combination also proved effective against B-ALL cells and in a mouse model of B-ALL. However, the effects were not as great as those observed in T-ALL.

Finally, the researchers evaluated the effects of thymidine and DI-39 in hematopoietic progenitor cells. They looked at the Lineage^- Sca-1⁺ c-Kit⁺ hematopoietic stem cell population, as well as short-term, long-term, and multipotent progenitor hematopoietic progenitor cells.

There was a minor decrease in the percentage of Lineage^- Sca-1⁺ c-Kit⁺ cells after thymidine treatment. However, there were no other significant changes in progenitor cells between the treatment and control groups. Why leukemic cells and normal hematopoietic progenitors respond so differently to this treatment requires further investigation, the researchers said.

But they also noted that this study advances our understanding of DNA synthesis in leukemic cells and suggests that targeted metabolic intervention could be a new therapeutic approach in ALL.

ALL in the bone marrow

Inhibiting two biosynthesis pathways can override treatment resistance in acute lymphoblastic leukemia (ALL), preclinical research suggests.

Researchers found that inhibiting only one pathway did not effectively kill ALL cells. The cells simply used another pathway to replicate their DNA and continue dividing.

But inhibiting both pathways induced apoptosis in human leukemia cells and reduced tumor burden in mouse models of T- and B-cell ALL.

“This new, dual-targeting approach shows that we can overcome the redundancy in DNA synthesis in ALL cells and identifies a potential target for metabolic intervention in ALL, and possibly in other hematological cancers,” said study author Caius Radu, MD, of the University of California, Los Angeles.

He and his colleagues described this approach in The Journal of Experimental Medicine.

The research began with the knowledge that deoxyribonucleotide triphosphates, including deoxycytidine triphosphate (dCTP), are required for DNA replication, which is necessary for cell division. And dCTP can be produced by the de novo pathway or the nucleoside salvage pathway.

Dr Radu and his colleagues discovered that inhibiting the de novo pathway with the compound thymidine caused leukemia cells to switch to the nucleoside salvage pathway for dCTP production.

However, inhibiting both the de novo and nucleoside salvage pathways prevented dCTP production and proved lethal for leukemia cells.

A number of experiments elicited these results. In one, the researchers knocked down the deoxycytidine kinase (dCK) in human T-ALL cells to inhibit the nucleoside salvage pathway. Then, they administered thymidine to inhibit the de novo pathway. This resulted in dCTP depletion, stalled DNA replication, replication stress, DNA damage, and apoptosis.

The researchers also used the small-molecule inhibitor DI-39 to target dCK. They found that co-administration of DI-39 and thymidine induced replication stress and apoptosis in several leukemia cell lines: CEM, Jurkat, MOLT-4, NALM-6 and RS4;116.

The team then tested DI-39 and thymidine in mice bearing CEM tumors. They found the combination reduced tumor growth in mice bearing established, subcutaneous CEM xenografts and in mice with systemic T-ALL.

In the systemic T-ALL model, treatment with thymidine alone resulted in a 7-fold reduction in tumor burden compared to vehicle control or DI-39 alone. But when thymidine and DI-39 were administered together, mice saw a 100-fold reduction in tumor burden compared to thymidine alone.

The thymidine-DI-39 combination also proved effective against B-ALL cells and in a mouse model of B-ALL. However, the effects were not as great as those observed in T-ALL.

Finally, the researchers evaluated the effects of thymidine and DI-39 in hematopoietic progenitor cells. They looked at the Lineage^- Sca-1⁺ c-Kit⁺ hematopoietic stem cell population, as well as short-term, long-term, and multipotent progenitor hematopoietic progenitor cells.

There was a minor decrease in the percentage of Lineage^- Sca-1⁺ c-Kit⁺ cells after thymidine treatment. However, there were no other significant changes in progenitor cells between the treatment and control groups. Why leukemic cells and normal hematopoietic progenitors respond so differently to this treatment requires further investigation, the researchers said.

But they also noted that this study advances our understanding of DNA synthesis in leukemic cells and suggests that targeted metabolic intervention could be a new therapeutic approach in ALL.

ALL in the bone marrow

Inhibiting two biosynthesis pathways can override treatment resistance in acute lymphoblastic leukemia (ALL), preclinical research suggests.

Researchers found that inhibiting only one pathway did not effectively kill ALL cells. The cells simply used another pathway to replicate their DNA and continue dividing.

But inhibiting both pathways induced apoptosis in human leukemia cells and reduced tumor burden in mouse models of T- and B-cell ALL.

“This new, dual-targeting approach shows that we can overcome the redundancy in DNA synthesis in ALL cells and identifies a potential target for metabolic intervention in ALL, and possibly in other hematological cancers,” said study author Caius Radu, MD, of the University of California, Los Angeles.

He and his colleagues described this approach in The Journal of Experimental Medicine.

The research began with the knowledge that deoxyribonucleotide triphosphates, including deoxycytidine triphosphate (dCTP), are required for DNA replication, which is necessary for cell division. And dCTP can be produced by the de novo pathway or the nucleoside salvage pathway.

Dr Radu and his colleagues discovered that inhibiting the de novo pathway with the compound thymidine caused leukemia cells to switch to the nucleoside salvage pathway for dCTP production.

However, inhibiting both the de novo and nucleoside salvage pathways prevented dCTP production and proved lethal for leukemia cells.

A number of experiments elicited these results. In one, the researchers knocked down the deoxycytidine kinase (dCK) in human T-ALL cells to inhibit the nucleoside salvage pathway. Then, they administered thymidine to inhibit the de novo pathway. This resulted in dCTP depletion, stalled DNA replication, replication stress, DNA damage, and apoptosis.

The researchers also used the small-molecule inhibitor DI-39 to target dCK. They found that co-administration of DI-39 and thymidine induced replication stress and apoptosis in several leukemia cell lines: CEM, Jurkat, MOLT-4, NALM-6 and RS4;116.

The team then tested DI-39 and thymidine in mice bearing CEM tumors. They found the combination reduced tumor growth in mice bearing established, subcutaneous CEM xenografts and in mice with systemic T-ALL.

In the systemic T-ALL model, treatment with thymidine alone resulted in a 7-fold reduction in tumor burden compared to vehicle control or DI-39 alone. But when thymidine and DI-39 were administered together, mice saw a 100-fold reduction in tumor burden compared to thymidine alone.

The thymidine-DI-39 combination also proved effective against B-ALL cells and in a mouse model of B-ALL. However, the effects were not as great as those observed in T-ALL.

Finally, the researchers evaluated the effects of thymidine and DI-39 in hematopoietic progenitor cells. They looked at the Lineage^- Sca-1⁺ c-Kit⁺ hematopoietic stem cell population, as well as short-term, long-term, and multipotent progenitor hematopoietic progenitor cells.

There was a minor decrease in the percentage of Lineage^- Sca-1⁺ c-Kit⁺ cells after thymidine treatment. However, there were no other significant changes in progenitor cells between the treatment and control groups. Why leukemic cells and normal hematopoietic progenitors respond so differently to this treatment requires further investigation, the researchers said.

But they also noted that this study advances our understanding of DNA synthesis in leukemic cells and suggests that targeted metabolic intervention could be a new therapeutic approach in ALL.

Adult chimpanzee
David Morgan & Crickette Sanz

Investigators have found evidence suggesting the malaria parasite Plasmodium vivax originated in Africa.

Until recently, the closest genetic relatives of human P vivax were found only in Asian macaques, leading researchers to believe that P vivax originated in Asia.

The current study, published in Nature Communications, showed that wild apes in central Africa are widely infected with parasites that are, genetically, nearly identical to human P vivax.

This finding overturns the dogma that P vivax originated in Asia, despite being most prevalent in humans there now, and also solves other questions about P vivax infection.

For example, it explains why the Duffy-null phenotype, which confers resistance to P vivax, is common among people indigenous to Africa. And it explains how travelers returning from regions where most people are Duffy-negative can be infected with P vivax.

Paul Sharp, PhD, of the University of Edinburgh in the UK, and his colleagues conducted this research, testing more than 5000 ape fecal samples from dozens of field stations and sanctuaries in Africa for P vivax DNA.

They found P vivax-like sequences in chimpanzees, western gorillas, and eastern gorillas, but not in bonobos. Ape P vivax was highly prevalent in wild communities, exhibiting infection rates consistent with stable transmission of the parasite within the wild apes.

To examine the evolutionary relationships between ape and human parasites, the researchers generated parasite DNA sequences from wild and sanctuary apes, as well as from a global sampling of human P vivax infections.

They constructed a family tree of the sequences and found that ape and human parasites were very closely related. But ape parasites were more diverse than the human parasites and did not group according to their host species. The human parasites formed a single lineage that fell within the branches of ape parasite sequences.

From these evolutionary relationships, the investigators concluded that P vivax is of African—not Asian—origin and that all existing human P vivax parasites evolved from a single ancestor that spread out of Africa.

The high prevalence of P vivax in wild apes, along with the recent finding of ape P vivax in a European traveler, indicates the existence of a substantial natural reservoir of P vivax in Africa.

Resolving the Duffy-negative paradox

Of the 5 Plasmodium species known to cause malaria in humans, P vivax is the most widespread. Although highly prevalent in Asia and Latin America, P vivax was thought to be absent from west and central Africa due to a mutation that causes the Duffy-negative phenotype in most indigenous African people.

P vivax parasites enter human red blood cells via the Duffy protein receptor. Because the absence of the receptor on the surface of these cells confers protection against P vivax malaria, this parasite has long been suspected to be the agent that selected for this mutation. However, this hypothesis had been difficult to reconcile with the belief that P vivax originated in Asia.

“Our finding that wild-living apes in central Africa show widespread infection with diverse strains of P vivax provides new insight into the evolutionary history of human P vivax and resolves the paradox that a mutation conferring resistance to P vivax occurs with high frequency in the very region where this parasite is absent in humans,” said study author Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.

“One interpretation of the relationships that we observed is that a single host switch from apes gave rise to human P vivax, analogous to the origin of human P falciparum,” Dr Sharp added. “However, this seems unlikely in this case, since ape P vivax does not divide into gorilla- and chimpanzee-specific lineages.”

A more plausible scenario, according to the researchers, is that an ancestral P vivax stock was able to infect humans, gorillas, and chimpanzees in Africa until the Duffy-negative mutation started to spread—around 30,000 years ago—and eliminated P vivax from humans there.

Under this scenario, existing human-infecting P vivax is a parasite that survived after spreading out of Africa.

“The existence of a P vivax reservoir within the forests of central Africa has public health implications,” said study author Martine Peeters, PhD, of the Institut de Recherche pour le Développement and the University of Montpellier in France.

“First, it solves the mystery of P vivax infections in travelers returning from regions where 99% of the human population is Duffy-negative. It also raises the possibility that Duffy-positive humans whose work may bring them in close proximity to chimpanzees and gorillas may become infected by ape P vivax. This has already happened once and may happen again, with unknown consequences.”

The investigators are also concerned about the possibility that ape P vivax may spread via international travel to countries where human P vivax is actively transmitted. Since ape P vivax is more genetically diverse than human P vivax, it may have more versatility to escape treatment and prevention measures, especially if human and ape parasites were able to recombine.

Given what biologists know about P vivax’s ability to switch hosts, the researchers suggest it is important to screen Duffy-positive and Duffy-negative humans in west central Africa, as well as transmitting mosquito vectors, for the presence of ape P vivax. The team believes this information is necessary to inform malaria control and eradication efforts of the propensity of ape P vivax to cross over to humans.

The investigators are also planning to compare and contrast the molecular and biological properties of human and ape parasites to identify host-specific interactions and transmission requirements, thereby uncovering vulnerabilities that can be exploited to combat human malaria.

Adult chimpanzee
David Morgan & Crickette Sanz

Investigators have found evidence suggesting the malaria parasite Plasmodium vivax originated in Africa.

Until recently, the closest genetic relatives of human P vivax were found only in Asian macaques, leading researchers to believe that P vivax originated in Asia.

The current study, published in Nature Communications, showed that wild apes in central Africa are widely infected with parasites that are, genetically, nearly identical to human P vivax.

This finding overturns the dogma that P vivax originated in Asia, despite being most prevalent in humans there now, and also solves other questions about P vivax infection.

For example, it explains why the Duffy-null phenotype, which confers resistance to P vivax, is common among people indigenous to Africa. And it explains how travelers returning from regions where most people are Duffy-negative can be infected with P vivax.

Paul Sharp, PhD, of the University of Edinburgh in the UK, and his colleagues conducted this research, testing more than 5000 ape fecal samples from dozens of field stations and sanctuaries in Africa for P vivax DNA.

They found P vivax-like sequences in chimpanzees, western gorillas, and eastern gorillas, but not in bonobos. Ape P vivax was highly prevalent in wild communities, exhibiting infection rates consistent with stable transmission of the parasite within the wild apes.

To examine the evolutionary relationships between ape and human parasites, the researchers generated parasite DNA sequences from wild and sanctuary apes, as well as from a global sampling of human P vivax infections.

They constructed a family tree of the sequences and found that ape and human parasites were very closely related. But ape parasites were more diverse than the human parasites and did not group according to their host species. The human parasites formed a single lineage that fell within the branches of ape parasite sequences.

From these evolutionary relationships, the investigators concluded that P vivax is of African—not Asian—origin and that all existing human P vivax parasites evolved from a single ancestor that spread out of Africa.

The high prevalence of P vivax in wild apes, along with the recent finding of ape P vivax in a European traveler, indicates the existence of a substantial natural reservoir of P vivax in Africa.

Resolving the Duffy-negative paradox

Of the 5 Plasmodium species known to cause malaria in humans, P vivax is the most widespread. Although highly prevalent in Asia and Latin America, P vivax was thought to be absent from west and central Africa due to a mutation that causes the Duffy-negative phenotype in most indigenous African people.

P vivax parasites enter human red blood cells via the Duffy protein receptor. Because the absence of the receptor on the surface of these cells confers protection against P vivax malaria, this parasite has long been suspected to be the agent that selected for this mutation. However, this hypothesis had been difficult to reconcile with the belief that P vivax originated in Asia.

“Our finding that wild-living apes in central Africa show widespread infection with diverse strains of P vivax provides new insight into the evolutionary history of human P vivax and resolves the paradox that a mutation conferring resistance to P vivax occurs with high frequency in the very region where this parasite is absent in humans,” said study author Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.

“One interpretation of the relationships that we observed is that a single host switch from apes gave rise to human P vivax, analogous to the origin of human P falciparum,” Dr Sharp added. “However, this seems unlikely in this case, since ape P vivax does not divide into gorilla- and chimpanzee-specific lineages.”

A more plausible scenario, according to the researchers, is that an ancestral P vivax stock was able to infect humans, gorillas, and chimpanzees in Africa until the Duffy-negative mutation started to spread—around 30,000 years ago—and eliminated P vivax from humans there.

Under this scenario, existing human-infecting P vivax is a parasite that survived after spreading out of Africa.

“The existence of a P vivax reservoir within the forests of central Africa has public health implications,” said study author Martine Peeters, PhD, of the Institut de Recherche pour le Développement and the University of Montpellier in France.

“First, it solves the mystery of P vivax infections in travelers returning from regions where 99% of the human population is Duffy-negative. It also raises the possibility that Duffy-positive humans whose work may bring them in close proximity to chimpanzees and gorillas may become infected by ape P vivax. This has already happened once and may happen again, with unknown consequences.”

The investigators are also concerned about the possibility that ape P vivax may spread via international travel to countries where human P vivax is actively transmitted. Since ape P vivax is more genetically diverse than human P vivax, it may have more versatility to escape treatment and prevention measures, especially if human and ape parasites were able to recombine.

Given what biologists know about P vivax’s ability to switch hosts, the researchers suggest it is important to screen Duffy-positive and Duffy-negative humans in west central Africa, as well as transmitting mosquito vectors, for the presence of ape P vivax. The team believes this information is necessary to inform malaria control and eradication efforts of the propensity of ape P vivax to cross over to humans.

The investigators are also planning to compare and contrast the molecular and biological properties of human and ape parasites to identify host-specific interactions and transmission requirements, thereby uncovering vulnerabilities that can be exploited to combat human malaria.

Adult chimpanzee
David Morgan & Crickette Sanz

Investigators have found evidence suggesting the malaria parasite Plasmodium vivax originated in Africa.

Until recently, the closest genetic relatives of human P vivax were found only in Asian macaques, leading researchers to believe that P vivax originated in Asia.

The current study, published in Nature Communications, showed that wild apes in central Africa are widely infected with parasites that are, genetically, nearly identical to human P vivax.

This finding overturns the dogma that P vivax originated in Asia, despite being most prevalent in humans there now, and also solves other questions about P vivax infection.

For example, it explains why the Duffy-null phenotype, which confers resistance to P vivax, is common among people indigenous to Africa. And it explains how travelers returning from regions where most people are Duffy-negative can be infected with P vivax.

Paul Sharp, PhD, of the University of Edinburgh in the UK, and his colleagues conducted this research, testing more than 5000 ape fecal samples from dozens of field stations and sanctuaries in Africa for P vivax DNA.

They found P vivax-like sequences in chimpanzees, western gorillas, and eastern gorillas, but not in bonobos. Ape P vivax was highly prevalent in wild communities, exhibiting infection rates consistent with stable transmission of the parasite within the wild apes.

To examine the evolutionary relationships between ape and human parasites, the researchers generated parasite DNA sequences from wild and sanctuary apes, as well as from a global sampling of human P vivax infections.

They constructed a family tree of the sequences and found that ape and human parasites were very closely related. But ape parasites were more diverse than the human parasites and did not group according to their host species. The human parasites formed a single lineage that fell within the branches of ape parasite sequences.

From these evolutionary relationships, the investigators concluded that P vivax is of African—not Asian—origin and that all existing human P vivax parasites evolved from a single ancestor that spread out of Africa.

The high prevalence of P vivax in wild apes, along with the recent finding of ape P vivax in a European traveler, indicates the existence of a substantial natural reservoir of P vivax in Africa.

Resolving the Duffy-negative paradox

Of the 5 Plasmodium species known to cause malaria in humans, P vivax is the most widespread. Although highly prevalent in Asia and Latin America, P vivax was thought to be absent from west and central Africa due to a mutation that causes the Duffy-negative phenotype in most indigenous African people.

P vivax parasites enter human red blood cells via the Duffy protein receptor. Because the absence of the receptor on the surface of these cells confers protection against P vivax malaria, this parasite has long been suspected to be the agent that selected for this mutation. However, this hypothesis had been difficult to reconcile with the belief that P vivax originated in Asia.

“Our finding that wild-living apes in central Africa show widespread infection with diverse strains of P vivax provides new insight into the evolutionary history of human P vivax and resolves the paradox that a mutation conferring resistance to P vivax occurs with high frequency in the very region where this parasite is absent in humans,” said study author Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.

“One interpretation of the relationships that we observed is that a single host switch from apes gave rise to human P vivax, analogous to the origin of human P falciparum,” Dr Sharp added. “However, this seems unlikely in this case, since ape P vivax does not divide into gorilla- and chimpanzee-specific lineages.”

A more plausible scenario, according to the researchers, is that an ancestral P vivax stock was able to infect humans, gorillas, and chimpanzees in Africa until the Duffy-negative mutation started to spread—around 30,000 years ago—and eliminated P vivax from humans there.

Under this scenario, existing human-infecting P vivax is a parasite that survived after spreading out of Africa.

“The existence of a P vivax reservoir within the forests of central Africa has public health implications,” said study author Martine Peeters, PhD, of the Institut de Recherche pour le Développement and the University of Montpellier in France.

“First, it solves the mystery of P vivax infections in travelers returning from regions where 99% of the human population is Duffy-negative. It also raises the possibility that Duffy-positive humans whose work may bring them in close proximity to chimpanzees and gorillas may become infected by ape P vivax. This has already happened once and may happen again, with unknown consequences.”

The investigators are also concerned about the possibility that ape P vivax may spread via international travel to countries where human P vivax is actively transmitted. Since ape P vivax is more genetically diverse than human P vivax, it may have more versatility to escape treatment and prevention measures, especially if human and ape parasites were able to recombine.

Given what biologists know about P vivax’s ability to switch hosts, the researchers suggest it is important to screen Duffy-positive and Duffy-negative humans in west central Africa, as well as transmitting mosquito vectors, for the presence of ape P vivax. The team believes this information is necessary to inform malaria control and eradication efforts of the propensity of ape P vivax to cross over to humans.

The investigators are also planning to compare and contrast the molecular and biological properties of human and ape parasites to identify host-specific interactions and transmission requirements, thereby uncovering vulnerabilities that can be exploited to combat human malaria.

P falciparum parasites in the

gametocyte stage (blue) and

uninfected red blood cells

Credit: The Llinás lab

Results of 2 new studies suggest that a single regulatory protein acts as a master switch to trigger development of the sexual forms of malaria parasites.

It appears that the protein, AP2-G, is necessary for activating a set of genes that initiate the development of Plasmodium gametocytes, the only forms of the parasite that are infectious to mosquitoes.

This suggests that if researchers can target AP2-G, they can stop sexual parasites from forming.

And if the sexual forms of the parasite never develop in an infected person’s blood, none will enter the mosquito’s gut, and the mosquito will be unable to infect anyone else with malaria.

“Exciting opportunities now lie ahead for finding an effective way to break the chain of malaria transmission by preventing the malaria parasite from completing its full lifecycle,” said Manuel Llinás, PhD, a professor at Pennsylvania State University who was involved in both studies.

The 2 studies, which were published as letters to Nature, had remarkably similar results, despite the fact that the groups worked with 2 different malaria parasites—Plasmodium falciparum and Plasmodium berghei.

In one study, researchers analyzed the whole-genome sequences of 2 P falciparum strains that were unable to produce gametocytes. The only mutated, non-functional gene common to both strains was the AP2-G gene.

In the other study, researchers sequenced P berghei parasites that had lost their ability to make gametocytes. Again, the only common mutated gene in these parasites was AP2-G.

To confirm these observations, both groups of researchers disabled the AP2-G gene in parasites that could generate gametocytes.

As expected, disabling the gene prevented the parasites from producing gametocytes. But the parasites regained their ability to make gametocytes when the mutated gene was repaired.

These results, as well as results of additional experiments, suggest that sexual-stage malaria parasites are produced only when the AP2-G protein is in working order.

“Our research has demonstrated unequivocally that the AP2-G transcription factor protein is essential for flipping the switch that initiates the transformation of malaria parasites in the blood from the asexual stage to the critical sexual stage of their life cycle,” Dr Llinás said.

He and his colleagues believe their discovery is exciting for the future of malaria research. It could spur the development of a sexual-stage vaccine, which would help a person infected with malaria mount an immune response to prevent their parasites from being transmitted to a mosquito, effectively ending the life cycle for that person’s batch of malaria parasites.

P falciparum parasites in the

gametocyte stage (blue) and

uninfected red blood cells

Credit: The Llinás lab

Results of 2 new studies suggest that a single regulatory protein acts as a master switch to trigger development of the sexual forms of malaria parasites.

It appears that the protein, AP2-G, is necessary for activating a set of genes that initiate the development of Plasmodium gametocytes, the only forms of the parasite that are infectious to mosquitoes.

This suggests that if researchers can target AP2-G, they can stop sexual parasites from forming.

And if the sexual forms of the parasite never develop in an infected person’s blood, none will enter the mosquito’s gut, and the mosquito will be unable to infect anyone else with malaria.

“Exciting opportunities now lie ahead for finding an effective way to break the chain of malaria transmission by preventing the malaria parasite from completing its full lifecycle,” said Manuel Llinás, PhD, a professor at Pennsylvania State University who was involved in both studies.

The 2 studies, which were published as letters to Nature, had remarkably similar results, despite the fact that the groups worked with 2 different malaria parasites—Plasmodium falciparum and Plasmodium berghei.

In one study, researchers analyzed the whole-genome sequences of 2 P falciparum strains that were unable to produce gametocytes. The only mutated, non-functional gene common to both strains was the AP2-G gene.

In the other study, researchers sequenced P berghei parasites that had lost their ability to make gametocytes. Again, the only common mutated gene in these parasites was AP2-G.

To confirm these observations, both groups of researchers disabled the AP2-G gene in parasites that could generate gametocytes.

As expected, disabling the gene prevented the parasites from producing gametocytes. But the parasites regained their ability to make gametocytes when the mutated gene was repaired.

These results, as well as results of additional experiments, suggest that sexual-stage malaria parasites are produced only when the AP2-G protein is in working order.

“Our research has demonstrated unequivocally that the AP2-G transcription factor protein is essential for flipping the switch that initiates the transformation of malaria parasites in the blood from the asexual stage to the critical sexual stage of their life cycle,” Dr Llinás said.

He and his colleagues believe their discovery is exciting for the future of malaria research. It could spur the development of a sexual-stage vaccine, which would help a person infected with malaria mount an immune response to prevent their parasites from being transmitted to a mosquito, effectively ending the life cycle for that person’s batch of malaria parasites.

P falciparum parasites in the

gametocyte stage (blue) and

uninfected red blood cells

Credit: The Llinás lab

Results of 2 new studies suggest that a single regulatory protein acts as a master switch to trigger development of the sexual forms of malaria parasites.

It appears that the protein, AP2-G, is necessary for activating a set of genes that initiate the development of Plasmodium gametocytes, the only forms of the parasite that are infectious to mosquitoes.

This suggests that if researchers can target AP2-G, they can stop sexual parasites from forming.

And if the sexual forms of the parasite never develop in an infected person’s blood, none will enter the mosquito’s gut, and the mosquito will be unable to infect anyone else with malaria.

“Exciting opportunities now lie ahead for finding an effective way to break the chain of malaria transmission by preventing the malaria parasite from completing its full lifecycle,” said Manuel Llinás, PhD, a professor at Pennsylvania State University who was involved in both studies.

The 2 studies, which were published as letters to Nature, had remarkably similar results, despite the fact that the groups worked with 2 different malaria parasites—Plasmodium falciparum and Plasmodium berghei.

In one study, researchers analyzed the whole-genome sequences of 2 P falciparum strains that were unable to produce gametocytes. The only mutated, non-functional gene common to both strains was the AP2-G gene.

In the other study, researchers sequenced P berghei parasites that had lost their ability to make gametocytes. Again, the only common mutated gene in these parasites was AP2-G.

To confirm these observations, both groups of researchers disabled the AP2-G gene in parasites that could generate gametocytes.

As expected, disabling the gene prevented the parasites from producing gametocytes. But the parasites regained their ability to make gametocytes when the mutated gene was repaired.

These results, as well as results of additional experiments, suggest that sexual-stage malaria parasites are produced only when the AP2-G protein is in working order.

“Our research has demonstrated unequivocally that the AP2-G transcription factor protein is essential for flipping the switch that initiates the transformation of malaria parasites in the blood from the asexual stage to the critical sexual stage of their life cycle,” Dr Llinás said.

He and his colleagues believe their discovery is exciting for the future of malaria research. It could spur the development of a sexual-stage vaccine, which would help a person infected with malaria mount an immune response to prevent their parasites from being transmitted to a mosquito, effectively ending the life cycle for that person’s batch of malaria parasites.

Patient receiving chemotherapy

Credit: Rhoda Baer

The drug spironolactone could improve the efficacy of platinum-based chemotherapy by preventing tumor cell repair, according to research published in Chemistry & Biology.

The researchers knew that platinum-based chemotherapy drugs bind to cellular DNA to induce damage.

So they theorized that blocking DNA repair mechanisms would help potentiate chemotherapy by reducing cancer cells’ resistance to treatment.

The team focused their efforts on inhibiting nucleotide excision repair (NER), in which a damaged DNA fragment is replaced with an intact fragment.

Frédéric Coin, PhD, of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, and his colleagues screened more than 1200 drugs looking for one that would inhibit NER activity.

And they found that spironolactone—a drug already used to treat fluid retention, high blood pressure, and other conditions—affects NER activity.

Specifically, the team found that, when combined with platinum derivatives, spironolactone significantly increased cytotoxicity in ovarian and colon cancer cells.

As platinum-based chemotherapy is used to treat a range of cancers, similar results might occur in other malignancies as well.

The researchers also noted that, because spironolactone is already in use for other purposes, it doesn’t require a new application for marketing authorization. And its side effects are already known.

The team said this suggests that protocols testing spironolactone in combination with platinum-based chemotherapy could be organized rather quickly.

Patient receiving chemotherapy

Credit: Rhoda Baer

The drug spironolactone could improve the efficacy of platinum-based chemotherapy by preventing tumor cell repair, according to research published in Chemistry & Biology.

The researchers knew that platinum-based chemotherapy drugs bind to cellular DNA to induce damage.

So they theorized that blocking DNA repair mechanisms would help potentiate chemotherapy by reducing cancer cells’ resistance to treatment.

The team focused their efforts on inhibiting nucleotide excision repair (NER), in which a damaged DNA fragment is replaced with an intact fragment.

Frédéric Coin, PhD, of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, and his colleagues screened more than 1200 drugs looking for one that would inhibit NER activity.

And they found that spironolactone—a drug already used to treat fluid retention, high blood pressure, and other conditions—affects NER activity.

Specifically, the team found that, when combined with platinum derivatives, spironolactone significantly increased cytotoxicity in ovarian and colon cancer cells.

As platinum-based chemotherapy is used to treat a range of cancers, similar results might occur in other malignancies as well.

The researchers also noted that, because spironolactone is already in use for other purposes, it doesn’t require a new application for marketing authorization. And its side effects are already known.

The team said this suggests that protocols testing spironolactone in combination with platinum-based chemotherapy could be organized rather quickly.

Patient receiving chemotherapy

Credit: Rhoda Baer

The drug spironolactone could improve the efficacy of platinum-based chemotherapy by preventing tumor cell repair, according to research published in Chemistry & Biology.

The researchers knew that platinum-based chemotherapy drugs bind to cellular DNA to induce damage.

So they theorized that blocking DNA repair mechanisms would help potentiate chemotherapy by reducing cancer cells’ resistance to treatment.

The team focused their efforts on inhibiting nucleotide excision repair (NER), in which a damaged DNA fragment is replaced with an intact fragment.

Frédéric Coin, PhD, of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, and his colleagues screened more than 1200 drugs looking for one that would inhibit NER activity.

And they found that spironolactone—a drug already used to treat fluid retention, high blood pressure, and other conditions—affects NER activity.

Specifically, the team found that, when combined with platinum derivatives, spironolactone significantly increased cytotoxicity in ovarian and colon cancer cells.

As platinum-based chemotherapy is used to treat a range of cancers, similar results might occur in other malignancies as well.

The researchers also noted that, because spironolactone is already in use for other purposes, it doesn’t require a new application for marketing authorization. And its side effects are already known.

The team said this suggests that protocols testing spironolactone in combination with platinum-based chemotherapy could be organized rather quickly.