Delaying kidney transplantation to allow for quiescence of systemic lupus erythematosus–related immune activity in patients with lupus nephritis and end-stage renal disease does not appear to improve graft outcomes, according to an analysis of national surveillance data.

Of 4,743 transplant recipients with lupus nephritis and end-stage renal disease (LN-ESRD), 1,239 experienced graft failure. Overall, wait times of 3-12 months and 12-24 months were associated with 25% and 37% increased risk of graft failure, respectively, compared with wait times of less than 3 months, after adjustment for age, race, insurance, hemoglobin, and donor type.

A similar pattern was seen in white patients, except that wait times of more than 36 months in white patients were associated with a near doubling of graft failure risk (hazard ratio, 1.98), Laura C. Plantinga of Emory University, Atlanta, and her colleagues reported (Arthritis Care Res. 2014 Sept. 23 [doi:10.1002/acr.22482]).

Among black patients, longer wait times were not associated with graft failure in the adjusted analysis, and, in fact, there was a nonstatistically significant suggestion of a protective effect for wait time of 2 years or more. This finding may reflect unexplained differences in disease pathology between white and black LN-ESRD patients, the investigators said, adding that there was no increased risk of graft failure in black patients who were transplanted early.

“Our results suggest U.S. recommendations for transplantation in LN-ESRD may not align with evidence from the target population,” they said, noting that the results should be considered hypotheses-generating because of the limitations of the study and that additional study is needed to examine the potential confounding effects of clinically recognized SLE activity on the associations observed in this study.

Some of the investigators were supported through grants from the National Institutes of Health.

Delaying kidney transplantation to allow for quiescence of systemic lupus erythematosus–related immune activity in patients with lupus nephritis and end-stage renal disease does not appear to improve graft outcomes, according to an analysis of national surveillance data.

Of 4,743 transplant recipients with lupus nephritis and end-stage renal disease (LN-ESRD), 1,239 experienced graft failure. Overall, wait times of 3-12 months and 12-24 months were associated with 25% and 37% increased risk of graft failure, respectively, compared with wait times of less than 3 months, after adjustment for age, race, insurance, hemoglobin, and donor type.

A similar pattern was seen in white patients, except that wait times of more than 36 months in white patients were associated with a near doubling of graft failure risk (hazard ratio, 1.98), Laura C. Plantinga of Emory University, Atlanta, and her colleagues reported (Arthritis Care Res. 2014 Sept. 23 [doi:10.1002/acr.22482]).

Among black patients, longer wait times were not associated with graft failure in the adjusted analysis, and, in fact, there was a nonstatistically significant suggestion of a protective effect for wait time of 2 years or more. This finding may reflect unexplained differences in disease pathology between white and black LN-ESRD patients, the investigators said, adding that there was no increased risk of graft failure in black patients who were transplanted early.

“Our results suggest U.S. recommendations for transplantation in LN-ESRD may not align with evidence from the target population,” they said, noting that the results should be considered hypotheses-generating because of the limitations of the study and that additional study is needed to examine the potential confounding effects of clinically recognized SLE activity on the associations observed in this study.

Some of the investigators were supported through grants from the National Institutes of Health.

Delaying kidney transplantation to allow for quiescence of systemic lupus erythematosus–related immune activity in patients with lupus nephritis and end-stage renal disease does not appear to improve graft outcomes, according to an analysis of national surveillance data.

Of 4,743 transplant recipients with lupus nephritis and end-stage renal disease (LN-ESRD), 1,239 experienced graft failure. Overall, wait times of 3-12 months and 12-24 months were associated with 25% and 37% increased risk of graft failure, respectively, compared with wait times of less than 3 months, after adjustment for age, race, insurance, hemoglobin, and donor type.

A similar pattern was seen in white patients, except that wait times of more than 36 months in white patients were associated with a near doubling of graft failure risk (hazard ratio, 1.98), Laura C. Plantinga of Emory University, Atlanta, and her colleagues reported (Arthritis Care Res. 2014 Sept. 23 [doi:10.1002/acr.22482]).

Among black patients, longer wait times were not associated with graft failure in the adjusted analysis, and, in fact, there was a nonstatistically significant suggestion of a protective effect for wait time of 2 years or more. This finding may reflect unexplained differences in disease pathology between white and black LN-ESRD patients, the investigators said, adding that there was no increased risk of graft failure in black patients who were transplanted early.

“Our results suggest U.S. recommendations for transplantation in LN-ESRD may not align with evidence from the target population,” they said, noting that the results should be considered hypotheses-generating because of the limitations of the study and that additional study is needed to examine the potential confounding effects of clinically recognized SLE activity on the associations observed in this study.

Some of the investigators were supported through grants from the National Institutes of Health.

National Suicide Prevention Day fell on Sept. 10 this year, surrounded by National Suicide Prevention Week Sept. 8-14. The conversation, as I’m sure everyone noticed, was focused on the suicide of actor Robin Williams. As we move out a few weeks, my patients – especially those who have contemplated ending their own lives – continue to talk about this tragic loss.

The fear is that the suicide of a celebrity will lead to an increase in the suicide rate in the general public – copycat suicides, if you will. In the month after Marilyn Monroe died of an overdose in 1962, the suicide rate rose by more than 10%. On the other hand, the death of a celebrity may lead to a decrease in the suicide rate, as happened after Kurt Cobain’s death from a self-inflicted gunshot wound in 1994. In the period after Cobain’s death, an effort was made to publicize resources for those who need help. The suicide rate dropped, while calls to hotlines rose.

After Robin Williams’ death, my own social media feeds were full of ads for the National Suicide Prevention Lifeline (NSPL), a hotline with the number 1-800-273-TALK. There are other hotlines, but this was the one I saw most. I wanted to learn about suicide hotlines, so I did a few things: I asked readers of our Shrink Rap blog to tell me about their experiences, and I called the hotline myself to see if I could learn about the structure of the organization, what resources they had to offer a distraught caller, and whether there had been a change in the number of calls they’d received in the time following Mr. Williams’ death.

I called from my cell phone, which is registered in Maryland, while sitting in my home in Baltimore City. The call was routed to Grassroots Crisis Intervention Center in Columbia, Md. Google Maps tells me the center is 25 miles from my house, and it would take me 32 minutes to drive there. In addition to being part of a network of 160 hotline centers across the country, Grassroots has a walk-in crisis center and a mobile treatment center, and is adjacent to a homeless shelter.

“Most of the people who call the National Suicide Prevention Lifeline are suicidal,” said Nicole DeChirico, director of crisis intervention services for Grassroots. “There is a gradation in suicidal thinking, but about 90% of our callers are considering it.”

“We first form rapport, and then we try to quickly assess if an attempt has already been made, and if they are in any danger. We use the assessment of suicidality that is put out by the NSPL. It’s a structured template that is used as a guideline.”

Ms. DeChirico noted that the people who man the hotlines have bachelor’s or master’s degrees – often in psychology, social work, counseling, or education. If feasible, a Safety Planning Intervention is implemented, based on the work of Barbara Stanley, Ph.D., at Columbia University in New York.

“We talk to people about what they need to do to feel safe. If they allow it, we set up a follow-up call. Of the total number of people who have attempted suicide once in the past and lived, 90%-96% never go on to attempt suicide again,” Ms. DeChirico noted. Suicide is a time-limited acute crisis.”

The Grassroots team can see patients on site while they wait for appointments with an outpatient clinician, and can send a mobile crisis team to those who need it if they are in the county served by the organization. I wondered if all 160 agencies that received calls from the NSPL could also provide crisis services.

Marcia Epstein, LMSW, was director of the Headquarters Counseling Center in Lawrence, Kan., from 1979 to 2013. The center became part of the first national suicide prevention hotline network, the National Hopeline Network, 1-800-SUICIDE, in 2001, and then became part of the National Suicide Prevention Lifeline, 1-800-274-TALK (8255), when that network began in January 2005.

“The types of programs and agencies which are part of NSPL vary greatly. The accreditation that allows them to be part of the NSPL network also varies. Some centers are staffed totally by licensed mental health therapists, while others might include trained volunteers and paid counselors who have no professional degree or licensure. Service may be delivered by phone, as well as in person, by text, and by live chat. In person might be on site or through mobile crisis outreach. Some centers are part of other organizations, while others are free-standing, and some serve entire states, while others serve geographically smaller regions,” Ms. Epstein explained in a series of e-mails. She noted that some centers assess and refer, while others, like Grassroots, are able to provide more counseling.

“So if it sounds like I’m saying there is little consistency between centers, yes, that is my experience. But the centers all bring strong commitment to preventing suicide.”

Ms. Epstein continued to discuss the power of the work done with hotline callers.

“The really helpful counseling comes from the heart, from connecting to people with caring and respect and patience, and using our skills in helping them stay safer through the crisis and then, when needed, to stay safer in the long run. It takes a lot of bravery from the people letting us help. And it takes a lot of creativity and flexibility in coming up together with realistic plans to support safety.”

I was curious about the patient response, and I found that was mixed. It was also notable that different patients found different forms of communication to be helpful.

A woman who identified herself only as “Virginia Woolf” wrote, “I have contacted the Samaritans on the [email protected] line because I could write to them via e-mail. I don’t like phones and I also know too many of the counselors on the local crisis line. Each time I was definitely close to suicide. I was in despair and I had the means at hand. I think what stopped me was knowing they would reply. They always did, within a few hours, but waiting for their reply kept me safe.”

Not every response was as positive.

One writer noted, “It was not a productive, supportive, or empathetic person. I felt like she was arrogant, judgmental, and didn’t really care about why I was calling.” The same writer, however, was able to find solace elsewhere. “I have texted CrisisChat and it was an excellent chat and I did feel better.”

Finally, Ms. DeChirico sent me information about the call volume from our local NPSL center in Columbia. From July 1, 2013, to July 31, 2014, the Lifeline received an average of 134 calls per month. December had the highest number of calls, with 163, while August had the lowest with 118. September, February, and April all had 120 calls or fewer.

Robin Williams died on Aug. 11, 2014, and the center received 200 calls in August – a 49% increase over the average volume. Hopefully, we’ll end up seeing a decline in suicide in the months following Mr. Williams’ tragic death.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

National Suicide Prevention Day fell on Sept. 10 this year, surrounded by National Suicide Prevention Week Sept. 8-14. The conversation, as I’m sure everyone noticed, was focused on the suicide of actor Robin Williams. As we move out a few weeks, my patients – especially those who have contemplated ending their own lives – continue to talk about this tragic loss.

The fear is that the suicide of a celebrity will lead to an increase in the suicide rate in the general public – copycat suicides, if you will. In the month after Marilyn Monroe died of an overdose in 1962, the suicide rate rose by more than 10%. On the other hand, the death of a celebrity may lead to a decrease in the suicide rate, as happened after Kurt Cobain’s death from a self-inflicted gunshot wound in 1994. In the period after Cobain’s death, an effort was made to publicize resources for those who need help. The suicide rate dropped, while calls to hotlines rose.

After Robin Williams’ death, my own social media feeds were full of ads for the National Suicide Prevention Lifeline (NSPL), a hotline with the number 1-800-273-TALK. There are other hotlines, but this was the one I saw most. I wanted to learn about suicide hotlines, so I did a few things: I asked readers of our Shrink Rap blog to tell me about their experiences, and I called the hotline myself to see if I could learn about the structure of the organization, what resources they had to offer a distraught caller, and whether there had been a change in the number of calls they’d received in the time following Mr. Williams’ death.

I called from my cell phone, which is registered in Maryland, while sitting in my home in Baltimore City. The call was routed to Grassroots Crisis Intervention Center in Columbia, Md. Google Maps tells me the center is 25 miles from my house, and it would take me 32 minutes to drive there. In addition to being part of a network of 160 hotline centers across the country, Grassroots has a walk-in crisis center and a mobile treatment center, and is adjacent to a homeless shelter.

“Most of the people who call the National Suicide Prevention Lifeline are suicidal,” said Nicole DeChirico, director of crisis intervention services for Grassroots. “There is a gradation in suicidal thinking, but about 90% of our callers are considering it.”

“We first form rapport, and then we try to quickly assess if an attempt has already been made, and if they are in any danger. We use the assessment of suicidality that is put out by the NSPL. It’s a structured template that is used as a guideline.”

Ms. DeChirico noted that the people who man the hotlines have bachelor’s or master’s degrees – often in psychology, social work, counseling, or education. If feasible, a Safety Planning Intervention is implemented, based on the work of Barbara Stanley, Ph.D., at Columbia University in New York.

“We talk to people about what they need to do to feel safe. If they allow it, we set up a follow-up call. Of the total number of people who have attempted suicide once in the past and lived, 90%-96% never go on to attempt suicide again,” Ms. DeChirico noted. Suicide is a time-limited acute crisis.”

The Grassroots team can see patients on site while they wait for appointments with an outpatient clinician, and can send a mobile crisis team to those who need it if they are in the county served by the organization. I wondered if all 160 agencies that received calls from the NSPL could also provide crisis services.

Marcia Epstein, LMSW, was director of the Headquarters Counseling Center in Lawrence, Kan., from 1979 to 2013. The center became part of the first national suicide prevention hotline network, the National Hopeline Network, 1-800-SUICIDE, in 2001, and then became part of the National Suicide Prevention Lifeline, 1-800-274-TALK (8255), when that network began in January 2005.

“The types of programs and agencies which are part of NSPL vary greatly. The accreditation that allows them to be part of the NSPL network also varies. Some centers are staffed totally by licensed mental health therapists, while others might include trained volunteers and paid counselors who have no professional degree or licensure. Service may be delivered by phone, as well as in person, by text, and by live chat. In person might be on site or through mobile crisis outreach. Some centers are part of other organizations, while others are free-standing, and some serve entire states, while others serve geographically smaller regions,” Ms. Epstein explained in a series of e-mails. She noted that some centers assess and refer, while others, like Grassroots, are able to provide more counseling.

“So if it sounds like I’m saying there is little consistency between centers, yes, that is my experience. But the centers all bring strong commitment to preventing suicide.”

Ms. Epstein continued to discuss the power of the work done with hotline callers.

“The really helpful counseling comes from the heart, from connecting to people with caring and respect and patience, and using our skills in helping them stay safer through the crisis and then, when needed, to stay safer in the long run. It takes a lot of bravery from the people letting us help. And it takes a lot of creativity and flexibility in coming up together with realistic plans to support safety.”

I was curious about the patient response, and I found that was mixed. It was also notable that different patients found different forms of communication to be helpful.

A woman who identified herself only as “Virginia Woolf” wrote, “I have contacted the Samaritans on the [email protected] line because I could write to them via e-mail. I don’t like phones and I also know too many of the counselors on the local crisis line. Each time I was definitely close to suicide. I was in despair and I had the means at hand. I think what stopped me was knowing they would reply. They always did, within a few hours, but waiting for their reply kept me safe.”

Not every response was as positive.

One writer noted, “It was not a productive, supportive, or empathetic person. I felt like she was arrogant, judgmental, and didn’t really care about why I was calling.” The same writer, however, was able to find solace elsewhere. “I have texted CrisisChat and it was an excellent chat and I did feel better.”

Finally, Ms. DeChirico sent me information about the call volume from our local NPSL center in Columbia. From July 1, 2013, to July 31, 2014, the Lifeline received an average of 134 calls per month. December had the highest number of calls, with 163, while August had the lowest with 118. September, February, and April all had 120 calls or fewer.

Robin Williams died on Aug. 11, 2014, and the center received 200 calls in August – a 49% increase over the average volume. Hopefully, we’ll end up seeing a decline in suicide in the months following Mr. Williams’ tragic death.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

National Suicide Prevention Day fell on Sept. 10 this year, surrounded by National Suicide Prevention Week Sept. 8-14. The conversation, as I’m sure everyone noticed, was focused on the suicide of actor Robin Williams. As we move out a few weeks, my patients – especially those who have contemplated ending their own lives – continue to talk about this tragic loss.

The fear is that the suicide of a celebrity will lead to an increase in the suicide rate in the general public – copycat suicides, if you will. In the month after Marilyn Monroe died of an overdose in 1962, the suicide rate rose by more than 10%. On the other hand, the death of a celebrity may lead to a decrease in the suicide rate, as happened after Kurt Cobain’s death from a self-inflicted gunshot wound in 1994. In the period after Cobain’s death, an effort was made to publicize resources for those who need help. The suicide rate dropped, while calls to hotlines rose.

After Robin Williams’ death, my own social media feeds were full of ads for the National Suicide Prevention Lifeline (NSPL), a hotline with the number 1-800-273-TALK. There are other hotlines, but this was the one I saw most. I wanted to learn about suicide hotlines, so I did a few things: I asked readers of our Shrink Rap blog to tell me about their experiences, and I called the hotline myself to see if I could learn about the structure of the organization, what resources they had to offer a distraught caller, and whether there had been a change in the number of calls they’d received in the time following Mr. Williams’ death.

I called from my cell phone, which is registered in Maryland, while sitting in my home in Baltimore City. The call was routed to Grassroots Crisis Intervention Center in Columbia, Md. Google Maps tells me the center is 25 miles from my house, and it would take me 32 minutes to drive there. In addition to being part of a network of 160 hotline centers across the country, Grassroots has a walk-in crisis center and a mobile treatment center, and is adjacent to a homeless shelter.

“Most of the people who call the National Suicide Prevention Lifeline are suicidal,” said Nicole DeChirico, director of crisis intervention services for Grassroots. “There is a gradation in suicidal thinking, but about 90% of our callers are considering it.”

“We first form rapport, and then we try to quickly assess if an attempt has already been made, and if they are in any danger. We use the assessment of suicidality that is put out by the NSPL. It’s a structured template that is used as a guideline.”

Ms. DeChirico noted that the people who man the hotlines have bachelor’s or master’s degrees – often in psychology, social work, counseling, or education. If feasible, a Safety Planning Intervention is implemented, based on the work of Barbara Stanley, Ph.D., at Columbia University in New York.

“We talk to people about what they need to do to feel safe. If they allow it, we set up a follow-up call. Of the total number of people who have attempted suicide once in the past and lived, 90%-96% never go on to attempt suicide again,” Ms. DeChirico noted. Suicide is a time-limited acute crisis.”

The Grassroots team can see patients on site while they wait for appointments with an outpatient clinician, and can send a mobile crisis team to those who need it if they are in the county served by the organization. I wondered if all 160 agencies that received calls from the NSPL could also provide crisis services.

Marcia Epstein, LMSW, was director of the Headquarters Counseling Center in Lawrence, Kan., from 1979 to 2013. The center became part of the first national suicide prevention hotline network, the National Hopeline Network, 1-800-SUICIDE, in 2001, and then became part of the National Suicide Prevention Lifeline, 1-800-274-TALK (8255), when that network began in January 2005.

“The types of programs and agencies which are part of NSPL vary greatly. The accreditation that allows them to be part of the NSPL network also varies. Some centers are staffed totally by licensed mental health therapists, while others might include trained volunteers and paid counselors who have no professional degree or licensure. Service may be delivered by phone, as well as in person, by text, and by live chat. In person might be on site or through mobile crisis outreach. Some centers are part of other organizations, while others are free-standing, and some serve entire states, while others serve geographically smaller regions,” Ms. Epstein explained in a series of e-mails. She noted that some centers assess and refer, while others, like Grassroots, are able to provide more counseling.

“So if it sounds like I’m saying there is little consistency between centers, yes, that is my experience. But the centers all bring strong commitment to preventing suicide.”

Ms. Epstein continued to discuss the power of the work done with hotline callers.

“The really helpful counseling comes from the heart, from connecting to people with caring and respect and patience, and using our skills in helping them stay safer through the crisis and then, when needed, to stay safer in the long run. It takes a lot of bravery from the people letting us help. And it takes a lot of creativity and flexibility in coming up together with realistic plans to support safety.”

I was curious about the patient response, and I found that was mixed. It was also notable that different patients found different forms of communication to be helpful.

A woman who identified herself only as “Virginia Woolf” wrote, “I have contacted the Samaritans on the [email protected] line because I could write to them via e-mail. I don’t like phones and I also know too many of the counselors on the local crisis line. Each time I was definitely close to suicide. I was in despair and I had the means at hand. I think what stopped me was knowing they would reply. They always did, within a few hours, but waiting for their reply kept me safe.”

Not every response was as positive.

One writer noted, “It was not a productive, supportive, or empathetic person. I felt like she was arrogant, judgmental, and didn’t really care about why I was calling.” The same writer, however, was able to find solace elsewhere. “I have texted CrisisChat and it was an excellent chat and I did feel better.”

Finally, Ms. DeChirico sent me information about the call volume from our local NPSL center in Columbia. From July 1, 2013, to July 31, 2014, the Lifeline received an average of 134 calls per month. December had the highest number of calls, with 163, while August had the lowest with 118. September, February, and April all had 120 calls or fewer.

Robin Williams died on Aug. 11, 2014, and the center received 200 calls in August – a 49% increase over the average volume. Hopefully, we’ll end up seeing a decline in suicide in the months following Mr. Williams’ tragic death.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

Three generations

of women in a family

By studying 3 generations of a family plagued by blood disorders, researchers discovered a genetic mutation that causes aplastic anemia.

The team performed whole-exome sequencing on DNA from the families and identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.

The mutation disrupts the interactions between telomeres and telomerase, which causes blood cells to die and results in aplastic anemia.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said Hakon Hakonarson, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

Dr Hakonarson and his colleagues described this research in Blood.

The team studied an Australian family with aplastic anemia and other hematopoietic disorders, including leukemia. Whole-exome sequencing of the family’s DNA revealed an inherited mutation on the ACD gene.

The mutation is an amino acid deletion in the TEL patch of TPP1 (ΔK170). All of the family members with this mutation had short telomeres, and those with wild-type TPP1 did not.

The researchers introduced TPP1 with the ΔK170 mutation into 293T cells and found the protein could localize to telomeres but failed to recruit telomerase. The team said this indicates a causal relationship between the mutation and bone marrow disorders.

Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

Nine other genes were previously found to play a role in bone marrow failure disorders. The current study adds ACD to the list and is the first time the gene has been shown to have a disease-causing role.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” Dr Hakonarson said. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

Three generations

of women in a family

By studying 3 generations of a family plagued by blood disorders, researchers discovered a genetic mutation that causes aplastic anemia.

The team performed whole-exome sequencing on DNA from the families and identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.

The mutation disrupts the interactions between telomeres and telomerase, which causes blood cells to die and results in aplastic anemia.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said Hakon Hakonarson, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

Dr Hakonarson and his colleagues described this research in Blood.

The team studied an Australian family with aplastic anemia and other hematopoietic disorders, including leukemia. Whole-exome sequencing of the family’s DNA revealed an inherited mutation on the ACD gene.

The mutation is an amino acid deletion in the TEL patch of TPP1 (ΔK170). All of the family members with this mutation had short telomeres, and those with wild-type TPP1 did not.

The researchers introduced TPP1 with the ΔK170 mutation into 293T cells and found the protein could localize to telomeres but failed to recruit telomerase. The team said this indicates a causal relationship between the mutation and bone marrow disorders.

Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

Nine other genes were previously found to play a role in bone marrow failure disorders. The current study adds ACD to the list and is the first time the gene has been shown to have a disease-causing role.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” Dr Hakonarson said. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

Three generations

of women in a family

By studying 3 generations of a family plagued by blood disorders, researchers discovered a genetic mutation that causes aplastic anemia.

The team performed whole-exome sequencing on DNA from the families and identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.

The mutation disrupts the interactions between telomeres and telomerase, which causes blood cells to die and results in aplastic anemia.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said Hakon Hakonarson, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

Dr Hakonarson and his colleagues described this research in Blood.

The team studied an Australian family with aplastic anemia and other hematopoietic disorders, including leukemia. Whole-exome sequencing of the family’s DNA revealed an inherited mutation on the ACD gene.

The mutation is an amino acid deletion in the TEL patch of TPP1 (ΔK170). All of the family members with this mutation had short telomeres, and those with wild-type TPP1 did not.

The researchers introduced TPP1 with the ΔK170 mutation into 293T cells and found the protein could localize to telomeres but failed to recruit telomerase. The team said this indicates a causal relationship between the mutation and bone marrow disorders.

Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

Nine other genes were previously found to play a role in bone marrow failure disorders. The current study adds ACD to the list and is the first time the gene has been shown to have a disease-causing role.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” Dr Hakonarson said. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

According to the DoD, 300,707 U.S. service members were diagnosed with a traumatic brain injury (TBI) between 2000 and the first quarter of 2014. Of those, 82% had mild TBI (mTBI), also known as a concussion. Usually, a patient recovers from concussion relatively quickly—in days to weeks. But some patients, especially those with preexisting and concomitant conditions, have persistent symptoms that interfere with daily life. The most common of these symptoms are sleep disturbances, usually insomnia, which is a critical issue, given that sleep is so important to the brain’s—and the rest of the body’s—ability to heal. Poor sleep also exacerbates other symptoms, such as pain and irritability, has a negative impact on cognition, and may partially mediate the development of posttraumatic stress disorder or depression.

The Defense and Veterans Brain Injury Center (DVBIC) has released a new clinical recommendation and support tools to help clinicians identify and treat post-TBI sleep disturbances. The suite includes Management of Sleep Disturbances Following Concussion/Mild Traumatic Brain Injury: Guidance for Primary Care Management in Deployed and Non-Deployed Settings, a companion clinical support tool, and a fact sheet for patients. The clinical recommendation (CR) and companion tool are based on a review of current literature and expert contributions from the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, in collaboration with clinical subject matter experts.

The CR strongly advises that all patients with concussion be screened for a sleep disorder. The key question to ask during the patient interview is “Are you experiencing frequent difficulty in falling or staying asleep, excessive daytime sleepiness, or unusual events during sleep?”

The DVBIC Clinical Affairs Officer PHS Capt. Cynthia Spells says “the initial step in the diagnosis of a sleep disorder includes a focused sleep assessment.” The clinical interview should include the “3 Ps”: predisposing, precipitating, and perpetuating factors. Predisposing factors include excessive weight, older age, and medications. Precipitating factors include concussion, deployment, and acute stress. Perpetuating factors include excessive use of caffeine or other stimulants, time zone changes, and familial stress. Noting that comorbid conditions are common with sleep disorders, the CR notes an anxiety disorder postinjury is a more significant predictor of sleep disruption than is pain, other comorbid conditions, or the adverse effects of medication.

A guide for primary care providers (PCPs) in addition to giving an overview of the suite and how to use the components provides insight into the research and science behind managing TBI-related sleep disturbances. The clinical support tool is an algorithm for PCPs to use in assessing sleep disturbances, a step-by-step process to determine the level of care required. The tool is offered as a pocket-sized reference card and can be downloaded. (Health care providers can also take a self-guided course in identifying and treating mTBI at http://www.brainlinemilitary.org.)

According to the CR, nonpharmacologic measures are the first-line treatment for post-TBI sleep problems. These include teaching patients good sleep hygiene and stimulus control; that is, doing as much as possible to physically and environmentally promote sleep. (See App Corner) The patient fact sheet gives tips on getting a healthy night’ s sleep, such as avoiding naps, avoiding alcohol close to bedtime, and getting exposure to natural light as much as possible.

The CR and other components are available at https://dvbic.dcoe.mil/resources/management-sleep-disturbances.

According to the DoD, 300,707 U.S. service members were diagnosed with a traumatic brain injury (TBI) between 2000 and the first quarter of 2014. Of those, 82% had mild TBI (mTBI), also known as a concussion. Usually, a patient recovers from concussion relatively quickly—in days to weeks. But some patients, especially those with preexisting and concomitant conditions, have persistent symptoms that interfere with daily life. The most common of these symptoms are sleep disturbances, usually insomnia, which is a critical issue, given that sleep is so important to the brain’s—and the rest of the body’s—ability to heal. Poor sleep also exacerbates other symptoms, such as pain and irritability, has a negative impact on cognition, and may partially mediate the development of posttraumatic stress disorder or depression.

The Defense and Veterans Brain Injury Center (DVBIC) has released a new clinical recommendation and support tools to help clinicians identify and treat post-TBI sleep disturbances. The suite includes Management of Sleep Disturbances Following Concussion/Mild Traumatic Brain Injury: Guidance for Primary Care Management in Deployed and Non-Deployed Settings, a companion clinical support tool, and a fact sheet for patients. The clinical recommendation (CR) and companion tool are based on a review of current literature and expert contributions from the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, in collaboration with clinical subject matter experts.

The CR strongly advises that all patients with concussion be screened for a sleep disorder. The key question to ask during the patient interview is “Are you experiencing frequent difficulty in falling or staying asleep, excessive daytime sleepiness, or unusual events during sleep?”

The DVBIC Clinical Affairs Officer PHS Capt. Cynthia Spells says “the initial step in the diagnosis of a sleep disorder includes a focused sleep assessment.” The clinical interview should include the “3 Ps”: predisposing, precipitating, and perpetuating factors. Predisposing factors include excessive weight, older age, and medications. Precipitating factors include concussion, deployment, and acute stress. Perpetuating factors include excessive use of caffeine or other stimulants, time zone changes, and familial stress. Noting that comorbid conditions are common with sleep disorders, the CR notes an anxiety disorder postinjury is a more significant predictor of sleep disruption than is pain, other comorbid conditions, or the adverse effects of medication.

A guide for primary care providers (PCPs) in addition to giving an overview of the suite and how to use the components provides insight into the research and science behind managing TBI-related sleep disturbances. The clinical support tool is an algorithm for PCPs to use in assessing sleep disturbances, a step-by-step process to determine the level of care required. The tool is offered as a pocket-sized reference card and can be downloaded. (Health care providers can also take a self-guided course in identifying and treating mTBI at http://www.brainlinemilitary.org.)

According to the CR, nonpharmacologic measures are the first-line treatment for post-TBI sleep problems. These include teaching patients good sleep hygiene and stimulus control; that is, doing as much as possible to physically and environmentally promote sleep. (See App Corner) The patient fact sheet gives tips on getting a healthy night’ s sleep, such as avoiding naps, avoiding alcohol close to bedtime, and getting exposure to natural light as much as possible.

The CR and other components are available at https://dvbic.dcoe.mil/resources/management-sleep-disturbances.

According to the DoD, 300,707 U.S. service members were diagnosed with a traumatic brain injury (TBI) between 2000 and the first quarter of 2014. Of those, 82% had mild TBI (mTBI), also known as a concussion. Usually, a patient recovers from concussion relatively quickly—in days to weeks. But some patients, especially those with preexisting and concomitant conditions, have persistent symptoms that interfere with daily life. The most common of these symptoms are sleep disturbances, usually insomnia, which is a critical issue, given that sleep is so important to the brain’s—and the rest of the body’s—ability to heal. Poor sleep also exacerbates other symptoms, such as pain and irritability, has a negative impact on cognition, and may partially mediate the development of posttraumatic stress disorder or depression.

The Defense and Veterans Brain Injury Center (DVBIC) has released a new clinical recommendation and support tools to help clinicians identify and treat post-TBI sleep disturbances. The suite includes Management of Sleep Disturbances Following Concussion/Mild Traumatic Brain Injury: Guidance for Primary Care Management in Deployed and Non-Deployed Settings, a companion clinical support tool, and a fact sheet for patients. The clinical recommendation (CR) and companion tool are based on a review of current literature and expert contributions from the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, in collaboration with clinical subject matter experts.

The CR strongly advises that all patients with concussion be screened for a sleep disorder. The key question to ask during the patient interview is “Are you experiencing frequent difficulty in falling or staying asleep, excessive daytime sleepiness, or unusual events during sleep?”

The DVBIC Clinical Affairs Officer PHS Capt. Cynthia Spells says “the initial step in the diagnosis of a sleep disorder includes a focused sleep assessment.” The clinical interview should include the “3 Ps”: predisposing, precipitating, and perpetuating factors. Predisposing factors include excessive weight, older age, and medications. Precipitating factors include concussion, deployment, and acute stress. Perpetuating factors include excessive use of caffeine or other stimulants, time zone changes, and familial stress. Noting that comorbid conditions are common with sleep disorders, the CR notes an anxiety disorder postinjury is a more significant predictor of sleep disruption than is pain, other comorbid conditions, or the adverse effects of medication.

A guide for primary care providers (PCPs) in addition to giving an overview of the suite and how to use the components provides insight into the research and science behind managing TBI-related sleep disturbances. The clinical support tool is an algorithm for PCPs to use in assessing sleep disturbances, a step-by-step process to determine the level of care required. The tool is offered as a pocket-sized reference card and can be downloaded. (Health care providers can also take a self-guided course in identifying and treating mTBI at http://www.brainlinemilitary.org.)

According to the CR, nonpharmacologic measures are the first-line treatment for post-TBI sleep problems. These include teaching patients good sleep hygiene and stimulus control; that is, doing as much as possible to physically and environmentally promote sleep. (See App Corner) The patient fact sheet gives tips on getting a healthy night’ s sleep, such as avoiding naps, avoiding alcohol close to bedtime, and getting exposure to natural light as much as possible.

The CR and other components are available at https://dvbic.dcoe.mil/resources/management-sleep-disturbances.

AML in the bone marrow

PHILADELPHIA—Super-enhancer profiling can unearth biomarkers and therapeutic targets for acute myeloid leukemia (AML), according to research presented at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

Researchers used high-throughput ChIP sequencing to identify super-enhancer domains in a cohort of AML patients.

And this revealed both known and previously unknown genes that are important for AML disease biology.

Eric Olson, PhD, and his colleagues from Syros Pharmaceuticals in Watertown, Massachusetts, presented this research during one of the meeting’s poster sessions.

The investigators explained that super-enhancers are a class of densely clustered cis-regulatory elements that are key to initiating and maintaining cell-type-specific gene expression in cancer and other settings. Tumor cells acquire super-enhancers at key oncogenes and at genes that participate in the acquisition of hallmark capabilities in cancer.

So the researchers set out to identify and characterize super-enhancer domains in a cohort of AML patients.

The team collected primary AML samples and performed chromatin fragmentation, chromatin immunoprecipitation, and DNA purification and sequencing.

They then mapped enhancer regions and characterized enhancer profiles. This revealed AML-specific super-enhancers and associated genes.

For example, in one patient, the investigators identified 392 AML-specific super-enhancers, which were associated with 11 genes important for AML disease biology: HOXA7, LMO2, HLX, MYADM, ETV6, AFF1, RUNX1, GFI1, SPI1, MEIS1, and MYB.

In another patient, the team identified 279 AML-specific super-enhancers that were associated with 9 genes: MLLT10, AKT3, FLT3, ETV6, KLF13, RELA, FOSB, BMI1, and RUNX1.

The researchers said these findings suggest that super-enhancer profiling provides a new option for identifying biomarkers and therapeutic targets in AML and other malignancies.

“Syros’s gene control platform can systematically and efficiently identify known and previously unrecognized tumor biomarkers and cancer dependencies directly from patient tissue,” Dr Olson said. “Our data demonstrate unique gene control elements in AML patient subsets that hold promise in the classification and treatment of AML.”

AML in the bone marrow

PHILADELPHIA—Super-enhancer profiling can unearth biomarkers and therapeutic targets for acute myeloid leukemia (AML), according to research presented at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

Researchers used high-throughput ChIP sequencing to identify super-enhancer domains in a cohort of AML patients.

And this revealed both known and previously unknown genes that are important for AML disease biology.

Eric Olson, PhD, and his colleagues from Syros Pharmaceuticals in Watertown, Massachusetts, presented this research during one of the meeting’s poster sessions.

The investigators explained that super-enhancers are a class of densely clustered cis-regulatory elements that are key to initiating and maintaining cell-type-specific gene expression in cancer and other settings. Tumor cells acquire super-enhancers at key oncogenes and at genes that participate in the acquisition of hallmark capabilities in cancer.

So the researchers set out to identify and characterize super-enhancer domains in a cohort of AML patients.

The team collected primary AML samples and performed chromatin fragmentation, chromatin immunoprecipitation, and DNA purification and sequencing.

They then mapped enhancer regions and characterized enhancer profiles. This revealed AML-specific super-enhancers and associated genes.

For example, in one patient, the investigators identified 392 AML-specific super-enhancers, which were associated with 11 genes important for AML disease biology: HOXA7, LMO2, HLX, MYADM, ETV6, AFF1, RUNX1, GFI1, SPI1, MEIS1, and MYB.

In another patient, the team identified 279 AML-specific super-enhancers that were associated with 9 genes: MLLT10, AKT3, FLT3, ETV6, KLF13, RELA, FOSB, BMI1, and RUNX1.

The researchers said these findings suggest that super-enhancer profiling provides a new option for identifying biomarkers and therapeutic targets in AML and other malignancies.

“Syros’s gene control platform can systematically and efficiently identify known and previously unrecognized tumor biomarkers and cancer dependencies directly from patient tissue,” Dr Olson said. “Our data demonstrate unique gene control elements in AML patient subsets that hold promise in the classification and treatment of AML.”

AML in the bone marrow

PHILADELPHIA—Super-enhancer profiling can unearth biomarkers and therapeutic targets for acute myeloid leukemia (AML), according to research presented at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

Researchers used high-throughput ChIP sequencing to identify super-enhancer domains in a cohort of AML patients.

And this revealed both known and previously unknown genes that are important for AML disease biology.

Eric Olson, PhD, and his colleagues from Syros Pharmaceuticals in Watertown, Massachusetts, presented this research during one of the meeting’s poster sessions.

The investigators explained that super-enhancers are a class of densely clustered cis-regulatory elements that are key to initiating and maintaining cell-type-specific gene expression in cancer and other settings. Tumor cells acquire super-enhancers at key oncogenes and at genes that participate in the acquisition of hallmark capabilities in cancer.

So the researchers set out to identify and characterize super-enhancer domains in a cohort of AML patients.

The team collected primary AML samples and performed chromatin fragmentation, chromatin immunoprecipitation, and DNA purification and sequencing.

They then mapped enhancer regions and characterized enhancer profiles. This revealed AML-specific super-enhancers and associated genes.

For example, in one patient, the investigators identified 392 AML-specific super-enhancers, which were associated with 11 genes important for AML disease biology: HOXA7, LMO2, HLX, MYADM, ETV6, AFF1, RUNX1, GFI1, SPI1, MEIS1, and MYB.

In another patient, the team identified 279 AML-specific super-enhancers that were associated with 9 genes: MLLT10, AKT3, FLT3, ETV6, KLF13, RELA, FOSB, BMI1, and RUNX1.

The researchers said these findings suggest that super-enhancer profiling provides a new option for identifying biomarkers and therapeutic targets in AML and other malignancies.

“Syros’s gene control platform can systematically and efficiently identify known and previously unrecognized tumor biomarkers and cancer dependencies directly from patient tissue,” Dr Olson said. “Our data demonstrate unique gene control elements in AML patient subsets that hold promise in the classification and treatment of AML.”

Pricked finger

The UK’s National Institute for Health and Care Excellence (NICE) has published a guidance recommending 2 technologies that enable patients on long-term anticoagulant therapy to self-monitor their clotting time.

The guidance supports use of the Coaguchek XS system (Roche Diagnostics) and the InRatio2 PT/INR Monitor (Alere) as options for some adults with atrial

fibrillation or heart valve disease who are on long-term anticoagulant therapy.

“The evidence shows that greater use of self-monitoring offers clinical and patient benefit and, over time, is likely to result in reductions in heart attacks and strokes caused by blood clots,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“Because self-monitoring provides almost instant results, self-monitoring can reduce anxiety, provide a sense of control for the patient, and remove the need to frequently attend clinics or hospitals.”

About the Coaguchek XS system

The Coaguchek XS system (Roche Diagnostics) consists of a meter and specifically designed test strips that can analyze a blood sample (fresh capillary blood or fresh untreated whole venous blood) and calculate the prothrombin time (PT) and the international normalized ratio (INR).

A code chip, which contains calibration data and the expiration date of the test strips, is inserted into the meter before it is switched on. Once the device is switched on, a test strip is inserted, and the blood sample is applied.

The test result is displayed approximately 1 minute after application of the sample, and the device automatically stores the result in its memory. The user is guided through the process by on-screen graphical instructions.

About the InRatio2 PT/INR Monitor

The INRatio2 PT/INR monitor (Alere) does a modified version of the 1-stage PT test using a recombinant human thromboplastin reagent. The clot formed in the reaction is detected by the change in the electrical impedance of the sample during the coagulation process.

The system consists of a monitor and disposable test strips. The monitor provides a user interface, heats the test strip to the appropriate reaction temperature, measures the impedance of blood samples, and calculates and reports PT and INR results.

Instructions and test results are displayed on an LCD. The monitor can store test results so that past results can be reviewed.

Pricked finger

The UK’s National Institute for Health and Care Excellence (NICE) has published a guidance recommending 2 technologies that enable patients on long-term anticoagulant therapy to self-monitor their clotting time.

The guidance supports use of the Coaguchek XS system (Roche Diagnostics) and the InRatio2 PT/INR Monitor (Alere) as options for some adults with atrial

fibrillation or heart valve disease who are on long-term anticoagulant therapy.

“The evidence shows that greater use of self-monitoring offers clinical and patient benefit and, over time, is likely to result in reductions in heart attacks and strokes caused by blood clots,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“Because self-monitoring provides almost instant results, self-monitoring can reduce anxiety, provide a sense of control for the patient, and remove the need to frequently attend clinics or hospitals.”

About the Coaguchek XS system

The Coaguchek XS system (Roche Diagnostics) consists of a meter and specifically designed test strips that can analyze a blood sample (fresh capillary blood or fresh untreated whole venous blood) and calculate the prothrombin time (PT) and the international normalized ratio (INR).

A code chip, which contains calibration data and the expiration date of the test strips, is inserted into the meter before it is switched on. Once the device is switched on, a test strip is inserted, and the blood sample is applied.

The test result is displayed approximately 1 minute after application of the sample, and the device automatically stores the result in its memory. The user is guided through the process by on-screen graphical instructions.

About the InRatio2 PT/INR Monitor

The INRatio2 PT/INR monitor (Alere) does a modified version of the 1-stage PT test using a recombinant human thromboplastin reagent. The clot formed in the reaction is detected by the change in the electrical impedance of the sample during the coagulation process.

The system consists of a monitor and disposable test strips. The monitor provides a user interface, heats the test strip to the appropriate reaction temperature, measures the impedance of blood samples, and calculates and reports PT and INR results.

Instructions and test results are displayed on an LCD. The monitor can store test results so that past results can be reviewed.

Pricked finger

The UK’s National Institute for Health and Care Excellence (NICE) has published a guidance recommending 2 technologies that enable patients on long-term anticoagulant therapy to self-monitor their clotting time.

The guidance supports use of the Coaguchek XS system (Roche Diagnostics) and the InRatio2 PT/INR Monitor (Alere) as options for some adults with atrial

fibrillation or heart valve disease who are on long-term anticoagulant therapy.

“The evidence shows that greater use of self-monitoring offers clinical and patient benefit and, over time, is likely to result in reductions in heart attacks and strokes caused by blood clots,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“Because self-monitoring provides almost instant results, self-monitoring can reduce anxiety, provide a sense of control for the patient, and remove the need to frequently attend clinics or hospitals.”

About the Coaguchek XS system

The Coaguchek XS system (Roche Diagnostics) consists of a meter and specifically designed test strips that can analyze a blood sample (fresh capillary blood or fresh untreated whole venous blood) and calculate the prothrombin time (PT) and the international normalized ratio (INR).

A code chip, which contains calibration data and the expiration date of the test strips, is inserted into the meter before it is switched on. Once the device is switched on, a test strip is inserted, and the blood sample is applied.

The test result is displayed approximately 1 minute after application of the sample, and the device automatically stores the result in its memory. The user is guided through the process by on-screen graphical instructions.

About the InRatio2 PT/INR Monitor

The INRatio2 PT/INR monitor (Alere) does a modified version of the 1-stage PT test using a recombinant human thromboplastin reagent. The clot formed in the reaction is detected by the change in the electrical impedance of the sample during the coagulation process.

The system consists of a monitor and disposable test strips. The monitor provides a user interface, heats the test strip to the appropriate reaction temperature, measures the impedance of blood samples, and calculates and reports PT and INR results.

Instructions and test results are displayed on an LCD. The monitor can store test results so that past results can be reviewed.

Lab mouse

PHILADELPHIA—Experiments in mice reinforce the idea that tyrosine kinase inhibitors (TKIs) can treat patients with Ph-like acute lymphoblastic leukemia (ALL).

Investigators recently identified genomic alterations in Ph-like ALL that suggest these patients might respond to TKIs, and tests in a small number of patients supported this theory.

Now, preclinical results show that kinase fusions in Ph-like ALL activate signaling pathways differently, and this affects sensitivity to TKIs.

Kathryn Roberts, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues presented these results at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

“We recently described a subtype of B-cell acute lymphoblastic leukemia with very poor outcome that is characterized by genetic alterations involving tyrosine kinases, termed Ph-like ALL,” Dr Roberts said. “We wanted to examine whether these alterations contribute to the development of Ph-like ALL and determine if they could be targeted with tyrosine kinase inhibitors.”

“We showed, for the first time, that the kinase alterations we tested contribute to the development of Ph-like ALL, and that Ph-like ALL can be treated effectively with tyrosine kinase inhibitors in animal models. These findings provide a strong rationale for treating Ph-like ALL patients with targeted therapies to improve their survival.”

Dr Roberts and her colleagues first introduced kinase alterations—RCSD1-ABL2, SSBP2-CSF1R, or PAX5-JAK2—in IL-7-dependent, Arf^-/- mouse pre-B cells expressing IK6.

They found that each fusion conferred cytokine-independent growth in vitro. And mice that received transplants of pre-B cells expressing RCSD1-ABL2 or SSBP2-CSF1R developed ALL with a pre-B immunophenotype.

The investigators then assessed the activation of kinase signaling pathways and TKI sensitivity in Arf^-/- pre-B cells and human leukemic cells harvested from xenografted mice expressing ETV6-ABL1, RANBP2-ABL1, PAG1-ABL2, RCSD1-ABL2, SSBP2-CSF1R, IGH-EPOR, ATF7IP-JAK2, and PAX5-JAK2.

In both cell types, signaling pathway activation and TKI sensitivity differed according to the kinase fusion.

Cells expressing ABL1-class kinase fusions (ABL1, ABL2, CSF1R, and PDGFRB) exhibited pSTAT5 activation that was inhibited by imatinib or dasatinib. But in cells expressing ATF7IP-JAK2, PAX5-JAK2, or IGH-EPOR, pSTAT5 activation was only inhibited by ruxolitinib.

Finally, the investigators tested dasatinib in xenograft models of ETV6-ABL1, RCSD1-ABL2, PAG1-ABL2, or SSBP2-CSF1R ALL.

They found that treated mice had significantly lower leukemic burdens and splenic weights than control mice. And STAT5 phosphorylation was attenuated in cells from treated mice.

“Our studies show that different FDA-approved TKIs such as imatinib, dasatinib, ruxolitinib, or crizotinib could potentially be used to treat Ph-like ALL patients, depending on the type of kinase alterations their tumors bear,” Dr Roberts said.

“We were able to gain a better understanding of the genetics underlying Ph-like ALL, and our studies could help identify patients who will not respond optimally to current therapy. By knowing the exact genetic alteration upfront, we may be able to implement different therapeutic strategies to improve the survival rate of future patients with ALL.”

Lab mouse

PHILADELPHIA—Experiments in mice reinforce the idea that tyrosine kinase inhibitors (TKIs) can treat patients with Ph-like acute lymphoblastic leukemia (ALL).

Investigators recently identified genomic alterations in Ph-like ALL that suggest these patients might respond to TKIs, and tests in a small number of patients supported this theory.

Now, preclinical results show that kinase fusions in Ph-like ALL activate signaling pathways differently, and this affects sensitivity to TKIs.

Kathryn Roberts, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues presented these results at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

“We recently described a subtype of B-cell acute lymphoblastic leukemia with very poor outcome that is characterized by genetic alterations involving tyrosine kinases, termed Ph-like ALL,” Dr Roberts said. “We wanted to examine whether these alterations contribute to the development of Ph-like ALL and determine if they could be targeted with tyrosine kinase inhibitors.”

“We showed, for the first time, that the kinase alterations we tested contribute to the development of Ph-like ALL, and that Ph-like ALL can be treated effectively with tyrosine kinase inhibitors in animal models. These findings provide a strong rationale for treating Ph-like ALL patients with targeted therapies to improve their survival.”

Dr Roberts and her colleagues first introduced kinase alterations—RCSD1-ABL2, SSBP2-CSF1R, or PAX5-JAK2—in IL-7-dependent, Arf^-/- mouse pre-B cells expressing IK6.

They found that each fusion conferred cytokine-independent growth in vitro. And mice that received transplants of pre-B cells expressing RCSD1-ABL2 or SSBP2-CSF1R developed ALL with a pre-B immunophenotype.

The investigators then assessed the activation of kinase signaling pathways and TKI sensitivity in Arf^-/- pre-B cells and human leukemic cells harvested from xenografted mice expressing ETV6-ABL1, RANBP2-ABL1, PAG1-ABL2, RCSD1-ABL2, SSBP2-CSF1R, IGH-EPOR, ATF7IP-JAK2, and PAX5-JAK2.

In both cell types, signaling pathway activation and TKI sensitivity differed according to the kinase fusion.

Cells expressing ABL1-class kinase fusions (ABL1, ABL2, CSF1R, and PDGFRB) exhibited pSTAT5 activation that was inhibited by imatinib or dasatinib. But in cells expressing ATF7IP-JAK2, PAX5-JAK2, or IGH-EPOR, pSTAT5 activation was only inhibited by ruxolitinib.

Finally, the investigators tested dasatinib in xenograft models of ETV6-ABL1, RCSD1-ABL2, PAG1-ABL2, or SSBP2-CSF1R ALL.

They found that treated mice had significantly lower leukemic burdens and splenic weights than control mice. And STAT5 phosphorylation was attenuated in cells from treated mice.

“Our studies show that different FDA-approved TKIs such as imatinib, dasatinib, ruxolitinib, or crizotinib could potentially be used to treat Ph-like ALL patients, depending on the type of kinase alterations their tumors bear,” Dr Roberts said.

“We were able to gain a better understanding of the genetics underlying Ph-like ALL, and our studies could help identify patients who will not respond optimally to current therapy. By knowing the exact genetic alteration upfront, we may be able to implement different therapeutic strategies to improve the survival rate of future patients with ALL.”

Lab mouse

PHILADELPHIA—Experiments in mice reinforce the idea that tyrosine kinase inhibitors (TKIs) can treat patients with Ph-like acute lymphoblastic leukemia (ALL).

Investigators recently identified genomic alterations in Ph-like ALL that suggest these patients might respond to TKIs, and tests in a small number of patients supported this theory.

Now, preclinical results show that kinase fusions in Ph-like ALL activate signaling pathways differently, and this affects sensitivity to TKIs.

Kathryn Roberts, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues presented these results at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

“We recently described a subtype of B-cell acute lymphoblastic leukemia with very poor outcome that is characterized by genetic alterations involving tyrosine kinases, termed Ph-like ALL,” Dr Roberts said. “We wanted to examine whether these alterations contribute to the development of Ph-like ALL and determine if they could be targeted with tyrosine kinase inhibitors.”

“We showed, for the first time, that the kinase alterations we tested contribute to the development of Ph-like ALL, and that Ph-like ALL can be treated effectively with tyrosine kinase inhibitors in animal models. These findings provide a strong rationale for treating Ph-like ALL patients with targeted therapies to improve their survival.”

Dr Roberts and her colleagues first introduced kinase alterations—RCSD1-ABL2, SSBP2-CSF1R, or PAX5-JAK2—in IL-7-dependent, Arf^-/- mouse pre-B cells expressing IK6.

They found that each fusion conferred cytokine-independent growth in vitro. And mice that received transplants of pre-B cells expressing RCSD1-ABL2 or SSBP2-CSF1R developed ALL with a pre-B immunophenotype.

The investigators then assessed the activation of kinase signaling pathways and TKI sensitivity in Arf^-/- pre-B cells and human leukemic cells harvested from xenografted mice expressing ETV6-ABL1, RANBP2-ABL1, PAG1-ABL2, RCSD1-ABL2, SSBP2-CSF1R, IGH-EPOR, ATF7IP-JAK2, and PAX5-JAK2.

In both cell types, signaling pathway activation and TKI sensitivity differed according to the kinase fusion.

Cells expressing ABL1-class kinase fusions (ABL1, ABL2, CSF1R, and PDGFRB) exhibited pSTAT5 activation that was inhibited by imatinib or dasatinib. But in cells expressing ATF7IP-JAK2, PAX5-JAK2, or IGH-EPOR, pSTAT5 activation was only inhibited by ruxolitinib.

Finally, the investigators tested dasatinib in xenograft models of ETV6-ABL1, RCSD1-ABL2, PAG1-ABL2, or SSBP2-CSF1R ALL.

They found that treated mice had significantly lower leukemic burdens and splenic weights than control mice. And STAT5 phosphorylation was attenuated in cells from treated mice.

“Our studies show that different FDA-approved TKIs such as imatinib, dasatinib, ruxolitinib, or crizotinib could potentially be used to treat Ph-like ALL patients, depending on the type of kinase alterations their tumors bear,” Dr Roberts said.

“We were able to gain a better understanding of the genetics underlying Ph-like ALL, and our studies could help identify patients who will not respond optimally to current therapy. By knowing the exact genetic alteration upfront, we may be able to implement different therapeutic strategies to improve the survival rate of future patients with ALL.”

Fish oil may reduce seizure frequency in patients with epilepsy, according to a study published online ahead of print September 8 in the Journal of Neurology, Neurosurgery, and Psychiatry. Twenty-four patients with drug-resistant epilepsy were given three separate treatments for 10 weeks and separated by a six-week period. Participants were given three capsules of fish oil daily, plus three capsules of corn oil (placebo); six capsules of fish oil daily; and three capsules of corn oil twice daily. The average number of seizures among those taking low-dose fish oil was around 12 per month, compared with slightly more than 17 for the high dose, and slightly more than 18 for the placebo. Two people who had the low dose were seizure free during the 10-week trial. No one taking the high-dose fish oil or the placebo was seizure free.

Blood type AB and higher factor VIII (FVIII) are associated with increased incidence of cognitive impairment, according to a study published online ahead of print September 10 in Neurology. Findings are based on a cohort from the REGARDS Study, in which more than 30,000 people were followed for an average of 3.4 years. After adjusting for age, race, region, and sex, the researchers found that people with blood group AB (odds ratio [OR], 1.82) and those with higher FVIII (OR, 1.24) had an increased risk of cognitive impairment. The mean FVIII was higher in people with blood type AB (142 IU/dL), compared with O (104 IU/dL), and FVIII mediated 18% of the association between AB group and incident cognitive impairment, according to the researchers.

Magnesium sulfate administered IV to pregnant women at risk of giving birth before 30 weeks gestation was not associated with neurologic, cognitive, behavioral, growth, or functional outcomes in their children at school age, investigators reported in the September 17 issue of JAMA. Researchers randomly assigned magnesium sulfate or placebo to pregnant women (n = 535 magnesium; n = 527 placebo) for whom birth was planned or expected before 30 weeks gestation; 1,255 fetuses were known to be alive at randomization. Of the 867 survivors available for follow-up, outcomes at school age (6 to 11) were determined for 669 children (77%). The investigators found that receiving antenatal magnesium sulfate was not associated with any long-term benefits or harms, compared with placebo. The study authors also observed a nonsignificant reduction in the risk of death in the magnesium sulfate group.

Older patients with Parkinson’s disease who underwent deep brain stimulation (DBS) had a similar 90-day complication risk, compared with that in younger patients, according to a study published online ahead of print August 25 in JAMA Neurology. Researchers analyzed data from more than 1,750 patients who had DBS from 2000 to 2009. Of those, 7.5% of subjects experienced at least one complication within 90 days of having the device implanted. The investigators determined that increasing age did not significantly affect the overall complication rates. The findings suggest that age alone should not be a primary exclusion factor for determining candidacy for DBS. “Instead, a clear focus on patients with medication-refractory and difficult to control on-off fluctuations with preserved cognition, regardless of age, may allow for an expansion of the traditional therapeutic window,” the researchers concluded.

Confusional arousals are highly prevalent in the general population, according to a study published in the August 26 issue of Neurology. A total of 19,136 people age 18 and older were interviewed about their sleep habits and whether they had experienced symptoms of the disorder. Participants also were asked about any medications they took and about mental illness diagnoses. Results showed that 15% had experienced an episode in the last year, with more than half reporting more than one episode per week. In the majority of cases, 84% of those with confusional arousals (also known as sleep drunkenness) also had a sleep disorder, mental health disorder, or were taking psychotropic drugs. Fewer than 1% of the people with confusional arousals had no known cause or related condition. “These episodes of waking up confused have received considerably less attention than sleepwalking even though the consequences can be just as serious,” stated researchers.

High potassium intake is associated with a lower risk of all stroke and ischemic stroke and all-cause mortality in older women, investigators reported online ahead of print September 4 in Stroke. Researchers studied 90,137 postmenopausal women ages 50 to 79 for an average of 11 years. Women who consumed the most potassium were 10% less likely to die than were those who had consumed the least amount. The women also were 12% less likely to have a stroke and 16% less likely to have an ischemic stroke than were women who consumed the least amount. Those without hypertension who had consumed the most potassium had a 27% lower ischemic stroke risk and 21% reduced risk for all stroke types, compared with women who had the least potassium in their diets. Among women with hypertension, those who consumed the most potassium had a lower risk of mortality.

Regular blood transfusion therapy significantly reduced the recurrence of cerebral infarct in children with sickle cell anemia, according to a study published in the August 21 issue of the New England Journal of Medicine. During the three-year study, 196 children ages 5 through 15 with sickle cell anemia who had previously had a silent stroke were followed. Children who underwent regular transfusions were 58% less likely to have another silent stroke or an overt stroke, while those who had no transfusions were more than twice as likely to experience repeat strokes. In addition, children who had monthly transfusions were less likely to have a range of other sickle cell anemia–related problems, such as episodes of extreme pain. Overall, 295 pain episodes occurred among children who did not receive transfusions, compared with 126 episodes among those receiving treatment.

Stroke incidence and mortality rates decreased from 1987 to 2011, according to a study published in the July 16 issue of JAMA. The findings were based on data from the Atherosclerosis Risk in Communities cohort of 15,792 US residents between the ages of 45 and 64 who were monitored during the 1980s. The new study followed the progress of 14,357 participants who were free of stroke in 1987 and monitored hospitalizations from stroke and deaths from 1987 to 2011. Stroke incidence decreased over time in Caucasians and African Americans, with an age-adjusted incidence rate ratio of 0.76. The absolute decrease was 0.93 per 1,000 person-years overall. The overall mortality rate after stroke decreased over time (hazard ratio, 0.80), with an absolute decrease of 8.09 per 100 strokes after 10 years.

The FDA has approved Vimpat (lacosamide) C-V as monotherapy in the treatment of partial-onset seizures in patients with epilepsy ages 17 and older. The monotherapy approval for Vimpat is based on a phase III historical-control conversion to lacosamide monotherapy study in adult patients with epilepsy with partial-onset seizures. This study met its primary end point, demonstrating that the exit percentage for patients converting to lacosamide (400 mg/day) was lower than the historical control exit percentage used as a comparator. Lacosamide (300 mg/day) also met the prespecified criteria for efficacy. Based on individual patients’ needs, physicians can choose between Vimpat formulations—tablets, oral solution, or injection. Vimpat (UCB; Brussels) is already approved in the US as adjunctive treatment for partial-onset seizures in patients in this age group.

Disruption of intestinal homeostasis is an early and immune-mediated event in experimental autoimmune encephalomyelitis, according to a study published September 3 in PLoS ONE. Investigators observed structural changes in the mucous membrane of the small intestine and an increase in inflammatory T cells, as well as a reduction in immunosuppressive cells. “Our findings provide support for the idea that a damaged intestinal barrier can prevent the body ending an autoimmune reaction in the normal manner, leading to a chronic disease such as multiple sclerosis,” stated the study authors. “In particular, an increased understanding of the regulation of tight junctions at the blood–brain barrier and in the intestinal wall may be crucial for design of future innovative therapies.”

Children and adolescents with autism have a surplus of synapses in the brain due to reduced developmental spine pruning, investigators reported in the September 3 issue of Neuron. Researchers examined brains from children with autism who had died from other causes. Thirteen brains were from children ages 2 to 9, 13 brains were from children ages 13 to 20, and 22 brains were from children without autism. The investigators measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from the cortical neurons. During late childhood, spine density had decreased by about half in the control brains, compared with 16% in the brains from patients with autism. “Hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning,” stated study authors.

Macromolecular proton fraction (MPF) mapping enables quantitative assessment of demyelination in normal-appearing brain tissues and shows primary clinical relevance of gray matter damage in multiple sclerosis (MS), according to a study published online ahead of print September 10 in Radiology. Researchers examined 30 patients with MS, 18 with relapsing-remitting MS (RRMS) and 12 with secondary progressive MS. Fourteen healthy controls also were included. Each participant underwent MRI on a 3-T imager, and the investigators reconstructed 3-D whole-brain MPF maps to examine normal-appearing white matter, gray matter, and MS lesions. MPF was significantly lower in both white and gray matter in patients with RRMS, compared with healthy controls, and it was significantly reduced in normal-appearing brain tissues and lesions of patients with secondary progressive MS, compared with patients with RRMS with the largest relative decrease in gray matter.

Type 2 diabetes mellitus is associated with mild cognitive impairment (MCI) and MCI subtypes in middle-aged, but not in elderly participants, according to a study published online ahead of print July 7 in the Journal of Alzheimer’s Disease. A total of 560 participants diagnosed with MCI were compared with 1,376 cognitively normal participants from the Heinz Nixdorf Recall study. Of participants with MCI, 289 had amnestic MCI and 271 had nonamnestic MCI. Type 2 diabetes mellitus was strongly associated with MCI and MCI subtypes in those ages 50 to 65. Examination of differences by gender revealed a stronger association of diabetes with amnestic MCI in middle-aged women and an even stronger association with nonamnestic MCI in middle-aged men.

—Kimberly D. Williams

Fish oil may reduce seizure frequency in patients with epilepsy, according to a study published online ahead of print September 8 in the Journal of Neurology, Neurosurgery, and Psychiatry. Twenty-four patients with drug-resistant epilepsy were given three separate treatments for 10 weeks and separated by a six-week period. Participants were given three capsules of fish oil daily, plus three capsules of corn oil (placebo); six capsules of fish oil daily; and three capsules of corn oil twice daily. The average number of seizures among those taking low-dose fish oil was around 12 per month, compared with slightly more than 17 for the high dose, and slightly more than 18 for the placebo. Two people who had the low dose were seizure free during the 10-week trial. No one taking the high-dose fish oil or the placebo was seizure free.

Blood type AB and higher factor VIII (FVIII) are associated with increased incidence of cognitive impairment, according to a study published online ahead of print September 10 in Neurology. Findings are based on a cohort from the REGARDS Study, in which more than 30,000 people were followed for an average of 3.4 years. After adjusting for age, race, region, and sex, the researchers found that people with blood group AB (odds ratio [OR], 1.82) and those with higher FVIII (OR, 1.24) had an increased risk of cognitive impairment. The mean FVIII was higher in people with blood type AB (142 IU/dL), compared with O (104 IU/dL), and FVIII mediated 18% of the association between AB group and incident cognitive impairment, according to the researchers.

Magnesium sulfate administered IV to pregnant women at risk of giving birth before 30 weeks gestation was not associated with neurologic, cognitive, behavioral, growth, or functional outcomes in their children at school age, investigators reported in the September 17 issue of JAMA. Researchers randomly assigned magnesium sulfate or placebo to pregnant women (n = 535 magnesium; n = 527 placebo) for whom birth was planned or expected before 30 weeks gestation; 1,255 fetuses were known to be alive at randomization. Of the 867 survivors available for follow-up, outcomes at school age (6 to 11) were determined for 669 children (77%). The investigators found that receiving antenatal magnesium sulfate was not associated with any long-term benefits or harms, compared with placebo. The study authors also observed a nonsignificant reduction in the risk of death in the magnesium sulfate group.

Older patients with Parkinson’s disease who underwent deep brain stimulation (DBS) had a similar 90-day complication risk, compared with that in younger patients, according to a study published online ahead of print August 25 in JAMA Neurology. Researchers analyzed data from more than 1,750 patients who had DBS from 2000 to 2009. Of those, 7.5% of subjects experienced at least one complication within 90 days of having the device implanted. The investigators determined that increasing age did not significantly affect the overall complication rates. The findings suggest that age alone should not be a primary exclusion factor for determining candidacy for DBS. “Instead, a clear focus on patients with medication-refractory and difficult to control on-off fluctuations with preserved cognition, regardless of age, may allow for an expansion of the traditional therapeutic window,” the researchers concluded.

Confusional arousals are highly prevalent in the general population, according to a study published in the August 26 issue of Neurology. A total of 19,136 people age 18 and older were interviewed about their sleep habits and whether they had experienced symptoms of the disorder. Participants also were asked about any medications they took and about mental illness diagnoses. Results showed that 15% had experienced an episode in the last year, with more than half reporting more than one episode per week. In the majority of cases, 84% of those with confusional arousals (also known as sleep drunkenness) also had a sleep disorder, mental health disorder, or were taking psychotropic drugs. Fewer than 1% of the people with confusional arousals had no known cause or related condition. “These episodes of waking up confused have received considerably less attention than sleepwalking even though the consequences can be just as serious,” stated researchers.

High potassium intake is associated with a lower risk of all stroke and ischemic stroke and all-cause mortality in older women, investigators reported online ahead of print September 4 in Stroke. Researchers studied 90,137 postmenopausal women ages 50 to 79 for an average of 11 years. Women who consumed the most potassium were 10% less likely to die than were those who had consumed the least amount. The women also were 12% less likely to have a stroke and 16% less likely to have an ischemic stroke than were women who consumed the least amount. Those without hypertension who had consumed the most potassium had a 27% lower ischemic stroke risk and 21% reduced risk for all stroke types, compared with women who had the least potassium in their diets. Among women with hypertension, those who consumed the most potassium had a lower risk of mortality.

Regular blood transfusion therapy significantly reduced the recurrence of cerebral infarct in children with sickle cell anemia, according to a study published in the August 21 issue of the New England Journal of Medicine. During the three-year study, 196 children ages 5 through 15 with sickle cell anemia who had previously had a silent stroke were followed. Children who underwent regular transfusions were 58% less likely to have another silent stroke or an overt stroke, while those who had no transfusions were more than twice as likely to experience repeat strokes. In addition, children who had monthly transfusions were less likely to have a range of other sickle cell anemia–related problems, such as episodes of extreme pain. Overall, 295 pain episodes occurred among children who did not receive transfusions, compared with 126 episodes among those receiving treatment.

Stroke incidence and mortality rates decreased from 1987 to 2011, according to a study published in the July 16 issue of JAMA. The findings were based on data from the Atherosclerosis Risk in Communities cohort of 15,792 US residents between the ages of 45 and 64 who were monitored during the 1980s. The new study followed the progress of 14,357 participants who were free of stroke in 1987 and monitored hospitalizations from stroke and deaths from 1987 to 2011. Stroke incidence decreased over time in Caucasians and African Americans, with an age-adjusted incidence rate ratio of 0.76. The absolute decrease was 0.93 per 1,000 person-years overall. The overall mortality rate after stroke decreased over time (hazard ratio, 0.80), with an absolute decrease of 8.09 per 100 strokes after 10 years.

The FDA has approved Vimpat (lacosamide) C-V as monotherapy in the treatment of partial-onset seizures in patients with epilepsy ages 17 and older. The monotherapy approval for Vimpat is based on a phase III historical-control conversion to lacosamide monotherapy study in adult patients with epilepsy with partial-onset seizures. This study met its primary end point, demonstrating that the exit percentage for patients converting to lacosamide (400 mg/day) was lower than the historical control exit percentage used as a comparator. Lacosamide (300 mg/day) also met the prespecified criteria for efficacy. Based on individual patients’ needs, physicians can choose between Vimpat formulations—tablets, oral solution, or injection. Vimpat (UCB; Brussels) is already approved in the US as adjunctive treatment for partial-onset seizures in patients in this age group.

Disruption of intestinal homeostasis is an early and immune-mediated event in experimental autoimmune encephalomyelitis, according to a study published September 3 in PLoS ONE. Investigators observed structural changes in the mucous membrane of the small intestine and an increase in inflammatory T cells, as well as a reduction in immunosuppressive cells. “Our findings provide support for the idea that a damaged intestinal barrier can prevent the body ending an autoimmune reaction in the normal manner, leading to a chronic disease such as multiple sclerosis,” stated the study authors. “In particular, an increased understanding of the regulation of tight junctions at the blood–brain barrier and in the intestinal wall may be crucial for design of future innovative therapies.”

Children and adolescents with autism have a surplus of synapses in the brain due to reduced developmental spine pruning, investigators reported in the September 3 issue of Neuron. Researchers examined brains from children with autism who had died from other causes. Thirteen brains were from children ages 2 to 9, 13 brains were from children ages 13 to 20, and 22 brains were from children without autism. The investigators measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from the cortical neurons. During late childhood, spine density had decreased by about half in the control brains, compared with 16% in the brains from patients with autism. “Hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning,” stated study authors.

Macromolecular proton fraction (MPF) mapping enables quantitative assessment of demyelination in normal-appearing brain tissues and shows primary clinical relevance of gray matter damage in multiple sclerosis (MS), according to a study published online ahead of print September 10 in Radiology. Researchers examined 30 patients with MS, 18 with relapsing-remitting MS (RRMS) and 12 with secondary progressive MS. Fourteen healthy controls also were included. Each participant underwent MRI on a 3-T imager, and the investigators reconstructed 3-D whole-brain MPF maps to examine normal-appearing white matter, gray matter, and MS lesions. MPF was significantly lower in both white and gray matter in patients with RRMS, compared with healthy controls, and it was significantly reduced in normal-appearing brain tissues and lesions of patients with secondary progressive MS, compared with patients with RRMS with the largest relative decrease in gray matter.

Type 2 diabetes mellitus is associated with mild cognitive impairment (MCI) and MCI subtypes in middle-aged, but not in elderly participants, according to a study published online ahead of print July 7 in the Journal of Alzheimer’s Disease. A total of 560 participants diagnosed with MCI were compared with 1,376 cognitively normal participants from the Heinz Nixdorf Recall study. Of participants with MCI, 289 had amnestic MCI and 271 had nonamnestic MCI. Type 2 diabetes mellitus was strongly associated with MCI and MCI subtypes in those ages 50 to 65. Examination of differences by gender revealed a stronger association of diabetes with amnestic MCI in middle-aged women and an even stronger association with nonamnestic MCI in middle-aged men.

—Kimberly D. Williams

Fish oil may reduce seizure frequency in patients with epilepsy, according to a study published online ahead of print September 8 in the Journal of Neurology, Neurosurgery, and Psychiatry. Twenty-four patients with drug-resistant epilepsy were given three separate treatments for 10 weeks and separated by a six-week period. Participants were given three capsules of fish oil daily, plus three capsules of corn oil (placebo); six capsules of fish oil daily; and three capsules of corn oil twice daily. The average number of seizures among those taking low-dose fish oil was around 12 per month, compared with slightly more than 17 for the high dose, and slightly more than 18 for the placebo. Two people who had the low dose were seizure free during the 10-week trial. No one taking the high-dose fish oil or the placebo was seizure free.

Blood type AB and higher factor VIII (FVIII) are associated with increased incidence of cognitive impairment, according to a study published online ahead of print September 10 in Neurology. Findings are based on a cohort from the REGARDS Study, in which more than 30,000 people were followed for an average of 3.4 years. After adjusting for age, race, region, and sex, the researchers found that people with blood group AB (odds ratio [OR], 1.82) and those with higher FVIII (OR, 1.24) had an increased risk of cognitive impairment. The mean FVIII was higher in people with blood type AB (142 IU/dL), compared with O (104 IU/dL), and FVIII mediated 18% of the association between AB group and incident cognitive impairment, according to the researchers.

Magnesium sulfate administered IV to pregnant women at risk of giving birth before 30 weeks gestation was not associated with neurologic, cognitive, behavioral, growth, or functional outcomes in their children at school age, investigators reported in the September 17 issue of JAMA. Researchers randomly assigned magnesium sulfate or placebo to pregnant women (n = 535 magnesium; n = 527 placebo) for whom birth was planned or expected before 30 weeks gestation; 1,255 fetuses were known to be alive at randomization. Of the 867 survivors available for follow-up, outcomes at school age (6 to 11) were determined for 669 children (77%). The investigators found that receiving antenatal magnesium sulfate was not associated with any long-term benefits or harms, compared with placebo. The study authors also observed a nonsignificant reduction in the risk of death in the magnesium sulfate group.

Older patients with Parkinson’s disease who underwent deep brain stimulation (DBS) had a similar 90-day complication risk, compared with that in younger patients, according to a study published online ahead of print August 25 in JAMA Neurology. Researchers analyzed data from more than 1,750 patients who had DBS from 2000 to 2009. Of those, 7.5% of subjects experienced at least one complication within 90 days of having the device implanted. The investigators determined that increasing age did not significantly affect the overall complication rates. The findings suggest that age alone should not be a primary exclusion factor for determining candidacy for DBS. “Instead, a clear focus on patients with medication-refractory and difficult to control on-off fluctuations with preserved cognition, regardless of age, may allow for an expansion of the traditional therapeutic window,” the researchers concluded.

Confusional arousals are highly prevalent in the general population, according to a study published in the August 26 issue of Neurology. A total of 19,136 people age 18 and older were interviewed about their sleep habits and whether they had experienced symptoms of the disorder. Participants also were asked about any medications they took and about mental illness diagnoses. Results showed that 15% had experienced an episode in the last year, with more than half reporting more than one episode per week. In the majority of cases, 84% of those with confusional arousals (also known as sleep drunkenness) also had a sleep disorder, mental health disorder, or were taking psychotropic drugs. Fewer than 1% of the people with confusional arousals had no known cause or related condition. “These episodes of waking up confused have received considerably less attention than sleepwalking even though the consequences can be just as serious,” stated researchers.

High potassium intake is associated with a lower risk of all stroke and ischemic stroke and all-cause mortality in older women, investigators reported online ahead of print September 4 in Stroke. Researchers studied 90,137 postmenopausal women ages 50 to 79 for an average of 11 years. Women who consumed the most potassium were 10% less likely to die than were those who had consumed the least amount. The women also were 12% less likely to have a stroke and 16% less likely to have an ischemic stroke than were women who consumed the least amount. Those without hypertension who had consumed the most potassium had a 27% lower ischemic stroke risk and 21% reduced risk for all stroke types, compared with women who had the least potassium in their diets. Among women with hypertension, those who consumed the most potassium had a lower risk of mortality.

Regular blood transfusion therapy significantly reduced the recurrence of cerebral infarct in children with sickle cell anemia, according to a study published in the August 21 issue of the New England Journal of Medicine. During the three-year study, 196 children ages 5 through 15 with sickle cell anemia who had previously had a silent stroke were followed. Children who underwent regular transfusions were 58% less likely to have another silent stroke or an overt stroke, while those who had no transfusions were more than twice as likely to experience repeat strokes. In addition, children who had monthly transfusions were less likely to have a range of other sickle cell anemia–related problems, such as episodes of extreme pain. Overall, 295 pain episodes occurred among children who did not receive transfusions, compared with 126 episodes among those receiving treatment.

Stroke incidence and mortality rates decreased from 1987 to 2011, according to a study published in the July 16 issue of JAMA. The findings were based on data from the Atherosclerosis Risk in Communities cohort of 15,792 US residents between the ages of 45 and 64 who were monitored during the 1980s. The new study followed the progress of 14,357 participants who were free of stroke in 1987 and monitored hospitalizations from stroke and deaths from 1987 to 2011. Stroke incidence decreased over time in Caucasians and African Americans, with an age-adjusted incidence rate ratio of 0.76. The absolute decrease was 0.93 per 1,000 person-years overall. The overall mortality rate after stroke decreased over time (hazard ratio, 0.80), with an absolute decrease of 8.09 per 100 strokes after 10 years.

The FDA has approved Vimpat (lacosamide) C-V as monotherapy in the treatment of partial-onset seizures in patients with epilepsy ages 17 and older. The monotherapy approval for Vimpat is based on a phase III historical-control conversion to lacosamide monotherapy study in adult patients with epilepsy with partial-onset seizures. This study met its primary end point, demonstrating that the exit percentage for patients converting to lacosamide (400 mg/day) was lower than the historical control exit percentage used as a comparator. Lacosamide (300 mg/day) also met the prespecified criteria for efficacy. Based on individual patients’ needs, physicians can choose between Vimpat formulations—tablets, oral solution, or injection. Vimpat (UCB; Brussels) is already approved in the US as adjunctive treatment for partial-onset seizures in patients in this age group.

Disruption of intestinal homeostasis is an early and immune-mediated event in experimental autoimmune encephalomyelitis, according to a study published September 3 in PLoS ONE. Investigators observed structural changes in the mucous membrane of the small intestine and an increase in inflammatory T cells, as well as a reduction in immunosuppressive cells. “Our findings provide support for the idea that a damaged intestinal barrier can prevent the body ending an autoimmune reaction in the normal manner, leading to a chronic disease such as multiple sclerosis,” stated the study authors. “In particular, an increased understanding of the regulation of tight junctions at the blood–brain barrier and in the intestinal wall may be crucial for design of future innovative therapies.”

Children and adolescents with autism have a surplus of synapses in the brain due to reduced developmental spine pruning, investigators reported in the September 3 issue of Neuron. Researchers examined brains from children with autism who had died from other causes. Thirteen brains were from children ages 2 to 9, 13 brains were from children ages 13 to 20, and 22 brains were from children without autism. The investigators measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from the cortical neurons. During late childhood, spine density had decreased by about half in the control brains, compared with 16% in the brains from patients with autism. “Hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning,” stated study authors.

Macromolecular proton fraction (MPF) mapping enables quantitative assessment of demyelination in normal-appearing brain tissues and shows primary clinical relevance of gray matter damage in multiple sclerosis (MS), according to a study published online ahead of print September 10 in Radiology. Researchers examined 30 patients with MS, 18 with relapsing-remitting MS (RRMS) and 12 with secondary progressive MS. Fourteen healthy controls also were included. Each participant underwent MRI on a 3-T imager, and the investigators reconstructed 3-D whole-brain MPF maps to examine normal-appearing white matter, gray matter, and MS lesions. MPF was significantly lower in both white and gray matter in patients with RRMS, compared with healthy controls, and it was significantly reduced in normal-appearing brain tissues and lesions of patients with secondary progressive MS, compared with patients with RRMS with the largest relative decrease in gray matter.

Type 2 diabetes mellitus is associated with mild cognitive impairment (MCI) and MCI subtypes in middle-aged, but not in elderly participants, according to a study published online ahead of print July 7 in the Journal of Alzheimer’s Disease. A total of 560 participants diagnosed with MCI were compared with 1,376 cognitively normal participants from the Heinz Nixdorf Recall study. Of participants with MCI, 289 had amnestic MCI and 271 had nonamnestic MCI. Type 2 diabetes mellitus was strongly associated with MCI and MCI subtypes in those ages 50 to 65. Examination of differences by gender revealed a stronger association of diabetes with amnestic MCI in middle-aged women and an even stronger association with nonamnestic MCI in middle-aged men.

—Kimberly D. Williams

One highlight of the AGA Postgraduate Course was the esophageal disease session. The presentation by Dr. Michael B. Wallace summarized recent studies using advanced imaging modalities in patients with Barrett’s esophagus. Studies using chromoscopy and virtual chromoscopy techniques such as narrow-band imaging have increased the detection of dysplasia in BE patients. These are so-called red flag techniques that image large areas of mucosa to detect mucosal abnormalities suspicious for the presence of dysplasia or neoplasia.

Endomicroscopy describes the use of real-time, targeted endoscopic imaging modalities that are capable of producing histologic-like images of mucosa at depths up to 200 microns. Confocal laser endomicroscopy (CLE) uses a blue light laser (405 nm) and collimated light detection and analysis to produce 1000-fold magnified images. When used with a fluorescent contrast agent such as fluorescein or acriflavin dye, these systems produce cellular level images that are comparable to those images seen with optical microscopy. A recent study from Canto et al found that the use of CLE detected BE dysplasia at rates similar to targeted plus random biopsy protocols. Further, a multicenter study will soon begin using a tethered-capsule (nonendoscopic) form of volumetric laser endomicroscopy as a method to screen for BE.

Dr. Amitabh Chak expanded on these issues and reviewed the issues surrounding screening and surveillance of BE patients for the early detection and treatment of esophageal adenocarcinoma. This presentation suggested that necessary future improvements include cost-effective advanced imaging techniques optimized for use in clinical practice, molecular biomarker panels for prediction of which patients may progress to dysplasia and neoplasia, and high-quality intensive endoscopic surveillance for high risk BE patients.

Dr. Joe Murray’s comprehensive presentation of celiac disease described the protean clinical presentations of this disease as well as optimal use of serologic and endoscopic testing. Celiac disease is increasingly identified in middle-aged patients (median 45 years) without diarrhea. Classic malabsorption symptoms of diarrhea, weight loss, steatorrhea, and nutritional deficiencies are found in 25% of patients. Half of celiac patients will have only one symptom such as anemia, diarrhea, lactose intolerance, or weight loss. Nongastrointestinal symptoms are present in another 25% of patients such as infertility, bone disease, chronic fatigue, or abnormal liver enzyme test results.

Optimal use of serologic and endoscopic testing was reviewed, including the differential diagnosis of lymphocytic duodenosis including use of nonsteroidal anti-inflammatory agents (NSAIDs), Helicobacter pylori infection, Crohn’s disease, and Sjogren’s syndrome. Proper duodenal biopsy technique was emphasized with two forceps biopsy samples obtained from the duodenal bulb and four biopsy samples obtained from the second portion of the duodenum. Also discussed was the utility of HLA typing for DQ2/8 in patients currently using a gluten free diet, patients with negative serology results but abnormal duodenal biopsy findings, and those with negative serology results who are at increased genetic risk.

Dr. James Scheiman discussed management of the complex interaction and risks associated with the use of NSAIDs, aspirin, clopidogrel, and proton pump inhibitors in the setting of previous ulcer disease, gastrointestinal bleeding, and Helicobacter pylori infection. Results from randomized controlled studies and observational studies were the basis for the Consensus Group to recommend the use of proton pump inhibitor therapy as the GI bleeding protective strategy of choice. PPI therapy was also recommended as cost-effective treatment for aspirin-using patients, although the risks and benefits of long-term PPI treatment require patient education and individualization.

Finally, Dr. Rhonda Souza discussed eosinophilic esophagitis (EoE), a chronic immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction associated with eosinophil-predominant inflammation such as dysphagia, food impaction, chest pain, heartburn, abdominal pain, and refractory reflux dyspepsia. Endoscopic features include the ringed esophagus, white specks, linear furrows and stricture. Histologic features of EoE are eosinophilia (more than 15 intraepithelial eosinophils per high power field), basal zone hyperplasia, and dilated intercellular spaces. These eosinophils are activated via T-helper 2 immune system via interleukins-4, -5 and -13. This inflammation is mediated by the dramatic upregulation involving the eotaxin-3 gene that produces a potent chemoattractant for eosinophils. Treatment of EoE usually requires the use of proton pump inhibitors based on their acid suppression, anti-oxidant and anti-inflammatory effects. The use of topical corticosteroids and endoscopic dilation for symptomatic strictures may also be necessary. Nondrug treatment approaches such as the six food elimination diet (SFED) of the most common food allergens such as milk, soy, eggs, wheat, nuts and seafood have also been successful.

Dr. Wolfsen is in the division of gastroenterology and hepatology, Mayo Clinic, Jacksonville, Fla. He moderated this session during the 2014 Digestive Diseases Week. 


One highlight of the AGA Postgraduate Course was the esophageal disease session. The presentation by Dr. Michael B. Wallace summarized recent studies using advanced imaging modalities in patients with Barrett’s esophagus. Studies using chromoscopy and virtual chromoscopy techniques such as narrow-band imaging have increased the detection of dysplasia in BE patients. These are so-called red flag techniques that image large areas of mucosa to detect mucosal abnormalities suspicious for the presence of dysplasia or neoplasia.

Endomicroscopy describes the use of real-time, targeted endoscopic imaging modalities that are capable of producing histologic-like images of mucosa at depths up to 200 microns. Confocal laser endomicroscopy (CLE) uses a blue light laser (405 nm) and collimated light detection and analysis to produce 1000-fold magnified images. When used with a fluorescent contrast agent such as fluorescein or acriflavin dye, these systems produce cellular level images that are comparable to those images seen with optical microscopy. A recent study from Canto et al found that the use of CLE detected BE dysplasia at rates similar to targeted plus random biopsy protocols. Further, a multicenter study will soon begin using a tethered-capsule (nonendoscopic) form of volumetric laser endomicroscopy as a method to screen for BE.

Dr. Amitabh Chak expanded on these issues and reviewed the issues surrounding screening and surveillance of BE patients for the early detection and treatment of esophageal adenocarcinoma. This presentation suggested that necessary future improvements include cost-effective advanced imaging techniques optimized for use in clinical practice, molecular biomarker panels for prediction of which patients may progress to dysplasia and neoplasia, and high-quality intensive endoscopic surveillance for high risk BE patients.

Dr. Joe Murray’s comprehensive presentation of celiac disease described the protean clinical presentations of this disease as well as optimal use of serologic and endoscopic testing. Celiac disease is increasingly identified in middle-aged patients (median 45 years) without diarrhea. Classic malabsorption symptoms of diarrhea, weight loss, steatorrhea, and nutritional deficiencies are found in 25% of patients. Half of celiac patients will have only one symptom such as anemia, diarrhea, lactose intolerance, or weight loss. Nongastrointestinal symptoms are present in another 25% of patients such as infertility, bone disease, chronic fatigue, or abnormal liver enzyme test results.

Optimal use of serologic and endoscopic testing was reviewed, including the differential diagnosis of lymphocytic duodenosis including use of nonsteroidal anti-inflammatory agents (NSAIDs), Helicobacter pylori infection, Crohn’s disease, and Sjogren’s syndrome. Proper duodenal biopsy technique was emphasized with two forceps biopsy samples obtained from the duodenal bulb and four biopsy samples obtained from the second portion of the duodenum. Also discussed was the utility of HLA typing for DQ2/8 in patients currently using a gluten free diet, patients with negative serology results but abnormal duodenal biopsy findings, and those with negative serology results who are at increased genetic risk.

Dr. James Scheiman discussed management of the complex interaction and risks associated with the use of NSAIDs, aspirin, clopidogrel, and proton pump inhibitors in the setting of previous ulcer disease, gastrointestinal bleeding, and Helicobacter pylori infection. Results from randomized controlled studies and observational studies were the basis for the Consensus Group to recommend the use of proton pump inhibitor therapy as the GI bleeding protective strategy of choice. PPI therapy was also recommended as cost-effective treatment for aspirin-using patients, although the risks and benefits of long-term PPI treatment require patient education and individualization.

Finally, Dr. Rhonda Souza discussed eosinophilic esophagitis (EoE), a chronic immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction associated with eosinophil-predominant inflammation such as dysphagia, food impaction, chest pain, heartburn, abdominal pain, and refractory reflux dyspepsia. Endoscopic features include the ringed esophagus, white specks, linear furrows and stricture. Histologic features of EoE are eosinophilia (more than 15 intraepithelial eosinophils per high power field), basal zone hyperplasia, and dilated intercellular spaces. These eosinophils are activated via T-helper 2 immune system via interleukins-4, -5 and -13. This inflammation is mediated by the dramatic upregulation involving the eotaxin-3 gene that produces a potent chemoattractant for eosinophils. Treatment of EoE usually requires the use of proton pump inhibitors based on their acid suppression, anti-oxidant and anti-inflammatory effects. The use of topical corticosteroids and endoscopic dilation for symptomatic strictures may also be necessary. Nondrug treatment approaches such as the six food elimination diet (SFED) of the most common food allergens such as milk, soy, eggs, wheat, nuts and seafood have also been successful.

Dr. Wolfsen is in the division of gastroenterology and hepatology, Mayo Clinic, Jacksonville, Fla. He moderated this session during the 2014 Digestive Diseases Week. 


One highlight of the AGA Postgraduate Course was the esophageal disease session. The presentation by Dr. Michael B. Wallace summarized recent studies using advanced imaging modalities in patients with Barrett’s esophagus. Studies using chromoscopy and virtual chromoscopy techniques such as narrow-band imaging have increased the detection of dysplasia in BE patients. These are so-called red flag techniques that image large areas of mucosa to detect mucosal abnormalities suspicious for the presence of dysplasia or neoplasia.

Endomicroscopy describes the use of real-time, targeted endoscopic imaging modalities that are capable of producing histologic-like images of mucosa at depths up to 200 microns. Confocal laser endomicroscopy (CLE) uses a blue light laser (405 nm) and collimated light detection and analysis to produce 1000-fold magnified images. When used with a fluorescent contrast agent such as fluorescein or acriflavin dye, these systems produce cellular level images that are comparable to those images seen with optical microscopy. A recent study from Canto et al found that the use of CLE detected BE dysplasia at rates similar to targeted plus random biopsy protocols. Further, a multicenter study will soon begin using a tethered-capsule (nonendoscopic) form of volumetric laser endomicroscopy as a method to screen for BE.

Dr. Amitabh Chak expanded on these issues and reviewed the issues surrounding screening and surveillance of BE patients for the early detection and treatment of esophageal adenocarcinoma. This presentation suggested that necessary future improvements include cost-effective advanced imaging techniques optimized for use in clinical practice, molecular biomarker panels for prediction of which patients may progress to dysplasia and neoplasia, and high-quality intensive endoscopic surveillance for high risk BE patients.

Dr. Joe Murray’s comprehensive presentation of celiac disease described the protean clinical presentations of this disease as well as optimal use of serologic and endoscopic testing. Celiac disease is increasingly identified in middle-aged patients (median 45 years) without diarrhea. Classic malabsorption symptoms of diarrhea, weight loss, steatorrhea, and nutritional deficiencies are found in 25% of patients. Half of celiac patients will have only one symptom such as anemia, diarrhea, lactose intolerance, or weight loss. Nongastrointestinal symptoms are present in another 25% of patients such as infertility, bone disease, chronic fatigue, or abnormal liver enzyme test results.

Optimal use of serologic and endoscopic testing was reviewed, including the differential diagnosis of lymphocytic duodenosis including use of nonsteroidal anti-inflammatory agents (NSAIDs), Helicobacter pylori infection, Crohn’s disease, and Sjogren’s syndrome. Proper duodenal biopsy technique was emphasized with two forceps biopsy samples obtained from the duodenal bulb and four biopsy samples obtained from the second portion of the duodenum. Also discussed was the utility of HLA typing for DQ2/8 in patients currently using a gluten free diet, patients with negative serology results but abnormal duodenal biopsy findings, and those with negative serology results who are at increased genetic risk.

Dr. James Scheiman discussed management of the complex interaction and risks associated with the use of NSAIDs, aspirin, clopidogrel, and proton pump inhibitors in the setting of previous ulcer disease, gastrointestinal bleeding, and Helicobacter pylori infection. Results from randomized controlled studies and observational studies were the basis for the Consensus Group to recommend the use of proton pump inhibitor therapy as the GI bleeding protective strategy of choice. PPI therapy was also recommended as cost-effective treatment for aspirin-using patients, although the risks and benefits of long-term PPI treatment require patient education and individualization.

Finally, Dr. Rhonda Souza discussed eosinophilic esophagitis (EoE), a chronic immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction associated with eosinophil-predominant inflammation such as dysphagia, food impaction, chest pain, heartburn, abdominal pain, and refractory reflux dyspepsia. Endoscopic features include the ringed esophagus, white specks, linear furrows and stricture. Histologic features of EoE are eosinophilia (more than 15 intraepithelial eosinophils per high power field), basal zone hyperplasia, and dilated intercellular spaces. These eosinophils are activated via T-helper 2 immune system via interleukins-4, -5 and -13. This inflammation is mediated by the dramatic upregulation involving the eotaxin-3 gene that produces a potent chemoattractant for eosinophils. Treatment of EoE usually requires the use of proton pump inhibitors based on their acid suppression, anti-oxidant and anti-inflammatory effects. The use of topical corticosteroids and endoscopic dilation for symptomatic strictures may also be necessary. Nondrug treatment approaches such as the six food elimination diet (SFED) of the most common food allergens such as milk, soy, eggs, wheat, nuts and seafood have also been successful.

Dr. Wolfsen is in the division of gastroenterology and hepatology, Mayo Clinic, Jacksonville, Fla. He moderated this session during the 2014 Digestive Diseases Week.