Monoclonal antibodies

Credit: Linda Bartlett

The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.

The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.

The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.

Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full

approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.

The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.

The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.

Phase 2 study

Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.

Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.

Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m² for the untreated patients and 70 mg/m² for relapsed patients.

However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m², and the relapsed patients were reduced to 50 mg/m².

The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.

CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.

Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.

This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).

There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of  treatment.

Phase 3 study

Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.

Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.

Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.

In both arms, patients received chlorambucil at a dose of 10 mg/m² orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.

The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.

At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).

Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.

Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.

In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.

Monoclonal antibodies

Credit: Linda Bartlett

The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.

The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.

The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.

Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full

approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.

The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.

The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.

Phase 2 study

Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.

Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.

Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m² for the untreated patients and 70 mg/m² for relapsed patients.

However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m², and the relapsed patients were reduced to 50 mg/m².

The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.

CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.

Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.

This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).

There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of  treatment.

Phase 3 study

Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.

Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.

Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.

In both arms, patients received chlorambucil at a dose of 10 mg/m² orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.

The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.

At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).

Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.

Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.

In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.

Monoclonal antibodies

Credit: Linda Bartlett

The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.

The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.

The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.

Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full

approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.

The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.

The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.

Phase 2 study

Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.

Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.

Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m² for the untreated patients and 70 mg/m² for relapsed patients.

However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m², and the relapsed patients were reduced to 50 mg/m².

The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.

CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.

Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.

This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).

There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of  treatment.

Phase 3 study

Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.

Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.

Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.

In both arms, patients received chlorambucil at a dose of 10 mg/m² orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.

The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.

At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).

Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.

Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.

In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.

At the 2014 National Comprehensive Cancer Network annual conference in Hollywood, Florida, Dr Andrew D Zelenetz, chair of the NCCN Non-Hodgkin Lymphomas Guidelines panel, presented guideline updates for non-Hodgkin lymphomas.

Click on the PDF icon at the top of this introduction to read the full article.

At the 2014 National Comprehensive Cancer Network annual conference in Hollywood, Florida, Dr Andrew D Zelenetz, chair of the NCCN Non-Hodgkin Lymphomas Guidelines panel, presented guideline updates for non-Hodgkin lymphomas.

Click on the PDF icon at the top of this introduction to read the full article.

At the 2014 National Comprehensive Cancer Network annual conference in Hollywood, Florida, Dr Andrew D Zelenetz, chair of the NCCN Non-Hodgkin Lymphomas Guidelines panel, presented guideline updates for non-Hodgkin lymphomas.

Click on the PDF icon at the top of this introduction to read the full article.

The introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for treatment of chronic myeloid leukemia (CML) has made it possible for this cancer to be controlled in many patients for long periods with chronic medication and regular monitoring of disease status. Hematologic and cytogenetic testing, molecular monitoring, and BCR-ABL1 mutational analysis have become integral to the routine management of CML. The information that each type of test provides is essential to confirm a diagnosis, determine the disease stage, assess response to treatment, and monitor for signals of disease progression – all of which can be used to identify patients who might require further evaluation, closer follow-up, and additional intervention, and to guide clinical decisions.


Click on the PDF icon at the top of this introduction to read the full article.
 

The introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for treatment of chronic myeloid leukemia (CML) has made it possible for this cancer to be controlled in many patients for long periods with chronic medication and regular monitoring of disease status. Hematologic and cytogenetic testing, molecular monitoring, and BCR-ABL1 mutational analysis have become integral to the routine management of CML. The information that each type of test provides is essential to confirm a diagnosis, determine the disease stage, assess response to treatment, and monitor for signals of disease progression – all of which can be used to identify patients who might require further evaluation, closer follow-up, and additional intervention, and to guide clinical decisions.


Click on the PDF icon at the top of this introduction to read the full article.
 

The introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for treatment of chronic myeloid leukemia (CML) has made it possible for this cancer to be controlled in many patients for long periods with chronic medication and regular monitoring of disease status. Hematologic and cytogenetic testing, molecular monitoring, and BCR-ABL1 mutational analysis have become integral to the routine management of CML. The information that each type of test provides is essential to confirm a diagnosis, determine the disease stage, assess response to treatment, and monitor for signals of disease progression – all of which can be used to identify patients who might require further evaluation, closer follow-up, and additional intervention, and to guide clinical decisions.


Click on the PDF icon at the top of this introduction to read the full article.
 

The introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in 2001 for treatment of chronic myelogenous leukemia (CML) marked a paradigm shift in management of the disease. With that advance, CML has been largely managed as a chronic condition, with daily medication and frequent monitoring. Optimizing monitoring methods and identifying factors associated with response and long-term outcomes has thus been a major clinical research focus. Given the improved understanding of surveillance techniques in CML and the advent of several recently approved second- and third-generation TKIs, there have been recent updates to clinical practice guidelines.

Click on the PDF icon at the top of this introduction to read the full article.
 

The introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in 2001 for treatment of chronic myelogenous leukemia (CML) marked a paradigm shift in management of the disease. With that advance, CML has been largely managed as a chronic condition, with daily medication and frequent monitoring. Optimizing monitoring methods and identifying factors associated with response and long-term outcomes has thus been a major clinical research focus. Given the improved understanding of surveillance techniques in CML and the advent of several recently approved second- and third-generation TKIs, there have been recent updates to clinical practice guidelines.

Click on the PDF icon at the top of this introduction to read the full article.
 

The introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in 2001 for treatment of chronic myelogenous leukemia (CML) marked a paradigm shift in management of the disease. With that advance, CML has been largely managed as a chronic condition, with daily medication and frequent monitoring. Optimizing monitoring methods and identifying factors associated with response and long-term outcomes has thus been a major clinical research focus. Given the improved understanding of surveillance techniques in CML and the advent of several recently approved second- and third-generation TKIs, there have been recent updates to clinical practice guidelines.

Click on the PDF icon at the top of this introduction to read the full article.
 

When I was in high school, one of my friends told me he intended to kill another one of my friends. It was a different day and age back then, and with more than 4,000 students, my high school was rather large and impersonal – it was easy to get lost in the crowd.

"Juan" (not his real name) confided in me that he wanted to kill "Joe" (also not his real name), which I found a bit odd. Joe was well liked but not did really stand out. Juan was perhaps quieter and more studious, but he also did not stand out. Both boys had friends, did well in school, and were not obviously troubled. When I asked Juan why he wanted to kill Joe, he responded, "Because he’s the all-American boy."

I worried about this. I told my mother, and I told a teacher I trusted. No one knew what to do, and Juan’s plan did not sound feasible. He was going to bring a knife to school in a folder, and when Joe was walking in a crowded hallway, Juan would walk behind him and thrust out the folder to sent the knife flying. The physics of this just didn’t make sense to me, and I didn’t see how the knife would gain enough momentum to travel very far, much less penetrate a person through their clothes. Feasible, or not, however, the equation changed on a day that Juan and I were sitting together in the back row of Latin class. Juan opened his calculus book and showed me the butcher knife.

I excused myself from class, went to a pay phone, and called my mother. She called the school, the principal called the police, and Juan was quietly removed from school when the period ended. It would be hard to imagine that a teenager who plotted the murder of another student, by illogical means for an illogical reason, wasn’t emotionally disturbed. I don’t know what happens to someone like Juan in 2014 – I’m thinking nothing good – but let me tell you what happened to Juan in the late 1970s.

Juan was out of high school for 6 weeks. I heard he had psychological testing, but aside from that, I have no idea what transpired. One of his friends told me it was a joke. He returned to high school, never said another word to me, graduated, and attended an Ivy League university – one of several prestigious schools to which he gained admission. A Google search reveals that Juan later earned a graduate degree and works as an executive making a six-figure salary. (Isn’t Google great?) He’s an adjunct professor at a college where he gets glowing reviews on RateMyProfessors.com. He was elected to serve on a local government committee. He’s married and has children. Compliments of Facebook, I know that he continues to have contact with high school friends.

From what I can tell, Juan’s brief period of being a disturbed adolescent did not progress to a life defined by chronic mental illness, and he did not go on to become a violent felon. I have no idea if I did Juan a favor, prevented a murder, got him much-needed treatment, or simply added an embarrassing diversion to his life. I don’t know if he ever really would have harmed Joe, or if it was in fact a joke designed to yank my chain.

Apparently, my threshold is on the low side, and not long ago I called a friend late one night and insisted she check on her teenager when a Facebook post struck me as alarming and a bit too final. The response I got was, "They were lyrics from a song and you’re overreacting." So be it. I called the mother and not the National Guard, and if the teen had become a statistic, I would have regretted not reacting.

I did wonder, while writing this article, how it would be received if I were to contact Juan and ask his thoughts on those events decades ago. Somehow, it seemed best not to uncover old wounds.

The media talk about the dangerously mentally ill as though they are a separate breed of humans, ones who can be easily distinguished by simply assessing who stands on which side of a well-marked "us-versus-them" line. Human beings, especially young human beings, may go through phases, and they may struggle with controlling their emotions, behaviors, and impulses and with finding their identity at a time in life when fitting in has undue importance. Some of them, no doubt, have these crises in the throes of an acute episode of mental distress – illness, if you’d prefer – and others do so at the genesis of what will prove to be a chronic and persistent psychiatric disorder. It may not be clear at any given moment who is going through a phase, who is suffering from an acute episode of mental illness, and who is beginning their course of a severe and persistent disorder.

Still, there are those who want to neatly categorize those with "serious" mental illness so that we can focus more of our resources on their needs and not on those who they deem to be the "worried well." Juan, it appears, did not fall into that category of chronically or persistently mentally ill. Similarly, all of us know chaotic, misbehaving, and even suicidal teenagers who go on to live productive lives. Does that designation matter if those not-so-seriously (or not-so-obviously) mentally ill individuals kill someone or die during their brief moments of emotional turbulence?

It seems to me that the goal is to keep people safe and help usher them through difficult periods in their lives, regardless of any diagnostic certainty or severity. I would contend that the mentally healthy among us also are subject to impulsive, distressed, and dangerous moments and that the world does not always neatly divide people into proper categorical entities.

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

When I was in high school, one of my friends told me he intended to kill another one of my friends. It was a different day and age back then, and with more than 4,000 students, my high school was rather large and impersonal – it was easy to get lost in the crowd.

"Juan" (not his real name) confided in me that he wanted to kill "Joe" (also not his real name), which I found a bit odd. Joe was well liked but not did really stand out. Juan was perhaps quieter and more studious, but he also did not stand out. Both boys had friends, did well in school, and were not obviously troubled. When I asked Juan why he wanted to kill Joe, he responded, "Because he’s the all-American boy."

I worried about this. I told my mother, and I told a teacher I trusted. No one knew what to do, and Juan’s plan did not sound feasible. He was going to bring a knife to school in a folder, and when Joe was walking in a crowded hallway, Juan would walk behind him and thrust out the folder to sent the knife flying. The physics of this just didn’t make sense to me, and I didn’t see how the knife would gain enough momentum to travel very far, much less penetrate a person through their clothes. Feasible, or not, however, the equation changed on a day that Juan and I were sitting together in the back row of Latin class. Juan opened his calculus book and showed me the butcher knife.

I excused myself from class, went to a pay phone, and called my mother. She called the school, the principal called the police, and Juan was quietly removed from school when the period ended. It would be hard to imagine that a teenager who plotted the murder of another student, by illogical means for an illogical reason, wasn’t emotionally disturbed. I don’t know what happens to someone like Juan in 2014 – I’m thinking nothing good – but let me tell you what happened to Juan in the late 1970s.

Juan was out of high school for 6 weeks. I heard he had psychological testing, but aside from that, I have no idea what transpired. One of his friends told me it was a joke. He returned to high school, never said another word to me, graduated, and attended an Ivy League university – one of several prestigious schools to which he gained admission. A Google search reveals that Juan later earned a graduate degree and works as an executive making a six-figure salary. (Isn’t Google great?) He’s an adjunct professor at a college where he gets glowing reviews on RateMyProfessors.com. He was elected to serve on a local government committee. He’s married and has children. Compliments of Facebook, I know that he continues to have contact with high school friends.

From what I can tell, Juan’s brief period of being a disturbed adolescent did not progress to a life defined by chronic mental illness, and he did not go on to become a violent felon. I have no idea if I did Juan a favor, prevented a murder, got him much-needed treatment, or simply added an embarrassing diversion to his life. I don’t know if he ever really would have harmed Joe, or if it was in fact a joke designed to yank my chain.

Apparently, my threshold is on the low side, and not long ago I called a friend late one night and insisted she check on her teenager when a Facebook post struck me as alarming and a bit too final. The response I got was, "They were lyrics from a song and you’re overreacting." So be it. I called the mother and not the National Guard, and if the teen had become a statistic, I would have regretted not reacting.

I did wonder, while writing this article, how it would be received if I were to contact Juan and ask his thoughts on those events decades ago. Somehow, it seemed best not to uncover old wounds.

The media talk about the dangerously mentally ill as though they are a separate breed of humans, ones who can be easily distinguished by simply assessing who stands on which side of a well-marked "us-versus-them" line. Human beings, especially young human beings, may go through phases, and they may struggle with controlling their emotions, behaviors, and impulses and with finding their identity at a time in life when fitting in has undue importance. Some of them, no doubt, have these crises in the throes of an acute episode of mental distress – illness, if you’d prefer – and others do so at the genesis of what will prove to be a chronic and persistent psychiatric disorder. It may not be clear at any given moment who is going through a phase, who is suffering from an acute episode of mental illness, and who is beginning their course of a severe and persistent disorder.

Still, there are those who want to neatly categorize those with "serious" mental illness so that we can focus more of our resources on their needs and not on those who they deem to be the "worried well." Juan, it appears, did not fall into that category of chronically or persistently mentally ill. Similarly, all of us know chaotic, misbehaving, and even suicidal teenagers who go on to live productive lives. Does that designation matter if those not-so-seriously (or not-so-obviously) mentally ill individuals kill someone or die during their brief moments of emotional turbulence?

It seems to me that the goal is to keep people safe and help usher them through difficult periods in their lives, regardless of any diagnostic certainty or severity. I would contend that the mentally healthy among us also are subject to impulsive, distressed, and dangerous moments and that the world does not always neatly divide people into proper categorical entities.

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

When I was in high school, one of my friends told me he intended to kill another one of my friends. It was a different day and age back then, and with more than 4,000 students, my high school was rather large and impersonal – it was easy to get lost in the crowd.

"Juan" (not his real name) confided in me that he wanted to kill "Joe" (also not his real name), which I found a bit odd. Joe was well liked but not did really stand out. Juan was perhaps quieter and more studious, but he also did not stand out. Both boys had friends, did well in school, and were not obviously troubled. When I asked Juan why he wanted to kill Joe, he responded, "Because he’s the all-American boy."

I worried about this. I told my mother, and I told a teacher I trusted. No one knew what to do, and Juan’s plan did not sound feasible. He was going to bring a knife to school in a folder, and when Joe was walking in a crowded hallway, Juan would walk behind him and thrust out the folder to sent the knife flying. The physics of this just didn’t make sense to me, and I didn’t see how the knife would gain enough momentum to travel very far, much less penetrate a person through their clothes. Feasible, or not, however, the equation changed on a day that Juan and I were sitting together in the back row of Latin class. Juan opened his calculus book and showed me the butcher knife.

I excused myself from class, went to a pay phone, and called my mother. She called the school, the principal called the police, and Juan was quietly removed from school when the period ended. It would be hard to imagine that a teenager who plotted the murder of another student, by illogical means for an illogical reason, wasn’t emotionally disturbed. I don’t know what happens to someone like Juan in 2014 – I’m thinking nothing good – but let me tell you what happened to Juan in the late 1970s.

Juan was out of high school for 6 weeks. I heard he had psychological testing, but aside from that, I have no idea what transpired. One of his friends told me it was a joke. He returned to high school, never said another word to me, graduated, and attended an Ivy League university – one of several prestigious schools to which he gained admission. A Google search reveals that Juan later earned a graduate degree and works as an executive making a six-figure salary. (Isn’t Google great?) He’s an adjunct professor at a college where he gets glowing reviews on RateMyProfessors.com. He was elected to serve on a local government committee. He’s married and has children. Compliments of Facebook, I know that he continues to have contact with high school friends.

From what I can tell, Juan’s brief period of being a disturbed adolescent did not progress to a life defined by chronic mental illness, and he did not go on to become a violent felon. I have no idea if I did Juan a favor, prevented a murder, got him much-needed treatment, or simply added an embarrassing diversion to his life. I don’t know if he ever really would have harmed Joe, or if it was in fact a joke designed to yank my chain.

Apparently, my threshold is on the low side, and not long ago I called a friend late one night and insisted she check on her teenager when a Facebook post struck me as alarming and a bit too final. The response I got was, "They were lyrics from a song and you’re overreacting." So be it. I called the mother and not the National Guard, and if the teen had become a statistic, I would have regretted not reacting.

I did wonder, while writing this article, how it would be received if I were to contact Juan and ask his thoughts on those events decades ago. Somehow, it seemed best not to uncover old wounds.

The media talk about the dangerously mentally ill as though they are a separate breed of humans, ones who can be easily distinguished by simply assessing who stands on which side of a well-marked "us-versus-them" line. Human beings, especially young human beings, may go through phases, and they may struggle with controlling their emotions, behaviors, and impulses and with finding their identity at a time in life when fitting in has undue importance. Some of them, no doubt, have these crises in the throes of an acute episode of mental distress – illness, if you’d prefer – and others do so at the genesis of what will prove to be a chronic and persistent psychiatric disorder. It may not be clear at any given moment who is going through a phase, who is suffering from an acute episode of mental illness, and who is beginning their course of a severe and persistent disorder.

Still, there are those who want to neatly categorize those with "serious" mental illness so that we can focus more of our resources on their needs and not on those who they deem to be the "worried well." Juan, it appears, did not fall into that category of chronically or persistently mentally ill. Similarly, all of us know chaotic, misbehaving, and even suicidal teenagers who go on to live productive lives. Does that designation matter if those not-so-seriously (or not-so-obviously) mentally ill individuals kill someone or die during their brief moments of emotional turbulence?

It seems to me that the goal is to keep people safe and help usher them through difficult periods in their lives, regardless of any diagnostic certainty or severity. I would contend that the mentally healthy among us also are subject to impulsive, distressed, and dangerous moments and that the world does not always neatly divide people into proper categorical entities.

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

Older patients with migraine may be more likely to have silent brain injury than older patients without migraine, according to research published online ahead of print May 15 in Stroke. Researchers analyzed data from the Northern Manhattan Study, which quantified subclinical brain infarctions and white matter hyperintensity volumes among participants with migraine. Of the 546 participants analyzed, 41% were men, 65% were Hispanic, and mean age at MRI was 71. Patients with migraine had double the odds of subclinical brain infarction, compared with those reporting no migraine, after the investigators adjusted for sociodemographics and vascular risk factors. No association was observed between migraine with or without aura and white matter hyperintensity volume. Patients with migraine should not worry, because their risk of ischemic stroke is small, said the authors.

People who are exposed to paint, glue, or degreaser fumes at work may experience memory and thinking problems in retirement, according to a study published May 13 in Neurology. Researchers examined data for 2,143 retired utility workers who underwent cognitive testing in 2010. The authors assessed workers’ lifetime exposure to chlorinated solvents, petroleum solvents, and benzene using a job exposure matrix. Approximately 33% of participants were exposed to chlorinated solvents, 26% to benzene, and 25% to petroleum solvents. Workers highly exposed to chlorinated solvents were at risk of impairment on the Mini-Mental State Examination, the Digit Symbol Substitution Test, semantic fluency test, and the Trail Making Test B. Retirees at greatest risk for deficits had high lifetime exposure to solvents and were last exposed 12 to 30 years before testing.

Females susceptible to multiple sclerosis (MS) produce higher levels of the blood vessel receptor protein S1PR2 than males, according to data published online ahead of print May 8 in the Journal of Clinical Investigation. S1PR2 is present at high levels in the brain areas that MS typically damages. Investigators studied a mouse model of MS and found increased activity of S1PR2, which opens up the blood–brain barrier. When the researchers tested brain tissue samples obtained from 20 human patients after death, they found more S1PR2 in patients with MS than in those without the disorder. Brain tissue from females also had higher levels of S1PR2, compared with male brain tissue. These findings may help explain why more women than men get the disease, said the authors.

The FDA has required the manufacturer of the sleep drug Lunesta (eszopiclone) to lower the recommended starting dose from 2 mg to 1 mg for men and women. Data show that eszopiclone levels in some patients may be high enough on the morning after treatment to impair activities that require alertness, including driving. The 1-mg dose, taken at bedtime, can be increased to 2 mg or 3 mg if needed, but the higher doses are more likely to result in next-day impairment. Using lower doses ensures that less drug will remain in the body during the morning hours. Patients currently taking the 2-mg and 3-mg doses of Lunesta should contact their health care professional to ask for instructions, according to the FDA.

The rate of visits to an emergency department (ED) for traumatic brain injury (TBI) increased by approximately 30% between 2006 and 2010, according to research published in the May 14 issue of JAMA. The increase may be attributable to various factors, including increased awareness and diagnoses, said the authors. The investigators examined data from the Nationwide Emergency Department Sample database to determine national trends in ED visits for TBI from 2006 through 2010. An estimated 2.5 million ED visits for TBI occurred in 2010, representing a 29% increase in the rate of visits for TBI during the study period. By comparison, total ED visits increased by 3.6%. Children younger than 3 and adults older than 60 had the largest increase in TBI rates.

The pathophysiologic biomarkers and the topographic markers of Alzheimer’s disease should be revised, according to a position paper by the International Working Group published in the June issue of Lancet Neurology. The group proposed that biomarkers of Alzheimer’s pathology be restricted to those indicating the presence of tau pathology (ie, CSF or PET tau) and amyloid pathology (ie, CSF or PET amyloid). These biomarkers are specific enough to diagnose Alzheimer’s disease at any point on the disease continuum, said the authors. Downstream topographic markers of brain regional structural and metabolic changes have insufficient pathologic specificity and should not be used in diagnosis, according to the researchers. Instead, these markers can be used to measure disease progression. The group also provided diagnostic criteria for atypical, mixed, and preclinical Alzheimer’s disease.

Prenatal supplementation with docosahexaenoic acid (DHA) does not result in improved cognitive, problem-solving, or language abilities for children at age 4, according to the results of a trial published in the May 7 issue of JAMA. Investigators conducted longer-term follow-up from a previous study in which pregnant women received 800 mg/day of DHA or placebo. In the initial study, the researchers found that average cognitive, language, and motor scores did not differ between children at 18 months of age. Approximately 92% of eligible families participated in the follow-up study. The DHA group included 313 participants, and the control group included 333 participants. The investigators found that measures of cognition, the ability to perform complex mental processing, language, and executive functioning (eg, memory, reasoning, and problem solving) did not differ significantly between groups at age 4.

The FDA has informed Acorda Therapeutics that it has completed its review of the company’s new drug application for Plumiaz (diazepam) nasal spray and that the application cannot be approved in its present form. The drug was developed for the treatment of people with epilepsy who experience cluster seizures. Acorda Therapeutics is developing a response to address the items outlined in the letter. Based on the requirements for approval outlined in the letter, the company does not expect Plumiaz to receive FDA approval in 2014. Plumiaz previously received orphan drug designation for the treatment of cluster seizures. [For related news, see page 9.]

Older people with memory and thinking problems who do not have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems, according to a study published April 22 in Neurology. Researchers studied 2,627 people age 65 and older who did not have dementia at baseline. Participants underwent tests of memory and thinking skills at baseline and at three years. Follow-up lasted for an average of approximately 13 years. During the study, 1,003 participants died. About 34% of deaths occurred among patients with the fastest decline in thinking skills. Approximately 21% of participants in the group with the fastest decline in thinking skills died of cancer, compared with 29% of participants in the other two groups.

A new technique may predict with 95% accuracy which patients with stroke will benefit from IV t-PA and which will have potentially lethal bleeding in the brain, according to a study published online ahead of print May 15 in Stroke. Researchers used a computer program that shows physicians the amount of gadolinium, injected during an MRI scan, that has leaked into the brain tissue from surrounding blood vessels. By quantifying this damage in 75 patients with stroke, the researchers identified a threshold for determining how much leakage was dangerous. They applied this threshold to the records for the 75 patients to determine how well it would predict who had had a brain hemorrhage and who had not. The new test correctly predicted the outcome with 95% accuracy.

Freezing of gait in patients with Parkinson’s disease may correlate with poor quality of life, disease severity, apathy, and exposure to antimuscarinics, according to a study published online ahead of print May 19 in JAMA Neurology. Investigators performed a cross-sectional survey of 672 patients with idiopathic Parkinson’s disease. Patients with freezing of gait were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson’s Disease Rating Scale (UPDRS) in the on condition. Approximately 38% of patients reported freezing of gait during the on state, which was significantly related to lower quality of life scores. Freezing of gait was also correlated with longer disease duration, higher UPDRS parts II and III scores, apathy, and a higher levodopa equivalent daily dose.

Among college football players, concussion and years of football played may have a significant inverse relationship with hippocampal volume, according to research published May 14 in JAMA. Years of football experience also may correlate with slower reaction time. Investigators conducted a cross-sectional study of 25 college football players with a history of clinician-diagnosed concussion, 25 college football players without a history of concussion, and 25 nonfootball-playing, age-, sex-, and education-matched healthy controls. Players with and without a history of concussion had smaller hippocampal volumes, compared with healthy controls. Players with a history of concussion had smaller hippocampal volumes than players without concussion. In both athlete groups, investigators found a statistically significant inverse relationship between left hippocampal volume and number of years of football played.

Deficiencies in hyaluronan can lead to spontaneous epileptic seizures, according to research published April 30 in the Journal of Neuroscience. In a multicenter study, investigators examined the role of hyaluronan using mutant mice deficient in each of the three hyaluronan synthase genes (ie, Has1, Has2, Has3). The mutant mice were prone to epileptic seizures. In Has3(-/-) mice, this phenotype likely results from a reduction in the size of the brain extracellular space (ECS), said the researchers. Among the three Has knockout models, seizures were most prevalent in Has3(-/-) mice, which also had the greatest hyaluronan reduction in the hippocampus. The results provide the first direct evidence for the physiologic role of hyaluronan in the regulation of ECS volume, according to the investigators.

—Erik Greb

Older patients with migraine may be more likely to have silent brain injury than older patients without migraine, according to research published online ahead of print May 15 in Stroke. Researchers analyzed data from the Northern Manhattan Study, which quantified subclinical brain infarctions and white matter hyperintensity volumes among participants with migraine. Of the 546 participants analyzed, 41% were men, 65% were Hispanic, and mean age at MRI was 71. Patients with migraine had double the odds of subclinical brain infarction, compared with those reporting no migraine, after the investigators adjusted for sociodemographics and vascular risk factors. No association was observed between migraine with or without aura and white matter hyperintensity volume. Patients with migraine should not worry, because their risk of ischemic stroke is small, said the authors.

People who are exposed to paint, glue, or degreaser fumes at work may experience memory and thinking problems in retirement, according to a study published May 13 in Neurology. Researchers examined data for 2,143 retired utility workers who underwent cognitive testing in 2010. The authors assessed workers’ lifetime exposure to chlorinated solvents, petroleum solvents, and benzene using a job exposure matrix. Approximately 33% of participants were exposed to chlorinated solvents, 26% to benzene, and 25% to petroleum solvents. Workers highly exposed to chlorinated solvents were at risk of impairment on the Mini-Mental State Examination, the Digit Symbol Substitution Test, semantic fluency test, and the Trail Making Test B. Retirees at greatest risk for deficits had high lifetime exposure to solvents and were last exposed 12 to 30 years before testing.

Females susceptible to multiple sclerosis (MS) produce higher levels of the blood vessel receptor protein S1PR2 than males, according to data published online ahead of print May 8 in the Journal of Clinical Investigation. S1PR2 is present at high levels in the brain areas that MS typically damages. Investigators studied a mouse model of MS and found increased activity of S1PR2, which opens up the blood–brain barrier. When the researchers tested brain tissue samples obtained from 20 human patients after death, they found more S1PR2 in patients with MS than in those without the disorder. Brain tissue from females also had higher levels of S1PR2, compared with male brain tissue. These findings may help explain why more women than men get the disease, said the authors.

The FDA has required the manufacturer of the sleep drug Lunesta (eszopiclone) to lower the recommended starting dose from 2 mg to 1 mg for men and women. Data show that eszopiclone levels in some patients may be high enough on the morning after treatment to impair activities that require alertness, including driving. The 1-mg dose, taken at bedtime, can be increased to 2 mg or 3 mg if needed, but the higher doses are more likely to result in next-day impairment. Using lower doses ensures that less drug will remain in the body during the morning hours. Patients currently taking the 2-mg and 3-mg doses of Lunesta should contact their health care professional to ask for instructions, according to the FDA.

The rate of visits to an emergency department (ED) for traumatic brain injury (TBI) increased by approximately 30% between 2006 and 2010, according to research published in the May 14 issue of JAMA. The increase may be attributable to various factors, including increased awareness and diagnoses, said the authors. The investigators examined data from the Nationwide Emergency Department Sample database to determine national trends in ED visits for TBI from 2006 through 2010. An estimated 2.5 million ED visits for TBI occurred in 2010, representing a 29% increase in the rate of visits for TBI during the study period. By comparison, total ED visits increased by 3.6%. Children younger than 3 and adults older than 60 had the largest increase in TBI rates.

The pathophysiologic biomarkers and the topographic markers of Alzheimer’s disease should be revised, according to a position paper by the International Working Group published in the June issue of Lancet Neurology. The group proposed that biomarkers of Alzheimer’s pathology be restricted to those indicating the presence of tau pathology (ie, CSF or PET tau) and amyloid pathology (ie, CSF or PET amyloid). These biomarkers are specific enough to diagnose Alzheimer’s disease at any point on the disease continuum, said the authors. Downstream topographic markers of brain regional structural and metabolic changes have insufficient pathologic specificity and should not be used in diagnosis, according to the researchers. Instead, these markers can be used to measure disease progression. The group also provided diagnostic criteria for atypical, mixed, and preclinical Alzheimer’s disease.

Prenatal supplementation with docosahexaenoic acid (DHA) does not result in improved cognitive, problem-solving, or language abilities for children at age 4, according to the results of a trial published in the May 7 issue of JAMA. Investigators conducted longer-term follow-up from a previous study in which pregnant women received 800 mg/day of DHA or placebo. In the initial study, the researchers found that average cognitive, language, and motor scores did not differ between children at 18 months of age. Approximately 92% of eligible families participated in the follow-up study. The DHA group included 313 participants, and the control group included 333 participants. The investigators found that measures of cognition, the ability to perform complex mental processing, language, and executive functioning (eg, memory, reasoning, and problem solving) did not differ significantly between groups at age 4.

The FDA has informed Acorda Therapeutics that it has completed its review of the company’s new drug application for Plumiaz (diazepam) nasal spray and that the application cannot be approved in its present form. The drug was developed for the treatment of people with epilepsy who experience cluster seizures. Acorda Therapeutics is developing a response to address the items outlined in the letter. Based on the requirements for approval outlined in the letter, the company does not expect Plumiaz to receive FDA approval in 2014. Plumiaz previously received orphan drug designation for the treatment of cluster seizures. [For related news, see page 9.]

Older people with memory and thinking problems who do not have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems, according to a study published April 22 in Neurology. Researchers studied 2,627 people age 65 and older who did not have dementia at baseline. Participants underwent tests of memory and thinking skills at baseline and at three years. Follow-up lasted for an average of approximately 13 years. During the study, 1,003 participants died. About 34% of deaths occurred among patients with the fastest decline in thinking skills. Approximately 21% of participants in the group with the fastest decline in thinking skills died of cancer, compared with 29% of participants in the other two groups.

A new technique may predict with 95% accuracy which patients with stroke will benefit from IV t-PA and which will have potentially lethal bleeding in the brain, according to a study published online ahead of print May 15 in Stroke. Researchers used a computer program that shows physicians the amount of gadolinium, injected during an MRI scan, that has leaked into the brain tissue from surrounding blood vessels. By quantifying this damage in 75 patients with stroke, the researchers identified a threshold for determining how much leakage was dangerous. They applied this threshold to the records for the 75 patients to determine how well it would predict who had had a brain hemorrhage and who had not. The new test correctly predicted the outcome with 95% accuracy.

Freezing of gait in patients with Parkinson’s disease may correlate with poor quality of life, disease severity, apathy, and exposure to antimuscarinics, according to a study published online ahead of print May 19 in JAMA Neurology. Investigators performed a cross-sectional survey of 672 patients with idiopathic Parkinson’s disease. Patients with freezing of gait were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson’s Disease Rating Scale (UPDRS) in the on condition. Approximately 38% of patients reported freezing of gait during the on state, which was significantly related to lower quality of life scores. Freezing of gait was also correlated with longer disease duration, higher UPDRS parts II and III scores, apathy, and a higher levodopa equivalent daily dose.

Among college football players, concussion and years of football played may have a significant inverse relationship with hippocampal volume, according to research published May 14 in JAMA. Years of football experience also may correlate with slower reaction time. Investigators conducted a cross-sectional study of 25 college football players with a history of clinician-diagnosed concussion, 25 college football players without a history of concussion, and 25 nonfootball-playing, age-, sex-, and education-matched healthy controls. Players with and without a history of concussion had smaller hippocampal volumes, compared with healthy controls. Players with a history of concussion had smaller hippocampal volumes than players without concussion. In both athlete groups, investigators found a statistically significant inverse relationship between left hippocampal volume and number of years of football played.

Deficiencies in hyaluronan can lead to spontaneous epileptic seizures, according to research published April 30 in the Journal of Neuroscience. In a multicenter study, investigators examined the role of hyaluronan using mutant mice deficient in each of the three hyaluronan synthase genes (ie, Has1, Has2, Has3). The mutant mice were prone to epileptic seizures. In Has3(-/-) mice, this phenotype likely results from a reduction in the size of the brain extracellular space (ECS), said the researchers. Among the three Has knockout models, seizures were most prevalent in Has3(-/-) mice, which also had the greatest hyaluronan reduction in the hippocampus. The results provide the first direct evidence for the physiologic role of hyaluronan in the regulation of ECS volume, according to the investigators.

—Erik Greb

Older patients with migraine may be more likely to have silent brain injury than older patients without migraine, according to research published online ahead of print May 15 in Stroke. Researchers analyzed data from the Northern Manhattan Study, which quantified subclinical brain infarctions and white matter hyperintensity volumes among participants with migraine. Of the 546 participants analyzed, 41% were men, 65% were Hispanic, and mean age at MRI was 71. Patients with migraine had double the odds of subclinical brain infarction, compared with those reporting no migraine, after the investigators adjusted for sociodemographics and vascular risk factors. No association was observed between migraine with or without aura and white matter hyperintensity volume. Patients with migraine should not worry, because their risk of ischemic stroke is small, said the authors.

People who are exposed to paint, glue, or degreaser fumes at work may experience memory and thinking problems in retirement, according to a study published May 13 in Neurology. Researchers examined data for 2,143 retired utility workers who underwent cognitive testing in 2010. The authors assessed workers’ lifetime exposure to chlorinated solvents, petroleum solvents, and benzene using a job exposure matrix. Approximately 33% of participants were exposed to chlorinated solvents, 26% to benzene, and 25% to petroleum solvents. Workers highly exposed to chlorinated solvents were at risk of impairment on the Mini-Mental State Examination, the Digit Symbol Substitution Test, semantic fluency test, and the Trail Making Test B. Retirees at greatest risk for deficits had high lifetime exposure to solvents and were last exposed 12 to 30 years before testing.

Females susceptible to multiple sclerosis (MS) produce higher levels of the blood vessel receptor protein S1PR2 than males, according to data published online ahead of print May 8 in the Journal of Clinical Investigation. S1PR2 is present at high levels in the brain areas that MS typically damages. Investigators studied a mouse model of MS and found increased activity of S1PR2, which opens up the blood–brain barrier. When the researchers tested brain tissue samples obtained from 20 human patients after death, they found more S1PR2 in patients with MS than in those without the disorder. Brain tissue from females also had higher levels of S1PR2, compared with male brain tissue. These findings may help explain why more women than men get the disease, said the authors.

The FDA has required the manufacturer of the sleep drug Lunesta (eszopiclone) to lower the recommended starting dose from 2 mg to 1 mg for men and women. Data show that eszopiclone levels in some patients may be high enough on the morning after treatment to impair activities that require alertness, including driving. The 1-mg dose, taken at bedtime, can be increased to 2 mg or 3 mg if needed, but the higher doses are more likely to result in next-day impairment. Using lower doses ensures that less drug will remain in the body during the morning hours. Patients currently taking the 2-mg and 3-mg doses of Lunesta should contact their health care professional to ask for instructions, according to the FDA.

The rate of visits to an emergency department (ED) for traumatic brain injury (TBI) increased by approximately 30% between 2006 and 2010, according to research published in the May 14 issue of JAMA. The increase may be attributable to various factors, including increased awareness and diagnoses, said the authors. The investigators examined data from the Nationwide Emergency Department Sample database to determine national trends in ED visits for TBI from 2006 through 2010. An estimated 2.5 million ED visits for TBI occurred in 2010, representing a 29% increase in the rate of visits for TBI during the study period. By comparison, total ED visits increased by 3.6%. Children younger than 3 and adults older than 60 had the largest increase in TBI rates.

The pathophysiologic biomarkers and the topographic markers of Alzheimer’s disease should be revised, according to a position paper by the International Working Group published in the June issue of Lancet Neurology. The group proposed that biomarkers of Alzheimer’s pathology be restricted to those indicating the presence of tau pathology (ie, CSF or PET tau) and amyloid pathology (ie, CSF or PET amyloid). These biomarkers are specific enough to diagnose Alzheimer’s disease at any point on the disease continuum, said the authors. Downstream topographic markers of brain regional structural and metabolic changes have insufficient pathologic specificity and should not be used in diagnosis, according to the researchers. Instead, these markers can be used to measure disease progression. The group also provided diagnostic criteria for atypical, mixed, and preclinical Alzheimer’s disease.

Prenatal supplementation with docosahexaenoic acid (DHA) does not result in improved cognitive, problem-solving, or language abilities for children at age 4, according to the results of a trial published in the May 7 issue of JAMA. Investigators conducted longer-term follow-up from a previous study in which pregnant women received 800 mg/day of DHA or placebo. In the initial study, the researchers found that average cognitive, language, and motor scores did not differ between children at 18 months of age. Approximately 92% of eligible families participated in the follow-up study. The DHA group included 313 participants, and the control group included 333 participants. The investigators found that measures of cognition, the ability to perform complex mental processing, language, and executive functioning (eg, memory, reasoning, and problem solving) did not differ significantly between groups at age 4.

The FDA has informed Acorda Therapeutics that it has completed its review of the company’s new drug application for Plumiaz (diazepam) nasal spray and that the application cannot be approved in its present form. The drug was developed for the treatment of people with epilepsy who experience cluster seizures. Acorda Therapeutics is developing a response to address the items outlined in the letter. Based on the requirements for approval outlined in the letter, the company does not expect Plumiaz to receive FDA approval in 2014. Plumiaz previously received orphan drug designation for the treatment of cluster seizures. [For related news, see page 9.]

Older people with memory and thinking problems who do not have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems, according to a study published April 22 in Neurology. Researchers studied 2,627 people age 65 and older who did not have dementia at baseline. Participants underwent tests of memory and thinking skills at baseline and at three years. Follow-up lasted for an average of approximately 13 years. During the study, 1,003 participants died. About 34% of deaths occurred among patients with the fastest decline in thinking skills. Approximately 21% of participants in the group with the fastest decline in thinking skills died of cancer, compared with 29% of participants in the other two groups.

A new technique may predict with 95% accuracy which patients with stroke will benefit from IV t-PA and which will have potentially lethal bleeding in the brain, according to a study published online ahead of print May 15 in Stroke. Researchers used a computer program that shows physicians the amount of gadolinium, injected during an MRI scan, that has leaked into the brain tissue from surrounding blood vessels. By quantifying this damage in 75 patients with stroke, the researchers identified a threshold for determining how much leakage was dangerous. They applied this threshold to the records for the 75 patients to determine how well it would predict who had had a brain hemorrhage and who had not. The new test correctly predicted the outcome with 95% accuracy.

Freezing of gait in patients with Parkinson’s disease may correlate with poor quality of life, disease severity, apathy, and exposure to antimuscarinics, according to a study published online ahead of print May 19 in JAMA Neurology. Investigators performed a cross-sectional survey of 672 patients with idiopathic Parkinson’s disease. Patients with freezing of gait were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson’s Disease Rating Scale (UPDRS) in the on condition. Approximately 38% of patients reported freezing of gait during the on state, which was significantly related to lower quality of life scores. Freezing of gait was also correlated with longer disease duration, higher UPDRS parts II and III scores, apathy, and a higher levodopa equivalent daily dose.

Among college football players, concussion and years of football played may have a significant inverse relationship with hippocampal volume, according to research published May 14 in JAMA. Years of football experience also may correlate with slower reaction time. Investigators conducted a cross-sectional study of 25 college football players with a history of clinician-diagnosed concussion, 25 college football players without a history of concussion, and 25 nonfootball-playing, age-, sex-, and education-matched healthy controls. Players with and without a history of concussion had smaller hippocampal volumes, compared with healthy controls. Players with a history of concussion had smaller hippocampal volumes than players without concussion. In both athlete groups, investigators found a statistically significant inverse relationship between left hippocampal volume and number of years of football played.

Deficiencies in hyaluronan can lead to spontaneous epileptic seizures, according to research published April 30 in the Journal of Neuroscience. In a multicenter study, investigators examined the role of hyaluronan using mutant mice deficient in each of the three hyaluronan synthase genes (ie, Has1, Has2, Has3). The mutant mice were prone to epileptic seizures. In Has3(-/-) mice, this phenotype likely results from a reduction in the size of the brain extracellular space (ECS), said the researchers. Among the three Has knockout models, seizures were most prevalent in Has3(-/-) mice, which also had the greatest hyaluronan reduction in the hippocampus. The results provide the first direct evidence for the physiologic role of hyaluronan in the regulation of ECS volume, according to the investigators.

—Erik Greb

Physicians should screen all asymptomatic but high-risk adolescents and adults for hepatitis B virus infection, according to an updated recommendation by the U.S. Preventive Services Task Force that was published online May 27 in Annals of Internal Medicine.

Since the last USPSTF recommendation on HBV screening in 2004, which focused on the general population and didn’t advocate screening of this subset of patients, research has documented that antiviral treatment improves both intermediate outcomes such as virologic and histologic responses and long-term outcomes such as prevention of hepatocellular carcinoma, cirrhosis, and end-stage liver disease.

Given this effectiveness, along with the 98% sensitivity and specificity of HBV screening tests, the group has now issued a level B recommendation that high-risk patients be screened, said Dr. Michael L. LeFevre, chair of the USPSTF and professor of family and community medicine at the University of Missouri, Columbia, and his associates.

High-risk patients include the following:

• People born in regions where the prevalence of HBV infection is 2% or greater, such as sub-Saharan Africa, central and southeast Asia, China, the Pacific Islands, and parts of Latin America. People born in these areas account for 47%-95% of the chronic HBV infection in the United States.

• American-born children of parents from these regions, who may not have been vaccinated in infancy.

• HIV-positive persons.

• IV-drug users.

• Household contacts of people with HBV infection.

• Men who have sex with men.

The updated USPSTF recommendations are in line with those of the Centers for Disease Control and Prevention, the American Association for the Study of Liver Diseases, the Institute of Medicine, and the American Academy of Family Physicians. The CDC additionally recommends HBV screening for blood, organ, or tissue donors; people with occupational or other exposure to infectious blood or body fluids; and patients receiving hemodialysis, cytotoxic therapy, or immunosuppressive therapy.

The USPSTF still does not recommend HBV screening for the general population. The prevalence of the infection is low in the U.S. general population, and most members of the general population who are infected with HBV do not develop the chronic form of the infection and do not develop complications like hepatocellular carcinoma or cirrhosis. The potential harms of general screening, then, probably exceed the potential benefits, Dr. LeFevre and his associates noted (Ann Intern. Med. 2014 May 27 [doi:10.7326/M14-1018]).

The USPSTF has separate recommendations regarding hepatitis B in pregnant women. These, along with the updated recommendations for high-risk patients, are available at www.uspreventiveservicestaskforce.org.

The USPSTF is a voluntary group funded by the Agency for Healthcare Research and Quality but otherwise independent of the federal government. Dr. LeFevre and his associates reported no potential financial conflicts of interest.

Physicians should screen all asymptomatic but high-risk adolescents and adults for hepatitis B virus infection, according to an updated recommendation by the U.S. Preventive Services Task Force that was published online May 27 in Annals of Internal Medicine.

Since the last USPSTF recommendation on HBV screening in 2004, which focused on the general population and didn’t advocate screening of this subset of patients, research has documented that antiviral treatment improves both intermediate outcomes such as virologic and histologic responses and long-term outcomes such as prevention of hepatocellular carcinoma, cirrhosis, and end-stage liver disease.

Given this effectiveness, along with the 98% sensitivity and specificity of HBV screening tests, the group has now issued a level B recommendation that high-risk patients be screened, said Dr. Michael L. LeFevre, chair of the USPSTF and professor of family and community medicine at the University of Missouri, Columbia, and his associates.

High-risk patients include the following:

• People born in regions where the prevalence of HBV infection is 2% or greater, such as sub-Saharan Africa, central and southeast Asia, China, the Pacific Islands, and parts of Latin America. People born in these areas account for 47%-95% of the chronic HBV infection in the United States.

• American-born children of parents from these regions, who may not have been vaccinated in infancy.

• HIV-positive persons.

• IV-drug users.

• Household contacts of people with HBV infection.

• Men who have sex with men.

The updated USPSTF recommendations are in line with those of the Centers for Disease Control and Prevention, the American Association for the Study of Liver Diseases, the Institute of Medicine, and the American Academy of Family Physicians. The CDC additionally recommends HBV screening for blood, organ, or tissue donors; people with occupational or other exposure to infectious blood or body fluids; and patients receiving hemodialysis, cytotoxic therapy, or immunosuppressive therapy.

The USPSTF still does not recommend HBV screening for the general population. The prevalence of the infection is low in the U.S. general population, and most members of the general population who are infected with HBV do not develop the chronic form of the infection and do not develop complications like hepatocellular carcinoma or cirrhosis. The potential harms of general screening, then, probably exceed the potential benefits, Dr. LeFevre and his associates noted (Ann Intern. Med. 2014 May 27 [doi:10.7326/M14-1018]).

The USPSTF has separate recommendations regarding hepatitis B in pregnant women. These, along with the updated recommendations for high-risk patients, are available at www.uspreventiveservicestaskforce.org.

The USPSTF is a voluntary group funded by the Agency for Healthcare Research and Quality but otherwise independent of the federal government. Dr. LeFevre and his associates reported no potential financial conflicts of interest.

Physicians should screen all asymptomatic but high-risk adolescents and adults for hepatitis B virus infection, according to an updated recommendation by the U.S. Preventive Services Task Force that was published online May 27 in Annals of Internal Medicine.

Since the last USPSTF recommendation on HBV screening in 2004, which focused on the general population and didn’t advocate screening of this subset of patients, research has documented that antiviral treatment improves both intermediate outcomes such as virologic and histologic responses and long-term outcomes such as prevention of hepatocellular carcinoma, cirrhosis, and end-stage liver disease.

Given this effectiveness, along with the 98% sensitivity and specificity of HBV screening tests, the group has now issued a level B recommendation that high-risk patients be screened, said Dr. Michael L. LeFevre, chair of the USPSTF and professor of family and community medicine at the University of Missouri, Columbia, and his associates.

High-risk patients include the following:

• People born in regions where the prevalence of HBV infection is 2% or greater, such as sub-Saharan Africa, central and southeast Asia, China, the Pacific Islands, and parts of Latin America. People born in these areas account for 47%-95% of the chronic HBV infection in the United States.

• American-born children of parents from these regions, who may not have been vaccinated in infancy.

• HIV-positive persons.

• IV-drug users.

• Household contacts of people with HBV infection.

• Men who have sex with men.

The updated USPSTF recommendations are in line with those of the Centers for Disease Control and Prevention, the American Association for the Study of Liver Diseases, the Institute of Medicine, and the American Academy of Family Physicians. The CDC additionally recommends HBV screening for blood, organ, or tissue donors; people with occupational or other exposure to infectious blood or body fluids; and patients receiving hemodialysis, cytotoxic therapy, or immunosuppressive therapy.

The USPSTF still does not recommend HBV screening for the general population. The prevalence of the infection is low in the U.S. general population, and most members of the general population who are infected with HBV do not develop the chronic form of the infection and do not develop complications like hepatocellular carcinoma or cirrhosis. The potential harms of general screening, then, probably exceed the potential benefits, Dr. LeFevre and his associates noted (Ann Intern. Med. 2014 May 27 [doi:10.7326/M14-1018]).

The USPSTF has separate recommendations regarding hepatitis B in pregnant women. These, along with the updated recommendations for high-risk patients, are available at www.uspreventiveservicestaskforce.org.

The USPSTF is a voluntary group funded by the Agency for Healthcare Research and Quality but otherwise independent of the federal government. Dr. LeFevre and his associates reported no potential financial conflicts of interest.

Doctor with Syrian refugees

Credit: UK Department

for International Development

A new study published in The Lancet Oncology reveals a high demand for costly cancer treatment among refugees from the recent conflicts in Iraq and Syria, with host countries struggling to find the money and medicine to treat their new patients.

The findings prompted a call from study author Paul Spiegel, MD, the United Nations High Commissioner for Refugees (UNHCR) Chief Medical Expert, for schemes to improve access to affordable cancer care for refugees.

In the first study of its kind, Dr Spiegel and his colleagues examined data from funding applications made to the UNHCR Exceptional Care Committee (ECC) from refugees in Jordan and Syria whose cancer treatment costs were likely to exceed US$2000 a year.

The results indicate that cancer is an important public health problem in refugee settings, the researchers said. The study also highlights the challenges and costs national health systems and humanitarian organizations face when overwhelmed by massive influxes of refugees.

For example, in Jordan, the ECC assessed 1989 applications for treatment between 2010 and 2012. Roughly a quarter of these (511) were for cancer, with breast cancer and colorectal cancer being the most common. Around half (48%) of these cases were approved and funded.

Funding was often denied because the patient had a poor prognosis (43% of cases in 2011 and 31% in 2012) or the treatment was too costly (25% in 2011). The average amount requested from the ECC for cancer treatment was $11,540 in 2011 and $5151 in 2012. However, the amounts approved were substantially lower—$4626 in 2011 and $3501 in 2012.

“The countries in the Middle East have welcomed millions of refugees, first from Iraq and then Syria,” Dr Spiegel said. “This massive influx has strained health systems at all levels. Despite help from international organizations and donors to expand health facilities and pay for additional personnel and drugs, it has been insufficient.”

“The burden has fallen disproportionately on the host countries to absorb the costs. For example, the Jordanian Ministry of Health footed an estimated $53 million bill for medical care for refugees in the first 4 months of 2013.”

Dr Spiegel and his colleagues are therefore calling for improved cancer prevention and treatment in refugee settings through the use of innovative financing schemes; better primary care, including screening for common cancers (eg, colonoscopies and mammograms); and the development of web-based cancer registries to prevent the interruption of treatment.

“Until now, the responses to humanitarian crises have been primarily based on experiences from refugee camps in sub-Saharan Africa where infectious diseases and malnutrition have been the priority,” Dr Spiegel said. “In the 21st century, refugee situations are substantially longer and increasingly occur in middle-income countries where the levels of chronic diseases, including cancer, are higher.”

“Cancer diagnosis and care in humanitarian emergencies typifies a growing trend towards more costly chronic disease care, something that seems to have been overlooked but is of increasing importance because the number of refugees is growing.”

Doctor with Syrian refugees

Credit: UK Department

for International Development

A new study published in The Lancet Oncology reveals a high demand for costly cancer treatment among refugees from the recent conflicts in Iraq and Syria, with host countries struggling to find the money and medicine to treat their new patients.

The findings prompted a call from study author Paul Spiegel, MD, the United Nations High Commissioner for Refugees (UNHCR) Chief Medical Expert, for schemes to improve access to affordable cancer care for refugees.

In the first study of its kind, Dr Spiegel and his colleagues examined data from funding applications made to the UNHCR Exceptional Care Committee (ECC) from refugees in Jordan and Syria whose cancer treatment costs were likely to exceed US$2000 a year.

The results indicate that cancer is an important public health problem in refugee settings, the researchers said. The study also highlights the challenges and costs national health systems and humanitarian organizations face when overwhelmed by massive influxes of refugees.

For example, in Jordan, the ECC assessed 1989 applications for treatment between 2010 and 2012. Roughly a quarter of these (511) were for cancer, with breast cancer and colorectal cancer being the most common. Around half (48%) of these cases were approved and funded.

Funding was often denied because the patient had a poor prognosis (43% of cases in 2011 and 31% in 2012) or the treatment was too costly (25% in 2011). The average amount requested from the ECC for cancer treatment was $11,540 in 2011 and $5151 in 2012. However, the amounts approved were substantially lower—$4626 in 2011 and $3501 in 2012.

“The countries in the Middle East have welcomed millions of refugees, first from Iraq and then Syria,” Dr Spiegel said. “This massive influx has strained health systems at all levels. Despite help from international organizations and donors to expand health facilities and pay for additional personnel and drugs, it has been insufficient.”

“The burden has fallen disproportionately on the host countries to absorb the costs. For example, the Jordanian Ministry of Health footed an estimated $53 million bill for medical care for refugees in the first 4 months of 2013.”

Dr Spiegel and his colleagues are therefore calling for improved cancer prevention and treatment in refugee settings through the use of innovative financing schemes; better primary care, including screening for common cancers (eg, colonoscopies and mammograms); and the development of web-based cancer registries to prevent the interruption of treatment.

“Until now, the responses to humanitarian crises have been primarily based on experiences from refugee camps in sub-Saharan Africa where infectious diseases and malnutrition have been the priority,” Dr Spiegel said. “In the 21st century, refugee situations are substantially longer and increasingly occur in middle-income countries where the levels of chronic diseases, including cancer, are higher.”

“Cancer diagnosis and care in humanitarian emergencies typifies a growing trend towards more costly chronic disease care, something that seems to have been overlooked but is of increasing importance because the number of refugees is growing.”

Doctor with Syrian refugees

Credit: UK Department

for International Development

A new study published in The Lancet Oncology reveals a high demand for costly cancer treatment among refugees from the recent conflicts in Iraq and Syria, with host countries struggling to find the money and medicine to treat their new patients.

The findings prompted a call from study author Paul Spiegel, MD, the United Nations High Commissioner for Refugees (UNHCR) Chief Medical Expert, for schemes to improve access to affordable cancer care for refugees.

In the first study of its kind, Dr Spiegel and his colleagues examined data from funding applications made to the UNHCR Exceptional Care Committee (ECC) from refugees in Jordan and Syria whose cancer treatment costs were likely to exceed US$2000 a year.

The results indicate that cancer is an important public health problem in refugee settings, the researchers said. The study also highlights the challenges and costs national health systems and humanitarian organizations face when overwhelmed by massive influxes of refugees.

For example, in Jordan, the ECC assessed 1989 applications for treatment between 2010 and 2012. Roughly a quarter of these (511) were for cancer, with breast cancer and colorectal cancer being the most common. Around half (48%) of these cases were approved and funded.

Funding was often denied because the patient had a poor prognosis (43% of cases in 2011 and 31% in 2012) or the treatment was too costly (25% in 2011). The average amount requested from the ECC for cancer treatment was $11,540 in 2011 and $5151 in 2012. However, the amounts approved were substantially lower—$4626 in 2011 and $3501 in 2012.

“The countries in the Middle East have welcomed millions of refugees, first from Iraq and then Syria,” Dr Spiegel said. “This massive influx has strained health systems at all levels. Despite help from international organizations and donors to expand health facilities and pay for additional personnel and drugs, it has been insufficient.”

“The burden has fallen disproportionately on the host countries to absorb the costs. For example, the Jordanian Ministry of Health footed an estimated $53 million bill for medical care for refugees in the first 4 months of 2013.”

Dr Spiegel and his colleagues are therefore calling for improved cancer prevention and treatment in refugee settings through the use of innovative financing schemes; better primary care, including screening for common cancers (eg, colonoscopies and mammograms); and the development of web-based cancer registries to prevent the interruption of treatment.

“Until now, the responses to humanitarian crises have been primarily based on experiences from refugee camps in sub-Saharan Africa where infectious diseases and malnutrition have been the priority,” Dr Spiegel said. “In the 21st century, refugee situations are substantially longer and increasingly occur in middle-income countries where the levels of chronic diseases, including cancer, are higher.”

“Cancer diagnosis and care in humanitarian emergencies typifies a growing trend towards more costly chronic disease care, something that seems to have been overlooked but is of increasing importance because the number of refugees is growing.”

Doctor examines SCD patient

Credit: St Jude Children’s

Research Hospital

A new study reveals differences in the pneumococcal genome that explain why current vaccines do not sufficiently protect children with sickle cell disease (SCD) from pneumococcal infections.

Researchers performed whole-genome sequencing of hundreds of pneumococcal bacteria collected from healthy subjects and patients with SCD.

The team found that disease-causing strains of the bacteria differed between the 2 groups.

And the pneumococcal strains from the SCD patients differed from the 13 pneumococcal strains included in the current vaccine recommended for children age 5 and younger.

“The results help explain why current vaccines haven’t been as successful at protecting children with sickle cell disease from pneumococcal infections as they have in protecting other children,” said Joshua Wolf, MD, of St Jude Children’s Research Hospital.

Dr Wolf and his colleagues detailed these results in Cell Host & Microbe.

The researchers had compared the genomes of 322 pneumococcal bacteria collected from SCD patients between 1994 and 2011 to DNA from 327 strains obtained from individuals without SCD.

The analysis revealed that, over time, the genomes of bacteria isolated from SCD patients shrank, as genes and the corresponding DNA were discarded or combined. The changes reflected bacterial adaptation to the SCD host and contributed to the bacteria’s ability to persist despite advances in preventive care.

The researchers then used transposon sequencing to compare the bacterial fitness of pneumococcal genes in mice with and without SCD. This revealed 60 genes whose transposon disruption resulted in fitness differences between the 2 types of mice.

So the bacteria faced different conditions in animals with and without SCD. The bloodstream of normal mice was a more hostile environment for pneumococcal bacteria than the bloodstream of mice with SCD.

When the researchers evaluated the aforementioned 60 genes in bacteria isolated from SCD patients, they found 6 that were missing or altered in a significant percentage of samples (P<0.05). This included SP0511, SP0946, SP1032, SP1449, SP1483, and SP1835.

These genes are involved in transporting iron into bacteria, bacterial metabolism, and other processes that are likely altered in patients with SCD.

“We demonstrated that genes necessary to cause disease in the general public are expendable in patients with sickle cell disease,” said study author Jason Rosch, PhD, also of St Jude.

The researchers believe these findings will aid efforts to improve vaccine effectiveness and inform research into new ways to protect young SCD patients from life-threatening pneumococcal infections that can lead to pneumonia, meningitis, bloodstream infections, and other problems.

Doctor examines SCD patient

Credit: St Jude Children’s

Research Hospital

A new study reveals differences in the pneumococcal genome that explain why current vaccines do not sufficiently protect children with sickle cell disease (SCD) from pneumococcal infections.

Researchers performed whole-genome sequencing of hundreds of pneumococcal bacteria collected from healthy subjects and patients with SCD.

The team found that disease-causing strains of the bacteria differed between the 2 groups.

And the pneumococcal strains from the SCD patients differed from the 13 pneumococcal strains included in the current vaccine recommended for children age 5 and younger.

“The results help explain why current vaccines haven’t been as successful at protecting children with sickle cell disease from pneumococcal infections as they have in protecting other children,” said Joshua Wolf, MD, of St Jude Children’s Research Hospital.

Dr Wolf and his colleagues detailed these results in Cell Host & Microbe.

The researchers had compared the genomes of 322 pneumococcal bacteria collected from SCD patients between 1994 and 2011 to DNA from 327 strains obtained from individuals without SCD.

The analysis revealed that, over time, the genomes of bacteria isolated from SCD patients shrank, as genes and the corresponding DNA were discarded or combined. The changes reflected bacterial adaptation to the SCD host and contributed to the bacteria’s ability to persist despite advances in preventive care.

The researchers then used transposon sequencing to compare the bacterial fitness of pneumococcal genes in mice with and without SCD. This revealed 60 genes whose transposon disruption resulted in fitness differences between the 2 types of mice.

So the bacteria faced different conditions in animals with and without SCD. The bloodstream of normal mice was a more hostile environment for pneumococcal bacteria than the bloodstream of mice with SCD.

When the researchers evaluated the aforementioned 60 genes in bacteria isolated from SCD patients, they found 6 that were missing or altered in a significant percentage of samples (P<0.05). This included SP0511, SP0946, SP1032, SP1449, SP1483, and SP1835.

These genes are involved in transporting iron into bacteria, bacterial metabolism, and other processes that are likely altered in patients with SCD.

“We demonstrated that genes necessary to cause disease in the general public are expendable in patients with sickle cell disease,” said study author Jason Rosch, PhD, also of St Jude.

The researchers believe these findings will aid efforts to improve vaccine effectiveness and inform research into new ways to protect young SCD patients from life-threatening pneumococcal infections that can lead to pneumonia, meningitis, bloodstream infections, and other problems.

Doctor examines SCD patient

Credit: St Jude Children’s

Research Hospital

A new study reveals differences in the pneumococcal genome that explain why current vaccines do not sufficiently protect children with sickle cell disease (SCD) from pneumococcal infections.

Researchers performed whole-genome sequencing of hundreds of pneumococcal bacteria collected from healthy subjects and patients with SCD.

The team found that disease-causing strains of the bacteria differed between the 2 groups.

And the pneumococcal strains from the SCD patients differed from the 13 pneumococcal strains included in the current vaccine recommended for children age 5 and younger.

“The results help explain why current vaccines haven’t been as successful at protecting children with sickle cell disease from pneumococcal infections as they have in protecting other children,” said Joshua Wolf, MD, of St Jude Children’s Research Hospital.

Dr Wolf and his colleagues detailed these results in Cell Host & Microbe.

The researchers had compared the genomes of 322 pneumococcal bacteria collected from SCD patients between 1994 and 2011 to DNA from 327 strains obtained from individuals without SCD.

The analysis revealed that, over time, the genomes of bacteria isolated from SCD patients shrank, as genes and the corresponding DNA were discarded or combined. The changes reflected bacterial adaptation to the SCD host and contributed to the bacteria’s ability to persist despite advances in preventive care.

The researchers then used transposon sequencing to compare the bacterial fitness of pneumococcal genes in mice with and without SCD. This revealed 60 genes whose transposon disruption resulted in fitness differences between the 2 types of mice.

So the bacteria faced different conditions in animals with and without SCD. The bloodstream of normal mice was a more hostile environment for pneumococcal bacteria than the bloodstream of mice with SCD.

When the researchers evaluated the aforementioned 60 genes in bacteria isolated from SCD patients, they found 6 that were missing or altered in a significant percentage of samples (P<0.05). This included SP0511, SP0946, SP1032, SP1449, SP1483, and SP1835.

These genes are involved in transporting iron into bacteria, bacterial metabolism, and other processes that are likely altered in patients with SCD.

“We demonstrated that genes necessary to cause disease in the general public are expendable in patients with sickle cell disease,” said study author Jason Rosch, PhD, also of St Jude.

The researchers believe these findings will aid efforts to improve vaccine effectiveness and inform research into new ways to protect young SCD patients from life-threatening pneumococcal infections that can lead to pneumonia, meningitis, bloodstream infections, and other problems.