Jeffrey S. Eisenberg

High dietary intake of antioxidants, zinc and omega-3 fatty acids may reduce the risk of early age-related macular degeneration in patients with the high genetic risk, according to the findings of a prospective, population-based study in the June issue of Archives of Ophthalmology.

Studies have shown that some 80% of late age-related macular degeneration (AMD) cases are due to variants in the complement factor H (CFH) and LOC387715/HTRA1 genes. "To reduce the burden of this disease, it is therefore essential to find means to counteract these major gene effects," the researchers said. "The only protective factors for AMD known to date are nutrients."

With this in mind, Dr. Lintje Ho of Erasmus Medical Center, in Rotterdam, the Netherlands, and colleagues investigated whether antioxidant, zinc and omega-3 fatty acid intake from daily foods could reduce the risk of early AMD in patients with the various genotypes of CFH Y402H and LOC387715 A69S (Arch. Ophthalmol. 2011;129:758-66).

To do so, they analyzed a subset of patients from Rotterdam Study, a prospective, population-based cohort investigation of chronic diseases in residents aged 55 and older of a Rotterdam suburb. Subjects underwent a comprehensive eye examination at baseline (1990-1993) and at three follow-up visits (1993-1994, 1997-1999 and 2000-2004).

To be eligible, participants had no AMD during the entire study period or developed early AMD during follow-up. A total of 2,768 individuals were eligible for the study, and 2,167 individuals were included in the final analysis.

Of these subjects, 517 (24%) developed early AMD during a median follow-up period of 9 years. These patients were slightly older (mean age 68 years) than were those with no AMD (mean 66 years), fewer were diabetic (7% vs. 10%), and they had a higher frequency of CFH Y402H (62% vs. 55%) and LOC387715 A69S genotypes (41% vs. 33%).

Results showed significant interactions between the CFH Y402H genotype and intake of zinc, beta-carotene, lutein/zeaxanthin, and eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA). Specifically, dietary intake of zinc in the highest tertile reduced the hazard ratio for early AMD from 2.25 to 1.27. Hazard ratios were reduced from 2.54 to 1.47 for highest intakes of beta-carotene, 2.63 to 1.72 for lutein/zeaxanthin, and 1.97 to 1.30 for EPA/DHA.

Results also showed a significant interaction between LOC387715 A69S genotype and intake of zinc and EPA/DHA. Carriers with the highest intake of zinc reduced their risk from 1.70 to 1.17, while those with the highest intake of EPA/DHA reduced their risk from 1.59 to 0.95.

Dietary antioxidants may help counteract oxidative damage that can activate the complement system, which plays a role in the pathogenesis of AMD. For example, zinc may help reduce complement activation that is already underway. Also, omega-3 fatty acids help prevent inflammation in the retina, another factor in the pathogenesis of AMD, by lowering acute-phase proteins, including complement C4, immunoglobulin M (IgM), haptoglobin, C-reactive protein, and fibrinogen, the researchers say.

Individuals need only consume the recommended daily allowances rather than excessive amounts of these nutrients to benefit, the researchers said.

They recommend fortified cereals, meats, dairy products, nuts, and seeds as sources of zinc, dark green leafy vegetables and bright orange vegetables as sources of beta-carotene, and oily fish as a source of EPA and DHA.

The relatively low number of cases in the stratified analyses is a limitation, although the researchers said they still could identify clear trends of risk reduction.

The authors reported having no financial conflicts. This study was supported by the Netherlands Organization for Scientific Research, among other sources.

High dietary intake of antioxidants, zinc and omega-3 fatty acids may reduce the risk of early age-related macular degeneration in patients with the high genetic risk, according to the findings of a prospective, population-based study in the June issue of Archives of Ophthalmology.

Studies have shown that some 80% of late age-related macular degeneration (AMD) cases are due to variants in the complement factor H (CFH) and LOC387715/HTRA1 genes. "To reduce the burden of this disease, it is therefore essential to find means to counteract these major gene effects," the researchers said. "The only protective factors for AMD known to date are nutrients."

With this in mind, Dr. Lintje Ho of Erasmus Medical Center, in Rotterdam, the Netherlands, and colleagues investigated whether antioxidant, zinc and omega-3 fatty acid intake from daily foods could reduce the risk of early AMD in patients with the various genotypes of CFH Y402H and LOC387715 A69S (Arch. Ophthalmol. 2011;129:758-66).

To do so, they analyzed a subset of patients from Rotterdam Study, a prospective, population-based cohort investigation of chronic diseases in residents aged 55 and older of a Rotterdam suburb. Subjects underwent a comprehensive eye examination at baseline (1990-1993) and at three follow-up visits (1993-1994, 1997-1999 and 2000-2004).

To be eligible, participants had no AMD during the entire study period or developed early AMD during follow-up. A total of 2,768 individuals were eligible for the study, and 2,167 individuals were included in the final analysis.

Of these subjects, 517 (24%) developed early AMD during a median follow-up period of 9 years. These patients were slightly older (mean age 68 years) than were those with no AMD (mean 66 years), fewer were diabetic (7% vs. 10%), and they had a higher frequency of CFH Y402H (62% vs. 55%) and LOC387715 A69S genotypes (41% vs. 33%).

Results showed significant interactions between the CFH Y402H genotype and intake of zinc, beta-carotene, lutein/zeaxanthin, and eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA). Specifically, dietary intake of zinc in the highest tertile reduced the hazard ratio for early AMD from 2.25 to 1.27. Hazard ratios were reduced from 2.54 to 1.47 for highest intakes of beta-carotene, 2.63 to 1.72 for lutein/zeaxanthin, and 1.97 to 1.30 for EPA/DHA.

Results also showed a significant interaction between LOC387715 A69S genotype and intake of zinc and EPA/DHA. Carriers with the highest intake of zinc reduced their risk from 1.70 to 1.17, while those with the highest intake of EPA/DHA reduced their risk from 1.59 to 0.95.

Dietary antioxidants may help counteract oxidative damage that can activate the complement system, which plays a role in the pathogenesis of AMD. For example, zinc may help reduce complement activation that is already underway. Also, omega-3 fatty acids help prevent inflammation in the retina, another factor in the pathogenesis of AMD, by lowering acute-phase proteins, including complement C4, immunoglobulin M (IgM), haptoglobin, C-reactive protein, and fibrinogen, the researchers say.

Individuals need only consume the recommended daily allowances rather than excessive amounts of these nutrients to benefit, the researchers said.

They recommend fortified cereals, meats, dairy products, nuts, and seeds as sources of zinc, dark green leafy vegetables and bright orange vegetables as sources of beta-carotene, and oily fish as a source of EPA and DHA.

The relatively low number of cases in the stratified analyses is a limitation, although the researchers said they still could identify clear trends of risk reduction.

The authors reported having no financial conflicts. This study was supported by the Netherlands Organization for Scientific Research, among other sources.

High dietary intake of antioxidants, zinc and omega-3 fatty acids may reduce the risk of early age-related macular degeneration in patients with the high genetic risk, according to the findings of a prospective, population-based study in the June issue of Archives of Ophthalmology.

Studies have shown that some 80% of late age-related macular degeneration (AMD) cases are due to variants in the complement factor H (CFH) and LOC387715/HTRA1 genes. "To reduce the burden of this disease, it is therefore essential to find means to counteract these major gene effects," the researchers said. "The only protective factors for AMD known to date are nutrients."

With this in mind, Dr. Lintje Ho of Erasmus Medical Center, in Rotterdam, the Netherlands, and colleagues investigated whether antioxidant, zinc and omega-3 fatty acid intake from daily foods could reduce the risk of early AMD in patients with the various genotypes of CFH Y402H and LOC387715 A69S (Arch. Ophthalmol. 2011;129:758-66).

To do so, they analyzed a subset of patients from Rotterdam Study, a prospective, population-based cohort investigation of chronic diseases in residents aged 55 and older of a Rotterdam suburb. Subjects underwent a comprehensive eye examination at baseline (1990-1993) and at three follow-up visits (1993-1994, 1997-1999 and 2000-2004).

To be eligible, participants had no AMD during the entire study period or developed early AMD during follow-up. A total of 2,768 individuals were eligible for the study, and 2,167 individuals were included in the final analysis.

Of these subjects, 517 (24%) developed early AMD during a median follow-up period of 9 years. These patients were slightly older (mean age 68 years) than were those with no AMD (mean 66 years), fewer were diabetic (7% vs. 10%), and they had a higher frequency of CFH Y402H (62% vs. 55%) and LOC387715 A69S genotypes (41% vs. 33%).

Results showed significant interactions between the CFH Y402H genotype and intake of zinc, beta-carotene, lutein/zeaxanthin, and eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA). Specifically, dietary intake of zinc in the highest tertile reduced the hazard ratio for early AMD from 2.25 to 1.27. Hazard ratios were reduced from 2.54 to 1.47 for highest intakes of beta-carotene, 2.63 to 1.72 for lutein/zeaxanthin, and 1.97 to 1.30 for EPA/DHA.

Results also showed a significant interaction between LOC387715 A69S genotype and intake of zinc and EPA/DHA. Carriers with the highest intake of zinc reduced their risk from 1.70 to 1.17, while those with the highest intake of EPA/DHA reduced their risk from 1.59 to 0.95.

Dietary antioxidants may help counteract oxidative damage that can activate the complement system, which plays a role in the pathogenesis of AMD. For example, zinc may help reduce complement activation that is already underway. Also, omega-3 fatty acids help prevent inflammation in the retina, another factor in the pathogenesis of AMD, by lowering acute-phase proteins, including complement C4, immunoglobulin M (IgM), haptoglobin, C-reactive protein, and fibrinogen, the researchers say.

Individuals need only consume the recommended daily allowances rather than excessive amounts of these nutrients to benefit, the researchers said.

They recommend fortified cereals, meats, dairy products, nuts, and seeds as sources of zinc, dark green leafy vegetables and bright orange vegetables as sources of beta-carotene, and oily fish as a source of EPA and DHA.

The relatively low number of cases in the stratified analyses is a limitation, although the researchers said they still could identify clear trends of risk reduction.

The authors reported having no financial conflicts. This study was supported by the Netherlands Organization for Scientific Research, among other sources.

A new diagnostic tool may allow physicians to differentiate vegetative from minimally conscious states in severely brain-damaged patients at their bedside, investigators reported in the May 13 issue of Science.

The clinical diagnosis of these patients has been "extremely difficult," wrote study investigators Dr. Melanie Boly of the University of Liège (Belgium) and her colleagues. Previous neuroimaging experiments have attempted to identify accurate biomarkers of consciousness levels for both vegetative states (defined as preserved arousal without behavioral signs of awareness) and minimally conscious states (defined as nonreflexive and purposeful behaviors in a patient who is not able to communicate).

The findings reported by Dr. Boly and her team suggest that "selective disruption of backward connections, or top-down processes, in the cortical hierarchy can lead to loss of consciousness in brain-damaged patients and can clearly differentiate vegetative and minimally conscious states." The investigators added that the "present approach could constitute a new diagnostic tool to quantify the level of consciousness electrophysiologically at the patients’ bedside."

The researchers compared 22 healthy volunteers with 21 brain-damaged patients; study participants were aged 16-83 years. Overall, 13 brain-damaged patients were in a minimally conscious state, and 8 were in a vegetative state (Science 2011;332:858-62). In the study, the investigators included brain-damaged patients with different etiologies and clinical histories, hoping to find a common deficit that underlies changes in the level of consciousness.

Neuropsychologists performed behavioral assessments of consciousness using the French adaptation of the Coma Recovery Scale–Revised, which was developed to distinguish between patients in VS (vegetative state) and MCS (minimally conscious state), and between MCS patients and those who recovered their ability to communicate functionally.

Using a technique known as dynamic causal modeling, the researchers measured the connectivity of backward and forward connections in the temporal and frontal cortices of study participants, acquiring high-density ERP (event-related potential) recordings.

The only significant difference between patients in a vegetative state and the others was impaired backward connectivity from the frontal to the temporal cortex, the researchers found.

"Our analyses suggest that the (possibly diverse) pathophysiological causes of VS find a common expression in reducing top-down influences from frontal to temporal areas," they wrote. By contrast, patients in an MCS exhibited long-latency components in the scalp ERP and near-normal recurrent effective connectivity with higher-order cortices.

"This group difference cannot be attributable to differences in vigilance, as all patients were maintained in the same state of wakefulness throughout the experiment," they said. "Although forward connections are certainly needed for normal stimulus processing, these results suggest that the integrity of backward connections, or top-down processes, may be necessary for conscious perception."

Additional studies are needed to complement these findings in conditions such as sleep, epilepsy, or anesthesia-induced unconsciousness, the investigators noted.

The researchers received support from the Belgian national Fonds de la Recherche Scientifique (FNRS), European Commission, Mind Science Foundation, McDonnell Foundation, French-Speaking Community Concerted Research Action (ARC 06/11-340), Fondation Léon Frédéricq, and National Institutes of Health. Three authors are supported by the Wellcome Trust.

A new diagnostic tool may allow physicians to differentiate vegetative from minimally conscious states in severely brain-damaged patients at their bedside, investigators reported in the May 13 issue of Science.

The clinical diagnosis of these patients has been "extremely difficult," wrote study investigators Dr. Melanie Boly of the University of Liège (Belgium) and her colleagues. Previous neuroimaging experiments have attempted to identify accurate biomarkers of consciousness levels for both vegetative states (defined as preserved arousal without behavioral signs of awareness) and minimally conscious states (defined as nonreflexive and purposeful behaviors in a patient who is not able to communicate).

The findings reported by Dr. Boly and her team suggest that "selective disruption of backward connections, or top-down processes, in the cortical hierarchy can lead to loss of consciousness in brain-damaged patients and can clearly differentiate vegetative and minimally conscious states." The investigators added that the "present approach could constitute a new diagnostic tool to quantify the level of consciousness electrophysiologically at the patients’ bedside."

The researchers compared 22 healthy volunteers with 21 brain-damaged patients; study participants were aged 16-83 years. Overall, 13 brain-damaged patients were in a minimally conscious state, and 8 were in a vegetative state (Science 2011;332:858-62). In the study, the investigators included brain-damaged patients with different etiologies and clinical histories, hoping to find a common deficit that underlies changes in the level of consciousness.

Neuropsychologists performed behavioral assessments of consciousness using the French adaptation of the Coma Recovery Scale–Revised, which was developed to distinguish between patients in VS (vegetative state) and MCS (minimally conscious state), and between MCS patients and those who recovered their ability to communicate functionally.

Using a technique known as dynamic causal modeling, the researchers measured the connectivity of backward and forward connections in the temporal and frontal cortices of study participants, acquiring high-density ERP (event-related potential) recordings.

The only significant difference between patients in a vegetative state and the others was impaired backward connectivity from the frontal to the temporal cortex, the researchers found.

"Our analyses suggest that the (possibly diverse) pathophysiological causes of VS find a common expression in reducing top-down influences from frontal to temporal areas," they wrote. By contrast, patients in an MCS exhibited long-latency components in the scalp ERP and near-normal recurrent effective connectivity with higher-order cortices.

"This group difference cannot be attributable to differences in vigilance, as all patients were maintained in the same state of wakefulness throughout the experiment," they said. "Although forward connections are certainly needed for normal stimulus processing, these results suggest that the integrity of backward connections, or top-down processes, may be necessary for conscious perception."

Additional studies are needed to complement these findings in conditions such as sleep, epilepsy, or anesthesia-induced unconsciousness, the investigators noted.

The researchers received support from the Belgian national Fonds de la Recherche Scientifique (FNRS), European Commission, Mind Science Foundation, McDonnell Foundation, French-Speaking Community Concerted Research Action (ARC 06/11-340), Fondation Léon Frédéricq, and National Institutes of Health. Three authors are supported by the Wellcome Trust.

A new diagnostic tool may allow physicians to differentiate vegetative from minimally conscious states in severely brain-damaged patients at their bedside, investigators reported in the May 13 issue of Science.

The clinical diagnosis of these patients has been "extremely difficult," wrote study investigators Dr. Melanie Boly of the University of Liège (Belgium) and her colleagues. Previous neuroimaging experiments have attempted to identify accurate biomarkers of consciousness levels for both vegetative states (defined as preserved arousal without behavioral signs of awareness) and minimally conscious states (defined as nonreflexive and purposeful behaviors in a patient who is not able to communicate).

The findings reported by Dr. Boly and her team suggest that "selective disruption of backward connections, or top-down processes, in the cortical hierarchy can lead to loss of consciousness in brain-damaged patients and can clearly differentiate vegetative and minimally conscious states." The investigators added that the "present approach could constitute a new diagnostic tool to quantify the level of consciousness electrophysiologically at the patients’ bedside."

The researchers compared 22 healthy volunteers with 21 brain-damaged patients; study participants were aged 16-83 years. Overall, 13 brain-damaged patients were in a minimally conscious state, and 8 were in a vegetative state (Science 2011;332:858-62). In the study, the investigators included brain-damaged patients with different etiologies and clinical histories, hoping to find a common deficit that underlies changes in the level of consciousness.

Neuropsychologists performed behavioral assessments of consciousness using the French adaptation of the Coma Recovery Scale–Revised, which was developed to distinguish between patients in VS (vegetative state) and MCS (minimally conscious state), and between MCS patients and those who recovered their ability to communicate functionally.

Using a technique known as dynamic causal modeling, the researchers measured the connectivity of backward and forward connections in the temporal and frontal cortices of study participants, acquiring high-density ERP (event-related potential) recordings.

The only significant difference between patients in a vegetative state and the others was impaired backward connectivity from the frontal to the temporal cortex, the researchers found.

"Our analyses suggest that the (possibly diverse) pathophysiological causes of VS find a common expression in reducing top-down influences from frontal to temporal areas," they wrote. By contrast, patients in an MCS exhibited long-latency components in the scalp ERP and near-normal recurrent effective connectivity with higher-order cortices.

"This group difference cannot be attributable to differences in vigilance, as all patients were maintained in the same state of wakefulness throughout the experiment," they said. "Although forward connections are certainly needed for normal stimulus processing, these results suggest that the integrity of backward connections, or top-down processes, may be necessary for conscious perception."

Additional studies are needed to complement these findings in conditions such as sleep, epilepsy, or anesthesia-induced unconsciousness, the investigators noted.

The researchers received support from the Belgian national Fonds de la Recherche Scientifique (FNRS), European Commission, Mind Science Foundation, McDonnell Foundation, French-Speaking Community Concerted Research Action (ARC 06/11-340), Fondation Léon Frédéricq, and National Institutes of Health. Three authors are supported by the Wellcome Trust.

A new diagnostic tool may allow physicians to differentiate vegetative from minimally conscious states in severely brain-damaged patients at their bedside, investigators reported in the May 13 issue of Science.

The clinical diagnosis of these patients has been "extremely difficult," wrote study investigators Dr. Melanie Boly of the University of Liège (Belgium) and her colleagues. Previous neuroimaging experiments have attempted to identify accurate biomarkers of consciousness levels for both vegetative states (defined as preserved arousal without behavioral signs of awareness) and minimally conscious states (defined as nonreflexive and purposeful behaviors in a patient who is not able to communicate).

The findings reported by Dr. Boly and her team suggest that "selective disruption of backward connections, or top-down processes, in the cortical hierarchy can lead to loss of consciousness in brain-damaged patients and can clearly differentiate vegetative and minimally conscious states." The investigators added that the "present approach could constitute a new diagnostic tool to quantify the level of consciousness electrophysiologically at the patients’ bedside."

The researchers compared 22 healthy volunteers with 21 brain-damaged patients; study participants were aged 16-83 years. Overall, 13 brain-damaged patients were in a minimally conscious state, and 8 were in a vegetative state (Science 2011;332:858-62). In the study, the investigators included brain-damaged patients with different etiologies and clinical histories, hoping to find a common deficit that underlies changes in the level of consciousness.

Neuropsychologists performed behavioral assessments of consciousness using the French adaptation of the Coma Recovery Scale–Revised, which was developed to distinguish between patients in VS (vegetative state) and MCS (minimally conscious state), and between MCS patients and those who recovered their ability to communicate functionally.

Using a technique known as dynamic causal modeling, the researchers measured the connectivity of backward and forward connections in the temporal and frontal cortices of study participants, acquiring high-density ERP (event-related potential) recordings.

The only significant difference between patients in a vegetative state and the others was impaired backward connectivity from the frontal to the temporal cortex, the researchers found.

"Our analyses suggest that the (possibly diverse) pathophysiological causes of VS find a common expression in reducing top-down influences from frontal to temporal areas," they wrote. By contrast, patients in an MCS exhibited long-latency components in the scalp ERP and near-normal recurrent effective connectivity with higher-order cortices.

"This group difference cannot be attributable to differences in vigilance, as all patients were maintained in the same state of wakefulness throughout the experiment," they said. "Although forward connections are certainly needed for normal stimulus processing, these results suggest that the integrity of backward connections, or top-down processes, may be necessary for conscious perception."

Additional studies are needed to complement these findings in conditions such as sleep, epilepsy, or anesthesia-induced unconsciousness, the investigators noted.

The researchers received support from the Belgian national Fonds de la Recherche Scientifique (FNRS), European Commission, Mind Science Foundation, McDonnell Foundation, French-Speaking Community Concerted Research Action (ARC 06/11-340), Fondation Léon Frédéricq, and National Institutes of Health. Three authors are supported by the Wellcome Trust.

A new diagnostic tool may allow physicians to differentiate vegetative from minimally conscious states in severely brain-damaged patients at their bedside, investigators reported in the May 13 issue of Science.

The clinical diagnosis of these patients has been "extremely difficult," wrote study investigators Dr. Melanie Boly of the University of Liège (Belgium) and her colleagues. Previous neuroimaging experiments have attempted to identify accurate biomarkers of consciousness levels for both vegetative states (defined as preserved arousal without behavioral signs of awareness) and minimally conscious states (defined as nonreflexive and purposeful behaviors in a patient who is not able to communicate).

The findings reported by Dr. Boly and her team suggest that "selective disruption of backward connections, or top-down processes, in the cortical hierarchy can lead to loss of consciousness in brain-damaged patients and can clearly differentiate vegetative and minimally conscious states." The investigators added that the "present approach could constitute a new diagnostic tool to quantify the level of consciousness electrophysiologically at the patients’ bedside."

The researchers compared 22 healthy volunteers with 21 brain-damaged patients; study participants were aged 16-83 years. Overall, 13 brain-damaged patients were in a minimally conscious state, and 8 were in a vegetative state (Science 2011;332:858-62). In the study, the investigators included brain-damaged patients with different etiologies and clinical histories, hoping to find a common deficit that underlies changes in the level of consciousness.

Neuropsychologists performed behavioral assessments of consciousness using the French adaptation of the Coma Recovery Scale–Revised, which was developed to distinguish between patients in VS (vegetative state) and MCS (minimally conscious state), and between MCS patients and those who recovered their ability to communicate functionally.

Using a technique known as dynamic causal modeling, the researchers measured the connectivity of backward and forward connections in the temporal and frontal cortices of study participants, acquiring high-density ERP (event-related potential) recordings.

The only significant difference between patients in a vegetative state and the others was impaired backward connectivity from the frontal to the temporal cortex, the researchers found.

"Our analyses suggest that the (possibly diverse) pathophysiological causes of VS find a common expression in reducing top-down influences from frontal to temporal areas," they wrote. By contrast, patients in an MCS exhibited long-latency components in the scalp ERP and near-normal recurrent effective connectivity with higher-order cortices.

"This group difference cannot be attributable to differences in vigilance, as all patients were maintained in the same state of wakefulness throughout the experiment," they said. "Although forward connections are certainly needed for normal stimulus processing, these results suggest that the integrity of backward connections, or top-down processes, may be necessary for conscious perception."

Additional studies are needed to complement these findings in conditions such as sleep, epilepsy, or anesthesia-induced unconsciousness, the investigators noted.

The researchers received support from the Belgian national Fonds de la Recherche Scientifique (FNRS), European Commission, Mind Science Foundation, McDonnell Foundation, French-Speaking Community Concerted Research Action (ARC 06/11-340), Fondation Léon Frédéricq, and National Institutes of Health. Three authors are supported by the Wellcome Trust.

A new diagnostic tool may allow physicians to differentiate vegetative from minimally conscious states in severely brain-damaged patients at their bedside, investigators reported in the May 13 issue of Science.

The clinical diagnosis of these patients has been "extremely difficult," wrote study investigators Dr. Melanie Boly of the University of Liège (Belgium) and her colleagues. Previous neuroimaging experiments have attempted to identify accurate biomarkers of consciousness levels for both vegetative states (defined as preserved arousal without behavioral signs of awareness) and minimally conscious states (defined as nonreflexive and purposeful behaviors in a patient who is not able to communicate).

The findings reported by Dr. Boly and her team suggest that "selective disruption of backward connections, or top-down processes, in the cortical hierarchy can lead to loss of consciousness in brain-damaged patients and can clearly differentiate vegetative and minimally conscious states." The investigators added that the "present approach could constitute a new diagnostic tool to quantify the level of consciousness electrophysiologically at the patients’ bedside."

The researchers compared 22 healthy volunteers with 21 brain-damaged patients; study participants were aged 16-83 years. Overall, 13 brain-damaged patients were in a minimally conscious state, and 8 were in a vegetative state (Science 2011;332:858-62). In the study, the investigators included brain-damaged patients with different etiologies and clinical histories, hoping to find a common deficit that underlies changes in the level of consciousness.

Neuropsychologists performed behavioral assessments of consciousness using the French adaptation of the Coma Recovery Scale–Revised, which was developed to distinguish between patients in VS (vegetative state) and MCS (minimally conscious state), and between MCS patients and those who recovered their ability to communicate functionally.

Using a technique known as dynamic causal modeling, the researchers measured the connectivity of backward and forward connections in the temporal and frontal cortices of study participants, acquiring high-density ERP (event-related potential) recordings.

The only significant difference between patients in a vegetative state and the others was impaired backward connectivity from the frontal to the temporal cortex, the researchers found.

"Our analyses suggest that the (possibly diverse) pathophysiological causes of VS find a common expression in reducing top-down influences from frontal to temporal areas," they wrote. By contrast, patients in an MCS exhibited long-latency components in the scalp ERP and near-normal recurrent effective connectivity with higher-order cortices.

"This group difference cannot be attributable to differences in vigilance, as all patients were maintained in the same state of wakefulness throughout the experiment," they said. "Although forward connections are certainly needed for normal stimulus processing, these results suggest that the integrity of backward connections, or top-down processes, may be necessary for conscious perception."

Additional studies are needed to complement these findings in conditions such as sleep, epilepsy, or anesthesia-induced unconsciousness, the investigators noted.

The researchers received support from the Belgian national Fonds de la Recherche Scientifique (FNRS), European Commission, Mind Science Foundation, McDonnell Foundation, French-Speaking Community Concerted Research Action (ARC 06/11-340), Fondation Léon Frédéricq, and National Institutes of Health. Three authors are supported by the Wellcome Trust.

A new diagnostic tool may allow physicians to differentiate vegetative from minimally conscious states in severely brain-damaged patients at their bedside, investigators reported in the May 13 issue of Science.

The clinical diagnosis of these patients has been "extremely difficult," wrote study investigators Dr. Melanie Boly of the University of Liège (Belgium) and her colleagues. Previous neuroimaging experiments have attempted to identify accurate biomarkers of consciousness levels for both vegetative states (defined as preserved arousal without behavioral signs of awareness) and minimally conscious states (defined as nonreflexive and purposeful behaviors in a patient who is not able to communicate).

The findings reported by Dr. Boly and her team suggest that "selective disruption of backward connections, or top-down processes, in the cortical hierarchy can lead to loss of consciousness in brain-damaged patients and can clearly differentiate vegetative and minimally conscious states." The investigators added that the "present approach could constitute a new diagnostic tool to quantify the level of consciousness electrophysiologically at the patients’ bedside."

The researchers compared 22 healthy volunteers with 21 brain-damaged patients; study participants were aged 16-83 years. Overall, 13 brain-damaged patients were in a minimally conscious state, and 8 were in a vegetative state (Science 2011;332:858-62). In the study, the investigators included brain-damaged patients with different etiologies and clinical histories, hoping to find a common deficit that underlies changes in the level of consciousness.

Neuropsychologists performed behavioral assessments of consciousness using the French adaptation of the Coma Recovery Scale–Revised, which was developed to distinguish between patients in VS (vegetative state) and MCS (minimally conscious state), and between MCS patients and those who recovered their ability to communicate functionally.

Using a technique known as dynamic causal modeling, the researchers measured the connectivity of backward and forward connections in the temporal and frontal cortices of study participants, acquiring high-density ERP (event-related potential) recordings.

The only significant difference between patients in a vegetative state and the others was impaired backward connectivity from the frontal to the temporal cortex, the researchers found.

"Our analyses suggest that the (possibly diverse) pathophysiological causes of VS find a common expression in reducing top-down influences from frontal to temporal areas," they wrote. By contrast, patients in an MCS exhibited long-latency components in the scalp ERP and near-normal recurrent effective connectivity with higher-order cortices.

"This group difference cannot be attributable to differences in vigilance, as all patients were maintained in the same state of wakefulness throughout the experiment," they said. "Although forward connections are certainly needed for normal stimulus processing, these results suggest that the integrity of backward connections, or top-down processes, may be necessary for conscious perception."

Additional studies are needed to complement these findings in conditions such as sleep, epilepsy, or anesthesia-induced unconsciousness, the investigators noted.

The researchers received support from the Belgian national Fonds de la Recherche Scientifique (FNRS), European Commission, Mind Science Foundation, McDonnell Foundation, French-Speaking Community Concerted Research Action (ARC 06/11-340), Fondation Léon Frédéricq, and National Institutes of Health. Three authors are supported by the Wellcome Trust.

A new diagnostic tool may allow physicians to differentiate vegetative from minimally conscious states in severely brain-damaged patients at their bedside, investigators reported in the May 13 issue of Science.

The clinical diagnosis of these patients has been "extremely difficult," wrote study investigators Dr. Melanie Boly of the University of Liège (Belgium) and her colleagues. Previous neuroimaging experiments have attempted to identify accurate biomarkers of consciousness levels for both vegetative states (defined as preserved arousal without behavioral signs of awareness) and minimally conscious states (defined as nonreflexive and purposeful behaviors in a patient who is not able to communicate).

The findings reported by Dr. Boly and her team suggest that "selective disruption of backward connections, or top-down processes, in the cortical hierarchy can lead to loss of consciousness in brain-damaged patients and can clearly differentiate vegetative and minimally conscious states." The investigators added that the "present approach could constitute a new diagnostic tool to quantify the level of consciousness electrophysiologically at the patients’ bedside."

The researchers compared 22 healthy volunteers with 21 brain-damaged patients; study participants were aged 16-83 years. Overall, 13 brain-damaged patients were in a minimally conscious state, and 8 were in a vegetative state (Science 2011;332:858-62). In the study, the investigators included brain-damaged patients with different etiologies and clinical histories, hoping to find a common deficit that underlies changes in the level of consciousness.

Neuropsychologists performed behavioral assessments of consciousness using the French adaptation of the Coma Recovery Scale–Revised, which was developed to distinguish between patients in VS (vegetative state) and MCS (minimally conscious state), and between MCS patients and those who recovered their ability to communicate functionally.

Using a technique known as dynamic causal modeling, the researchers measured the connectivity of backward and forward connections in the temporal and frontal cortices of study participants, acquiring high-density ERP (event-related potential) recordings.

The only significant difference between patients in a vegetative state and the others was impaired backward connectivity from the frontal to the temporal cortex, the researchers found.

"Our analyses suggest that the (possibly diverse) pathophysiological causes of VS find a common expression in reducing top-down influences from frontal to temporal areas," they wrote. By contrast, patients in an MCS exhibited long-latency components in the scalp ERP and near-normal recurrent effective connectivity with higher-order cortices.

"This group difference cannot be attributable to differences in vigilance, as all patients were maintained in the same state of wakefulness throughout the experiment," they said. "Although forward connections are certainly needed for normal stimulus processing, these results suggest that the integrity of backward connections, or top-down processes, may be necessary for conscious perception."

Additional studies are needed to complement these findings in conditions such as sleep, epilepsy, or anesthesia-induced unconsciousness, the investigators noted.

The researchers received support from the Belgian national Fonds de la Recherche Scientifique (FNRS), European Commission, Mind Science Foundation, McDonnell Foundation, French-Speaking Community Concerted Research Action (ARC 06/11-340), Fondation Léon Frédéricq, and National Institutes of Health. Three authors are supported by the Wellcome Trust.

A new diagnostic tool may allow physicians to differentiate vegetative from minimally conscious states in severely brain-damaged patients at their bedside, investigators reported in the May 13 issue of Science.

The clinical diagnosis of these patients has been "extremely difficult," wrote study investigators Dr. Melanie Boly of the University of Liège (Belgium) and her colleagues. Previous neuroimaging experiments have attempted to identify accurate biomarkers of consciousness levels for both vegetative states (defined as preserved arousal without behavioral signs of awareness) and minimally conscious states (defined as nonreflexive and purposeful behaviors in a patient who is not able to communicate).

The findings reported by Dr. Boly and her team suggest that "selective disruption of backward connections, or top-down processes, in the cortical hierarchy can lead to loss of consciousness in brain-damaged patients and can clearly differentiate vegetative and minimally conscious states." The investigators added that the "present approach could constitute a new diagnostic tool to quantify the level of consciousness electrophysiologically at the patients’ bedside."

The researchers compared 22 healthy volunteers with 21 brain-damaged patients; study participants were aged 16-83 years. Overall, 13 brain-damaged patients were in a minimally conscious state, and 8 were in a vegetative state (Science 2011;332:858-62). In the study, the investigators included brain-damaged patients with different etiologies and clinical histories, hoping to find a common deficit that underlies changes in the level of consciousness.

Neuropsychologists performed behavioral assessments of consciousness using the French adaptation of the Coma Recovery Scale–Revised, which was developed to distinguish between patients in VS (vegetative state) and MCS (minimally conscious state), and between MCS patients and those who recovered their ability to communicate functionally.

Using a technique known as dynamic causal modeling, the researchers measured the connectivity of backward and forward connections in the temporal and frontal cortices of study participants, acquiring high-density ERP (event-related potential) recordings.

The only significant difference between patients in a vegetative state and the others was impaired backward connectivity from the frontal to the temporal cortex, the researchers found.

"Our analyses suggest that the (possibly diverse) pathophysiological causes of VS find a common expression in reducing top-down influences from frontal to temporal areas," they wrote. By contrast, patients in an MCS exhibited long-latency components in the scalp ERP and near-normal recurrent effective connectivity with higher-order cortices.

"This group difference cannot be attributable to differences in vigilance, as all patients were maintained in the same state of wakefulness throughout the experiment," they said. "Although forward connections are certainly needed for normal stimulus processing, these results suggest that the integrity of backward connections, or top-down processes, may be necessary for conscious perception."

Additional studies are needed to complement these findings in conditions such as sleep, epilepsy, or anesthesia-induced unconsciousness, the investigators noted.

The researchers received support from the Belgian national Fonds de la Recherche Scientifique (FNRS), European Commission, Mind Science Foundation, McDonnell Foundation, French-Speaking Community Concerted Research Action (ARC 06/11-340), Fondation Léon Frédéricq, and National Institutes of Health. Three authors are supported by the Wellcome Trust.

High levels of vitamin D in the bloodstream may help protect against early age-related macular degeneration (AMD) in women younger than 75 years, according to the latest findings from the Carotenoids in Age-Related Eye Disease Study (CAREDS), a study to investigate the relationship of carotenoids in the diet, serum and retina to AMD and cataract.

These findings, published in the April 2011 issue of Archives of Ophthalmology, confirm those of an earlier cross-sectional study that showed a strong protective association between serum concentrations of 25-hydroxyvitamin D, or 25(OH)D, and the prevalence of early AMD. Serum 25(OH)D reflects vitamin D exposure from oral sources and sunlight, making it the preferred biomarker for determining a patient’s vitamin D status.

Photo (c) Joss/Fotolia.com

Amy E. Millen, Ph.D., of the State University of New York at Buffalo and her colleagues wanted to confirm the protective effect of vitamin D among CAREDS subjects.

CAREDS, an ancillary study within the Women’s Health Initiative Observational Study (WHIOS), comprises women aged 50-79 years from 3 of the 40 WHIOS sites. Researchers initially recruited 3,143 women from the WHIOS for this analysis, but after accounting for those who declined to participate or were excluded for other reasons, the final sample consisted of 1,313 women (Arch. Ophthalmol. 2011;129:481-9).

Researchers obtained baseline serum samples between 1993 and 1998, an average of 6 years before the onset of early AMD. They also had participants complete a food frequency questionnaire at WHIOS baseline to assess vitamin D intake from foods and supplements; and asked participants at CAREDS baseline to report sunlight exposure for each city/town in which they lived from age 18 years to the present. Researchers determined AMD status based on stereoscopic fundus photos taken between 2001 and 2004.

After the researchers adjusted for age and other known risk factors for AMD, they found no significant overall relationship between vitamin D status and early or advanced AMD. However, women younger than 75 years who had 25(OH)D concentrations higher than 38 nmol/L, had a significant 48% decreased odds of early AMD, which researchers defined as more than one large drusen, extensive intermediate drusen, or pigmentary abnormalities.

Women who consumed the most vitamin D (food or supplements) had a 59% decreased odds of developing early AMD, compared with women who consumed the least vitamin D. The researchers found no relationship between self-reported time spent in direct sunlight and early AMD.

In women older than 75 years, higher concentrations of 25(OH)D were associated with a borderline statistically significant increased risk of early AMD. This latter finding is likely because of selective mortality bias, according to the researchers.

Vitamin D has both anti-inflammatory and immune-modulating properties, and might suppress the inflammatory cascade that is likely involved in the pathogenesis of AMD, the researchers stated. Vitamin D also may prevent early AMD from progressing to the neovascular form.

"Our data support the previous observation that vitamin D status may potentially protect against development of AMD," the authors concluded.

Limitations of the study included the fact that 36% of eligible subjects declined to participate, those younger than age 75 years had healthier diet and lifestyles, and there was limited minority participation, so selection bias may have occurred, the researchers say.

More longitudinal studies are necessary to confirm this association and to understand the potential interaction between vitamin D status and genetic and lifestyle factors with respect to the risk of early AMD, the authors added.

One of the coauthors is a consultant for Sequenom, a life sciences company. There were no other pertinent disclosures. The National Institutes of Health and Research to Prevent Blindness provided grants. WHIOS is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and U.S. Department of Health and Human Services.

High levels of vitamin D in the bloodstream may help protect against early age-related macular degeneration (AMD) in women younger than 75 years, according to the latest findings from the Carotenoids in Age-Related Eye Disease Study (CAREDS), a study to investigate the relationship of carotenoids in the diet, serum and retina to AMD and cataract.

These findings, published in the April 2011 issue of Archives of Ophthalmology, confirm those of an earlier cross-sectional study that showed a strong protective association between serum concentrations of 25-hydroxyvitamin D, or 25(OH)D, and the prevalence of early AMD. Serum 25(OH)D reflects vitamin D exposure from oral sources and sunlight, making it the preferred biomarker for determining a patient’s vitamin D status.

Photo (c) Joss/Fotolia.com

Amy E. Millen, Ph.D., of the State University of New York at Buffalo and her colleagues wanted to confirm the protective effect of vitamin D among CAREDS subjects.

CAREDS, an ancillary study within the Women’s Health Initiative Observational Study (WHIOS), comprises women aged 50-79 years from 3 of the 40 WHIOS sites. Researchers initially recruited 3,143 women from the WHIOS for this analysis, but after accounting for those who declined to participate or were excluded for other reasons, the final sample consisted of 1,313 women (Arch. Ophthalmol. 2011;129:481-9).

Researchers obtained baseline serum samples between 1993 and 1998, an average of 6 years before the onset of early AMD. They also had participants complete a food frequency questionnaire at WHIOS baseline to assess vitamin D intake from foods and supplements; and asked participants at CAREDS baseline to report sunlight exposure for each city/town in which they lived from age 18 years to the present. Researchers determined AMD status based on stereoscopic fundus photos taken between 2001 and 2004.

After the researchers adjusted for age and other known risk factors for AMD, they found no significant overall relationship between vitamin D status and early or advanced AMD. However, women younger than 75 years who had 25(OH)D concentrations higher than 38 nmol/L, had a significant 48% decreased odds of early AMD, which researchers defined as more than one large drusen, extensive intermediate drusen, or pigmentary abnormalities.

Women who consumed the most vitamin D (food or supplements) had a 59% decreased odds of developing early AMD, compared with women who consumed the least vitamin D. The researchers found no relationship between self-reported time spent in direct sunlight and early AMD.

In women older than 75 years, higher concentrations of 25(OH)D were associated with a borderline statistically significant increased risk of early AMD. This latter finding is likely because of selective mortality bias, according to the researchers.

Vitamin D has both anti-inflammatory and immune-modulating properties, and might suppress the inflammatory cascade that is likely involved in the pathogenesis of AMD, the researchers stated. Vitamin D also may prevent early AMD from progressing to the neovascular form.

"Our data support the previous observation that vitamin D status may potentially protect against development of AMD," the authors concluded.

Limitations of the study included the fact that 36% of eligible subjects declined to participate, those younger than age 75 years had healthier diet and lifestyles, and there was limited minority participation, so selection bias may have occurred, the researchers say.

More longitudinal studies are necessary to confirm this association and to understand the potential interaction between vitamin D status and genetic and lifestyle factors with respect to the risk of early AMD, the authors added.

One of the coauthors is a consultant for Sequenom, a life sciences company. There were no other pertinent disclosures. The National Institutes of Health and Research to Prevent Blindness provided grants. WHIOS is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and U.S. Department of Health and Human Services.

High levels of vitamin D in the bloodstream may help protect against early age-related macular degeneration (AMD) in women younger than 75 years, according to the latest findings from the Carotenoids in Age-Related Eye Disease Study (CAREDS), a study to investigate the relationship of carotenoids in the diet, serum and retina to AMD and cataract.

These findings, published in the April 2011 issue of Archives of Ophthalmology, confirm those of an earlier cross-sectional study that showed a strong protective association between serum concentrations of 25-hydroxyvitamin D, or 25(OH)D, and the prevalence of early AMD. Serum 25(OH)D reflects vitamin D exposure from oral sources and sunlight, making it the preferred biomarker for determining a patient’s vitamin D status.

Photo (c) Joss/Fotolia.com

Amy E. Millen, Ph.D., of the State University of New York at Buffalo and her colleagues wanted to confirm the protective effect of vitamin D among CAREDS subjects.

CAREDS, an ancillary study within the Women’s Health Initiative Observational Study (WHIOS), comprises women aged 50-79 years from 3 of the 40 WHIOS sites. Researchers initially recruited 3,143 women from the WHIOS for this analysis, but after accounting for those who declined to participate or were excluded for other reasons, the final sample consisted of 1,313 women (Arch. Ophthalmol. 2011;129:481-9).

Researchers obtained baseline serum samples between 1993 and 1998, an average of 6 years before the onset of early AMD. They also had participants complete a food frequency questionnaire at WHIOS baseline to assess vitamin D intake from foods and supplements; and asked participants at CAREDS baseline to report sunlight exposure for each city/town in which they lived from age 18 years to the present. Researchers determined AMD status based on stereoscopic fundus photos taken between 2001 and 2004.

After the researchers adjusted for age and other known risk factors for AMD, they found no significant overall relationship between vitamin D status and early or advanced AMD. However, women younger than 75 years who had 25(OH)D concentrations higher than 38 nmol/L, had a significant 48% decreased odds of early AMD, which researchers defined as more than one large drusen, extensive intermediate drusen, or pigmentary abnormalities.

Women who consumed the most vitamin D (food or supplements) had a 59% decreased odds of developing early AMD, compared with women who consumed the least vitamin D. The researchers found no relationship between self-reported time spent in direct sunlight and early AMD.

In women older than 75 years, higher concentrations of 25(OH)D were associated with a borderline statistically significant increased risk of early AMD. This latter finding is likely because of selective mortality bias, according to the researchers.

Vitamin D has both anti-inflammatory and immune-modulating properties, and might suppress the inflammatory cascade that is likely involved in the pathogenesis of AMD, the researchers stated. Vitamin D also may prevent early AMD from progressing to the neovascular form.

"Our data support the previous observation that vitamin D status may potentially protect against development of AMD," the authors concluded.

Limitations of the study included the fact that 36% of eligible subjects declined to participate, those younger than age 75 years had healthier diet and lifestyles, and there was limited minority participation, so selection bias may have occurred, the researchers say.

More longitudinal studies are necessary to confirm this association and to understand the potential interaction between vitamin D status and genetic and lifestyle factors with respect to the risk of early AMD, the authors added.

One of the coauthors is a consultant for Sequenom, a life sciences company. There were no other pertinent disclosures. The National Institutes of Health and Research to Prevent Blindness provided grants. WHIOS is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and U.S. Department of Health and Human Services.

High levels of vitamin D in the bloodstream may help protect against early age-related macular degeneration (AMD) in women younger than 75 years, according to the latest findings from the Carotenoids in Age-Related Eye Disease Study (CAREDS), a study to investigate the relationship of carotenoids in the diet, serum and retina to AMD and cataract.

These findings, published in the April 2011 issue of Archives of Ophthalmology, confirm those of an earlier cross-sectional study that showed a strong protective association between serum concentrations of 25-hydroxyvitamin D, or 25(OH)D, and the prevalence of early AMD. Serum 25(OH)D reflects vitamin D exposure from oral sources and sunlight, making it the preferred biomarker for determining a patient’s vitamin D status.

Photo (c) Joss/Fotolia.com

Amy E. Millen, Ph.D., of the State University of New York at Buffalo and her colleagues wanted to confirm the protective effect of vitamin D among CAREDS subjects.

CAREDS, an ancillary study within the Women’s Health Initiative Observational Study (WHIOS), comprises women aged 50-79 years from 3 of the 40 WHIOS sites. Researchers initially recruited 3,143 women from the WHIOS for this analysis, but after accounting for those who declined to participate or were excluded for other reasons, the final sample consisted of 1,313 women (Arch. Ophthalmol. 2011;129:481-9).

Researchers obtained baseline serum samples between 1993 and 1998, an average of 6 years before the onset of early AMD. They also had participants complete a food frequency questionnaire at WHIOS baseline to assess vitamin D intake from foods and supplements; and asked participants at CAREDS baseline to report sunlight exposure for each city/town in which they lived from age 18 years to the present. Researchers determined AMD status based on stereoscopic fundus photos taken between 2001 and 2004.

After the researchers adjusted for age and other known risk factors for AMD, they found no significant overall relationship between vitamin D status and early or advanced AMD. However, women younger than 75 years who had 25(OH)D concentrations higher than 38 nmol/L, had a significant 48% decreased odds of early AMD, which researchers defined as more than one large drusen, extensive intermediate drusen, or pigmentary abnormalities.

Women who consumed the most vitamin D (food or supplements) had a 59% decreased odds of developing early AMD, compared with women who consumed the least vitamin D. The researchers found no relationship between self-reported time spent in direct sunlight and early AMD.

In women older than 75 years, higher concentrations of 25(OH)D were associated with a borderline statistically significant increased risk of early AMD. This latter finding is likely because of selective mortality bias, according to the researchers.

Vitamin D has both anti-inflammatory and immune-modulating properties, and might suppress the inflammatory cascade that is likely involved in the pathogenesis of AMD, the researchers stated. Vitamin D also may prevent early AMD from progressing to the neovascular form.

"Our data support the previous observation that vitamin D status may potentially protect against development of AMD," the authors concluded.

Limitations of the study included the fact that 36% of eligible subjects declined to participate, those younger than age 75 years had healthier diet and lifestyles, and there was limited minority participation, so selection bias may have occurred, the researchers say.

More longitudinal studies are necessary to confirm this association and to understand the potential interaction between vitamin D status and genetic and lifestyle factors with respect to the risk of early AMD, the authors added.

One of the coauthors is a consultant for Sequenom, a life sciences company. There were no other pertinent disclosures. The National Institutes of Health and Research to Prevent Blindness provided grants. WHIOS is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and U.S. Department of Health and Human Services.

High levels of vitamin D in the bloodstream may help protect against early age-related macular degeneration (AMD) in women younger than 75 years, according to the latest findings from the Carotenoids in Age-Related Eye Disease Study (CAREDS), a study to investigate the relationship of carotenoids in the diet, serum and retina to AMD and cataract.

These findings, published in the April 2011 issue of Archives of Ophthalmology, confirm those of an earlier cross-sectional study that showed a strong protective association between serum concentrations of 25-hydroxyvitamin D, or 25(OH)D, and the prevalence of early AMD. Serum 25(OH)D reflects vitamin D exposure from oral sources and sunlight, making it the preferred biomarker for determining a patient’s vitamin D status.

Photo (c) Joss/Fotolia.com

Amy E. Millen, Ph.D., of the State University of New York at Buffalo and her colleagues wanted to confirm the protective effect of vitamin D among CAREDS subjects.

CAREDS, an ancillary study within the Women’s Health Initiative Observational Study (WHIOS), comprises women aged 50-79 years from 3 of the 40 WHIOS sites. Researchers initially recruited 3,143 women from the WHIOS for this analysis, but after accounting for those who declined to participate or were excluded for other reasons, the final sample consisted of 1,313 women (Arch. Ophthalmol. 2011;129:481-9).

Researchers obtained baseline serum samples between 1993 and 1998, an average of 6 years before the onset of early AMD. They also had participants complete a food frequency questionnaire at WHIOS baseline to assess vitamin D intake from foods and supplements; and asked participants at CAREDS baseline to report sunlight exposure for each city/town in which they lived from age 18 years to the present. Researchers determined AMD status based on stereoscopic fundus photos taken between 2001 and 2004.

After the researchers adjusted for age and other known risk factors for AMD, they found no significant overall relationship between vitamin D status and early or advanced AMD. However, women younger than 75 years who had 25(OH)D concentrations higher than 38 nmol/L, had a significant 48% decreased odds of early AMD, which researchers defined as more than one large drusen, extensive intermediate drusen, or pigmentary abnormalities.

Women who consumed the most vitamin D (food or supplements) had a 59% decreased odds of developing early AMD, compared with women who consumed the least vitamin D. The researchers found no relationship between self-reported time spent in direct sunlight and early AMD.

In women older than 75 years, higher concentrations of 25(OH)D were associated with a borderline statistically significant increased risk of early AMD. This latter finding is likely because of selective mortality bias, according to the researchers.

Vitamin D has both anti-inflammatory and immune-modulating properties, and might suppress the inflammatory cascade that is likely involved in the pathogenesis of AMD, the researchers stated. Vitamin D also may prevent early AMD from progressing to the neovascular form.

"Our data support the previous observation that vitamin D status may potentially protect against development of AMD," the authors concluded.

Limitations of the study included the fact that 36% of eligible subjects declined to participate, those younger than age 75 years had healthier diet and lifestyles, and there was limited minority participation, so selection bias may have occurred, the researchers say.

More longitudinal studies are necessary to confirm this association and to understand the potential interaction between vitamin D status and genetic and lifestyle factors with respect to the risk of early AMD, the authors added.

One of the coauthors is a consultant for Sequenom, a life sciences company. There were no other pertinent disclosures. The National Institutes of Health and Research to Prevent Blindness provided grants. WHIOS is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and U.S. Department of Health and Human Services.

High levels of vitamin D in the bloodstream may help protect against early age-related macular degeneration (AMD) in women younger than 75 years, according to the latest findings from the Carotenoids in Age-Related Eye Disease Study (CAREDS), a study to investigate the relationship of carotenoids in the diet, serum and retina to AMD and cataract.

These findings, published in the April 2011 issue of Archives of Ophthalmology, confirm those of an earlier cross-sectional study that showed a strong protective association between serum concentrations of 25-hydroxyvitamin D, or 25(OH)D, and the prevalence of early AMD. Serum 25(OH)D reflects vitamin D exposure from oral sources and sunlight, making it the preferred biomarker for determining a patient’s vitamin D status.

Photo (c) Joss/Fotolia.com

Amy E. Millen, Ph.D., of the State University of New York at Buffalo and her colleagues wanted to confirm the protective effect of vitamin D among CAREDS subjects.

CAREDS, an ancillary study within the Women’s Health Initiative Observational Study (WHIOS), comprises women aged 50-79 years from 3 of the 40 WHIOS sites. Researchers initially recruited 3,143 women from the WHIOS for this analysis, but after accounting for those who declined to participate or were excluded for other reasons, the final sample consisted of 1,313 women (Arch. Ophthalmol. 2011;129:481-9).

Researchers obtained baseline serum samples between 1993 and 1998, an average of 6 years before the onset of early AMD. They also had participants complete a food frequency questionnaire at WHIOS baseline to assess vitamin D intake from foods and supplements; and asked participants at CAREDS baseline to report sunlight exposure for each city/town in which they lived from age 18 years to the present. Researchers determined AMD status based on stereoscopic fundus photos taken between 2001 and 2004.

After the researchers adjusted for age and other known risk factors for AMD, they found no significant overall relationship between vitamin D status and early or advanced AMD. However, women younger than 75 years who had 25(OH)D concentrations higher than 38 nmol/L, had a significant 48% decreased odds of early AMD, which researchers defined as more than one large drusen, extensive intermediate drusen, or pigmentary abnormalities.

Women who consumed the most vitamin D (food or supplements) had a 59% decreased odds of developing early AMD, compared with women who consumed the least vitamin D. The researchers found no relationship between self-reported time spent in direct sunlight and early AMD.

In women older than 75 years, higher concentrations of 25(OH)D were associated with a borderline statistically significant increased risk of early AMD. This latter finding is likely because of selective mortality bias, according to the researchers.

Vitamin D has both anti-inflammatory and immune-modulating properties, and might suppress the inflammatory cascade that is likely involved in the pathogenesis of AMD, the researchers stated. Vitamin D also may prevent early AMD from progressing to the neovascular form.

"Our data support the previous observation that vitamin D status may potentially protect against development of AMD," the authors concluded.

Limitations of the study included the fact that 36% of eligible subjects declined to participate, those younger than age 75 years had healthier diet and lifestyles, and there was limited minority participation, so selection bias may have occurred, the researchers say.

More longitudinal studies are necessary to confirm this association and to understand the potential interaction between vitamin D status and genetic and lifestyle factors with respect to the risk of early AMD, the authors added.

One of the coauthors is a consultant for Sequenom, a life sciences company. There were no other pertinent disclosures. The National Institutes of Health and Research to Prevent Blindness provided grants. WHIOS is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and U.S. Department of Health and Human Services.

Having a parent with a history of myocardial infarction nearly doubled a person's own risk of future MI, even after accounting for other risk factors, according to an analysis of a large case-control study.

The findings are consistent in all regions of the world, added the authors of the analysis.

INTERHEART, a multinational case-control study, involved 15,152 patients who presented with a first MI and 14,820 age- and sex-matched control subjects between February 1999 and March 2003. Previous analysis of the study identified nine variables for determining MI risk: abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, physical activity, fruit and vegetable consumption, and alcohol consumption.

The current analysis included 12,149 patients presenting with a first MI and 14,467 control subjects. Dr. Clara K. Chow of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, and her colleagues obtained data on demographic factors, socioeconomic status, and risk factors for all participants, and performed genetic analysis in 8,795 participants using a panel of 1,536 single nucleotide polymorphisms (SNPs) from 103 genes believed to be associated with MI or risk factors for MI (J. Am. Coll. Cardiol. 2011;57:619-27).

In 18.1% of cases and 12% of controls, either parent had a history of MI, while both parents had a history of MI in 2.1% of cases and 0.9% of controls. A maternal history of MI was present in 7.5% of cases and 4.9% of controls, while 12.7% of cases and 8.1% of controls had a paternal history of MI. There were no significant differences in the risks associated with history of MI in either parent.

The relationship between parental history and MI risk remained after adjusting for the nine INTERHEART risk factors.

Genetic risk scores also didn’t alter the relationship. The researchers calculated genotype scores for 3,372 cases and 4,043 controls, and found that the genetic risk scores were not greater in those with a parental history of MI than in those without. The mean genotype score was 11.90 in controls with no parental history of MI, 11.84 in controls with a parental history of MI, 12.26 in cases with no parental history of MI, and 12.14 in cases with a parental history of MI.

Parental history approximately doubled an individual’s risk of MI, and the risk increased if both parents had a history of MI, especially if it occurred at a younger age.

Specifically, the odds ratio of an individual having MI was 1.81 if either parent had a history of MI (1.74 after adjusting for other risk factors). When either parent had an MI at age 50 years or older, the odds ratio fell to 1.67 – but it rose to 2.90 if both parents had an MI at age 50 or older.

The odds ratio was 2.36 for those patients with one parent who had an MI before age 50, but increased to 3.26 if both parents had an MI and one parent was younger than age 50. If both parents had an MI before age 50, the odds ratio reached 6.56.

The study results suggest that parental history of MI is an independent predictor of an individual’s risk of future MI – even after adjusting for age, sex, region, and other risk factors. The association between parental history of MI and MI is consistent across geographic regions, age, sex, and socioeconomic subgroups.

"While other studies have shown the relationship between parental history and risk, they have not established its independence from the extensive list of other potential explanatory factors, as measured by the INTERHEART Study, and not established it in other world regions or ethnic groups," the authors wrote.

The results raise another question: Are there factors other than shared risk factors and genetics that are involved in heart disease, such as early life exposures or home environmental factors? The genotype score obtained in the study analyses represents only a small percentage of possible genotype variants, the researchers noted.

The strengths of the study are its large international coverage; the large number of cases of MI; and the comprehensive measurement of risk factors, including genetic factors, the researchers said. Limitations included a lack of data collected from siblings or other relatives, limited measurement of SNPs in a limited number of individuals, and the possibility of recall biases due to the case-control nature of the study.

The researchers received support from the Royal Australasian College of Physicians, the National Health and Medical Research Council and National Heart Foundation of Australia, the Heart and Stroke Foundation of Ontario, the May Cohen Eli Lilly Chair in Women’s Health Research, and Michael G. DeGroote Heart and Stroke Foundation Chair in Population Health. The INTERHEART study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Ontario, and the International Clinical Epidemiology Network (INCLEN). Several pharmaceutical companies – particularly AstraZeneca, Novartis, Aventis, Abbott, Bristol-Myers Squibb, King Pharma, and Sanofi-Sythelabo – provided unrestricted research grants. Various national bodies in different countries also provided funding. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; or in the writing of the report.

Having a parent with a history of myocardial infarction nearly doubled a person's own risk of future MI, even after accounting for other risk factors, according to an analysis of a large case-control study.

The findings are consistent in all regions of the world, added the authors of the analysis.

INTERHEART, a multinational case-control study, involved 15,152 patients who presented with a first MI and 14,820 age- and sex-matched control subjects between February 1999 and March 2003. Previous analysis of the study identified nine variables for determining MI risk: abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, physical activity, fruit and vegetable consumption, and alcohol consumption.

The current analysis included 12,149 patients presenting with a first MI and 14,467 control subjects. Dr. Clara K. Chow of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, and her colleagues obtained data on demographic factors, socioeconomic status, and risk factors for all participants, and performed genetic analysis in 8,795 participants using a panel of 1,536 single nucleotide polymorphisms (SNPs) from 103 genes believed to be associated with MI or risk factors for MI (J. Am. Coll. Cardiol. 2011;57:619-27).

In 18.1% of cases and 12% of controls, either parent had a history of MI, while both parents had a history of MI in 2.1% of cases and 0.9% of controls. A maternal history of MI was present in 7.5% of cases and 4.9% of controls, while 12.7% of cases and 8.1% of controls had a paternal history of MI. There were no significant differences in the risks associated with history of MI in either parent.

The relationship between parental history and MI risk remained after adjusting for the nine INTERHEART risk factors.

Genetic risk scores also didn’t alter the relationship. The researchers calculated genotype scores for 3,372 cases and 4,043 controls, and found that the genetic risk scores were not greater in those with a parental history of MI than in those without. The mean genotype score was 11.90 in controls with no parental history of MI, 11.84 in controls with a parental history of MI, 12.26 in cases with no parental history of MI, and 12.14 in cases with a parental history of MI.

Parental history approximately doubled an individual’s risk of MI, and the risk increased if both parents had a history of MI, especially if it occurred at a younger age.

Specifically, the odds ratio of an individual having MI was 1.81 if either parent had a history of MI (1.74 after adjusting for other risk factors). When either parent had an MI at age 50 years or older, the odds ratio fell to 1.67 – but it rose to 2.90 if both parents had an MI at age 50 or older.

The odds ratio was 2.36 for those patients with one parent who had an MI before age 50, but increased to 3.26 if both parents had an MI and one parent was younger than age 50. If both parents had an MI before age 50, the odds ratio reached 6.56.

The study results suggest that parental history of MI is an independent predictor of an individual’s risk of future MI – even after adjusting for age, sex, region, and other risk factors. The association between parental history of MI and MI is consistent across geographic regions, age, sex, and socioeconomic subgroups.

"While other studies have shown the relationship between parental history and risk, they have not established its independence from the extensive list of other potential explanatory factors, as measured by the INTERHEART Study, and not established it in other world regions or ethnic groups," the authors wrote.

The results raise another question: Are there factors other than shared risk factors and genetics that are involved in heart disease, such as early life exposures or home environmental factors? The genotype score obtained in the study analyses represents only a small percentage of possible genotype variants, the researchers noted.

The strengths of the study are its large international coverage; the large number of cases of MI; and the comprehensive measurement of risk factors, including genetic factors, the researchers said. Limitations included a lack of data collected from siblings or other relatives, limited measurement of SNPs in a limited number of individuals, and the possibility of recall biases due to the case-control nature of the study.

The researchers received support from the Royal Australasian College of Physicians, the National Health and Medical Research Council and National Heart Foundation of Australia, the Heart and Stroke Foundation of Ontario, the May Cohen Eli Lilly Chair in Women’s Health Research, and Michael G. DeGroote Heart and Stroke Foundation Chair in Population Health. The INTERHEART study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Ontario, and the International Clinical Epidemiology Network (INCLEN). Several pharmaceutical companies – particularly AstraZeneca, Novartis, Aventis, Abbott, Bristol-Myers Squibb, King Pharma, and Sanofi-Sythelabo – provided unrestricted research grants. Various national bodies in different countries also provided funding. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; or in the writing of the report.

Having a parent with a history of myocardial infarction nearly doubled a person's own risk of future MI, even after accounting for other risk factors, according to an analysis of a large case-control study.

The findings are consistent in all regions of the world, added the authors of the analysis.

INTERHEART, a multinational case-control study, involved 15,152 patients who presented with a first MI and 14,820 age- and sex-matched control subjects between February 1999 and March 2003. Previous analysis of the study identified nine variables for determining MI risk: abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, physical activity, fruit and vegetable consumption, and alcohol consumption.

The current analysis included 12,149 patients presenting with a first MI and 14,467 control subjects. Dr. Clara K. Chow of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, and her colleagues obtained data on demographic factors, socioeconomic status, and risk factors for all participants, and performed genetic analysis in 8,795 participants using a panel of 1,536 single nucleotide polymorphisms (SNPs) from 103 genes believed to be associated with MI or risk factors for MI (J. Am. Coll. Cardiol. 2011;57:619-27).

In 18.1% of cases and 12% of controls, either parent had a history of MI, while both parents had a history of MI in 2.1% of cases and 0.9% of controls. A maternal history of MI was present in 7.5% of cases and 4.9% of controls, while 12.7% of cases and 8.1% of controls had a paternal history of MI. There were no significant differences in the risks associated with history of MI in either parent.

The relationship between parental history and MI risk remained after adjusting for the nine INTERHEART risk factors.

Genetic risk scores also didn’t alter the relationship. The researchers calculated genotype scores for 3,372 cases and 4,043 controls, and found that the genetic risk scores were not greater in those with a parental history of MI than in those without. The mean genotype score was 11.90 in controls with no parental history of MI, 11.84 in controls with a parental history of MI, 12.26 in cases with no parental history of MI, and 12.14 in cases with a parental history of MI.

Parental history approximately doubled an individual’s risk of MI, and the risk increased if both parents had a history of MI, especially if it occurred at a younger age.

Specifically, the odds ratio of an individual having MI was 1.81 if either parent had a history of MI (1.74 after adjusting for other risk factors). When either parent had an MI at age 50 years or older, the odds ratio fell to 1.67 – but it rose to 2.90 if both parents had an MI at age 50 or older.

The odds ratio was 2.36 for those patients with one parent who had an MI before age 50, but increased to 3.26 if both parents had an MI and one parent was younger than age 50. If both parents had an MI before age 50, the odds ratio reached 6.56.

The study results suggest that parental history of MI is an independent predictor of an individual’s risk of future MI – even after adjusting for age, sex, region, and other risk factors. The association between parental history of MI and MI is consistent across geographic regions, age, sex, and socioeconomic subgroups.

"While other studies have shown the relationship between parental history and risk, they have not established its independence from the extensive list of other potential explanatory factors, as measured by the INTERHEART Study, and not established it in other world regions or ethnic groups," the authors wrote.

The results raise another question: Are there factors other than shared risk factors and genetics that are involved in heart disease, such as early life exposures or home environmental factors? The genotype score obtained in the study analyses represents only a small percentage of possible genotype variants, the researchers noted.

The strengths of the study are its large international coverage; the large number of cases of MI; and the comprehensive measurement of risk factors, including genetic factors, the researchers said. Limitations included a lack of data collected from siblings or other relatives, limited measurement of SNPs in a limited number of individuals, and the possibility of recall biases due to the case-control nature of the study.

The researchers received support from the Royal Australasian College of Physicians, the National Health and Medical Research Council and National Heart Foundation of Australia, the Heart and Stroke Foundation of Ontario, the May Cohen Eli Lilly Chair in Women’s Health Research, and Michael G. DeGroote Heart and Stroke Foundation Chair in Population Health. The INTERHEART study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Ontario, and the International Clinical Epidemiology Network (INCLEN). Several pharmaceutical companies – particularly AstraZeneca, Novartis, Aventis, Abbott, Bristol-Myers Squibb, King Pharma, and Sanofi-Sythelabo – provided unrestricted research grants. Various national bodies in different countries also provided funding. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; or in the writing of the report.

HOUSTON – Treatment with intravitreal bevacizumab monotherapy showed significant benefit over conventional laser treatment in infants with stage 3+ retinopathy of prematurity, according to results of the BEAT-ROP clinical trial as reported in the Feb. 17 issue of the New England Journal of Medicine.

However, timing of treatment is critical, and significant questions remain about the safety of using intravitreal bevacizumab in this population and the appropriate dose of the drug, according to the researchers.

Results of the BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) trial further showed significant efficacy of bevacizumab treatment for zone I – but not zone II – disease.

Bevacizumab works by inhibiting vascular endothelial growth factor (VEGF), a key factor in the progression of ROP. The drug has been approved by the Food and Drug Administration for the treatment of metastatic colorectal and other cancers, but has been used off label to treat neovascular ocular disorders, such as age-related macular degeneration. The drug has not been approved by the FDA for the use in this study.

To study its emerging use in the treatment of ROP, Dr. Helen A. Mintz-Hittner of the University of Texas, Houston, and colleagues conducted a prospective, controlled, randomized, stratified, multicenter trial in which they compared the outcomes of intravitreal bevacizumab monotherapy and conventional laser therapy for stage 3+ ROP (N. Engl. J. Med. 2011;364:603-15).

The researchers enrolled 150 infants with a birth weight of 1,500 g or less and a gestational age of 30 weeks or less beginning at 4 weeks’ chronological age or 31 weeks’ postmenstrual age, whichever was later, between March 13, 2008, and Aug. 4, 2010. A total of 67 infants had zone I disease and 83 had zone II posterior disease. The researchers randomized 75 infants each to receive intravitreal bevacizumab monotherapy (0.625 mg in 0.025 mL of solution) and conventional laser therapy.

Seven infants (five with bevacizumab treatment and two with laser treatment) died before reaching 54 weeks’ postmenstrual age and without having reached the primary outcome. This 1.5-fold greater death rate with bevacizumab could not be evaluated as to significance because the trial was too small. For an assessment of mortality at 5% significance and 80% power, a sample size of 2,800 patients would have had to have been studied, according to the authors. Although the researchers observed no systemic or local toxic effects that were attributable to the administration of bevacizumab, they stated that "an assessment of local or systemic toxicity would have required an even larger sample."

The researchers evaluated the 143 surviving infants for recurrence at 54 weeks’ postmenstrual age, and had photos that were taken at 54 weeks assessed by six independent experts.

For zones I and II disease combined, ROP recurred in 6% of infants (4 of 70) who received intravitreal bevacizumab, significantly lower than the recurrence in 26% of infants (19 of 73) who received conventional laser therapy. The difference was even more significant for zone I disease alone: ROP recurred in 6% of infants (2 of 21) who received bevacizumab vs. 42% of infants (14 of 33) of infants who received conventional laser treatment. There was little significant treatment effect for zone II posterior disease alone, however, with recurrence in 12% of infants (5 of 40) in the laser group vs. 5% of the bevacizumab group.

Also, conventional laser therapy permanently destroyed vessels in the peripheral retina, whereas bevacizumab allowed continued vessel growth into the peripheral retina, the researchers found.

Nevertheless, they say, "safety is the primary reason for exercising caution when considering the use of intravitreal bevacizumab in the treatment of neonates. Both mortality and morbidity must be considered."

In addition, further research is necessary to determine an ideal dosage of bevacizumab for treating ROP, as well as the duration and frequency of follow-up and the management of recurrence.

In an editorial accompanying the article, Dr. James D. Reynolds of the Ross Eye Institute at the State University of New York at Buffalo favored the use of intravitreal bevacizumab (N. Engl. J. Med. 2011;364:677-8).

The results of the BEAT-ROP trial suggest that intravitreal bevacizumab monotherapy appears to be far safer and more effective than conventional laser for treating retinopathy of prematurity. These findings suggest that bevacizumab may represent a real breakthrough in treating this disease, he said.

Dr. Reynolds pointed out that intravitreal bevacizumab has numerous advantages, including simplicity of administration, a rapid effect, decreased loss of visual field compared with conventional laser treatment, and continued normal retinal vascularization.

However, the timing is critical, he added. If treatment is administered too early, it may interfere with necessary retinal vascularization. Treatment that occurs too late may accelerate the cicatricial phase of ROP, leading to early retinal detachment.

Also, intravitreal bevacizumab reaches the systemic circulation, which raises concern about untoward effects on an infant’s developing organs. Although there are no documented instances of this, a much larger sample size than that of this study is necessary to determine the statistical safety of the drug in premature infants. The dose of intravitreal bevacizumab is a fraction of the dose used for cancer treatment, and the amount of circulating bevacizumab is very small. "Bearing in mind the pharmacokinetics of bevacizumab, the extensive experience of adults taking this drug, and [the results of this study], it seems reasonable to assume that intravitreal bevacizumab is safe. However, continued vigilance will be important as use of the drug continues," Dr. Reynolds wrote.

"As our experience with bevacizumab grows, its indications and relative contraindications will be refined. In the meantime, intravitreal bevacizumab should become the treatment of choice in premature infants," Dr. Reynolds concluded.

The BEAT-ROP study was supported by grants from Research to Prevent Blindness, the U.S. National Eye Institute, and the Hermann Eye Fund as well as research funds from the Alfred W. Lasher III Professorship and a grant from the center for clinical and translational science at the University of Texas Health Science Center in Houston. Helen A. Mintz-Hittner, the corresponding author, receives honoraria from the Bascom Palmer Eye Institute and Clarity Medical Systems, as well as from testifying as an expert witness in a retinopathy of prematurity suit.

Dr. Reynolds received payment as an expert witness in trials concerning treatment of ROP from various legal firms and royalties for an up-to-date glaucoma chapter.

HOUSTON – Treatment with intravitreal bevacizumab monotherapy showed significant benefit over conventional laser treatment in infants with stage 3+ retinopathy of prematurity, according to results of the BEAT-ROP clinical trial as reported in the Feb. 17 issue of the New England Journal of Medicine.

However, timing of treatment is critical, and significant questions remain about the safety of using intravitreal bevacizumab in this population and the appropriate dose of the drug, according to the researchers.

Results of the BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) trial further showed significant efficacy of bevacizumab treatment for zone I – but not zone II – disease.

Bevacizumab works by inhibiting vascular endothelial growth factor (VEGF), a key factor in the progression of ROP. The drug has been approved by the Food and Drug Administration for the treatment of metastatic colorectal and other cancers, but has been used off label to treat neovascular ocular disorders, such as age-related macular degeneration. The drug has not been approved by the FDA for the use in this study.

To study its emerging use in the treatment of ROP, Dr. Helen A. Mintz-Hittner of the University of Texas, Houston, and colleagues conducted a prospective, controlled, randomized, stratified, multicenter trial in which they compared the outcomes of intravitreal bevacizumab monotherapy and conventional laser therapy for stage 3+ ROP (N. Engl. J. Med. 2011;364:603-15).

The researchers enrolled 150 infants with a birth weight of 1,500 g or less and a gestational age of 30 weeks or less beginning at 4 weeks’ chronological age or 31 weeks’ postmenstrual age, whichever was later, between March 13, 2008, and Aug. 4, 2010. A total of 67 infants had zone I disease and 83 had zone II posterior disease. The researchers randomized 75 infants each to receive intravitreal bevacizumab monotherapy (0.625 mg in 0.025 mL of solution) and conventional laser therapy.

Seven infants (five with bevacizumab treatment and two with laser treatment) died before reaching 54 weeks’ postmenstrual age and without having reached the primary outcome. This 1.5-fold greater death rate with bevacizumab could not be evaluated as to significance because the trial was too small. For an assessment of mortality at 5% significance and 80% power, a sample size of 2,800 patients would have had to have been studied, according to the authors. Although the researchers observed no systemic or local toxic effects that were attributable to the administration of bevacizumab, they stated that "an assessment of local or systemic toxicity would have required an even larger sample."

The researchers evaluated the 143 surviving infants for recurrence at 54 weeks’ postmenstrual age, and had photos that were taken at 54 weeks assessed by six independent experts.

For zones I and II disease combined, ROP recurred in 6% of infants (4 of 70) who received intravitreal bevacizumab, significantly lower than the recurrence in 26% of infants (19 of 73) who received conventional laser therapy. The difference was even more significant for zone I disease alone: ROP recurred in 6% of infants (2 of 21) who received bevacizumab vs. 42% of infants (14 of 33) of infants who received conventional laser treatment. There was little significant treatment effect for zone II posterior disease alone, however, with recurrence in 12% of infants (5 of 40) in the laser group vs. 5% of the bevacizumab group.

Also, conventional laser therapy permanently destroyed vessels in the peripheral retina, whereas bevacizumab allowed continued vessel growth into the peripheral retina, the researchers found.

Nevertheless, they say, "safety is the primary reason for exercising caution when considering the use of intravitreal bevacizumab in the treatment of neonates. Both mortality and morbidity must be considered."

In addition, further research is necessary to determine an ideal dosage of bevacizumab for treating ROP, as well as the duration and frequency of follow-up and the management of recurrence.

In an editorial accompanying the article, Dr. James D. Reynolds of the Ross Eye Institute at the State University of New York at Buffalo favored the use of intravitreal bevacizumab (N. Engl. J. Med. 2011;364:677-8).

The results of the BEAT-ROP trial suggest that intravitreal bevacizumab monotherapy appears to be far safer and more effective than conventional laser for treating retinopathy of prematurity. These findings suggest that bevacizumab may represent a real breakthrough in treating this disease, he said.

Dr. Reynolds pointed out that intravitreal bevacizumab has numerous advantages, including simplicity of administration, a rapid effect, decreased loss of visual field compared with conventional laser treatment, and continued normal retinal vascularization.

However, the timing is critical, he added. If treatment is administered too early, it may interfere with necessary retinal vascularization. Treatment that occurs too late may accelerate the cicatricial phase of ROP, leading to early retinal detachment.

Also, intravitreal bevacizumab reaches the systemic circulation, which raises concern about untoward effects on an infant’s developing organs. Although there are no documented instances of this, a much larger sample size than that of this study is necessary to determine the statistical safety of the drug in premature infants. The dose of intravitreal bevacizumab is a fraction of the dose used for cancer treatment, and the amount of circulating bevacizumab is very small. "Bearing in mind the pharmacokinetics of bevacizumab, the extensive experience of adults taking this drug, and [the results of this study], it seems reasonable to assume that intravitreal bevacizumab is safe. However, continued vigilance will be important as use of the drug continues," Dr. Reynolds wrote.

"As our experience with bevacizumab grows, its indications and relative contraindications will be refined. In the meantime, intravitreal bevacizumab should become the treatment of choice in premature infants," Dr. Reynolds concluded.

The BEAT-ROP study was supported by grants from Research to Prevent Blindness, the U.S. National Eye Institute, and the Hermann Eye Fund as well as research funds from the Alfred W. Lasher III Professorship and a grant from the center for clinical and translational science at the University of Texas Health Science Center in Houston. Helen A. Mintz-Hittner, the corresponding author, receives honoraria from the Bascom Palmer Eye Institute and Clarity Medical Systems, as well as from testifying as an expert witness in a retinopathy of prematurity suit.

Dr. Reynolds received payment as an expert witness in trials concerning treatment of ROP from various legal firms and royalties for an up-to-date glaucoma chapter.

HOUSTON – Treatment with intravitreal bevacizumab monotherapy showed significant benefit over conventional laser treatment in infants with stage 3+ retinopathy of prematurity, according to results of the BEAT-ROP clinical trial as reported in the Feb. 17 issue of the New England Journal of Medicine.

However, timing of treatment is critical, and significant questions remain about the safety of using intravitreal bevacizumab in this population and the appropriate dose of the drug, according to the researchers.

Results of the BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) trial further showed significant efficacy of bevacizumab treatment for zone I – but not zone II – disease.

Bevacizumab works by inhibiting vascular endothelial growth factor (VEGF), a key factor in the progression of ROP. The drug has been approved by the Food and Drug Administration for the treatment of metastatic colorectal and other cancers, but has been used off label to treat neovascular ocular disorders, such as age-related macular degeneration. The drug has not been approved by the FDA for the use in this study.

To study its emerging use in the treatment of ROP, Dr. Helen A. Mintz-Hittner of the University of Texas, Houston, and colleagues conducted a prospective, controlled, randomized, stratified, multicenter trial in which they compared the outcomes of intravitreal bevacizumab monotherapy and conventional laser therapy for stage 3+ ROP (N. Engl. J. Med. 2011;364:603-15).

The researchers enrolled 150 infants with a birth weight of 1,500 g or less and a gestational age of 30 weeks or less beginning at 4 weeks’ chronological age or 31 weeks’ postmenstrual age, whichever was later, between March 13, 2008, and Aug. 4, 2010. A total of 67 infants had zone I disease and 83 had zone II posterior disease. The researchers randomized 75 infants each to receive intravitreal bevacizumab monotherapy (0.625 mg in 0.025 mL of solution) and conventional laser therapy.

Seven infants (five with bevacizumab treatment and two with laser treatment) died before reaching 54 weeks’ postmenstrual age and without having reached the primary outcome. This 1.5-fold greater death rate with bevacizumab could not be evaluated as to significance because the trial was too small. For an assessment of mortality at 5% significance and 80% power, a sample size of 2,800 patients would have had to have been studied, according to the authors. Although the researchers observed no systemic or local toxic effects that were attributable to the administration of bevacizumab, they stated that "an assessment of local or systemic toxicity would have required an even larger sample."

The researchers evaluated the 143 surviving infants for recurrence at 54 weeks’ postmenstrual age, and had photos that were taken at 54 weeks assessed by six independent experts.

For zones I and II disease combined, ROP recurred in 6% of infants (4 of 70) who received intravitreal bevacizumab, significantly lower than the recurrence in 26% of infants (19 of 73) who received conventional laser therapy. The difference was even more significant for zone I disease alone: ROP recurred in 6% of infants (2 of 21) who received bevacizumab vs. 42% of infants (14 of 33) of infants who received conventional laser treatment. There was little significant treatment effect for zone II posterior disease alone, however, with recurrence in 12% of infants (5 of 40) in the laser group vs. 5% of the bevacizumab group.

Also, conventional laser therapy permanently destroyed vessels in the peripheral retina, whereas bevacizumab allowed continued vessel growth into the peripheral retina, the researchers found.

Nevertheless, they say, "safety is the primary reason for exercising caution when considering the use of intravitreal bevacizumab in the treatment of neonates. Both mortality and morbidity must be considered."

In addition, further research is necessary to determine an ideal dosage of bevacizumab for treating ROP, as well as the duration and frequency of follow-up and the management of recurrence.

In an editorial accompanying the article, Dr. James D. Reynolds of the Ross Eye Institute at the State University of New York at Buffalo favored the use of intravitreal bevacizumab (N. Engl. J. Med. 2011;364:677-8).

The results of the BEAT-ROP trial suggest that intravitreal bevacizumab monotherapy appears to be far safer and more effective than conventional laser for treating retinopathy of prematurity. These findings suggest that bevacizumab may represent a real breakthrough in treating this disease, he said.

Dr. Reynolds pointed out that intravitreal bevacizumab has numerous advantages, including simplicity of administration, a rapid effect, decreased loss of visual field compared with conventional laser treatment, and continued normal retinal vascularization.

However, the timing is critical, he added. If treatment is administered too early, it may interfere with necessary retinal vascularization. Treatment that occurs too late may accelerate the cicatricial phase of ROP, leading to early retinal detachment.

Also, intravitreal bevacizumab reaches the systemic circulation, which raises concern about untoward effects on an infant’s developing organs. Although there are no documented instances of this, a much larger sample size than that of this study is necessary to determine the statistical safety of the drug in premature infants. The dose of intravitreal bevacizumab is a fraction of the dose used for cancer treatment, and the amount of circulating bevacizumab is very small. "Bearing in mind the pharmacokinetics of bevacizumab, the extensive experience of adults taking this drug, and [the results of this study], it seems reasonable to assume that intravitreal bevacizumab is safe. However, continued vigilance will be important as use of the drug continues," Dr. Reynolds wrote.

"As our experience with bevacizumab grows, its indications and relative contraindications will be refined. In the meantime, intravitreal bevacizumab should become the treatment of choice in premature infants," Dr. Reynolds concluded.

The BEAT-ROP study was supported by grants from Research to Prevent Blindness, the U.S. National Eye Institute, and the Hermann Eye Fund as well as research funds from the Alfred W. Lasher III Professorship and a grant from the center for clinical and translational science at the University of Texas Health Science Center in Houston. Helen A. Mintz-Hittner, the corresponding author, receives honoraria from the Bascom Palmer Eye Institute and Clarity Medical Systems, as well as from testifying as an expert witness in a retinopathy of prematurity suit.

Dr. Reynolds received payment as an expert witness in trials concerning treatment of ROP from various legal firms and royalties for an up-to-date glaucoma chapter.

Major Finding: Larger central retinal venular diameter is an independent and early indicator of progression to proliferative diabetic retinopathy with or without high-risk characteristics in black patients with type 1 diabetes mellitus.

Data Source: A 6-year follow-up evaluation of a cohort of 468 black patients from the New Jersey 725 study.

Disclosures: The authors had no financial disclosures. The research was supported by grants from the National Eye Institute and by a Lew Wasserman Merit Award from Research to Prevent Blindness Inc.

Central retinal venular diameter may help predict the progression of retinal disease in black patients with type 1 diabetes, especially those with less-severe baseline diabetic retinopathy, according to the results of a cohort substudy.

These results may lead to another early clinical indicator for progression to more severe forms.

Dilation of the retinal venules has been associated with diabetic retinopathy, but cross-sectional studies have not indicated whether these changes simply reflect disease severity or if they may help predict progression of diabetic retinopathy.

Dr. Monique S. Roy of the New Jersey Medical School, Newark, and her colleagues examined 725 black patients with type 1 diabetes who participated in the New Jersey 725 study in 1993-1998, and reexamined a cohort of 468 of these patients 6 years later (Arch. Ophthalmol. 2011;129:8-15). The exams included seven-field retinal photographs that were evaluated in a masked fashion. Also, graders used a computer-assisted technique to measure retinal vessel diameters.

In the 468 follow-up patients, the mean central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were 168.8 mcm and 254.2 mcm, respectively. The study found no association between CRAE and incident diabetic retinopathy outcomes, even after adjustment for other risk factors. However, increasing CRVE at baseline was associated with triple the risk of progression to proliferative diabetic retinopathy, or to proliferative diabetic retinopathy with high-risk characteristics, even when researchers adjusted for other risk factors.

“The relative dilation of the retinal veins seen in diabetic retinopathy and other retinopathies associated with ischemia has been variously interpreted,” the researchers said.

“Wider retinal venules may reflect metabolic changes associated with [diabetes mellitus], such as increased lactic acidosis,” they added.

Strengths of the study include its prospective design with high rates of follow-up for a large cohort of well-characterized black patients with type 1 diabetes, the use of standardized protocols to document potential confounding variables, the masked grading of diabetic retinopathy using stereoscopic seven-field retinal photographs, and measurements of the retinal vascular diameters with a validated computerized program, the researchers said.

However, they cautioned that measurement of retinal vessel diameter from color retinal photographs may underestimate the true vascular width because only the red blood cell column is being measured. Also, the increased retinal pigmentation that is present in blacks may lead to an overestimation of retinal diameter sizes.

“It remains to be seen whether such a measure may be used in the future to monitor treatments for [diabetes] and other vascular diseases that specifically target the microvasculature,” the researchers noted.

Major Finding: Larger central retinal venular diameter is an independent and early indicator of progression to proliferative diabetic retinopathy with or without high-risk characteristics in black patients with type 1 diabetes mellitus.

Data Source: A 6-year follow-up evaluation of a cohort of 468 black patients from the New Jersey 725 study.

Disclosures: The authors had no financial disclosures. The research was supported by grants from the National Eye Institute and by a Lew Wasserman Merit Award from Research to Prevent Blindness Inc.

Central retinal venular diameter may help predict the progression of retinal disease in black patients with type 1 diabetes, especially those with less-severe baseline diabetic retinopathy, according to the results of a cohort substudy.

These results may lead to another early clinical indicator for progression to more severe forms.

Dilation of the retinal venules has been associated with diabetic retinopathy, but cross-sectional studies have not indicated whether these changes simply reflect disease severity or if they may help predict progression of diabetic retinopathy.

Dr. Monique S. Roy of the New Jersey Medical School, Newark, and her colleagues examined 725 black patients with type 1 diabetes who participated in the New Jersey 725 study in 1993-1998, and reexamined a cohort of 468 of these patients 6 years later (Arch. Ophthalmol. 2011;129:8-15). The exams included seven-field retinal photographs that were evaluated in a masked fashion. Also, graders used a computer-assisted technique to measure retinal vessel diameters.

In the 468 follow-up patients, the mean central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were 168.8 mcm and 254.2 mcm, respectively. The study found no association between CRAE and incident diabetic retinopathy outcomes, even after adjustment for other risk factors. However, increasing CRVE at baseline was associated with triple the risk of progression to proliferative diabetic retinopathy, or to proliferative diabetic retinopathy with high-risk characteristics, even when researchers adjusted for other risk factors.

“The relative dilation of the retinal veins seen in diabetic retinopathy and other retinopathies associated with ischemia has been variously interpreted,” the researchers said.

“Wider retinal venules may reflect metabolic changes associated with [diabetes mellitus], such as increased lactic acidosis,” they added.

Strengths of the study include its prospective design with high rates of follow-up for a large cohort of well-characterized black patients with type 1 diabetes, the use of standardized protocols to document potential confounding variables, the masked grading of diabetic retinopathy using stereoscopic seven-field retinal photographs, and measurements of the retinal vascular diameters with a validated computerized program, the researchers said.

However, they cautioned that measurement of retinal vessel diameter from color retinal photographs may underestimate the true vascular width because only the red blood cell column is being measured. Also, the increased retinal pigmentation that is present in blacks may lead to an overestimation of retinal diameter sizes.

“It remains to be seen whether such a measure may be used in the future to monitor treatments for [diabetes] and other vascular diseases that specifically target the microvasculature,” the researchers noted.

Major Finding: Larger central retinal venular diameter is an independent and early indicator of progression to proliferative diabetic retinopathy with or without high-risk characteristics in black patients with type 1 diabetes mellitus.

Data Source: A 6-year follow-up evaluation of a cohort of 468 black patients from the New Jersey 725 study.

Disclosures: The authors had no financial disclosures. The research was supported by grants from the National Eye Institute and by a Lew Wasserman Merit Award from Research to Prevent Blindness Inc.

Central retinal venular diameter may help predict the progression of retinal disease in black patients with type 1 diabetes, especially those with less-severe baseline diabetic retinopathy, according to the results of a cohort substudy.

These results may lead to another early clinical indicator for progression to more severe forms.

Dilation of the retinal venules has been associated with diabetic retinopathy, but cross-sectional studies have not indicated whether these changes simply reflect disease severity or if they may help predict progression of diabetic retinopathy.

Dr. Monique S. Roy of the New Jersey Medical School, Newark, and her colleagues examined 725 black patients with type 1 diabetes who participated in the New Jersey 725 study in 1993-1998, and reexamined a cohort of 468 of these patients 6 years later (Arch. Ophthalmol. 2011;129:8-15). The exams included seven-field retinal photographs that were evaluated in a masked fashion. Also, graders used a computer-assisted technique to measure retinal vessel diameters.

In the 468 follow-up patients, the mean central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were 168.8 mcm and 254.2 mcm, respectively. The study found no association between CRAE and incident diabetic retinopathy outcomes, even after adjustment for other risk factors. However, increasing CRVE at baseline was associated with triple the risk of progression to proliferative diabetic retinopathy, or to proliferative diabetic retinopathy with high-risk characteristics, even when researchers adjusted for other risk factors.

“The relative dilation of the retinal veins seen in diabetic retinopathy and other retinopathies associated with ischemia has been variously interpreted,” the researchers said.

“Wider retinal venules may reflect metabolic changes associated with [diabetes mellitus], such as increased lactic acidosis,” they added.

Strengths of the study include its prospective design with high rates of follow-up for a large cohort of well-characterized black patients with type 1 diabetes, the use of standardized protocols to document potential confounding variables, the masked grading of diabetic retinopathy using stereoscopic seven-field retinal photographs, and measurements of the retinal vascular diameters with a validated computerized program, the researchers said.

However, they cautioned that measurement of retinal vessel diameter from color retinal photographs may underestimate the true vascular width because only the red blood cell column is being measured. Also, the increased retinal pigmentation that is present in blacks may lead to an overestimation of retinal diameter sizes.

“It remains to be seen whether such a measure may be used in the future to monitor treatments for [diabetes] and other vascular diseases that specifically target the microvasculature,” the researchers noted.