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Possible autoimmune enteropathy found in autistic children
SCIENCE AND MEDICINE
Intranasal delivery could be used to administer drugs directly to the brain melanocortin and insulin were transported directly to the brain,
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
A quick drug delivery system?
thus bypassing the blood–brain barrier (Nat Neurosci; published online 6 May 2002; DOI: 10.1038/ nn849). Although it is difficult to control how much of the drug reaches the cerebrospinal fluid, intranasal administration of drugs such as neuropeptides offers an advantage over traditional treatment methods, Born says. “Since many neuropeptides share structural similarities with hormones, they usually have considerable hormonal side-effects
Science Photo Library
octors who treat patients with a diverse array of problems such as stroke, Alzheimer’s disease, or traumatic brain or spinal cord injury struggle with one seemingly intractable problem: how to deliver drugs quickly to the brain. A new study by a team of international researchers bolsters the case for a pathway proposed in the past few years—go through the nose. Jan Born (University of Lübeck, Germany) and co-workers administered three peptides, melanocortin(4–10), vasopressin, and insulin—all of which are known for their effects on the brain—to healthy human beings using an intranasal spray. Concentrations of the peptides were measured in participants’ cerebrospinal fluid and blood before administration and then periodically for 80 min afterwards. Peptide concentrations were increased in the cerebrospinal fluid within minutes after nasal administration. With the exception of vasopressin, however, raised concentrations were not detected in the blood, suggesting that
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when they enter the blood”, he notes. “With nasal administration, the amount entering the blood can be distinctly reduced to the advantage of a greater amount reaching the brain.” Intranasal administration of drugs offers several other advantages, adds William H Frey (Director, Alzheimer’s Research Center, Regions Hospital, St Paul, MN, USA). “This is a very important paper which clearly demonstrates the potential usefulness of non-invasive intranasal delivery of protein therapeutic agents to the central nervous system”, he says. “In combination with published work from other laboratories which has demonstrated direct delivery of protein therapeutic agents, such as [nerve growth factor], from the nose to the parenchyma of the brain, this paper is even more significant.” “Further research will show whether or not intranasal delivery will help to treat these and other central nervous system disorders”, adds Frey David Lawrence
Possible autoimmune enteropathy found in autistic children
A
team of UK researchers has found evidence supporting an autoimmune basis for bowel abnormalities in children with autism. The investigators reported IgG binding to the epithelial cell surface, lymphocyte infiltration, and increased crypt cell proliferation in the small bowel of children with autism. “These features raise the possibility of autoimmunity in severe autism”, concludes Julio Licinio (University of California, Los Angeles, CA, USA) in an accompanying editorial (Mol Psych 2002; 7: 329). Simon Murch (Royal Free and University College Medical School, London, UK) and colleagues studied intestinal samples from 25 autistic children with small intestine lesions using various immunochemical techniques. For comparison, they also used samples obtained from 18 normal controls, 11 children with coeliac disease, and five children with cerebral palsy. Routine staining showed only minor differences between autistic children and controls, but immunochemistry highlighted
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striking abnormalities in the group with autism. The density of CD8 intraepithelial lymphocytes was significantly greater in autistic children than in normal controls or children with cerebral palsy, but was was not as high as in children with coeliac disease. Autistic children also showed a higher density of excess T cell infiltration within the lamina propria than any other group. However, the most striking finding was the deposition of IgG1 and IgG4 on the basolateral enterocyte membrane and the subepithelial basement membrane in 23 of 25 autistic children, but in none of the other groups. In some, deposition was patchy and incomplete; in others it was striking and extensive (Mol Psych 2002; 7: 375–82). “Intestinal inflammation genuinely does occur in at least a proportion of autistic children”, concludes Murch. However, he says that the big question is whether such unexpected gut involvement either causes or exacerbates the cognitive abnormalities that typify autism. “If the answer is yes, this may point towards the logical use of
immune-based therapy in future children at the time of first regression”, he says. An important next step towards understanding the significance of intestinal abnormalities to autism will be to find out whether localisation of IgG represents specific binding to an individual epithelial antigen, and if so the identification of this antigen. Other questions still to be answered relate to lymphocytic infiltration, which is apparently panenteric. “Follow-up research has indicated that these autistic children show enhanced spontaneous tumour necrosis factor production by duodenal and colonic lymphocytes and evidence of focal lymphocytic gastritis”, reports Murch. In the meantime, he doubts that the histological findings can be used to aid diagnosis of autism. “The straightforward histology is too subtle for routine diagnosis, but the same was true for H pylori infection for many years; maybe we’ll get better at pattern recognition”, he says. Kathryn Senior
THE LANCET • Vol 359 • May 11, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Intranasal delivery could be used to administer drugs directly to the brain melanocortin and insulin were transported directly to the brain,
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
A quick drug delivery system?
thus bypassing the blood–brain barrier (Nat Neurosci; published online 6 May 2002; DOI: 10.1038/ nn849). Although it is difficult to control how much of the drug reaches the cerebrospinal fluid, intranasal administration of drugs such as neuropeptides offers an advantage over traditional treatment methods, Born says. “Since many neuropeptides share structural similarities with hormones, they usually have considerable hormonal side-effects
Science Photo Library
octors who treat patients with a diverse array of problems such as stroke, Alzheimer’s disease, or traumatic brain or spinal cord injury struggle with one seemingly intractable problem: how to deliver drugs quickly to the brain. A new study by a team of international researchers bolsters the case for a pathway proposed in the past few years—go through the nose. Jan Born (University of Lübeck, Germany) and co-workers administered three peptides, melanocortin(4–10), vasopressin, and insulin—all of which are known for their effects on the brain—to healthy human beings using an intranasal spray. Concentrations of the peptides were measured in participants’ cerebrospinal fluid and blood before administration and then periodically for 80 min afterwards. Peptide concentrations were increased in the cerebrospinal fluid within minutes after nasal administration. With the exception of vasopressin, however, raised concentrations were not detected in the blood, suggesting that
D
when they enter the blood”, he notes. “With nasal administration, the amount entering the blood can be distinctly reduced to the advantage of a greater amount reaching the brain.” Intranasal administration of drugs offers several other advantages, adds William H Frey (Director, Alzheimer’s Research Center, Regions Hospital, St Paul, MN, USA). “This is a very important paper which clearly demonstrates the potential usefulness of non-invasive intranasal delivery of protein therapeutic agents to the central nervous system”, he says. “In combination with published work from other laboratories which has demonstrated direct delivery of protein therapeutic agents, such as [nerve growth factor], from the nose to the parenchyma of the brain, this paper is even more significant.” “Further research will show whether or not intranasal delivery will help to treat these and other central nervous system disorders”, adds Frey David Lawrence
Possible autoimmune enteropathy found in autistic children
A
team of UK researchers has found evidence supporting an autoimmune basis for bowel abnormalities in children with autism. The investigators reported IgG binding to the epithelial cell surface, lymphocyte infiltration, and increased crypt cell proliferation in the small bowel of children with autism. “These features raise the possibility of autoimmunity in severe autism”, concludes Julio Licinio (University of California, Los Angeles, CA, USA) in an accompanying editorial (Mol Psych 2002; 7: 329). Simon Murch (Royal Free and University College Medical School, London, UK) and colleagues studied intestinal samples from 25 autistic children with small intestine lesions using various immunochemical techniques. For comparison, they also used samples obtained from 18 normal controls, 11 children with coeliac disease, and five children with cerebral palsy. Routine staining showed only minor differences between autistic children and controls, but immunochemistry highlighted
1674
striking abnormalities in the group with autism. The density of CD8 intraepithelial lymphocytes was significantly greater in autistic children than in normal controls or children with cerebral palsy, but was was not as high as in children with coeliac disease. Autistic children also showed a higher density of excess T cell infiltration within the lamina propria than any other group. However, the most striking finding was the deposition of IgG1 and IgG4 on the basolateral enterocyte membrane and the subepithelial basement membrane in 23 of 25 autistic children, but in none of the other groups. In some, deposition was patchy and incomplete; in others it was striking and extensive (Mol Psych 2002; 7: 375–82). “Intestinal inflammation genuinely does occur in at least a proportion of autistic children”, concludes Murch. However, he says that the big question is whether such unexpected gut involvement either causes or exacerbates the cognitive abnormalities that typify autism. “If the answer is yes, this may point towards the logical use of
immune-based therapy in future children at the time of first regression”, he says. An important next step towards understanding the significance of intestinal abnormalities to autism will be to find out whether localisation of IgG represents specific binding to an individual epithelial antigen, and if so the identification of this antigen. Other questions still to be answered relate to lymphocytic infiltration, which is apparently panenteric. “Follow-up research has indicated that these autistic children show enhanced spontaneous tumour necrosis factor production by duodenal and colonic lymphocytes and evidence of focal lymphocytic gastritis”, reports Murch. In the meantime, he doubts that the histological findings can be used to aid diagnosis of autism. “The straightforward histology is too subtle for routine diagnosis, but the same was true for H pylori infection for many years; maybe we’ll get better at pattern recognition”, he says. Kathryn Senior
THE LANCET • Vol 359 • May 11, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.