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Zinc cuts childhood respiratory infections
SCIENCE AND MEDICINE
Cancer molecules reveal their mechanisms “gain-of-function” p53 mutation that he tenth Pezcoller Symposium leads to genetic instability, she conwas about the genetics of cancer cluded, is an additional mechanism susceptibility (Trento, Italy; June to the classic loss of the tumour29–July 1). The “downstream” suppressor activity of this protein. events after activation of the p53 Joseph F Fraumeni Jr (National protein include arrest of the cell cycle Cancer Institute, Bethesda, MD, or apoptosis. Carol Prives (Columbia USA) reminded the meeting of University, NY, USA) has been the importance of the interaction studying “upstream” signalling to between polymorphic p53. She found that the cancer-susceptibility negative regulator progenes, which usually tein MDM2 binds to confer low relative and p53 and inhibits downabsolute risk, and stream events. In this environmental expomodel (figure), DNA sure, which can lead damage leads to phosto high populationphorylation and a attributable risk. conformational change Heavy drinkers of in the MDM2-binding alcohol, for example, site, such that reduced who are homozygous binding of MDM2 now for the 1-1 genotype of allows the p53 protein alcohol dehydrogenase to escape into its rapidly accumulate postactivation cascade. acetaldehyde (which is Thea D Tlsty of the carcinogenic in aniUniversity of California MDM2 binding to p53 mals) and are at high at San Francisco (CA, risk of oral cancer. But, as Fraumeni USA) is investigating checkpoint pointed out, the implications of controls in the cell cycle. In fibrounderstanding gene–environment blasts from people with Li-Fraumeni interactions for cancer prevention, syndrome, she found that class II prediction, screening, and treatment mutations in p53 (which alter conforremain unclear. mation of the protein) affect the spindle-assembly checkpoint and so allow accumulation of polyploid cells. This David McNamee
T
Zinc cuts childhood respiratory infections study done in India has shown that zinc supplements cut the incidence of acute lower-respiratory infection (ALRI) in young children by as much as 45%. Sunil Sazawal and co-workers from the All India Institute of Medical Sciences in New Delhi and Johns Hopkins School of Public Health (Baltimore, MD, USA) randomly assigned 609 children to receive either a daily multivitamin supplement or a multivitamin supplement plus elemental zinc 10 mg for 6 months (Pediatrics 1998; 102: 1–5). Field workers administered supplements daily while another team visited the families every 5 days to ask if the children had had fever, cough, or difficulty breathing in the preceding 5 days. Children with raised respiratory rates were treated with antibiotics. 24 episodes of ALRI occurred in the zinc group compared with 44 episodes in the control group, a 45% reduction (odds ratio 0·55, 95% CI 0·33–0·90; p=0·02). These findings, plus other known benefits of zinc on immunity, growth, &c, “indicate that interventions to improve zinc intake deserve more attention as means to improve child health”, they conclude.
A
Michael McCarthy
US FDA warns doctors to use cisapride as last resort only
T
he US FDA warned physicians on June 29 against use of the gastric-emptying drug cisapride (Propulsid; Janssen) except as a last resort. The recommendation came after new information linked cisapride to severe cardiac events such as arrhythmia.
Since 1993, FDA has received reports of 38 deaths in US patients taking cisapride. The deaths were not definitely linked to cisapride, but enough concern existed to issue a warning, said FDA. Cisapride should not be taken in conjunction with specified drugs or by very ill
patients, such as those with heart failure, advanced cancer, severe dehydration, or malnutrition. The warning comes as FDA’s postmarketing surveillance is under scrutiny. Some say it is too lax. Alicia Ault
Lithium’s mood-stabilising mechanism could point way to new drugs ithium effectively curbs extreme moods in patients with bipolar disorder by stabilising glutamate uptake into presynaptic nerve endings, says Lowell Hokin of the University of Wisconsin Medical School (Madison, WI, USA). Abnormally low glutamate concentrations are associated with depression, he suggests, while high values are associated with mania. The drug “exerts a push/pull effect on glutamate” to bring values within a narrow, normal range, says Hokin. Hokin and co-workers showed that
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acute exposure to lithium inhibited glutamate uptake in mouse cerebral cortex, whereas chronic (2 weeks’) treatment resulted in upregulation of glutamate uptake, which would “tend to exert an antimanic effect”, notes Hokin. “Perhaps the most exciting finding was that if you look at the glutamate-uptake mechanism in [untreated] control mice, there’s quite a wide range, which is just a normal distribution, since mice vary in aggressiveness and passivity anyway, just like people”; in lithium-treated mice, glutamate uptake was stabilised within
“a very narrow range” (Proc Natl Acad Sci USA 1998; 95: 8363–68). Fine-tuning this compensatory mechanism takes time, which could explain why, clinically, “it takes a few weeks before lithium begins to relieve depression and mania in patients”, adds Hokin. Because lithium’s effective dose is very near the toxic dose, screening drugs for glutamatereuptake inhibition could identify new mood-stabilising drugs with fewer side-effects. Marilynn Larkin
THE LANCET • Vol 352 • July 11, 1998
Cancer molecules reveal their mechanisms “gain-of-function” p53 mutation that he tenth Pezcoller Symposium leads to genetic instability, she conwas about the genetics of cancer cluded, is an additional mechanism susceptibility (Trento, Italy; June to the classic loss of the tumour29–July 1). The “downstream” suppressor activity of this protein. events after activation of the p53 Joseph F Fraumeni Jr (National protein include arrest of the cell cycle Cancer Institute, Bethesda, MD, or apoptosis. Carol Prives (Columbia USA) reminded the meeting of University, NY, USA) has been the importance of the interaction studying “upstream” signalling to between polymorphic p53. She found that the cancer-susceptibility negative regulator progenes, which usually tein MDM2 binds to confer low relative and p53 and inhibits downabsolute risk, and stream events. In this environmental expomodel (figure), DNA sure, which can lead damage leads to phosto high populationphorylation and a attributable risk. conformational change Heavy drinkers of in the MDM2-binding alcohol, for example, site, such that reduced who are homozygous binding of MDM2 now for the 1-1 genotype of allows the p53 protein alcohol dehydrogenase to escape into its rapidly accumulate postactivation cascade. acetaldehyde (which is Thea D Tlsty of the carcinogenic in aniUniversity of California MDM2 binding to p53 mals) and are at high at San Francisco (CA, risk of oral cancer. But, as Fraumeni USA) is investigating checkpoint pointed out, the implications of controls in the cell cycle. In fibrounderstanding gene–environment blasts from people with Li-Fraumeni interactions for cancer prevention, syndrome, she found that class II prediction, screening, and treatment mutations in p53 (which alter conforremain unclear. mation of the protein) affect the spindle-assembly checkpoint and so allow accumulation of polyploid cells. This David McNamee
T
Zinc cuts childhood respiratory infections study done in India has shown that zinc supplements cut the incidence of acute lower-respiratory infection (ALRI) in young children by as much as 45%. Sunil Sazawal and co-workers from the All India Institute of Medical Sciences in New Delhi and Johns Hopkins School of Public Health (Baltimore, MD, USA) randomly assigned 609 children to receive either a daily multivitamin supplement or a multivitamin supplement plus elemental zinc 10 mg for 6 months (Pediatrics 1998; 102: 1–5). Field workers administered supplements daily while another team visited the families every 5 days to ask if the children had had fever, cough, or difficulty breathing in the preceding 5 days. Children with raised respiratory rates were treated with antibiotics. 24 episodes of ALRI occurred in the zinc group compared with 44 episodes in the control group, a 45% reduction (odds ratio 0·55, 95% CI 0·33–0·90; p=0·02). These findings, plus other known benefits of zinc on immunity, growth, &c, “indicate that interventions to improve zinc intake deserve more attention as means to improve child health”, they conclude.
A
Michael McCarthy
US FDA warns doctors to use cisapride as last resort only
T
he US FDA warned physicians on June 29 against use of the gastric-emptying drug cisapride (Propulsid; Janssen) except as a last resort. The recommendation came after new information linked cisapride to severe cardiac events such as arrhythmia.
Since 1993, FDA has received reports of 38 deaths in US patients taking cisapride. The deaths were not definitely linked to cisapride, but enough concern existed to issue a warning, said FDA. Cisapride should not be taken in conjunction with specified drugs or by very ill
patients, such as those with heart failure, advanced cancer, severe dehydration, or malnutrition. The warning comes as FDA’s postmarketing surveillance is under scrutiny. Some say it is too lax. Alicia Ault
Lithium’s mood-stabilising mechanism could point way to new drugs ithium effectively curbs extreme moods in patients with bipolar disorder by stabilising glutamate uptake into presynaptic nerve endings, says Lowell Hokin of the University of Wisconsin Medical School (Madison, WI, USA). Abnormally low glutamate concentrations are associated with depression, he suggests, while high values are associated with mania. The drug “exerts a push/pull effect on glutamate” to bring values within a narrow, normal range, says Hokin. Hokin and co-workers showed that
L
120
acute exposure to lithium inhibited glutamate uptake in mouse cerebral cortex, whereas chronic (2 weeks’) treatment resulted in upregulation of glutamate uptake, which would “tend to exert an antimanic effect”, notes Hokin. “Perhaps the most exciting finding was that if you look at the glutamate-uptake mechanism in [untreated] control mice, there’s quite a wide range, which is just a normal distribution, since mice vary in aggressiveness and passivity anyway, just like people”; in lithium-treated mice, glutamate uptake was stabilised within
“a very narrow range” (Proc Natl Acad Sci USA 1998; 95: 8363–68). Fine-tuning this compensatory mechanism takes time, which could explain why, clinically, “it takes a few weeks before lithium begins to relieve depression and mania in patients”, adds Hokin. Because lithium’s effective dose is very near the toxic dose, screening drugs for glutamatereuptake inhibition could identify new mood-stabilising drugs with fewer side-effects. Marilynn Larkin
THE LANCET • Vol 352 • July 11, 1998