Nitirc oxide link to AIDS dementia

THE LANCET

SCIENCE AND MEDICINE

Nitric oxide link to AIDS dementia

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verproduction of nitric oxide (NO), triggered by a coat protein of HIV-1, may play a role in the pathogenesis of AIDS dementia, report scientists in the USA. Their observations may help clinicians find new ways to tackle AIDS-associated dementia. Between 20% and 30% of patients with advanced AIDS develop dementia associated with cortical neuronal loss. Although HIV-1 can enter the central nervous system at an early stage of infection in microglia and macrophages, the virus is rarely found in neurons. Therefore, some indirect mechanism of neuronal destruction has long been suspected. One potential mediator of destruction is nitric oxide, a potent neurotoxin that kills cells by either necrosis or apoptosis, depending on its concentration. Valina Dawson (Johns Hopkins University School of Medicine, Baltimore, USA) and colleagues examined brain tissue from 25 patients diagnosed with AIDS before death, and from four controls who were HIV-1 negative (Science 1996; 274: 1917–20). Eight of the AIDS patients had severe dementia. Tissue from these patients had eight times more nitric oxide synthase activity (NOS) than the controls. Elevated amounts of the HIV-1 coat protein gp41 were also found in these patients. In experiments with rat neuronal and microglial cell cultures, gp41 concentrations above a “threshold” value induced NOS activity, leading to neuronal cell death. The cells were protected by the addition of NOS inhibitors. It is not known why gp41 is elevated in AIDS dementia, or how it induces NOS. It may be more stable than other HIV-1 proteins and thus produce a prolonged immunological response, including the production of NOS within adjacent cells. According to Dawson, this study should encourage physicians to develop a way of blocking NO production and so reduce the incidence of AIDS-associated dementia. This is particularly important as more people with AIDS are now surviving to the stage where dementia is likely to develop. Susan Aldridge

Vol 348 • December 21/28, 1996

Outcome predictor for colorectal cancer reported

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esearchers from the Memorial Sloan-Kettering Cancer Centre, New York City, USA, report that quantification of RNA coding for matrix metalloproteinase-9 (MMP-9) may predict colorectal cancer outcomes. MMP-9 RNA concentrations may help to stratify patients into low and high risk groups for disease recurrence and allow oncologists to tailor adjuvant therapy accordingly. Most patients with colorectal cancer die from metastatic disease, not their primary tumour. Despite gross and microscopic similarities, some colorectal cancers are far more aggressive than others. The determinants of such behaviour are complex, but for a tumour to spread, it must be able to penetrate the extracellular matrix and basement membrane of adjacent tissues. Metalloproteinases can destroy extracellular matrix, and increased expression of one of these, MMP-9, has been reported in many cancers, including colorectal cancer. In fact, high concentrations of MMP9 are localised to the invasive edge of colorectal carcinomas. Zhao Shi Zeng and colleagues quantitated MMP-9 RNA in speci-

mens taken from 71 patients during surgery for colorectal cancer (J Clin Oncol 1996; 14: 3133–40). Overall, MMP-9 RNA values in cancerous tissue were nine-fold higher than the values found in adjacent normal mucosa. In a multivariate analysis, an MMP-9 RNA concentration more than five-fold higher than normal was a statistically significant, independent predictor of disease-free survival, even when the equation included Dukes’ stage, histological differentiation, and lymphatic and/or blood-vessel invasion as covariates. Patients with Dukes’ C and D carcinomas and MMP-9 RNA concentrations five times higher than normal had a 40% chance of survival at 30 months, but similar patients with MMP-9 RNA values less than five times normal had an 85% chance of survival. This algorithm needs prospective validation, but it suggests that MMP9 RNA measurement may be helpful in disease management. MMP-9 could also be developed as a chemotherapy target—animal models have shown some early promise. Ishan Bhattacharya

Safe mistletoe and holiday indigestion

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t is said that retail stores in the USA earn nearly half their yearly profits between Thanksgiving in late November and Christmas Eve. But the profitability of the holidays to the merchant often stands in contrast to the abdominal distress provoked by their commercial pursuit. Stores are jammed, parking lots are full, and tempers are on deadline. Although the phenomenon of “holiday indigestion” is well known to astute practitioners, its seeming communicability has remained a mystery. But there is now good evidence from Tennessee that, as in all others things pathophysiological these days, holiday gut may be yet another condition caused by the ubiquitous doyenne of daily existence, Helicobacter pylori. Researchers from East Tennessee

State University, Johnson City, USA, have developed a new assay that uses PCR to detect the presence of H pylori in saliva, faeces, and gastric biopsy specimens (Dig Dis Sci 1996; 41: 2142–49). Of 68 patients with biopsy-proven or culture-proven H pylori in the gut, 57 also had H pylori detected by PCR in the saliva. The faecal exam was positive only 25% of the time. Investigators conclude that the oral–oral mode of transmission of H pylori may be more likely than the faecal–oral route. Should public-health officials be issuing seasonal guidelines? Perhaps, but in any event, it may be assumed that work up of any patients with holiday indigestion should include questions concerning degree, frequency, and anonymity of unprotected mistletoe. David H Frankel

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