Frontiers
Biochemistry
Nitric oxide's signalling pathway
Nature Chemical Biology 2007;3:727-35 doi: 10.1038/nchembio.2007.33
Nitric oxide (NO) is an otherwise poisonous gas that in minuscule quantities is an important biochemical signalling molecule, exerting autocrine and paracrine actions in the nervous and cardiovascular systems of many higher organisms, including humans. More recently, it has been recognised as an agent involved in the regulation of apoptosis (programmed cell death). The nitric oxide pathway is targeted by some drugs that regulate flow of blood, including sildenafil.
Until recently though, it was thought that nitric oxide acted without intracellular second messengers, which in the case of many hormones, are cyclic nucleotides. Researchers have now described a new pathway whereby the gas combines with guanosine cyclic monophosphate (GMP), to form a "second messenger," 8-nitroGMP. They also found that this messenger tags other proteins through a newly identified process called S-guanylation. This, researchers hope, will offer new therapeutic targets for some cardiovascular disorders.
Cervical screening
DNA testing for HPV
N Engl J Med 2007;357:1579-88, 1589-97
Two more large trials suggest that a DNA test for human papillomavirus (HPV) could help improve screening for cervical cancer and its precursor, high grade cervical intraepithelial neoplasia (CIN). The first trial, in more than 10 000 Canadian women, confirms that a test for HPV is substantially more sensitive than a standard Papanicolaou smear (94.6% v 55.4%) but a little less specific (94.1% v 96.8%). All the women had both tests, and were referred for colposcopy, biopsy, and possible treatment if either was positive. The second trial, in more than 12 000 Swedish women, showed that adding an HPV test to a conventional smear test in one round of screening reduced the incidence of high grade CIN at the next round by about 40%. The authors say the combined test picked up enduring grade 3 lesions earlier than a smear alone.
While HPV tests looked good in both trials, it is still too early to abandon traditional cytology, says an editorial (p 1650). Cervical screening is a coordinated sequence of diagnostic tests and treatments, and we still don't know where HPV testing fits in. Should it be used alone? With cytology? Or perhaps one after the other? Will a single HPV test do, or should women have at least two positive tests to indicate persistent infection before they are referred for colposcopy? Further trials will help to answer these questions. Yet more trials will be needed to count the cost.
Surgery
Link between hysterectomy and incontinence?
Lancet 2007;370:1494-9
Hysterectomy is a common operation in developed countries, and experts have been arguing for years about possible late side effects including urinary incontinence. The latest evidence comes from a large observational study comparing 165,260 women who had a hysterectomy for benign disease with 479,506 age matched controls who didn't. Women who had had a hysterectomy were more than twice as likely to need surgery for stress incontinence (hazard ratio 2.4, 95% confidence interval 2.3 to 2.5), particularly in the first five years after surgery.
Having children multiplied the risk, which was more than 16 times greater for women having four or more vaginal births. The authors are now fairly certain that hysterectomy causes incontinence, and urge women and their doctors to try less invasive treatments before opting for surgery.
At least one commentator disagrees (p 1462). Despite its size, this observational study simply isn't robust enough to resolve the debate either way, he says. Perhaps hysterectomy does predispose women to later incontinence, but important confounding factors-as yet unidentified-may exist.
Cardiology
Treating heart attacks
Lancet 2007;370:1483-93
Early treatments for heart attack have come a long way in recent years, but researchers are still looking for a drug to help protect the myocardium from ischaemic and reperfusion injuries. Atrial natriuretic peptide (ANP) is one candidate that looked promising in a recent clinical trial. Patients given the drug for three days after a percutaneous coronary intervention ended up with infarcts that were nearly 15% smaller than placebo controls (95% confidence interval 3.0% to 24.9%). They also had slightly better ventricular function at six months and a lower risk of heart failure or death from cardiac disease (hazard ratio 0.27, 0.09 to 0.8). Another candidate drug, nicorandil, worked no better than placebo in a parallel trial by the same authors. Both drugs caused more serious hypotension than placebo.
ANP and nicorandil both target a mitochondrial pore that is central to mechanisms of cell death during myocardial infarction. So it is odd that they performed so differently in these trials, says an editorial (p 1461). Perhaps the dose of nicorandil was too low. Or perhaps we have more to learn about the way it works. The evaluation of ANP is still at an early stage too, say the editorial's authors. Patients and doctors must wait for better data on dosing and safety, preferably from double blind trials.
Neuroscience
Sensory system development
Nature Neuroscience 2007;10:1243-5 doi:
10.1038/nn1978
Animal studies have shown that visual deprivation in the first few months of life permanently impairs the interaction between sensory systems. This was thought plausible, even in humans, as the findings are consistent with current (although limited) understanding of the neuronal architecture underlying the sensory areas in vertebrates. Scientists have now provided the first direct evidence of this effect in human beings.
They examined people born with congenital binocular cataracts who had no proper vision for at least the first five months of their life but then went on to gain good vision. Compared with a control group, people born with cataracts were less likely to be distracted by a burst of noise interrupting a test containing visual cues. This shows that the interaction between audio and visual systems is reduced. These subjects were also less able than controls to recognise the words of speakers in videos with degraded audio tracks, despite having similar lip reading skills, showing poorer audio-visual integration. Adequate multisensory input in the first few months of postpartum life is therefore crucial, the authors think.
Parts of this article have been published in the BMJ (2007;335:850, 908-9).
