Nitric oxide production and heart failure

and breakfast cereals than those in classes I and 11.1 Women in socially disadvantaged populations, with low folic acid intakes and a high prevalence of unplanned pregnancies, are likely to be future mothers at risk. Offering possible exposure to prophylactic advice is an unresponsible position for policy makers to take. In many areas so-called nanny state attitudes are rightly being questioned, but every year 400 babies are born in the UK severely disabled by spina bifida, a disease that everyone agrees is potentially preventable. Statutory fortification of a staple food such as flour is the practical route to ensuring a distribution of folic acid to mothers before planned and

vegetables, fruit,

unplanned pregnancies. Wendy Doyle Institute of Brain Chemistry and Human Nutrition, Queen Elizabeth Hospital for Children, London E2 8PS, UK

1

Wynn SW, Wynn AHA, Doyle W, Crawford MA. The association of maternal social class with maternal diet and the dimensions of babies in a population of London women. Nutr Health 1994; 9: 303-15.

HIV testing in prison SiR-In her Dec 17 commentary Diamond advocates voluntary HIV testing with the provision of counselling and comprehensive care. As director of HIV medical care for HIV-infected incarcerated men and women in Rhode Island, I wholeheartedly endorse this recommendation. Although testing is mandatory by law in Rhode Island for convicted inmates, in practice all persons who are seen on intake at the state prison are offered voluntary HIV testing with signed consent at the same time that blood is being drawn for syphilis and pregnancy testing. All persons who are HIV positive receive individual counselling and comprehensive medical care. There is no segregation of HIV-positive persons, and only the medical team has access to records of HIV serostatus. In this setting in which HIV testing is offered routinely on entry to all, 93% of individuals accept testing with signed informed consent.1,2 Between 1988 and 1993, 35% of all the HIV-positive individuals in the State of Rhode Island were identified at the state prison. If HIV testing had not been available, many would never have known their HIV status and would not have had access to antiretroviral therapy and opportunistic infection prophylaxis and treatment. In addition, all HIVpositive men and women, before release from prison, undergo personal counselling and planning for referral for medical services, substance abuse treatment, financial support, and housing in the community. Over 70% of individuals who have undergone pre-release discharge planning have attended for substance abuse treatment and medical care six months after release. This practice has resulted in an over 50% decrease in the rate of recidivism among HIV-positive women.3 Comprehensive HIV testing should be offered on a routine basis with the provision of individual counselling to all HIV-positive inmates, and comprehensive medical care with linkage to services in the community on release. If we do not address this epidemic in prison, we will be ignoring the solo site with the highest number of infected persons. Paradoxically, incarceration could provide the first opportunity for many HIV-infected individuals to receive appropriate counselling and comprehensive medical and substance abuse treatment which, in the long term, can only help us in the battle with the AIDS epidemic.

Dixon PS, Flanigan TP, DeBuono BA, et al. HIV Infection in prisoners: meeting the health care challenge. Am J Med 1993; 95:

1

629-35. 2

3

Burzynski J, Flanigan TP, Kim J, De Ciantis ML. Comprehensive prison HIV medical care and pre-release counseling. Xth International Conference on AIDS, Aug 7-12, 1994, Yokohama, Japan. Kim J, Flanigan TP, Lourie K, Snead M, Maynard DB. A prison release program for HIV positive women. New York: American Federation for Clinical Research. 1994; October: 708.

Nitric oxide

production

and heart failure

SIR-We reported that endogenous nitric oxide (NO) production is increased in patients with heart failure.’ We now report a significant positive correlation between plasma nitrate (the stable metabolite of NO, and an index of endogenous NO production) and severity of heart failure as measured by New York Heart Association (NYHA) class. We previously reported a trend towards increased plasma nitrate with increasing severity of heart failure, but the small number of subjects in NYHA classes I and II (1 and 4, respectively) precluded proper estimation of significance. Plasma specimens for nitrate analysis were collected prospectively from an additional 11 patients attending a specialist heart failure clinic, and these data were added to that of the 39 patients previously reported. 8 of the 11 new patients were in NYHA class I or II. For the 50 patients, there was a positive correlation between plasma nitrate concentrations and NYHA class (r=0.45, p=0001) (see figure). There was no relation between plasma nitrate and age, sex, administration of nitrate-containing medication, or aetiology of heart failure. Increased NO production in heart failure may compensate for the vasoconstrictor effect of neurohumoral adaptations to heart failure, and may explain the exaggerated decrease in forearm blood flow with NG-monomethyl-L-arginine (L-NMMA), a selective inhibitor of nitric oxide synthase, in patients with heart failure.2 We have shown that plasma nitrate rises with increasing severity of heart failure. This is consistent with the findings of Habib et aP who demonstrated that in a population of patients with heart failure, the vasoconstrictor response to L-NMMA was proportional to the increase in basal systemic vascular resistance.

Figure: Regression of plasma nitrate (pmol/L)

vs

NYHA class,

with 95% CI

Timothy

P

Flanigan

Brown University, The Minam

390

Plasma nitrate for normals,

Hospital, Providence, RI 02906, USA

(19.1-30-0) pmol/L.

as

previously reported,

was

24.6

Increased plasma nitrate levels in heart failure may also be explained by increased activity of the high capacity inducible isoform of nitric oxide synthase (iNOS), which has been documented in right ventricular tissue from patients with dilated cardiomyopathy.4 Increased levels of cytokines

present in heart failure may activate iNOS and NO has been shown to enhance myocardial relaxation in vitro.5 D S Winlaw, G A Smythe, A M Keogh, C G Schyvens, P M Spratt, *P S Macdonald Departments of *Cardiopulmonary Transplantation and Chemical Pathology, St Vincent’s

Table: Age and cause of death of parents of patients with sporadic ALS and SOD-1 mutations

Hospital, Sydney, NSW, 2010, Australia

Winlaw DS, Smythe GA, Keogh AM, Schyvens CG, Spratt PM, Macdonald PS. Increased nitric oxide production in heart failure. Lancet 1994; 344: 373-74. 2 Drexler H, Hayoz D, Munzel T, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992; 69: 1596-601. 3 Habib F, Dutka D, Crossman D, Oakley CM, Cleland JGF. Enhanced basal nitric oxide production in heart failure: another failed counterregulatory vasodilator mechanism? Lancet 1994; 344: 371-73. 4 de Belder AJ, Radomski MW, Why HJF, et al. Nitric oxide synthase activities in human myocardium. Lancet 1993; 341: 84-85. 5 Grocott-Mason R, Fort S, Lewis MJ, Shah AM. Myocardial relaxant effect of exogenous nitric oxide in isolated ejecting hearts. Am J Physiol 1994; 266: H1699-705. 1

Superoxide dismutase

mutations in

amyotrophic

lateral sclerosis SiR-In their Dec 17 commentary Orrell and deBelleroche state that, although Cu-Zn superoxide dismutase (SOD-1) gene mutations are found in patients with apparently sporadic amyotrophic lateral sclerosis (ALS), further inquiry has "usually revealed a previously unknown family history". We think that this statement may misrepresent our work. We reported SOD-1 mutations in patients with apparently sporadic ALS.1,2 Blood samples were obtained from 57 patients recruited from the Scottish Motor Neurone Disease Register. This prospective, collaborative, population-based study allowed near-complete case-ascertainment and followup of all patients diagnosed in Scotland since 1989.3 The patients fulfilled local diagnostic criteria and were classified as sporadic if the patient and/or carer could not recall a family history of ALS or motoneuron-like syndrome at interview in 1991/92. This classification was made blind before the discovery of SOD-1 mutations. Specimens were screened and sequenced locally. 3 patients had the Ile113Thr mutation and 1 had a novel Glu21Lys defect. The findings were surprising but were independently confirmed by separate analyses of DNA obtained from cell lines in 3 patients. To learn more about the pedigrees we contacted general practitioners, inspected the death certificates of the parents and grandparents and, in 1 case, re-interviewed surviving family members. The table shows age and cause of death of the parents of patients with sporadic disease. No history of motoneuron-like illness was shown in the grandparents. We have now detected SOD-1 mutations in 5 of 10 unrelated patients with familial ALS who were ascertained at the same time, and 3 have the same Ilell3Thr mutation.’ Although the sporadic patients might be distantly related to these pedigrees, this cannot be ascertained. We could not test samples from the parents of the sporadics because they had all died, or establish kinship with the familial ALS pedigrees. However, we are planning a study of flanking GT alleles to see whether they share a similar haplotype. Elshafey and colleagues in Glasgow were unable to detect an exon 4 mutation in 64 patients with sporadic diseases drawn from the same population but, as far as we are aware, there is no other report describing the frequency of SOD-1

population-based study

of incident

sporadic

patients. Suthers and

colleagues (Dec 24/31, p 1773) have also of apparently sporadic ALS in a family with reported the Ile113Thr mutation, but further investigation showed two other relatives with creeping paralysis. Because there seemed to be 3 symptom-free obligate carriers of the mutation, including 1 individual who died aged 91, they a case

conclude that the penetrance of this mutation might be at 50% by age 60. Our experience seems to indicate that the risk might be even lower in the Scottish population. most

*R J

and

a

Swingler,

C Jones, D J H Brock

*Department of Neurology, Dundee Royal Infirmary, Dundee DD1 9NX, UK; and Human Genetics Unit, Department of Medicine, University of Edinburgh 1

2

3

4

5

Jones C, Brock D, Chancellor A, Warlow C, Swingler RJ. SOD1 mutations in patients with sporadic amyotrophic lateral sclerosis. Lancet 1993; 342: 1050-51. Jones C, Swingler RJ, Brock D. Identification of a novel SOD1 mutation in an apparently sporadic amyotrophic lateral sclerosis

patient and the detection of ILE 113 THR in three others. Hum Mol Genet 1994; 3: 649-50. Chancellor A, Swingler RJ, Fraser H, Warlow CP, for the Scottish Motor Neuron Disease Research Group. The Scottish Motor Neuron Disease Register: a prospective study of adult onset of motor neuron disease in Scotland: methodology, demography and clinical features of incident cases in 1989. J Neurol Neurosurg Psychiatry 1992; 55: 536-41. Jones C, Swingler RJ, Simpson S, Brock D. Superoxide dismutase mutations in an unselected cohort of Scottish amyotrophic lateral sclerosis patients. J Med Genet (in press). Elshafey A, Lanyon WG, Connor JM. Identification of a new missense point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD-1) gene in a family with amyotrophic lateral sclerosis. Hum Mol Genet 1994; 3: 363-64.

Parental influence on inheritance of familial amyotrophic lateral sclerosis SIR-Leone et al (Dec 10, p 1639) suggest the existence of a gene with an unstable mutation with a selection against a presumed large expansion in the female gamete, based on a review of previously reported cases of familial amyotrophic lateral sclerosis. We have examined the pedigrees of 17 families with evidence of autosomal dominant inheritance of amyotrophic lateral sclerosis through at least three generations. These pedigrees contain 106 affected subjects and 15 assumed obligate carriers. Using a similar analysis to Leone et al, we found no significant change (X2) in the proportion of cases inheriting the disease from female parents or grandparents (table). The percentage increased from one generation to the next, by contrast with the findings of Leone and colleagues. The median age of onset was 46 or 49 years for those who inherited the disease from a female or male parent, respectively; and 48 or 49 years for those with a female or male grandparent. The median age of onset was highest in the line grandfather-to-mother (53 years) and lowest in the The lines line (42 grandfather-to-father years). 391