1560

looked at four police stations in Leeds and London. The comments on police custody are generally favourable, though the committee requested assurances about the right of a detainee held incommunicado to be examined by a doctor other than a police surgeon and concern about the interrogation of mentally disordered persons and individuals with drug withdrawal states. The main criticisms are about conditions in prisons. Overcrowding of an "outrageous level" existed at Leeds prison, with two-thirds of the prisoners three to a cell. In Leeds, Brixton, and Wandsworth prisoners have to defaecate and urinate into buckets, in the confined space used as a living area: the committee judged this degrading both for the bucket-user and for those who are obliged to listen and smell. The many hours spent with the excreta-filled buckets and the slopping out process "are scarcely less objectionable", are obviously unhygienic, and are also debasing for prison officers. The lack of work, training, and other activities means that many prisoners spend over 22 hours a day locked up in their cells. In the opinion of the CPT, the combination of overcrowding, lack of sanitation, and inadequate activities constitutes "inhuman and degrading treatment". This is an explosive conclusion with extremely grave consequences: it implies violation of the European Convention of Human Rights on a massive scale, involving several thousand persons, any of whom could introduce a complaint against the UK Government to the European Commission of Human

Rights. the CPT of medical care for prisoners, already the subject of widespread criticism,1 is shocking. The description of medical consultations shows that normal ethical standards are systematically violated: examinations are perfunctory and confidentiality is at hazard; the medical services are overwhelmed by day-to-day needs and unable to plan preventive measures. At the time of the CPT’s visit there were 163 men in Brixton’s F wing, many of them with major mental disorders. The conditions in F wing were thought likely to exacerbate rather than alleviate psychiatric disorders, with patients spending large amounts of time locked in single or double cells. Seriously disturbed or violent patients are placed in a bare cell with only a mattress on the floor. As in Herstvedester, there is serious ambivalence about the status of mentally disordered prisoners: F wing is next to the hospital wing but not regarded as a psychiatric hospital in terms of the Mental Health Act. Transfer to F wing is not subject to consent, but once there prisoners do not benefit from the legal rights and access to treatment of patients admitted involuntarily to hospital. A further medical issue raised was the segregation of HIV- infected prisoners. At Leeds and Brixton such prisoners are housed in the hospital wings. At Wandsworth, they are housed on K wing, together with prisoners "who it was feared might be HIV + but who refused to take the blood test". The The assessment

by

regimen is described as very impoverished and discriminatory. In Holloway no such segregation is practised. The CPT underlined the patent discrepancy between the stated policy of the Prison Medical Service (no routine segregation of HIVinfected prisoners) and the realities of prison life. In its reply, the UK Government rejects the assertion concerning inhuman and degrading treatment but accepts that improvements are necessary. Indeed, it maintains that substantial changes have been made since the CPT’s visit, in particular concerning overcrowding at Leeds prison. Provision of integral sanitation is being given high priority: slopping out will end in 1994 in Brixton and Wandsworth prisons and in 1996 in Leeds. The response concerning medical and psychiatric care is essentially that a working group and a task force have been established and consultants have been engaged. Since then, the Home Secretary has appointed Sir Donald Acheson as chairman of the new Health Advisory Committee for the Prison Service. In these three reports the CPT has shown initiative and imagination. For health workers the messages are threefold: objective medical examinations can provide evidence of physical and psychological ill treatment,

including the effects of lengthy solitary confinement; the health care of prisoners requires a clearly defined framework independent of the prison administration, providing a quality of care akin to that available in the community, and good health care cannot readily be provided in an environment of squalor and unnecessary suffering. The blame for the piteous state of medical care for prisoners does not lie with those within the prison medical services. The health establishment

as a whole-health authorities, and medical schools-has associations, professional allowed unethical and unsound practices to by neglect develop. The CPT will help to overcome the psychological and administrative barriers that separate prison from society and prison health from community health.

1. Editorial. Health care for prisoners: Lancet 1991; 337: 647-48.

implications

of "Kalk’s refusal".

Nitric oxide in the clinical

arena

Endotoxin and certain cytokines (eg, interferon-y, necrosis factor [TNF] and some interleukins) enhance endogenous synthesis of nitric oxide (NO) via induction of an NO synthase in both endothelial and vascular smooth muscle cells.1 This inducible enzyme differs from the constitutive isoform found in endothelial and other cell types, and is now believed to be responsible for the sustained vasodilatation, hypotension, and pharmacological hyporeactivity that characterise septic shock.l-4 Some studies have suggested that enhanced NO formation may be beneficial. Thus, administration of exogenous NO tumour

1561

feline model of circulatory shock,5and endogenous NO production may help to maintain vascular integrity after acute endotoxininduced intestinal damage in rats.66 However, it is now clear that in septic shock the effects of agents that block NO synthesis from L-arginine (eg, the substituted analogue Nc-

prolongs

survival in

a

monomethyl-L-arginine [L-NMMA]), depend critically on differences in the degree of inhibition of the constitutive and inducible NO synthase enzymes. High concentrations may inhibit both types. Nava and colleagues on p 1555 show that this effect, coupled with the presence of circulating vasoconstrictors, can lead to a dramatic fall in blood pressure, end-organ damage, and death. Lower concentrations may nevertheless provide a therapeutic avenue to reverse the vasodilatation that is one of the main adverse features of the septic syndrome and results in high-output cardiac failure. Administration of appropriate doses of L-NMMA to rats or dogs treated with endotoxin or TNF can increase blood pressure without causing death.2,4,7 Also in this issue (p 1557), Petros et al describe beneficial cardiovascular effects in two patients with septic shock refractory to conventional treatment: L-NMMA and L-NAME

(NG-nitro-L-arginine methyl ester) significantly increased systemic resistance and raised the blood pressure. Vallance and Moncada8

lately proposed that the circulation which hyperdynamic frequently develops in patients with cirrhosis is the consequence of low-grade endotoxaemia and an associated induction of NO synthase. Preliminary evidence in support of this hypothesis is presented in this issue (p 1590) by Midgley et al. In a patient with severe hepatic failure and hypotension, a bolus injection of the dye methylene blue (which blocks stimulation of soluble guanylate cyclase by NO and therefore its vasodilator effect) raised the blood pressure for over 60 minutes. Similar strategies may likewise become a useful adjunct to the therapeutic use of cytokines such as interleukin-2, which is normally restricted because of the concomitant hypotension caused by induction of NO-synthase and overproduction of NO.9 Pretreatment with glucocorticoids, which inhibit the expression rather than the activity of the inducible NO synthase without affecting the constitutive enzyme,10 could potentially become useful in this way. Does manipulation of NO synthesis by other means have a therapeutic role? Although infusion of the enzyme arginase can depress plasma L-arginine levels by over 90% without affecting resting blood pressure, the supply of L-arginine becomes rate limiting for both agonist-stimulation of the constitutive NO synthase and NO synthesis by its inducible isoform.ll This observation may explain why administration of exogenous L-arginine reverses the impairment of endothelium-dependent vasodilatation observed in laboratory animals12 and in man (see p 1546) with hypercholesterolaemia.

Agents

that

block

the

synthesis of tetrahydrobiopterin, an essential co-factor synthase, may offer a novel alternative approach in conditions characterised by NO overproduction. 13 Other therapeutic advances may eventually come from observations that certain other aminoacids (eg, L-lysine, L-ornithine) and various substituted L-arginine analogues can differentially affect L-arginine transport, inhibition of NO synthase, or in some cases, both.14

for NO

Gaseous NO may itself have a therapeutic role when administered by inhalation.15,16 The rationale behind such treatment is that low concentrations of NO combine only very slowly with oxygen to give toxic products. When NO is present at 10 ppm in air, 50% conversion to N02 takes 7 hours.17 Subsequent formation of nitric and nitrous acids (which cause parenchymal damage, decrease lung compliance, and increase extravascular water) may therefore not be a problem clinically, even with lengthy exposure. No adverse effects have been noted in laboratory animals, even with concentrations as high as 100 ppm.18 In normal lambs spontaneously breathing an air/NO (80 ppm) mixture, pulmonary vascular resistance does not alter unless pre-existing tone and pulmonary hypertension is induced either by pharmacologically or by hypoxia-induced constriction.l5 Inspired NO then acts as a highly selective pulmonary vasodilator, because haemoglobin scavenges it rapidly and prevents systemic effects, and pulmonary resistance arteries are closely associated with alveoli and bronchioli.ls Similar findings have been reported in human beings with pulmonary hypertension breathing an air/NO (40 ppm) mixture.16 This combination induced a rapid and specific fall in pulmonary vascular resistance, in striking contrast to systemically administered vasodilators such as prostacyclin which affect both the pulmonary and the systemic circulations. The effects of NO were sustained and readily reversible; and the patients were not able to distinguish between the air/NO mixture and air alone. It also seems likely that therapeutic inhalation of NO will provide a new clinical strategy for the management of patients with adult respiratory distress syndrome (ARDS). Preliminary evidence suggests that NO may lead to preferential vasodilatation of ventilated regions of lung (as might be predicted for ready access of an agent with a very short biological half-life), and thereby significantly improve gas exchange and decrease

shunting. 19 In some circumstances the role of NO remains controversial. Under various experimental conditions NO has been reported either to limit or to exacerbate ischaemia-reperfusion injury. 2021 Such differences may result from complex free-radical reactions. Although NO can "scavenge" the superoxide anion (0-) through direct chemical interaction, the product formed, peroxynitrite, may decompose to form other tissue-damaging agents such as the hydroxyl radical. 21 In other conditions where there is abnormal tissue

1562

arterial occlusion-flow-induced release of NO may control and facilitate the opening of collateral vessels.23 It is certain that other therapeutic strategies will emerge as more is learnt about the biology of NO.

perfusion-eg,

22. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxl radical production by peroxynitrite: implications for endothelial injury from nitnc oxide and superoxide. Proc Natl Acad Sci USA 1990; 87: 1620-24. 23. Randall MD, Griffith TM. Does EDRF have a role in collateral perfusion following arterial occlusion? Second International Meeting on the Biology of Nitric Oxide. London, October, 1991.

1. Moncada S, Palmer

RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109-42.

SS, Jubran A, et al. NG-methyl-L-arginine inhibits necrosis factor-induced hypotension: implications for the

2. Kilbourn RG, Gross tumor

involvement of nitric oxide. Proc Natl Acad Sci USA 1990; 87: 3629-32. 3. Joulou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet J-C. Loss of vascular responsiveness induced by endotoxin involves the L-arginine pathway. Am J Physiol 1990; 259: H1038-H1043. 4. Thiemermann C, Vane J. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol 1990; 182: 591-95. 5. Acki N, Johnson G, Lefer AM. Beneficial effects of two forms of NO administration in feline splanchnic occlusion shock. Am J Physiol 1990; 2587: G275-81. 6. Hutcheson IR, Whittle BJR, Boughton-Smith NK. Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol 1990; 101: 815-20. 7. Klabunde RE, Ritger RC. NG-monomethyl-L-arginine (NMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Commun 1990; 178: 1135-40. 8. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet 1991; 337: 776-78. 9. Hibbs JR, Westenfelder C, Samlowski WE. Endogenous nitrate synthesis from a terminal guanidino nitrogen atom of L-arginine and physiology of nitrate excretion in patients receiving interleukin-2 therapy. Second International Meeting on the Biology of Nitric Oxide. London, October, 1991. 10. Rees DD, Cellek S, Palmer RMJ, Moncada S. Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: an insight into endotoxin shock. Biochem Biophys Res Commun 1990; 173: 541-47. 11. Griffith OW, Park KH, Levi R, Gross SS. The role of plasma arginine in nitric oxide synthesis: studies with arginase-treated rats. Second International Meeting on the Biology of Nitric Oxide. London, October, 1991. 12. Girerd XJ, Hirsch AT, Cooke JP, Dzau VJ, Creager MA. L-arginine augments endothelium-dependent vasodilation in cholesterol-fed rabbits. Circ Res 1990; 67: 1301-08. 13. Prast H, Werner ER, Heistracher M, Werner-Felmayer G, Philippu A, Wachter H. Effects of sepiapterin treatment on tetrahydrobiopterin levels and blood pressure in spontaneously hypertensive rats. Second International Meeting on the Biology of Nitric Oxide. London,

October,

1991.

Bogle RG, Moncada S, Pearson JD, Mann GE. Identification of selective inhibitors of arginine transport and nitric oxide synthase in vascular endothelial cells. Second International Meeting on the Biology of Nitric Oxide. London, October, 1991. 15. Frostell C, Fratacci M-D, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary 14.

vasoconstnction. Circulation 1991; 83: 2038-47. 16. Pepke-Zaba J, Higenbottam TW, Tuan Dinh-Xuan A, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991; 338: 1173-74. 17. Rabson SR, Quilliam JH, Goldblatt E. The elimination of nitrous fumes from blasting gases. J S Afr Inst Min Metall 1960; 61: 152-99. 18. Stavert DM, Lehnert BE. Nitrogen oxide and nitrogen dioxide as inducers of acute pulmonary injury when inhaled at relatively high concentrations for brief periods. Inhal Toxicol 1990; 2: 53-57. 19. Faule KJ, Rossaint R, Keitel M, et al. Successful treatment of severe adult respiratory distress syndrome with nitric oxide—the first three patients. Second International Meeting on the Biology of Nitric Oxide, London, October, 1991. 20. Buckberg GD, Haybron DM, Matheis G, Sherman MP, Ignarro LJ. Myocardial reoxygenation injury after ischaemia is mediated by the L-arginine-nitric oxide pathway. Second International Meeting on the Biology of Nitric Oxide. London, October, 1991. 21. Lefer AM. Cytoprotective actions of nitric-oxide and NO donors in ischaemia-reperfusion of coronary and splanchnic circulations. Second International Meeting on the Biology of Nitric Oxide. London, October, 1991.

More bad luck for the X chromosome: &agr;-thalassaemia/mental retardation again the X chromosome stands accused of harbouring the locus of a mental retardation syndrome. It has long been recognised that severe retardation is more common in males than females, and a substantial proportion of this excess is now known to be attributable to sex-linked disorders, most notably the fragile X syndrome.1 To an already long list we can now add another entity-the retardation a-thalassaemia/mental (ATR-X) syndrome. The assocation of haemoglobin H (HbH) disease Once

with mental retardation was first documented in three boys by Weatherall et al in 1981.2 Subsequent analysis of these three cases plus ten new patients indicated that they could be divided into two groups on the basis of clinical, cytogenetic, and molecular fmdings. In eight patients (six male and two female) there was a deletion involving the ot-globin gene complex on chromosome 16p.3 These individuals had mild to moderate mental retardation and variable clinical abnormalities that reflected different degrees of chromosome imbalance. By contrast, no abnormality of the a-globin genes could be identified in blood from the second group (five patients), all of whom were severely retarded.4 These patients had a similar and unusual facial appearance: microcephaly, hypertelorism, mid-face hypoplasia, and pouting lower lip. A review of sixteen published cases5 confirms that other common findings include a high frequency of convulsions, genital abnormalities, neonatal hypotonia, and short stature. Curiously, the HbH disease in these patients takes a very mild form; the haematological indices may even be normal. Absence of HbH on electrophoresis does not exclude the diagnosis, which is best achieved by identification of HbH inclusions in red cells after incubation at room temperature with 1% brilliant cresyl blue. The observation that all the non-deletion patients were chromosomal males (the only "female" had a 46, XY karykotype) rapidly prompted suggestions that their condition might be due to a mutation on the X-chromosome.4,6 Absolute confirmation of Xlinkage is still awaited, but reports of several families7-9 with multiple affected males related through healthy females provide strong circumstantial evidence for sex-linked recessive inheritance. But how might a mutation on the X chromosome influence the synthesis of a-globin chains coded for by genes on

Nitric oxide in the clinical arena.

1560 looked at four police stations in Leeds and London. The comments on police custody are generally favourable, though the committee requested assu...
485KB Sizes 0 Downloads 0 Views