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 assessment by 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 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 HIV- infected 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, professional associations, and medical schools-has by neglect allowed unethical and unsound practices to 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: implications of "Kalk’s refusal". Lancet 1991; 337: 647-48. Nitric oxide in the clinical arena Endotoxin and certain cytokines (eg, interferon-y, tumour 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
Transcript
1560
looked at four police stations in Leeds and London.The comments on police custody are generallyfavourable, though the committee requestedassurances about the right of a detainee heldincommunicado to be examined by a doctor otherthan a police surgeon and concern about the
interrogation of mentally disordered persons andindividuals with drug withdrawal states. The maincriticisms are about conditions in prisons.Overcrowding of an "outrageous level" existed atLeeds prison, with two-thirds of the prisoners three toa cell. In Leeds, Brixton, and Wandsworth prisonershave to defaecate and urinate into buckets, in theconfined space used as a living area: the committeejudged this degrading both for the bucket-user and forthose who are obliged to listen and smell. The manyhours spent with the excreta-filled buckets and the
slopping out process "are scarcely less objectionable",are obviously unhygienic, and are also debasing forprison officers. The lack of work, training, and otheractivities means that many prisoners spend over 22hours a day locked up in their cells. In the opinion ofthe CPT, the combination of overcrowding, lack ofsanitation, and inadequate activities constitutes"inhuman and degrading treatment". This is an
explosive conclusion with extremely grave
consequences: it implies violation of the EuropeanConvention of Human Rights on a massive scale,involving several thousand persons, any of whomcould introduce a complaint against the UKGovernment to the European Commission of HumanRights.The assessment by the CPT of medical care for
prisoners, already the subject of widespreadcriticism,1 is shocking. The description of medicalconsultations shows that normal ethical standards are
systematically violated: examinations are perfunctoryand confidentiality is at hazard; the medical servicesare overwhelmed by day-to-day needs and unable toplan preventive measures. At the time of the CPT’svisit there were 163 men in Brixton’s F wing, many ofthem with major mental disorders. The conditions inF wing were thought likely to exacerbate rather thanalleviate psychiatric disorders, with patients spendinglarge amounts of time locked in single or double cells.Seriously disturbed or violent patients are placed in abare cell with only a mattress on the floor. As inHerstvedester, there is serious ambivalence about thestatus of mentally disordered prisoners: F wing is nextto the hospital wing but not regarded as a psychiatrichospital in terms of the Mental Health Act. Transferto F wing is not subject to consent, but once thereprisoners do not benefit from the legal rights andaccess to treatment of patients admitted involuntarilyto hospital. A further medical issue raised was thesegregation of HIV- infected prisoners. At Leeds andBrixton such prisoners are housed in the hospitalwings. At Wandsworth, they are housed on K wing,together with prisoners "who it was feared might beHIV + but who refused to take the blood test". The
regimen is described as very impoverished anddiscriminatory. In Holloway no such segregation ispractised. The CPT underlined the patentdiscrepancy between the stated policy of the PrisonMedical Service (no routine segregation of HIV-infected prisoners) and the realities of prison life.
In its reply, the UK Government rejects theassertion concerning inhuman and degradingtreatment but accepts that improvements are
necessary. Indeed, it maintains that substantial
changes have been made since the CPT’s visit, inparticular concerning overcrowding at Leeds prison.Provision of integral sanitation is being given highpriority: slopping out will end in 1994 in Brixton andWandsworth prisons and in 1996 in Leeds. Theresponse concerning medical and psychiatric care isessentially that a working group and a task force havebeen established and consultants have been engaged.Since then, the Home Secretary has appointed SirDonald Acheson as chairman of the new Health
Advisory Committee for the Prison Service.
In these three reports the CPT has shown initiativeand imagination. For health workers the messages arethreefold: objective medical examinations can provideevidence of physical and psychological ill treatment,including the effects of lengthy solitary confinement;the health care of prisoners requires a clearly definedframework independent of the prison administration,providing a quality of care akin to that available in thecommunity, and good health care cannot readily beprovided in an environment of squalor and
unnecessary suffering. The blame for the piteous stateof medical care for prisoners does not lie with thosewithin the prison medical services. The healthestablishment as a whole-health authorities,professional associations, and medical schools-hasby neglect allowed unethical and unsound practices todevelop. The CPT will help to overcome the
psychological and administrative barriers that
separate prison from society and prison health fromcommunity health.
1. Editorial. Health care for prisoners: implications of "Kalk’s refusal".Lancet 1991; 337: 647-48.
Nitric oxide in the clinical arena
Endotoxin and certain cytokines (eg, interferon-y,tumour necrosis factor [TNF] and some interleukins)enhance endogenous synthesis of nitric oxide (NO) viainduction of an NO synthase in both endothelial andvascular smooth muscle cells.1 This inducible enzymediffers from the constitutive isoform found inendothelial and other cell types, and is now believed tobe responsible for the sustained vasodilatation,hypotension, and pharmacological hyporeactivity thatcharacterise septic shock.l-4 Some studies have
suggested that enhanced NO formation may bebeneficial. Thus, administration of exogenous NO
1561
prolongs survival in a feline model of circulatory synthesis of tetrahydrobiopterin, an essential co-factorshock,5and endogenous NO production may help to for NO synthase, may offer a novel alternativemaintain vascular integrity after acute endotoxin- approach in conditions characterised by NOinduced intestinal damage in rats.6 6 overproduction. 13 Other therapeutic advances mayHowever, it is now clear that in septic shock the eventually come from observations that certain other
effects of agents that block NO synthesis from aminoacids (eg, L-lysine, L-ornithine) and variousL-arginine (eg, the substituted analogue Nc- substituted L-arginine analogues can differentiallymonomethyl-L-arginine [L-NMMA]), depend affect L-arginine transport, inhibition of NO
critically on differences in the degree of inhibition of synthase, or in some cases, both.14the constitutive and inducible NO synthase enzymes. Gaseous NO may itself have a therapeutic roleHigh concentrations may inhibit both types. Nava and when administered by inhalation.15,16 The rationalecolleagues on p 1555 show that this effect, coupled behind such treatment is that low concentrations ofwith the presence of circulating vasoconstrictors, can NO combine only very slowly with oxygen to givelead to a dramatic fall in blood pressure, end-organ toxic products. When NO is present at 10 ppm in air,damage, and death. Lower concentrations may 50% conversion to N02 takes 7 hours.17 Subsequentnevertheless provide a therapeutic avenue to reverse formation of nitric and nitrous acids (which causethe vasodilatation that is one of the main adverse parenchymal damage, decrease lung compliance, andfeatures of the septic syndrome and results in increase extravascular water) may therefore not be ahigh-output cardiac failure. Administration of problem clinically, even with lengthy exposure. Noappropriate doses of L-NMMA to rats or dogs treated adverse effects have been noted in laboratory animals,with endotoxin or TNF can increase blood pressure even with concentrations as high as 100 ppm.18 Inwithout causing death.2,4,7 Also in this issue (p 1557), normal lambs spontaneously breathing an air/NO (80Petros et al describe beneficial cardiovascular effects ppm) mixture, pulmonary vascular resistance does notin two patients with septic shock refractory to alter unless pre-existing tone and pulmonaryconventional treatment: L-NMMA and L-NAME hypertension is induced either by pharmacologically(NG-nitro-L-arginine methyl ester) significantly or by hypoxia-induced constriction.l5 Inspired NOincreased systemic resistance and raised the blood then acts as a highly selective pulmonary vasodilator,pressure. because haemoglobin scavenges it rapidly and
Vallance and Moncada8 lately proposed that the prevents systemic effects, and pulmonary resistancehyperdynamic circulation which frequently develops arteries are closely associated with alveoli andin patients with cirrhosis is the consequence of bronchioli.ls Similar findings have been reported inlow-grade endotoxaemia and an associated induction human beings with pulmonary hypertensionof NO synthase. Preliminary evidence in support of breathing an air/NO (40 ppm) mixture.16 Thisthis hypothesis is presented in this issue (p 1590) by combination induced a rapid and specific fall in
Midgley et al. In a patient with severe hepatic failure pulmonary vascular resistance, in striking contrast toand hypotension, a bolus injection of the dye systemically administered vasodilators such as
methylene blue (which blocks stimulation of soluble prostacyclin which affect both the pulmonary and theguanylate cyclase by NO and therefore its vasodilator systemic circulations. The effects of NO were
effect) raised the blood pressure for over 60 minutes. sustained and readily reversible; and the patients wereSimilar strategies may likewise become a useful not able to distinguish between the air/NO mixtureadjunct to the therapeutic use of cytokines such as and air alone. It also seems likely that therapeuticinterleukin-2, which is normally restricted because of inhalation of NO will provide a new clinical strategythe concomitant hypotension caused by induction of for the management of patients with adult respiratoryNO-synthase and overproduction of NO.9 Pre- distress syndrome (ARDS). Preliminary evidencetreatment with glucocorticoids, which inhibit the suggests that NO may lead to preferentialexpression rather than the activity of the inducible NO vasodilatation of ventilated regions of lung (as mightsynthase without affecting the constitutive enzyme,10 be predicted for ready access of an agent withcould potentially become useful in this way. a very short biological half-life), and therebyDoes manipulation of NO synthesis by other means significantly improve gas exchange and decrease
have a therapeutic role? Although infusion of the shunting. 19enzyme arginase can depress plasma L-arginine levels In some circumstances the role of NO remains
by over 90% without affecting resting blood pressure, controversial. Under various experimental conditionsthe supply of L-arginine becomes rate limiting for NO has been reported either to limit or to exacerbateboth agonist-stimulation of the constitutive NO ischaemia-reperfusion injury. 2021 Such differences
synthase and NO synthesis by its inducible isoform.ll may result from complex free-radical reactions.This observation may explain why administration of Although NO can "scavenge" the superoxide anionexogenous L-arginine reverses the impairment of (0-) through direct chemical interaction, the productendothelium-dependent vasodilatation observed in formed, peroxynitrite, may decompose to form otherlaboratory animals12 and in man (see p 1546) with tissue-damaging agents such as the hydroxyl radical. 21hypercholesterolaemia. Agents that block the In other conditions where there is abnormal tissue
1562
perfusion-eg, arterial occlusion-flow-inducedrelease of NO may control and facilitate the opening ofcollateral vessels.23 It is certain that other therapeuticstrategies will emerge as more is learnt about thebiology of NO.
2. Kilbourn RG, Gross SS, Jubran A, et al. NG-methyl-L-arginine inhibitstumor necrosis factor-induced hypotension: implications for theinvolvement of nitric oxide. Proc Natl Acad Sci USA 1990; 87:3629-32.
3. Joulou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, StocletJ-C. Loss of vascular responsiveness induced by endotoxin involves theL-arginine pathway. Am J Physiol 1990; 259: H1038-H1043.
4. Thiemermann C, Vane J. Inhibition of nitric oxide synthesis reduces thehypotension 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 NOadministration in feline splanchnic occlusion shock. Am J Physiol 1990;2587: G275-81.
6. Hutcheson IR, Whittle BJR, Boughton-Smith NK. Role of nitric oxidein maintaining vascular integrity in endotoxin-induced acute intestinaldamage in the rat. Br J Pharmacol 1990; 101: 815-20.
7. Klabunde RE, Ritger RC. NG-monomethyl-L-arginine (NMA) restoresarterial blood pressure but reduces cardiac output in a canine model ofendotoxic shock. Biochem Biophys Res Commun 1990; 178: 1135-40.
8. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role fornitric oxide? Lancet 1991; 337: 776-78.
synthesis from a terminal guanidino nitrogen atom of L-arginine andphysiology of nitrate excretion in patients receiving interleukin-2therapy. Second International Meeting on the Biology of Nitric Oxide.London, October, 1991.
10. Rees DD, Cellek S, Palmer RMJ, Moncada S. Dexamethasone preventsthe induction by endotoxin of a nitric oxide synthase and the associatedeffects on vascular tone: an insight into endotoxin shock. BiochemBiophys Res Commun 1990; 173: 541-47.
11. Griffith OW, Park KH, Levi R, Gross SS. The role of plasma arginine innitric oxide synthesis: studies with arginase-treated rats. Second
International Meeting on the Biology of Nitric Oxide. London,October, 1991.
13. Prast H, Werner ER, Heistracher M, Werner-Felmayer G, Philippu A,Wachter H. Effects of sepiapterin treatment on tetrahydrobiopterinlevels and blood pressure in spontaneously hypertensive rats. SecondInternational Meeting on the Biology of Nitric Oxide. London,October, 1991.
14. Bogle RG, Moncada S, Pearson JD, Mann GE. Identification of selectiveinhibitors of arginine transport and nitric oxide synthase in vascularendothelial cells. Second International Meeting on the Biology ofNitric Oxide. London, October, 1991.
16. Pepke-Zaba J, Higenbottam TW, Tuan Dinh-Xuan A, Stone D,Wallwork J. Inhaled nitric oxide as a cause of selective pulmonaryvasodilatation in pulmonary hypertension. Lancet 1991; 338:1173-74.
17. Rabson SR, Quilliam JH, Goldblatt E. The elimination of nitrousfumes from blasting gases. J S Afr Inst Min Metall 1960; 61:152-99.
18. Stavert DM, Lehnert BE. Nitrogen oxide and nitrogen dioxide asinducers of acute pulmonary injury when inhaled at relatively highconcentrations for brief periods. Inhal Toxicol 1990; 2: 53-57.
19. Faule KJ, Rossaint R, Keitel M, et al. Successful treatment of severe adultrespiratory 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 theL-arginine-nitric oxide pathway. Second International Meeting on theBiology of Nitric Oxide. London, October, 1991.
21. Lefer AM. Cytoprotective actions of nitric-oxide and NO donors inischaemia-reperfusion of coronary and splanchnic circulations. SecondInternational Meeting on the Biology of Nitric Oxide. London,October, 1991.
22. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA.Apparent hydroxl radical production by peroxynitrite: implications forendothelial injury from nitnc oxide and superoxide. Proc Natl Acad SciUSA 1990; 87: 1620-24.
23. Randall MD, Griffith TM. Does EDRF have a role in collateral
perfusion following arterial occlusion? Second International Meetingon the Biology of Nitric Oxide. London, October, 1991.
More bad luck for the X chromosome:&agr;-thalassaemia/mental retardation
Once again the X chromosome stands accused ofharbouring the locus of a mental retardation
syndrome. It has long been recognised that severeretardation is more common in males than females,and a substantial proportion of this excess is nowknown to be attributable to sex-linked disorders, mostnotably the fragile X syndrome.1 To an already longlist we can now add another entity-thea-thalassaemia/mental retardation (ATR-X)syndrome.The assocation of haemoglobin H (HbH) disease
with mental retardation was first documented in three
boys by Weatherall et al in 1981.2 Subsequent analysisof these three cases plus ten new patients indicatedthat they could be divided into two groups on the basisof clinical, cytogenetic, and molecular fmdings. Ineight patients (six male and two female) there was adeletion involving the ot-globin gene complex onchromosome 16p.3 These individuals had mild tomoderate mental retardation and variable clinicalabnormalities that reflected different degrees ofchromosome imbalance.
By contrast, no abnormality of the a-globin genescould be identified in blood from the second group(five patients), all of whom were severely retarded.4These patients had a similar and unusual facial
appearance: microcephaly, hypertelorism, mid-facehypoplasia, and pouting lower lip. A review of sixteenpublished cases5 confirms that other common findingsinclude a high frequency of convulsions, genitalabnormalities, neonatal hypotonia, and short stature.Curiously, the HbH disease in these patients takes avery mild form; the haematological indices may evenbe normal. Absence of HbH on electrophoresis doesnot exclude the diagnosis, which is best achieved byidentification of HbH inclusions in red cells afterincubation 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 thattheir condition might be due to a mutation on theX-chromosome.4,6 Absolute confirmation of X-
linkage is still awaited, but reports of several families7-9with multiple affected males related through healthyfemales provide strong circumstantial evidence forsex-linked recessive inheritance. But how might amutation on the X chromosome influence the
synthesis of a-globin chains coded for by genes on
