the near future. To be accepted, however, the nitrate
respiratory rate and a greater increase in oxygen saturation
formulation may need further refinement.
with isosorbide dinitrate than with furosemide. The fall in
heart rate is of interest, because it suggests reduced
Department of Cardiovascular Medicine, University of Birmingham and
sympathetic drive; in other studies heart rate did not
University Hospital Birmingham NHS Trust, Edgbaston,
change significantly with infusion of isosorbide dinitrate or
nitroprusside,1,2 but it did fall with isosorbide mononitrategiven as bolus9 (table). However, the mean initial heart
Chatterjee K, Parmley WW, Ganz W, et al. Haemodynamic andmetabolic responses to vasodilator therapy in acute myocardial
rate was only 91 (SD 5) beats per minute in the study by
infarction. Circulation 1973; 48: 1183–93.
Nelson and colleagues and 94 (14) in that by Chatterjee
Nelson GIC, Silke B, Ahuja RC, Hussain M, Taylor SH.
and colleagues; these heart rates suggest that the
Haemodynamic advantages of isosorbide dinitrate over frusemide in
pulmonary oedema in these two studies was not too
acute heart failure following myocardial infarction. Lancet 1983; i:730–32.
severe, although nine out of 36 patients had clinical
Biddle TL,Yu PN. Effect of furosemide on haemodynamics and lung
features of cardiogenic shock at presentation and there
water in acute pulmonary edema secondary to myocardial infarction.
was significant mortality among Chatterjee’s patients.1,2
Am J Cardiol 1979; 43: 86–90.
Another interpretation of the lack of effect on heart rate of
Mukherjee SK, Katz MA, Michael UF, Ogden DA. Mechanisms ofhemodynamic actions of furosemide: differentiation of vascular and
isosorbide dinitrate infusion is that it was not very
renal effects on blood pressure in functionally anephric hypertensive
effective at reducing sympathetic drive, perhaps because of
patients. Am Heart J 1981; 101: 313–18.
prolonged vasodilatation and hence relative hypotension.
Pickkers P, Dormans T, Smits P. Direct vasoactivity of frusemide. Lancet 1996; 347: 1338–39.
As with many other studies, all patients in the Cotter
Northridge D. Frusemide or nitrates for acute heart failure? Lancet
study received 40 mg furosemide (along with oxygen and
1996; 347: 667–68.
morphine) intravenously before randomisation; local
Lal S, Murtagh JG, Pollock AM, Fletcher E, Binnion PF. Acute
ethical considerations also dictated the use of low-dose
haemodynamic effects of frusemide in patients with normal and raised left atrial pressures. Br Heart J 1969; 31: 711–17.
infusion of isosorbide dinitrate as adjunctive therapy in the
Gammage MD, Murray RG, Littler WA. Isosorbide-5-mononitrate in
furosemide group. In effect, therefore, this study compares
the treatment of acute left ventricular failure following acute
low-dose furosemide plus bolus isosorbide dinitrate
myocardial infarction. Eur J Clin Pharmacol 1986; 29: 639–43.
against high-dose furosemide plus low-dose isosorbide
Bosc E, Bertinchant JP, Hertault J. Utilisation de la trinitrine injectable(bolus de 3 mg) dans le traitement de l’edeme pulmonaire
dinitrate infusion. Unlike most other studies, data were
cardiogenique. Ann Cardiol Angiol 1982; 31: 477–80.
10 Morrison RA, Weigand UW, Jahnchem E, et al. Isosorbide dinitrate
haemodynamic and oxygen-consumption benefits are
kinetics and dynamics after intravenous, sublingual and percutaneous
inferred rather than demonstrated. In addition, the
dosing in angina. Clin Pharmacol Ther 1983; 33: 747–56.
11 Sporl-Radun S, Betzein G, Kaufmann B, Liede V, Abshagen U. Effect
conclusions are further limited by the need to exclude
and pharmacokinetics of isosorbide dinitrate in normal man. Eur Clin J
certain categories of patients—those on chronic nitrate or
Pharmacol 1980; 18: 237–44.
diuretic therapy or with blood pressure lower than 110/70
12 Taylor T, Chasseaud LF, Doyle E. Pharmacokinetics of isosorbide
mm Hg on admission. This latter exclusion may not (in
dinitrate after intravenous infusion in human subjects. Biopharm Drugs Dispos 1980; 1: 149–56.
retrospect) have been necessary since mean arterial
13 Down WH, Chasseaud LF, Grundy RK. Biotransformation of
pressure fell by similar amounts in both groups (132 [SD
isosorbide dinitrate in humans. J Pharm Sci 1974; 63: 1147–49.
14] to 107  mm Hg with isosorbide dinitrate and 124 to 103  mm Hg with furosemide).
Intravenous isosorbide dinitrate has a rapid onset of
action, with peak vasodilatation at 5 min,10–12 but the short
elimination half-life (0·6 h) requires frequent repeat
dosing when given by bolus. Isosorbide-5-mononitrate
Genetic deafness is common, with an estimated prevalence
shares the pharmacological actions of the dinitrate and is
of 1 per 2000 births. Writing in 1853, before the laws of
the main active metabolite formed after administration of
mendelian inheritance had even been promulgated, Sir
isosorbide dinitrate,13 but it has a much longer half-life
William Wilde recognised that the pattern of transmission
(5·1 h). The mononitrate therefore seems to represent a
of deafness varied from family to family, and he clearly
better long-acting nitrate for intravenous bolus use in
identified autosomal dominant, autosomal recessive, and
X-linked forms.1 Latterly, attempts by researchers to
symptomatic and haemodynamic benefits in an open
identify homogeneous families on the basis of associated
study of acute pulmonary oedema,8 but no randomised,
clinical features have led to the recognition of the clinically
prospective comparison has been made with furosemide,
distinct syndromic forms of deafness, which have formed
and no intravenous preparation is yet available.
the basis of much recent progress.2–5 These advances
For intravenous nitrate therapy to displace furosemide
represent a triumph for the rigorous clinical discipline of
for the management of acute pulmonary oedema, it needs
syndrome delineation, and the molecular diagnostic
to be effective in a single bolus injection in most cases,
applications accruing will be widely valued by geneticists
must be safe to use in the presence of moderate
and their patients. However, these new investigations are
hypotension, and must be effective in patients on chronic
likely to be limited in their application by the relative rarity
long-acting nitrate or diuretic therapy. Bolus isosorbide
of the individual syndromes to which they appertain. Most
dinitrate has not yet been shown to fulfil these criteria;
deaf patients, even with a family history suggesting a
genetic cause, have no associated clinical features and are
randomised prospective comparison with furosemide or a
said to have non-syndromic hearing loss.
furosemide/isosorbide dinitrate combination is required.
1997 will be seen as a watershed for genetic advances in
The evidence so far suggests that intravenous nitrates
non-syndromic deafness because of three separate
should have the potential to displace furoemide as first-
developments. First was the report from Kelsell and
line therapy for acute, cardiogenic pulmonary oedema in
colleagues6 that mutations in the connexin 26 (Cx 26) gene
THE LANCET • Vol 351 • February 7, 1998
caused deafness in families with both autosomal dominant
of the G deletion in Cx 26 may also vary in different
and recessive patterns of transmission. Second, a mutation
populations, as has previously been observed for the
in the human homologue of the Drosophila
⌬F508 mutation in the cystic fibrosis gene. Of more
diaphanous, was identified in a large Costa Rican family
immediate relevance is the challenge that the possibility of
with autosomal dominant deafness.7 Finally, the myosin
testing for this mutation in deaf individuals and their
VIIA gene, already known to be mutated in a subgroup of
families poses to clinicians investigating such cases.
patients with Usher’s syndrome, was additionally found to
The investigation of the congenitally deaf patient
cause both autosomal recessive and autosomal dominant
varies widely among paediatricians, otolaryngologists,
audiological physicians, and clinical geneticists. This
epidemiological significance of mutations in human
absence of agreed guidelines probably reflects the different
diaphanous and myosin VIIA remains unclear in terms of
backgrounds of clinicians investigating deafness. However,
their overall contribution to deafness in the general
there has also been a reluctance to investigate, on the
population, several reports have combined to underline the
grounds that a cause that might alter management was
importance of the Cx 26 gene with respect to the aetiology
unlikely to be identified. The data reported today render
of autosomal recessive forms of deafness.11–13 Initial data
this view obsolete and should prompt a re-evaluation of
suggest that 50–80% of autosomal recessive congenital
practice by all concerned, especially since identification of
deafness may be due to the Cx 26 mutation and that up to
Cx 26 mutation will preclude the need for other
70% of such mutations are due to deletion of a single
aetiological investigations, often of a more invasive nature.
nucleotide—loss of a guanine (G), leading, through a
To date, the mutations found have all been identified
frameshift mechanism, to premature termination of the
under the aegis of research. As with so many other
developments in molecular genetics, health services must
Inherited forms are thought to be responsible for
identify avenues by which research discoveries can be
approximately half of all cases of congenital deafness. The
rapidly incorporated into clinical service. For the UK,
commonest inheritance pattern among non-syndromic
what better test of the flexibility of the National Health
deaf families is autosomal recessive, estimated to account
Service in this much heralded anniversary year can there
for up to 75% of all such cases. However, in clinical
be than to see the development of pertinent research, such
practice, autosomal recessive non-syndromic deafness can
as Cx 26 mutation and non-syndromic deafness, for
be recognised only after the birth of a second affected
clinical services, where it clearly has a large part to play in
child, because of the clinical non-specificity of congenital
deafness as a presenting feature. Consequently, genetic
counselling of families with a single deaf child has always
Department of Clinical Genetics and Fetal Medicine, Institute of Child
had to be along unsatisfactory empirical lines, which
would take account of the known chance of recessivity inthe context of clinically indistinguishable deafness of
Wilde WR. Practical observations on aural surgery and the nature anddiagnosis of diseases of the ear. London: Churchill, 1853.
environmental aetiology, new dominant mutations, and so
Abdelkak S, Kalatzis V, Heilig R, et al. A human homologue of the
on. In practical terms, couples with one congenitally deaf
Drosophila eyes absent gene underlies branchio-oto-renal (BOR)
child are counselled a 10% recurrence risk, in the full
syndrome and identifies a novel gene family. Nat Genet 1997; 15: 157–64.
knowledge that, were it possible to identify those families
Neyroud N, Tesson F, Denjoy I, et al. A novel mutation in the
in which the deafness is autosomal recessive, the
potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen
cardioauditory syndrome. Nat Genet 1997; 15: 186–89.
The two related reports in today’s Lancet addressing the
Tyson J, Tranebjaerg L, Bellman S, et al. IsK and KvLQT1: mutation ineither of the two subunits of the slow component of the delayed rectifier
potassium channel can cause Jervell and Lange-Nielsen syndrome. Hum
sporadically occurring deafness are therefore important. Mol Genet 1997; 6: 2179–85.
Not only do these reports prompt a timely re-evaluation of
Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by
the appropriate investigation of the congenitally deaf child
mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997; 17: 411–22.
but they also serve to alter clinical practice in genetic
Kelsell DP, Dunlop J, Stevens HP, et al. Connexin 26 mutations in
hereditary non-syndromic sensorineural deafness. Nature 1997; 387:
Xavier Estivill and colleagues show that about 50% of
autosomal recessive non-syndromic deafness is due to Cx
Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, King M-C. Nonsyndromic deafness DFNA1 associated with a mutation of a
26 mutation, consistent with their previously published
human homolog of the Drosophila gene diaphanous. Science 1997; 278:
data.11 More importantly, these investigators identified
mutations at this locus in 37% of individuals with
Liu X-Z, Walsh J, Mburu P, et al. Mutations in the myosin VIIA gene
sporadically occurring deafness; almost a third of the
cause non-syndromic deafness. Nat Genet 1997; 16: 188–90.
Weil D, Kussel P, Blanchard S, et al. The autosomal recessive isolated
mutations were due to homozygosity for the G deletion.
deafness, DFNB2, and the Usher 1B syndrome and allelic defects of the
Less striking, but highly significant nonetheless, are the
myosin VIIA gene. Nat Genet 1997; 16: 191–93.
data from Nicholas Lench and colleagues suggesting that
10 Liu X-Z, Walsh J, Tamagawa Y, et al. Autosomal dominant non-
approximately 10% of patients with sporadically occurring
syndromic deafness caused by a mutation in the myosin VIIA gene. Nat Genet 1997; 17: 268–69.
deafness have Cx 26 mutations, and that three of the six
11 Zelante L, Gasparini P, Estivill X, et al. Connexin 26 mutations
mutations are homozygous for the G deletion. (It should
associated with the most common form of non-syndromic neurosensory
be noted that the various contributors to this rapidly
autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet 1997; 6: 1605–09.
emerging area of research have yet to agree on the
12 Carrasquillo MM, Zlotogora J, Barges S, Chakravarti A. Two different
terminology for the G deletion, some referring to 30delG
connexin 26 mutations in an inbred kindred segregating non-syndromic
and others preferring 35delG.) It remains to be
recessive deafness: implications for genetic studies in isolated
established, over much larger studies of sporadically
populations. Hum Mol Genet 1997; 6: 2163–72.
13 Denoyelle F, Weil D, Maw MA, et al. Prelingual deafness: high
occurring, congenital deafness whether the figure of 37%
prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol
or 10% applies to individual populations. The prevalence
Genet 1997; 6: 2173–77.
THE LANCET • Vol 351 • February 7, 1998
SCHIZOPHRENIA The Training and Education Center Network Mental Health Association of Southeastern Pennsylvania SCHIZOPHRENIA WHAT IS SCHIZOPHRENIA? A brain syndrome characterized by difficulties in thinking, perceiving reality, social functioning and self-care. There is currently no laboratory test which can tell us for sure that a person has Schizophrenia. To deal with this probl
Hipotensão Pós-exercício Aeróbio: Uma Revisão Sistemática Post-exercise Hypotension: a Systematic Review ARTIGO DE REVISÃO Diversos estudos investigaram os efeitos hipotensores após uma sessão de exercício aeróbio em humanos. No entanto, vários aspectos permanecem obscuros em relação à hipotensão pós-exercício (HPE), uma vez 1. Programa de Pós-Gradução Stricto