pendapat holy grail

8/11/2019 Pendapat Holy Grail

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2 Solimena M, Folli F, Denis-Sonini S, et al. Autoantibodies to glutamic aciddecarboxylase in a patient with stiff-man syndrome, epilepsy and type Idiabetes mellitus. N Engl J Med 1988; 318: 1012–20.

3 Folli F, Solimena M, Cofiell R, et al. Autoantibodies to a 128 kD synapticprotein in stiff-man syndrome with breast cancer. N Engl J Med 1993; 328:546–51.

4 Wessig C, Klein R, Schneider MF, Toyka KV, Naumann M, Sommer C.Neuropathology and binding studies in anti-amphiphysin-associated stiff-person syndrome. Neurology 2003; 61: 195–98.

5 Yoshida Y, Kinuta M, Abe T, et al. The stimulatory action of amphiphysinon dynamin function is dependent on lipid bilayer curvature. EMBO J 2004;23: 3483–91.

6 Dinkel K, Meinck HM, Jury KM, Karges W, Richter W. Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylaseautoantibodies in stiff-man syndrome. Ann Neurol 1998; 44: 194–201.

7 Lohmann T, Hawa M, Leslie RDG, Lane R, Picard J, Londei M. Immune

reactivity to glutamic acid decarboxylase 65 in stiff-man syndrome andtype 1 diabetes mellitus. Lancet 2000; 356: 31–36.

8 Atkinson MA. The $64 000 question in diabetes continues . . .Lancet 2000; 356: 4–6.

9 Dalakas MC, Li M, Fujii M, Jacobowitz DM. Stiff person syndrome:quantification, specificity, and intrathecal synthesis of GAD65 antibodies.Neurology 2001; 57: 780–84.

10 Brashear HR, Phillips LH. Autoantibodies to GABAergic neurons andresponse to plasmapheresis in stiff-man syndrome. Neurology 1991; 41:1588–92.

11 Koerner C, Wieland B, Richter W, Meinck H-M. Stiff-person syndromes:motor cortex hyperexcitability correlates with anti-GAD autoimmunity.Neurology 2004; 62: 1357–62.

12 Burns TM, Jones HR, Phillips LH, Bugawan TL, Erlich HA, Lennon VA.Clinically disparate stiff-person syndrome with GAD65 autoantibody in afather and daughter. Neurology 2003; 61: 1291–93.

13 Burns TM, Jones HR, Phillips LH. Stiff person syndrome does not alwaysoccur with maternal passive transfer of GAD65 antibodies. Neurology2005; 64: 399–400.

14 Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist andpredict cancer, not neurological syndrome. Ann Neurol 2004; 56: 715–19.

15 Antoine JC, Absi L, Honnorat J, et al. Antiamphiphysin antibodies areassociated with various paraneoplastic neurological syndromes and

tumors. Arch Neurol 1999; 56: 172–77.16 Saiz A, Dalmau J, Husta Butler M, et al. Anti-amphiphysin I antibodies in

patients with paraneoplastic neurological disorders associated with smallcell lung cancer. J Neurol Neurosurg Psych 1999; 66: 214–17.

17 Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteriafor paraneoplastic neurological syndromes. J Neurol Neurosurg Psych 2004;75: 1135–40.

Pre-eclampsia remains one of the most complex

challenges for perinatal clinicians and researchers. As a

major cause of maternal and perinatal mortality and

morbidity worldwide, this condition lacks an effective

prevention strategy or curative treatment. Furthermore,

the efforts to develop screening tests have been

disappointing for potential use in clinical practice.

Agustin Conde-Agudelo and co-workers recently

published a systematic review of screening tests for pre-

eclampsia, derived from 87 studies in 211369 women.1

On the basis of a comprehensive review of clinical,

biophysical, and biochemical tests, the authors conclude

that there is currently no clinically useful screening test

to predict the development of pre-eclampsia.

Why do we need an efficient screening tool for pre-

eclampsia? In general, risk screening is justified when a

test is able to define a population that will benefit from

an effective preventive treatment (primary prevention),

or when earlier diagnosis will lead to more timelyintervention that will decrease disease morbidity

(secondary prevention).2 For pre-eclampsia, primary

prevention with low-dose aspirin or calcium

supplementation is disappointing.3 A possible reason for

this lack of effect is that the large trials that tested

interventions recruited low-risk to moderate-risk

women, or women judged at high-risk solely on the

basis of clinical risk factors. Given that pre-eclampsia is

likely to be a heterogeneous condition, potentially

involving several separate pathophysiological pathways,

it is not surprising that simple clinical indicators areineffective in identifying women who would benefit

from a pathway-specific treatment

Screening for pre-eclampsia: the quest for the Holy Grail?

S c i e n c e

P h o t o L

i b r a r y

Rights were not granted to include thisimage in electronic media. Please refer

to the printed journal



Comment

A few studies have used screening tests as inclusion

criteria in trials. For instance, a trial of prevention of pre-

eclampsia with antioxidant vitamins recruited women

with abnormal two-stage uterine-artery doppler

analysis.4 This trial showed promising results and several

trials are underway to confirm this potential. In future

prevention trials, careful consideration must be given to

the choice of an appropriate screening strategy to select

women who are most likely to benefit from the

proposed treatments, thus increasing the chance of

showing a reduction in the incidence of the disease.

Furthermore, trials can provide a unique opportunity to

stratify randomisation according to screening-test

results.

What are the pathophysiological bases for pre-

eclampsia screening? Whilst the causes of pre-eclampsia

remain elusive, it is accepted that abnormal early

placentation and reduced placental perfusion have a role

in the start of the condition. Coagulation activation,

oxidative stress, endothelial damage, and inflammation

are all associated with pre-eclampsia.5 In their review,

Conde-Agudelo and co-workers distinguish four

categories of dysfunction-related tests: placental

perfusion and vascular resistance (particularly on

doppler scan); the endocrinology of the fetoplacental

unit; tests for renal dysfunction; and tests for

endothelial dysfunction and oxidant stress. The

disappointingly low likelihood ratios obtained with

various individual tests might be partly explained by the

heterogeneous nature of the disease. Some types of

pre-eclampsia might be best detected by uterine artery

doppler while others will lead to abnormal serum levels

of placental peptides or markers of endothelial stress. It

would therefore be of interest to explore combinationsof tests of different categories.

What is the current evidence about screening tests for

pre-eclampsia? From Conde-Agudelo and co-workers’

review,1 it appears that several tests have acceptable

positive and negative likelihood ratios, in the range of

4–6. Although heterogeneous, results of doppler

screening of the uterine artery are encouraging. Doppler

should probably be part of any future prospective

evaluation, ideally during the first trimester.6 Similarly,

screening by serum levels of inhibin A provides higher

likelihood ratios than most other biochemical testsalone.1 Moreover, we have reported elevated levels of

inhibin A as early as 7–13 weeks’ gestation in women

who subsequently developed pre-eclampsia.7 We agree

with Conde-Agudelo that, at present, there is no single

best screening test for pre-eclampsia. However, their

review provides an interesting overview of potential

candidates deserving further research.

What are the realistic expectations for pre-eclampsia

screening in the near future? Recent progress in

understanding of the disease process, combined with the

availability of powerful tools including proteomics and

metabolomics, will continue to provide promising new

markers. Consequently, the next important step in the

evaluation of screening tests for pre-eclampsia is to

assess the test properties of combinations of existing

tests.8,9 For instance, combining doppler analysis of the

uterine artery, placental markers such as human chorionic

gonadotropin, inhibin A, pregnancy-associated plasma

protein A, and markers of endothelial or oxidative stress

could provide a comprehensive approach to the different

pathways of the disorder. If markers of a different nature

prove to be statistically independent in the prediction of

pre-eclampsia, their combination will improve the

screening strategy. An example of the successful

combination of screening tests of a different nature is

given by first-trimester screening for Down’s syndrome,

in which the addition of ultrasound to biochemical

markers has greatly improved the performance of

screening.10 It is now time to start large prospective

studies evaluating multiple markers combining clinical,

biophysical, and biochemical tests for pre-eclampsia,

both in low-risk and high-risk populations.

François AudibertDepartment of Obstetrics and Gynecology,

Hospital Sainte-Justine, Université de Montreal, Montreal,Québec, Canada H3T 1C5

[email protected]

I declare that I have no conflict of interest.

1 Conde-Agudelo A, Villar J, Lindheimer M. World Health Organizationsystematic review of screening tests for preeclampsia. Obstet Gynecol2004; 104: 1367–91.

2 Dekker G, Sibai B. Primary, secondary, and tertiary prevention of pre-eclampsia. Lancet 2001; 357: 209–15.

3 Sibai BM. Prevention of preeclampsia: a big disappointment. Am J Obstet Gynecol 1998; 179: 1275–78.

4 Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on theoccurrence of pre-eclampsia in women at increased risk: a randomisedtrial. Lancet 1999; 354: 810–16.

5 Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia.Lancet 2001; 357: 53–56.

6 Harrington K, Carpenter RG, Goldfrad C, Campbell S. Transvaginal Dopplerultrasound of the uteroplacental circulation in the early prediction of pre-eclampsia and intrauterine growth retardation. Br J Obstet Gynaecol 1997;104: 674–81.



Comment

When a child presents to a medical provider with

suspicious bruising, one of the first tasks is to find out

whether the bruises are the result of abuse or merely a

side-effect of normal childhood activity. If an injury is

found to be a result of abuse, the next question will

invariably be a request about the age of the bruise.

These are the most frequent questions posed to

physicians evaluating maltreated children. How these

questions are answered can determine if a child is

removed from their home or if a parent or caregiver is

criminally prosecuted. The weight of the response

should be balanced by the knowledge of the science:

bruises are one of the most common manifestations of

child abuse. Bruises in active mobile children are very

common.

Recently, Sabine Maguire and colleagues summarised

the current literature about patterns of bruising and

ageing of bruises. In their first article,1 a review of the

literature on bruising in infants and children in general,

they describe their methods. When 6984 papers

spanning 53 years were reviewed, they found 23 papers

met their criteria for full analysis by 15 reviewers. Seven

papers addressed bruising in non-abused children while

two more discussed both abused and non-abused

children. No differences were noted between children

of various socioeconomic groups. Increased bruisingwas noted as age and development advances, during

summer months, and with increased family size. Also,

lack of bruising in children not yet independently

mobile was noted. There was a strong correlation in

areas of bruising in non-abused children: forward, bony

prominences. Abusive bruises had a typical pattern and

distribution as bruises were seen on soft parts of the

body. Fourteen papers covered bruising in abused

children alone and two more discussed both abused

and non-abused children. The head was the most

common site for bruises in abused children.The conclusions are clinically intuitive, but provide a

more empiric literature-based review that provides an

essential framework for any clinician attempting to

determine the cause of bruising. Jenny cautions that

“the aging of bruises is an inexact process” and that

“soft tissue injury is extremely uncommon” in younger

children and the distribution of bruises in abused and

non-abused children differed by development and

age.2 Jenny and colleagues also noted that in infants,

bruising might be an ominous indicator of more

serious maltreatment, namely abusive head injury.

Indeed, when apparently minor bruising was

overlooked in a non-mobile infant, serious and even

fatal injury could follow.3

Maguire and colleagues have done a comprehensive

review of the medical literature for evidence-based

medicine about bruising. Their findings on patterns of

Bruising in children

7 Salomon LJ, Benattar C, Audibert F, et al. Severe preeclampsia is associatedwith high inhibin A levels and normal leptin levels at 7 to 13 weeks intopregnancy. Am J Obstet Gynecol 2003; 189: 1517–22.

8 Florio P, Reis FM, Pezzani I, Luisi S, Severi FM, Petraglia F. The addition of activin A and inhibin A measurement to uterine artery Dopplervelocimetry to improve the early prediction of pre-eclampsia.Ultrasound Obstet Gynecol 2003; 21: 165–69.

9 Audibert F, Benchimol Y, Benattar C, Champagne C, Frydman R. Prediction

of preeclampsia or intrauterine growth restriction by second trimesterserum screening and uterine Doppler velocimetry. Fetal Diagn Ther 2005;20: 48–53.

10 Audibert F, Dommergues M, Benattar C, Taieb J, Thalabard JC, Frydman R.Screening for Down syndrome using first-trimester ultrasound andsecond-trimester maternal serum markers in a low-risk population: aprospective longitudinal study. Ultrasound Obstet Gynecol 2001; 18:26–31.

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