Evaluation and Treatment of Enuresis KALYANAKRISHNAN RAMAKRISHNAN, MD, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Enuresis is defined as repeated, spontaneous voiding of urine during sleep in a child five years or older. It affects 5 to 7 million children in the United States. Primary nocturnal enuresis is caused by a disparity between bladder capac- ity and nocturnal urine production and failure of the child to awaken in response to a full bladder. Less commonly, enuresis is secondary to a medical, psychological, or behavioral problem. A diagnosis usually can be made with a his- tory focusing on enuresis and a physical examination followed by urinalysis. Imaging and urodynamic studies gener- ally are not needed unless specifically indicated (e.g., to exclude suspected neurologic or urologic disease). Primary nocturnal enuresis almost always resolves spontaneously over time. Treatment should be delayed until the child is able and willing to adhere to the treatment program; medications are rarely indicated in children younger than seven years. If the condition is not distressing to the child, treatment is not needed. However, parents should be reassured about their child’s physical and emotional health and counseled about eliminating guilt, shame, and punishment. Enuresis alarms are effective in children with primary nocturnal enuresis and should be considered for older, moti- vated children from cooperative families when behavioral measures are unsuccessful. Desmopressin is most effective in children with nocturnal polyuria and normal bladder capacity. Patients respond to desmopressin more quickly than to alarm systems. Combined treatment is effective for resistant cases. (Am Fam Physician. 2008;78(4):489-496, 498. Copyright 2008 American Academy of Family Physicians.)
▲ Patient information: A handout on enuresis, written by the author of this article, is provided on page 498.
Enuresis is defined as repeated, spon- uninhibited bladder contractions before
taneous voiding of urine during sleep voiding (i.e., detrusor-dependent enuresis).9 in a child five years or older.1 Enure-
A variety of medical and psychological dis-
sis may be classified as primary or orders are associated with secondary enure-
secondary, and monosymptomatic (uncom-
sis (Table 3 2,6). Underlying psychological
plicated) or nonmonosymptomatic (i.e., con-
stressors are suspected when a child who has
comitant lower urinary tract symptoms are not had enuresis develops the condition dur-present). Table 1 summarizes the types of ing a period of stress.2 In one study, 11 per-enuresis.1,2 Children with primary nocturnal cent of girls who had been sexually abused enuresis are monosymptomatic, have no lower presented with enuresis.12 However, there urinary tract symptoms other than nocturia, is little, if any, association between sexual and have no history of bladder dysfunction.1
Nocturnal enuresis is three times more
Genetic influences on nocturnal enure-
common than daytime wetting and affects 6.7 sis are heterogenous and complex.10 A his-percent of younger children and 2.8 percent tory of enuresis in parents increases the risk. of older children.3,4 It occurs three times more When one or both parents have a history of often in boys.5 Secondary causes account for enuresis, the incidence in children is 44 and less than 25 percent of cases.6,7
77 percent, respectively, compared with a 15 percent incidence in children whose parents
Pathophysiology
do not have a history of enuresis.2 If one twin
Primary nocturnal enuresis is caused by has enuresis, the other twin usually is also a disparity between bladder capacity and affected.10,11 An autosomal dominant mode of nocturnal urine production and the child’s transmission with high penetrance is present failure to awaken in response to a full in some families, and many possible locations bladder.8 Factors associated with enuresis for the responsible genes (in chromosomes 8, (Table 2) include nocturnal polyuria, detru-
sor instability, and an abnormally deep sleep pattern.2,8-12 A small subgroup of children Clinical Features with primary nocturnal enuresis have little or A cross-sectional study comparing patients no arousal to bladder distention and exhibit presenting with primary and secondary
Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2008 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. SORT: KEY RECOMMENDATIONS FOR PRACTICE
Treatment for primary nocturnal enuresis begins with educating the child and parents about the
condition; daytime symptoms should be actively identified and managed before addressing primary nocturnal enuresis; and, if identified, secondary causes should be treated appropriately.
If primary nocturnal enuresis is not distressing to the child, treatment is unnecessary, although parents
should be reassured about their child’s physical and emotional health and counseled about eliminating guilt, shame, and punishment.
An enuresis alarm is effective in children with monosymptomatic nocturnal enuresis; overlearning
(i.e., encouraging the child to drink extra fluids before bedtime to improve bladder capacity) should be added when continence has been achieved for 14 consecutive nights.
Dry-bed training and bladder training alone are not recommended to treat primary nocturnal enuresis.
Anticholinergics are useful in children with urgency, restricted bladder capacity from detrusor
hyperactivity at night, and combined daytime wetting and nocturnal incontinence and in children who do not respond to desmopressin (DDAVP).
Desmopressin is most effective in children who have monosymptomatic enuresis with nocturnal polyuria
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see http://www.aafp. org/afpsort.xml.Table 1. Types of Enuresis Table 2. Factors Associated with and Contributing to Enuresis
Decreased functional bladder capacity; inability
Lack of arousal to bladder distention and
uninhibited bladder contractions (occurs in a
Increased incidence of enuresis in children if one
or both parents have a history of enuresis; in the
case of twins, both children are usual y affected
Delay in central nervous system maturation and in
the development of language and motor skil s
Decreased nocturnal secretion of antidiuretic
hormone causes nocturnal polyuria; blunted
Not common with primary nocturnal enuresis;
response to stress or trauma (e.g., parental
divorce, sexual abuse, trauma at school,
Enuresis occurs in all stages of sleep; an
NOTE: Enuresis is the repeated, spontaneous voiding of urine during
abnormal y deep sleep pattern may occur in
sleep in a child five years or older. *—Standing on the tiptoes, crossing the legs, or squatting with the heel pressed into the perineum (“curtsy sign”).
NOTE: Several factors may contribute to primary nocturnal enuresis.Information from references 1 and 2.Information from references 2, and 8 through 12.
nocturnal enuresis showed that frequency, urgency, secondary nocturnal enuresis and in nearly 75 percent nocturia, constipation, and daytime wetting are com-
of children with primary nocturnal enuresis, is also
mon in both forms of enuresis.13 Constipation, which associated with daytime wetting.13 A more recent pro-occurs in more than 50 percent of children with spective cross-sectional study of children with primary
490 American Family Physician Volume 78, Number 4 ◆ August 15, 2008Enuresis Table 3. Precipitating Conditions Associated with Secondary Enuresis
Urinalysis and urine culture help detect infection.
Select laboratory tests are useful in diagnosing causes
of secondary enuresis (e.g., elevated serum glucose
level from diabetes, elevated blood urea nitrogen and
creatinine levels from chronic renal failure, low serum thyroid-stimulating hormone level from hyperthyroid-
ism). Imaging and urodynamic studies are reserved for
Information from references 2 and 6.
children with significant daytime symptoms, history or diagnosis of urinary tract infections, features suggesting
nocturnal enuresis showed that more than one third of structural renal abnormalities, or refractory cases.2,8patients have constipation.14
Behavioral problems are uncommon in children with Treatment of Primary Nocturnal Enuresis
primary nocturnal enuresis, especially those older than Treatment of primary nocturnal enuresis (Figure 1 and 10 years. These problems are more common in children Table 5 2,8,17,19-35) should begin with educating the child with daytime wetting and over seven times more com-
and parents about the condition. The family should
mon in children with secondary enuresis.15 Behavioral be reassured that primary nocturnal enuresis usually problems include depression, anxiety, social phobias, resolves spontaneously (15 percent annual cure rate).17 conduct disorders, and attention-deficit/hyperactivity Secondary causes that were identified with the history, disorder (ADHD). The association with ADHD is more examination, or laboratory testing should be treated. pronounced in older children (nine to 12 years of age); Simple behavioral interventions are first-line treatment children with ADHD are three times more likely to have approaches. Arousal alarm systems and pharmacother-persistent voiding problems.16 Children with enuresis are apy should be considered in older children who have more likely than other children to have subclinical psy-
greater social pressures and low self-esteem.
chological symptoms (e.g., inferiority complex, shame,
Medication should be initiated in children seven years
irritability, timidity, impatience, isolation). Parental stress and older only if nonpharmacologic measures fail. Chil-(e.g., emotional, social, and financial stress; intolerance; dren who do not respond to one or more measures may frustration) may also occur.8
benefit from combined treatment strategies (e.g., com-bining nonpharmacologic and pharmacologic treatment
Evaluation
or multiple pharmacologic therapies). Children with per-
Most children with primary nocturnal enuresis require sistent enuresis should be referred to a subspecialist. Pres-only an enuresis-focused history, physical examina-
ence of daytime wetting or abnormal voiding, straining
tion, and urinalysis before initiation of treatment; or poor stream, genital abnormalities, or a history of uri- imaging and urodynamic studies are rarely needed nary tract infections also indicates the need for referral.2 (Table 41,2,6,8,10,11,17). The history should include the onset, duration, and severity of enuresis; presence of daytime NONPhARMACOlOgIC OPTIONS wetting, constipation, genitourinary symptoms, and If primary nocturnal enuresis is not distressing to the neurologic symptoms; family history of enuresis; patient child, treatment is not needed. However, parents should medical and psychosocial history; and details of previous be reassured about their child’s physical and emotional treatment. The parents and child should be interviewed.2 health and counseled about eliminating guilt, shame, and A two-week baseline record of the enuresis pattern (blad-
punishment.2,19 Treatment of primary nocturnal enure-
der diary) is helpful in the assessment of enuresis sever-
sis should be delayed until the child is able and willing to
adhere to the treatment program and is rarely indicated in
The physical examination should include evaluation children younger than seven years. It may take months for
of the ears, nose, throat, abdomen, spine, genitalia, and a treatment program to be successful; therefore, the child rectum and a focused neurologic examination. In chil-
must be highly motivated. Daytime symptoms should be
dren with secondary or persistent enuresis, the possibil-
actively identified and managed before addressing primary
ity of sexual abuse must be considered. Signs suggestive nocturnal enuresis.17 Treatment is considered success-of sexual abuse include bruising in areas that are typi-
ful when the child achieves continence for 14 consecutive
cally protected (e.g., buttocks, back, trunk, inner thighs, nights within a 16-week period. Nonresponse to treatment cheeks, neck); multiple bruises; and patterned bruises is defined as less than a 50 percent decrease in enuresis; a (e.g., handprints, belt buckle, bite marks).18
50 to 90 percent decrease suggests a partial response.1
August 15, 2008 ◆ Volume 78, Number 4American Family Physician 491 Enuresis Table 4. Evaluation of Children with Enuresis
Age at onset of enuresis, duration and severity of enuresis, duration of continence (enuresis is not diagnosed
in children younger than five years; recurrence after at least six months of urinary continence suggests secondary enuresis)1,2
Presence of lower urinary tract symptoms* (symptoms other than nocturia suggest nonmonosymptomatic
History of medical il ness (e.g., diabetes mel itus, sleep apnea) may suggest nonmonosymptomatic enuresis6Psychosocial history (psychological disturbances are present in one third of patients with secondary enuresis)8Family history of enuresis (the condition is more common in patients with a family history; in the case of
twins, both children are usual y affected)2,10,11
Fluid-intake diary, bladder and stooling diary, frequency/volume chart (records help assess constipation,
enuresis severity, and treatment response)2,8
Investigation and treatment history Red flags: dysuria, genital or rectal pain or discharge, straining to urinate, combined diurnal and nocturnal
frequency with enuresis (suggests nonmonosymptomatic enuresis)
Ears, nose, and throat examination to detect adenotonsil ar hypertrophyAbdominal examination to detect enlarged bladder or kidneys and fecal masses indicating encopresisGenital examination to detect hypospadias or epispadias, meatal stenosis, ectopic ureter, and labial adhesionsRectal examination to evaluate perianal and perineal sensation and rectal sphincter tone and to detect
Focused neurologic evaluation, including gait, muscle tone, strength, and perineal sensationRed flags (indicate need for further investigation): adenotonsil ar hypertrophy, spinal pathology (deformity,
sacral dimple or hair tuft suggesting underlying spinal dysraphism), motor sensory loss and abnormal tendon reflexes in the lower limbs, enlarged bladder or kidneys, abnormal gait, signs of sexual abuse
Detection of urinary tract infection, diabetes mel itus, diabetes insipidus
Blood urea nitrogen and serum creatinine levels to detect chronic renal failure, serum glucose levels to detect
diabetes, hemoglobin electrophoresis to detect sickle cell disease, serum thyroid-stimulating hormone level to detect hyperthyroidism
Renal and bladder ultrasonography and voiding cystourethrography for a suspected structural abnormality,
significant daytime wetting, or recurrent urinary infections to detect vesicoureteral reflux
Magnetic resonance imaging of the lumbosacral spine for suspected spinal dysraphism or abnormal
Measurement of residual urine and cystometry to evaluate bladder dysfunction (dysfunctional voiding)
*—Nocturia, urgency, daytime wetting, squatting, incontinence, constipation. †—Required only if secondary causes are suspected, red flags are detected on history or examination, or the patient does not respond to standard treatment. Information from references 1, 2, 6, 8, 10, 11, and 17.
Motivational therapy includes reassurance, emo-
are used, failure to achieve dry nights may worsen the
tional support, eliminating guilt, and encouraging child’s self-esteem.19the child to take responsibility for the enuresis (i.e.,
Enuresis alarms (bells or buzzers) triggered by a mois-
although the child did not cause the condition, he or ture sensor in the bed pad or pajamas have long-term she has a role in treating it).20 Simple behavioral inter-
effectiveness2,19,24 Alarms condition children to awaken
ventions include awakening the child to void at times or contract their pelvic muscles. Most children require usually associated with bed-wetting; positive reinforce-
six to 16 weeks of treatment. Enuresis resolves in nearly
ment for desired behavior (e.g., star or sticker charts two thirds of children during alarm use, and nearly one for rewarding periods of continence); bladder training; half of children who continue its use remain dry.24 No and minimizing fluid and caffeine intake before bed-
alarm system is superior to another.21 Sleep disruption
time. These methods are associated with significantly is a problem with alarm use. Factors that predict a good fewer wet nights, higher cure rates, and lower relapse response to enuresis alarms include a cooperative family, rates compared with control groups. However, behav-
no coexisting emotional and behavioral problems, small
ioral interventions have higher nonadherence rates bladder capacity, and frequent bed-wetting (four or more and require significant parental involvement.21,22 Tak-
wet nights per week).8 Enuresis alarms should be consid-
ing the child to the bathroom during the night is labor ered in older, motivated children from cooperative fami-intensive and can frustrate parents. If reward systems lies when behavioral measures are unsuccessful.17,19
492 American Family Physician Volume 78, Number 4 ◆ August 15, 2008Enuresis Evaluation and Treatment of Enuresis
Complete enuresis-specific history Perform physical examination (evaluation of ears, nose, throat, abdomen,
spine, genitalia, and rectum and a focused neurologic examination)
Look for red flags*Perform urinalysis; obtain urine culture, if indicated, based on urinalysis
Diurnal incontinence or nonmonosymptomatic enuresis
(voiding dysfunction, underlying medical condition)
Perform imaging or urodynamic studies, if indicatedSee Table 4 for more information about the
Parental and patient education and reassurance
Nonpharmacologic (behavioral) measures†
Oxybutynin (Ditropan)Combination treatment‡Subspecialist referral
*—Red flags from the patient history include dysuria, genital or rectal pain or discharge, straining to urinate, combined diurnal and nocturnal frequency with enuresis, snoring, and sleep apnea. Red flags from the examination include adenotonsil ar hypertrophy; spinal pathology (deformity, sacral dimple, hair tuft, or nevus); motor sensory loss and abnormal tendon reflexes in the lower limbs; enlarged bladder or kidneys; and abnormal gait. †—Nonpharmacologic measures include fluid restriction, motivation, bladder training, dry-bed training, biofeedback, and enuresis alarms. ‡—Combining nonpharmacologic measures with medication or using more than one medication may lead to better response and lower the risk of relapse, especial y in patients with resistant cases.Figure 1. Algorithm for the evaluation and treatment of children with enuresis.
Combining enuresis alarms with other behavioral or two to three hours after the child goes to sleep is effec-
modalities enhances treatment success. Adding over-
tive in 62 to 77 percent of children. However, relapse
learning (i.e., encouraging children to drink extra fluids rates three months after completion of treatment are the before bedtime to improve bladder capacity) when conti-
nence has been achieved for 14 consecutive nights reduces
Full-spectrum home training includes behavioral
relapse rates.24 Adding dry-bed training (i.e., awakening interventions such as encouraging the child to remove children at specified intervals until they learn to awaken soiled sheets and remake the bed, overlearning, dry-on their own when necessary 17) is effective in 75 percent bed training, and bladder training. A systematic review of children and reduces relapse rates compared with the showed that these measures led to minimal improvement use of an enuresis alarm alone.36 Combining an enuresis when used alone; however, when used with an enuresis alarm with arousal training (i.e., rewarding children for alarm, they reduced relapse rates.23awakening in response to the alarm) is effective in more than 90 percent of children.8
PhARMACOlOgIC OPTIONS
An alarm clock is a simple, inexpensive, safe, and mod-
Pharmacologic therapies are not curative, but they
estly effective alternative to an enuresis alarm and does decrease the frequency of enuresis or temporarily resolve not require bed-wetting to evoke a conditioned response. symptoms over time until spontaneous resolution Using the alarm clock to awaken the child for voiding occurs. Options include anticholinergic agents (oxy-when the bladder is full, but before incontinence occurs, butynin [Ditropan], hyoscyamine [Levsin]); tricyclic
August 15, 2008 ◆ Volume 78, Number 4American Family Physician 493 Enuresis Table 5. Treatment Options for Enuresis Nonpharmacologic* Motivational
emotional support, eliminates guilt, rewards continence (e.g., star or sticker charts)
Constipation: 73 percent effectiveDaytime wetting: 58 percent
Pharmacologic† Oral imipramine (Tofranil),
intoxication, al ergic reaction, hyponatremia, anorexia, nausea, visual disturbance, bad taste in the mouth
NOTE: Children who do not respond to one or more measures may benefit from combined treatment strategies (e.g., combining nonpharmacologic and pharmacologic treatment or multiple pharmacologic therapies).*—General y first-line treatments that should be attempted before pharmacologic therapy; treatments may be combined; requires significant paren-tal involvement. †—Of these therapies, only imipramine and oral desmopressin have been approved by the U.S. Food and Drug Administration for the treatment of enuresis in children. Indicated in children seven years and older. Information from references 2, 8, 17, and 19 through 35.
antidepressants (imipramine [Tofranil], desipramine
Tricyclic antidepressants reduce bed-wetting by one
[Norpramin]); and desmopressin (DDAVP). Of these wet night per week during treatment. Imipramine doses therapies, only imipramine and oral desmopressin have range from 25 mg for children older than six years (weigh-been approved by the U.S. Food and Drug Administra-
ing 20 to 25 kg [44 lb, 1 oz to 55 lb, 2 oz]) to 50 to 75 mg
tion for the treatment of enuresis in children.
for children older than 11 years. Some recommendations
494 American Family Physician Volume 78, Number 4 ◆ August 15, 2008Enuresis
advise limiting the treatment period to three months Combining desmopressin therapy with an enuresis (including gradual withdrawal).19 Imipramine, 25 mg, alarm improves the response rate and reduces relapse.33should be taken orally one hour before bedtime. If the
Adverse effects from desmopressin use occur in 5 per-
response is not satisfactory after one or two weeks, the cent of patients. Intranasal use may cause nasal conges-dose is increased to 50 mg in children seven to 12 years tion, epistaxis, sore throat, cough, or headaches. Systemic of age and up to 75 mg in older children.20 Most children adverse effects from intranasal or oral use are rare and relapse after discontinuing imipramine treatment.26
include allergic reactions (e.g., rash; swelling of the face,
Parents should be warned about the potentially seri-
lips, or tongue), anorexia, nausea, abdominal cramps,
ous, dose-related adverse effects of tricyclic antidepres-
visual disturbances, and a bad taste in the mouth. Hypona-
sant use.26 Drowsiness, lethargy, agitation, depression, tremia and water intoxication–induced seizures and coma sleep disturbance, and gastrointestinal upset may occur. are also rare, but more common after intranasal use.34 A Rare adverse effects include seizures, cardiac arrhyth-
systematic review suggests that the risk of water intoxica-
mias, and death from accidental overdose.26,27 Pretreat-
tion can be minimized with careful monitoring during
ment electrocardiography to identify underlying rhythm initiation of desmopressin therapy; supervised adminis-disorders is recommended.2
tration to minimize the risk of overdose; fluid restriction;
Anticholinergics (e.g., oxybutynin, 2.5 to 5 mg three prompt assessment for hyponatremia if nausea, vomiting,
times daily) decrease detrusor tone, frequency, and and headache occur; and oral administration.34,35 urgency and improve bladder capacity. Anticholinergic therapy may be used in children with primary nocturnal Treatment of Secondary and enuresis and daytime wetting (restricted bladder capacity Nonmonosymptomatic Enuresis caused by hyperactive detrusor muscle) and in patients If no cause for nocturnal enuresis is evident, primary who do not respond to desmopressin.8,17,28 Adverse effects nocturnal enuresis treatment options are appropri- include dry mouth, blurred vision, headache, nausea, ate. Most children with encopresis-associated enuresis dizziness, gastrointestinal upset, and tachycardia.29
and daytime wetting respond to disimpaction, preven-
Desmopressin, an analogue of vasopressin, reduces tion of reaccumulation of stools, and bowel retraining
urine volume by reabsorbing water from the distal con-
(decreases daytime wetting in 89 percent of patients and
voluted and collecting tubules. Sixty to 70 percent of chil-
nocturnal enuresis in 63 percent of patients).38
dren respond to treatment, although 80 percent relapse
A history of snoring, mouth breathing, behavioral
after discontinuing therapy.2,8,30 Desmopressin is recom-
problems, and daytime somnolence in patients with
mended if the family is unwilling or unable to adhere to enlarged tonsils or adenoids on examination may sug-nonpharmacologic measures. The drug is most effective gest obstructive sleep apnea. Surgical correction of in children eight years and older who have monosymp-
airway obstruction in these patients improves or cures
tomatic enuresis with nocturnal polyuria, normal blad-
nocturnal enuresis and daytime wetting.39
der capacity, and less frequent bed-wetting.31
Individual psychotherapy, crisis intervention, and
Desmopressin is available as an oral tablet (0.2 mg) family therapy are effective measures for psychogeni-
or as a nasal spray (10 mcg per spray); its duration of cally induced enuresis.2 Children with dysfunctional action is 12 hours.2 Initial treatment is usually one tablet voiding have abnormal urine flow patterns on cystom-or one spray every night; the dosage is increased weekly etry, a large amount of post-void residual urine, and a to 0.6 mg or 40 mcg daily. Desmopressin therapy is com-
normal upper urinary tract on imaging and benefit from
bined with fluid restriction (less than 240 mL on nights a voiding regimen. Biofeedback is effective for moti-when the drug is administered) and voiding before bed-
vated children with primary nocturnal enuresis and
time. Equivalent oral and intranasal doses have simi-
dysfunctional voiding.25 Biofeedback improves noctur-
lar potency.30 Another option is rapid titration upward nal enuresis, daytime wetting, constipation, frequency, until continence is achieved within one to three days.32 urgency, voiding patterns, and bladder hyperactivity for The lowest effective dose of desmopressin should be up to two years after completion of therapy.25used. Maintenance therapy of at least four to six weeks
Children with urge incontinence, normal urine flow,
and a slow stepwise dose reduction over six to seven small bladder capacity on urodynamic testing, and nor-months decrease relapse rates after discontinuation of mal imaging results benefit from anticholinergic ther-therapy.32
apy.28 These medications may also be useful in children
Adding oxybutynin to desmopressin therapy increases with both daytime and nocturnal incontinence and in
the response rate in children with daytime wetting.32 children who do not respond to desmopressin.8,17,28
August 15, 2008 ◆ Volume 78, Number 4American Family Physician 495 Enuresis
17. Bedwetting. Paediatric Society of New Zealand. Best practice evidence
The Author
based guideline. Nocturnal enuresis. http://www.paediatrics.org.nz/documents/2005%20documents%20denise/guidelines/Enuresis%20g
KAlyAnAKrishnAn rAmAKrishnAn, mD, is an associate professor
uideline%20final%20endorsed.pdf. Accessed November 26, 2007.
in the Department of Family and Preventive medicine at the University
18. Swerdlin A, Berkowitz C, Craft N. Cutaneous signs of child abuse. J Am
of Oklahoma health sciences Center, Oklahoma City. Dr. ramakrishnan
Acad Dermatol. 2007;57(3):371-392.
received his medical degree and his master’s degree in surgery from the
19. Canadian Paediatric Society. Community Paediatrics Committee. Man-
Jawaharlal institute of Postgraduate medical Education and research,
agement of primary nocturnal enuresis. Paediatrics & Child Health.
Pondicherry, india. he completed a family practice residency at the Uni-
versity of Oklahoma health sciences Center.
20. Cendron M. Primary nocturnal enuresis: current concepts. Am Fam Phy-Address correspondence to Kalyanakrishnan Ramakrishnan, MD, Uni-sician. 1999;59(5):1205-1214, 1219-1220. versity of Oklahoma Health Sciences Center, Dept. of Family and Preven-
21. Glazener CM, Evans JH, Peto RE. Treating nocturnal enuresis in chil-
tive Medicine, 900 NE 10th St., Oklahoma City, OK 73104 (e-mail: kramak
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[email protected]). Reprints are not available from the author.
22. Glazener CM, Evans JH. Simple behavioural and physical interventions
Author disclosure: nothing to disclose.
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The ISME Journal (2008) 2, 171–179& 2008 International Society for Microbial Ecology All rights reserved 1751-7362/08 $30.00Enzyme improvement in the absenceof structural knowledge: a novelstatistical approachYoram Barak1,4, Yuval Nov2,4, David F Ackerley1,3 and A Matin11Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA;2Department of St