Effect of gatifloxacin against Mycoplasma genitalium-related urethritis: an open clinical trial

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Mycoplasma genitalium and Chlamydia trachomatis are the primary pathogens detected from non-gonococcal urethritis (NGU). In this study, the efficacy of gatifloxacin was examined against M genitalium-related urethritis.


The study was an open clinical trial evaluating the effectiveness of gatifloxacin with 200 mg doses twice a day for 7 days against male NGU.


Between March and September 2008, 169 male patients were enrolled, and microbiological and clinical cure rates could be evaluated in 86 patients detected with C trachomatis or M genitalium and in 135 with NGU, respectively. Microbiological cure rates of gatifloxacin against C trachomatis and M genitalium were 100% and 83%, respectively, and the total clinical cure rate was 99%.


Analysis of in-vivo and in-vitro data from the literature of fluoroquinolone efficacies against M genitalium suggests that a MIC90 of 0.125 μg/ml or less may be useful for optimal activity against M genitalium infection.

Keywords: Antibiotics, clinical trials, mycoplasma, NGU

The primary pathogens of non-gonococcal urethritis (NGU) are Chlamydia trachomatis and Mycoplasma genitalium. The symptoms of chlamydial urethritis and M genitalium-related urethritis are quite similar, and patients with NGU have been treated upon their first visit to clinics without knowledge of the specific pathogens underlying their conditions. In any guidelines, either azithromycin or doxycycline regimens are recommended for NGU.1 2 However, previous studies have demonstrated that doxycycline shows poor efficacy against M genitalium-related urethritis,3 whereas the eradication rates of azithromycin against M genitalium were approximately 80%.4 Fluoroquinolones show good antichlamydial activity, much like tetracycline and macrolides. The ability of moxifloxacin to eradicate azithromycin-resistant M genitalium at a lower minimum inhibitory concentration (MIC) has previously been demonstrated,4–6 but levofloxacin shows a poor activity.7

Gatifloxacin is an 8-methoxy fluoroquinolone that shows a broad spectrum and increased antibacterial activities against Gram-positive cocci bacteria, anaerobes, chlamydias and mycoplasmas.8 The antimicrobial activity of gatifloxacin against M genitalium has been shown to be intermediate between those of moxifloxacin and levofloxacin.6 As gatifloxacin also showed good activities against C trachomatis, it could be used as a potential treatment regimen for male NGU; thus, we started an open clinical trial evaluating the effectiveness of gatifloxacin in the treatment of NGU. Unfortunately, gatifloxacin was removed from the US Food and Drug Administration-approved drug list in September 2008 due to serious side effects including abnormal blood glucose levels.9 The US Food and Drug Administration determination ultimately prevented us from completing this study. Regardless of this, it was decided that this paper would be published because gatifloxacin was an available treatment for NGU at the time it was initiated, and our data provide a potentially useful insight into the treatment of M genitalium-related urethritis.

Materials and methods


Male outpatients more than 20 years old, who had symptoms of urethritis including pus discharge, micturation pain, urethral discomfort and itching, were recruited for this study. Patients gave their written consent and agreed to refrain from sexual activity without condoms between their first and last visits. Patients were excluded from the study if they had diabetes mellitus, displayed an allergy to gatifloxacin, were infected with Neisseria gonorrhoeae, were intolerant to gatifloxacin, required therapy with other antimicrobial agents, had severe dysfunction of the heart or liver, were treated with gatifloxacin within the 7 days before the first visit and whose symptoms of urethritis were improving or who had either a history of or diseases relating to epilepsy. The clinicians confirmed the selection and exclusion criteria of the patients for this study and enrolled patients to a specified non-profit corporation, the Supporting Center for Clinical Research and Education, Osaka, Japan, by fax. This study was approved by the ethics committee of Osaka University, Osaka, Japan.


Patients with NGU were given a 200 mg dose of gatifloxacin twice a day for 7 days. On the first visit by patients, clinical symptoms were recorded, the first voided urine of patient was analysed and urine specimens for microbiological examination were collected. Patients with less than five white blood cells (WBC) per high power field in the urinary sediments or 10 WBC/μl of uncentrifuged urine specimens were omitted. Patients re-visited the clinic for evaluation 2–3 weeks after gatifloxacin treatment and the same procedures as the first visit were performed. Finally, the efficacy of gatifloxacin was evaluated microbiologically and the clinical cure rates determined at the re-visit.

Urine collection and microbiological examinations are described below. Approximately 20–30 ml of first voided urine was collected from each patient at least 1 h after their latest urination. A total of 2 ml from these specimens was used for the detection of C trachomatis and N gonorrhoeae using the Aptima Combo2 assay (SRL Co. Ltd., Tokyo, Japan). Then, 8 ml was stored in a freezer until analysis for M genitalium and the rest was discarded. Analysis for M genitalium was performed at the laboratory of urology, Faculty of Medicine, Miyazaki University, Japan. M genitalium was screened by using a real-time PCR assay (TaqMan assay) as described by Jensen et al.10 Specimens with positive results were re-analysed using a 16S ribosomal RNA PCR assay for confirmation.


Between March and September 2008, 169 male patients were enrolled in this study. Among these patients, nine who had had sexual intercourse without a condom during the study period, 22 who did not participate in follow-up visits, two who used other antimicrobial agents and one with an adverse effect (diarrhoea) were omitted. Finally, microbiological and clinical cure rates could be evaluated in 86 patients detected with C trachomatis or M genitalium and in 135 with NGU, respectively.

In 135 patients with NGU, C trachomatis and M genitalium were detected from 53% and 13%, respectively (table 1). Microbiological cure rates against C trachomatis and M genitalium were 100% and 83%. M genitalium remained in three patients, but clinical symptoms were cured with or without the eradication of M genitalium. Micturition pain and urethral itching remained in two with chlamydial urethritis after the eradication of C trachomatis. The total clinical cure rate was 99%.

Table 1

Microbiological and clinical outcome of gatifloxacin against NGU


The effectiveness of fluoroquinolones against M genitalium-related urethritis is varied. Of the fluoroquinolone compounds tested, the MIC90 values of moxifloxacin, sitafloxacin, gatifloxacin, levofloxacin, ciprofloxacin and norfloxacin were 0.125 μg/ml, 0.125 μg/ml, 0.25 μg/ml, 2 μg/ml, 8 μg/ml and 64 μg/ml, respectively.6 Of these fluoroquinolones, moxifloxacin, gatifloxacin and levofloxacin were studied clinically, and their microbiological efficacies were 100%,4 83% and 25%,7 respectively. Assuming that fluoroquinolone tissue levels are equivalent for all drugs in this class, an MIC90 of 0.125 μg/ml or less may be necessary for optimal activity against M genitalium. These data may be useful in selecting new fluoroquinolones for clinical treatment trials in men with NGU, specifically for the treatment of M genitalium. Moxifloxacin is currently not recommended by any of the various sexually transmitted infection treatment guidelines for this purpose and should be studied further in order to be accorded such a recommendation.

In three patients, M genitalium was not eradicated. The M genitalium DNA loads increased after treatment in only one case (793–275 369 geq). On the last visit, this patient showed no signs of urethral discharge, although the WBC in the urinary sediments remained. In two cases, the M genitalium DNA loads decreased (23 373–11 geq, 167020–10 geq), but these specimens were still positive for M genitalium by 16S rRNA PCR assay.


Funding: This study received funding from the Supporting Center for Clinical Research and Education (SCCRE), Osaka, Japan.

Competing interests: None declared.

Patient consent: Obtained.

Ethics approval: This study was conducted with the approval of the ethics committee of Osaka University, Osaka, Japan.

Contributors: RH initiated the study, collected samples and was responsible for analysis of samples for M genitalium, participated in data analysis and wrote the first draft of the manuscript. ST, HK, MY, HH and SA participated in planning the study, collected samples and edited the manuscript. KT was a deputy of a specified non-profit corporation, the Supporting Center for Clinical Research and Education, Japan for enrolling patients. TM initiated the study, is a deputy of the study group and edited the manuscript.

Provenance and peer review: Not commissioned; externally peer reviewed.


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2. British Association for Sexual Health and HIV Clinical Effectiveness Group: 2007 UK National guideline on the management of non-gonococcal urethritis, Update Dec 2008. http// 21 Apr 2011).
3. Mena LA, Mroczkowski TF, Nsuami M, et al. A randomized comparison of azithromycin and doxycycline for the treatment of Mycoplasma genitalium-positive urethritis in men. Clin Infect Dis 2009;48:1649–54. [PubMed]
4. Bradshaw CS, Jensen JS, Tabrizi SN, et al. Azithromycin failure in Mycoplasma genitalium urethritis. Emerg Infect Dis 2006;12:1149–52. [PMC free article] [PubMed]
5. Jensen JS, Bradshaw CS, Tabrizi SN, et al. Azithromycin treatment failure in Mycoplasma genitalium-positive patients with nongonococcal urethritis is associated with induced macrolide resistance. Clin Infect Dis 2008;47:1546–53. [PubMed]
6. Hamasuna R, Jensen JS, Osada Y. Antimicrobial susceptibilities of Mycoplasma genitalium strains examined by broth dilution and quantitative PCR. Antimicrob Agents Chemother 2009;53:4938–9. [PMC free article] [PubMed]
7. Maeda S, Tamaki M, Kubota Y, et al. Treatment of men with urethritis negative for Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum and Ureaplasma urealyticum. Int J Urol 2007;14:422–5. [PubMed]
8. Fung-Tomc J, Minassian B, Kolek B, et al. In vitro antibacterial spectrum of a new broad-spectrum 8-methoxy fluoroquinolone, gatifloxacin. J Antimicrob Chemother 2000;45:437–46. [PubMed]
9. Determination that TEQUIN (gatifloxacin) was withdrawn from sale for reasons of safety or effectiveness. Fed Regit 2008;73:52357–8.
10. Jensen JS, Bjornelius E, Dohn B, et al. Use of TaqMan 5′ nuclease real-time PCR for quantitative detection of Mycoplasma genitalium DNA in males with and without urethritis who were attendees at a sexually transmitted disease clinic. J Clin Microbiol 2004;42:683–92. [PMC free article] [PubMed]

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A 12-Week, Randomized, Controlled Trial With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome With Constipation

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Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C).


This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administration’s (FDA’s) primary end point for IBS-C (responder: improvement of ≥30% in average daily worst abdominal pain score and increase by ≥1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50% of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.


The trial evaluated 800 patients (mean age=43.5 years, female=90.5%, white=76.9%). The FDA end point was met by 136/405 linaclotide-treated patients (33.6%), compared with 83/395 placebo-treated patients (21.0%) (P<0.0001) (number needed to treat: 8.0, 95% confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6/12 treatment period weeks, a reduction of ≥30% in abdominal pain (50.1 vs. 37.5%, P=0.0003) and an increase of ≥1 CSBM from baseline (48.6 vs. 29.6%, P<0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points (P<0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points (P<0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7% of linaclotide and 0.3% of placebo patients.


Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.


Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by frequent and intermittent episodes of abdominal pain and abdominal discomfort that are associated with altered bowel habits (1,2). The symptoms of IBS not only adversely affect a patient’s health-related quality of life (3) but also place a significant financial burden on society due to reduced work productivity and increased use of healthcare-related resources (4,5). IBS with constipation (IBS-C) affects approximately one-third of IBS patients (3), occurs more commonly in women than men (6), and frequently includes additional symptoms, such as abdominal bloating, hard stools, straining, and sensation of incomplete evacuation (7,8).

Traditional therapies for IBS-C, generally directed towards the patient’s predominant symptoms (9), are frequently associated with patient dissatisfaction (10). More recent therapies, including tegaserod and lubiprostone, have been shown to improve global symptoms of IBS-C (9). Tegaserod, a 5-HT4 partial agonist approved by the Food and Drug Administration (FDA) for the short-term treatment of women with IBS-C, was removed from the market in 2007 due to increased cardiovascular events in patients receiving the medication. Lubiprostone, a chloride channel activator that was approved by the FDA for the treatment of women with IBS-C in 2008, has shown efficacy using a global end point (global symptom relief) (11). Given the limited treatments currently available for patients with IBS-C, additional therapeutic options would be of value.

Linaclotide, a minimally absorbed 14-amino-acid peptide structurally related to the endogenous guanylin peptide family of hormones that regulate fluid and electrolyte homeostasis in the intestine, binds to and activates GCC (guanylate cyclase-C) on the luminal surface of the intestinal epithelium. Activation of GCC results in the generation of cyclic guanosine monophosphate (cGMP), which is increased in both the intracellular and extracellular compartments. The increase in cGMP within intestinal epithelial cells triggers a signal transduction cascade activating the cystic fibrosis transmembrane conductance regulator (12). This activation causes secretion of chloride and bicarbonate into the intestinal lumen; sodium ions and water follow, resulting in increased luminal fluid secretion and a reflex acceleration of intestinal transit. Extracellular cGMP, actively transported out of intestinal epithelial cells, is believed to reduce visceral hyperalgesia by modulating the activity of afferent pain fibers (13). In animal models, linaclotide treatment accelerated gastrointestinal transit and reduced visceral nociception (14); in human phase 2 clinical studies, it accelerated colonic transit (15) and improved abdominal pain and constipation associated with IBS-C (16). Likewise, in two large phase 3 trials in patients with chronic constipation, linaclotide significantly improved bowel and abdominal symptoms over 12 weeks (17).

The objective of this phase 3 clinical trial was to assess the efficacy and safety of linaclotide administered once daily as an oral capsule at a dose of 290 μg vs. placebo to patients with IBS-C. A 4-week randomized withdrawal (RW) period was included in this trial to assess the effect of discontinuing treatment with linaclotide.


Trial design

This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was conducted at 118 outpatient clinical research centers (111 in the United States, 7 in Canada) from 14 July 2009 (first patient enrolled) to 12 July 2010 (last patient completed). The protocol and all trial procedures were approved by an Institutional Review Board, and the trial was designed, conducted, and reported in accordance with the principles of Good Clinical Practice guidelines. All patients gave written informed consent before their participation in the trial.

After a screening period of up to 21 days followed by a pretreatment baseline period of 14–21 days, eligible patients were randomly assigned with the use of an interactive voice-response system (IVRS) to receive once daily an oral capsule of either linaclotide 290 μg or placebo, in a 1:1 ratio. Patients who completed all 12 weeks of the double-blind treatment period were eligible to enter the double-blind 4-week RW period in which patients initially randomized to linaclotide were re-randomized (1:1) to linaclotide 290 μg or placebo, and patients previously randomized to placebo were assigned to receive linaclotide 290 μg once a day. Randomization assignments were generated in blocks of four and stratified according to trial center. All sponsor staff involved in the trial, trial center personnel, and patients were blinded to the allocation of trial treatment. Trial visits were conducted at screening, at the start of the pretreatment baseline period, at randomization (day 1), throughout the treatment period (weeks 2, 4, 8, and 12), and at the beginning and end of the RW period (weeks 13 and 16 (end of trial)). Patients made daily calls to the IVRS to report their symptoms throughout the trial.

Trial patients

Female and male patients were eligible to participate if they were at least 18 years of age, and met modified Rome II criteria for IBS (18). In the 12 months before the screening visit, eligible patients were to have for at least 12 weeks, which need not be consecutive, abdominal pain, or abdominal discomfort that had ≥2 of these three features: (i) relieved with defecation, (ii) onset associated with a change in frequency of stool, and (iii) onset associated with a change in form (appearance) of stool, before starting chronic treatment with tegaserod or lubiprostone (if patients had taken these medications); and <3 spontaneous bowel movements (SBMs) per week (SBM=a bowel movement (BM) occurring in the absence of any laxative, suppository, or enema use during the preceding 24 h), and had at least one additional bowel symptom (straining, lumpy or hard stools, and sensation of incomplete evacuation during >25% of BMs), before starting chronic treatment with tegaserod, lubiprostone, polyethylene glycol 3350, or any laxative (if patients had taken these medications). In addition, patients had to report an average score ≥3.0 for daily abdominal pain at its worst (11-point NRS (numerical rating scale)) as well as an average of <3 complete SBMs (CSBMs) per week (CSBM=an SBM associated with a sense of complete evacuation, as reported by the patient) and ≤5 SBMs per week during the 14 days immediately before randomization (i.e., the baseline period).

Patients were excluded if they reported loose (mushy) or watery stools for >25% of their BMs during the 12 weeks before screening or, during the baseline period, a BSFS (Bristol Stool Form Scale) (19) score of 7 (watery, no solid pieces) for any SBM, or a BSFS score of 6 (fluffy pieces with ragged edges, a mushy stool) for >1 SBM. Other key exclusion criteria included history of cathartic colon, laxative or enema abuse, ischemic colitis, or pelvic floor dysfunction (unless successful treatment had been documented by a normal balloon expulsion test); bariatric surgery for treatment of obesity or surgery to remove a segment of the gastrointestinal tract at any time before the screening visit, surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months before the screening visit, appendectomy or cholecystectomy during the 60 days before the screening visit, or other major surgery during the 30 days before the screening visit; history of diverticulitis or any chronic condition that could be associated with abdominal pain or discomfort and could confound the assessments in the trial (e.g., inflammatory bowel disease, chronic pancreatitis, polycystic kidney disease, ovarian cysts, endometriosis, lactose intolerance); family history of a familial form of colorectal cancer. In general, patients were excluded if they were taking drugs that could cause constipation (e.g., narcotics); however, patients taking certain drugs for IBS that might be constipating (e.g., tricyclic antidepressants) were eligible provided that they were on a stable dose for at least 30 days before the screening visit and there was no plan to change the dose after the screening visit. Colonoscopy requirements were based on the American Gastroenterological Association guidelines (20). Women of childbearing potential were required to use contraceptives and have a negative serum pregnancy test. Patients were asked to refrain from making any major lifestyle changes (e.g., starting a new diet or changing their exercise pattern) during the trial.

Rescue medication (bisacodyl 5 mg tablet or 10 mg suppository) was allowed for severe constipation (i.e., 72 h after the patient’s previous BM or when symptoms became intolerable). Use of rescue medication was not allowed on the day before, the day of, and the calendar day after the randomization visit. Patients on a stable, continuous regimen of fiber, bulk laxatives, stool softeners, or probiotics during the 30 days before the screening visit were allowed to continue, provided they maintained a stable dosage throughout the trial.

Efficacy assessments and end points

Daily reports by patients to IVRS included symptom ratings of worst abdominal pain, abdominal discomfort, abdominal cramping, abdominal fullness, and abdominal bloating (all abdominal symptoms were measured using an 11-point NRS), as well as the number of BMs and whether rescue medication was used. Each BM was assessed for sensation of complete bowel emptying (yes/no), stool consistency (7-point BSFS with 1=“separate hard lumps like nuts” to 7=“watery, no solid pieces”), and severity of straining (5-point ordinal scale). Weekly IVRS assessments included IBS severity and constipation severity (both using a 5-point ordinal scale), degree of IBS relief (7-point balanced scale), and adequate relief of IBS-C symptoms (yes/no). Assessment of satisfaction with the trial-medication’s ability to relieve IBS symptoms (5-point ordinal scale) was captured at all study visits following randomization.

Primary end points

There were four prespecified primary end points in the trial, which were all responder end points. One of the four primary end points was based on the FDA recommendations for IBS-C trial design and end points in the recently finalized guidance for IBS clinical trials (May 2012) (21); a responder for this end point (to be referred to hereafter as “FDA end point”) was defined as a patient who met both of the following criteria in the same week for at least 6 of the 12 weeks of the treatment period: (i) an improvement of ≥30% from baseline in the average of the daily worst abdominal pain scores (to be referred to hereafter as “abdominal pain”) and (ii) an increase of ≥1 CSBM from baseline. This combined end point was added after the initiation of the trial, but before completion of enrollment and database lock, with a protocol amendment (no unblinding had occurred). The other three primary end points also required patients to meet weekly responder definitions, but for at least 9 of the 12 weeks of the treatment period. These weekly responder definitions were (i) an improvement of ≥30% in abdominal pain, (ii) ≥3 CSBMs and an increase of ≥1 CSBM from baseline, and (iii) a combined end point that defined a responder as a patient who met criteria for both i and ii in the same week.

Secondary end points

The secondary end points included 12-week change from baseline in abdominal pain, abdominal discomfort, abdominal bloating, stool frequency (CSBM and SBM weekly rates), stool consistency (BSFS), and severity of straining; secondary responder end points included abdominal pain and CSBM responders (using the individual components of the FDA end point). A number of other additional end points were also assessed, including 12-week change from baseline in abdominal fullness and abdominal cramping, IBS symptom severity, constipation severity, adequate relief of IBS-C symptoms, degree of relief of IBS symptoms, and treatment satisfaction.

Safety assessments

At each scheduled study visit, all patients were asked an open-ended question regarding adverse events (AEs). Patients reported AEs by recalling instances since the prior visit. The site investigator assessed all patient-reported AEs and judged each event for severity and relationship to the blinded trial medication. Other safety evaluations included physical examinations, electrocardiogram recordings, vital sign measurements, and standard clinical laboratory tests.

Pharmacokinetic assessments

During the treatment period, a subset of patients had blood samples taken at the randomization and week 4 visits to determine if linaclotide or its active metabolite, MM 419447, could be detected at quantifiable levels in the plasma.

Statistical methods and data analysis

The overall family-wise type I error rate for testing the primary and secondary efficacy end points was controlled at the 0.05 significance level using a five-step serial gate-keeping, multiple-comparison procedure. Based on this multiple-comparison procedure and the results of a previous phase 2b study (16), a sample size of 400 patients per treatment arm was selected to provide >85% overall power to simultaneously detect a difference between the placebo and linaclotide groups for the primary end points.

Responder end points were analyzed using a Cochran–Mantel–Haenszel (CMH) test controlling for geographic region. Continuous change-from-baseline end points were analyzed using an ANCOVA (analysis of covariance) model with fixed-effect terms for treatment group and geographic region and the corresponding baseline value as a covariate. Least-squares means (i.e., means adjusted for the other effects) from the ANCOVA model based on patients’ overall average scores (except for SBMs and CSBMs, for which the overall weekly rates were calculated) are presented. Geographic region was used as a factor in the analyses rather than individual trial centers due to the potential for very small numbers of patients at some trial centers.

If a patient dropped out of the trial or otherwise did not report efficacy data for a particular treatment-period week (patients were required to complete at least four IVRS calls during a treatment week), the patient was not considered a responder for that week. An observed-cases approach to missing data was applied to the change-from-baseline secondary end points, such that if a patient dropped out of the trial or otherwise did not report data, the average of the non-missing data over the 12 weeks of the treatment period was the patient’s value. Patients were assumed to have not had BMs nor taken rescue medication if the corresponding daily question was not answered. For the analysis of adequate relief, degree of relief of IBS symptoms, and treatment satisfaction, a last observation carried forward method was used. All P values were based on two-sided tests.

All randomized patients who took at least one dose of trial medication were included in safety analyses (safety population). Efficacy analyses were based on the ITT (intent-to-treat) population, which included all patients in the safety population who had at least one post-randomization entry of the primary efficacy assessment (i.e., IVRS assessment of abdominal pain or CSBMs).


Patient disposition, demographics, and baseline characteristics

Of the 2,424 patients who were screened for participation in this trial, 803 (33%) were randomized to treatment (Figure 1). Two patients were randomized at more than one trial center but only data from the trial center in which they were first randomized were included in statistical analyses. Of the 802 patients who received double-blind trial medication (safety population), 800 patients had at least one post-randomization entry of the primary efficacy assessment (ITT population). The demographics of the ITT population are shown in Table 1. Following completion of the treatment period, a total of 647 (81%) ITT patients entered the RW period of the trial, of which 645 received at least one dose of trial medication and were included in the RW population. Mean compliance with the trial-medication dosing (assessed by counting pills returned at trial visits) up to trial discontinuation/completion of the 12-week treatment period was 95 and 94% for the placebo and linaclotide groups, respectively. Compliance with the daily IVRS call-in (patients who completed ≥80% of scheduled calls) during the treatment period was 73 and 71% for placebo- and linaclotide-treated patients, respectively. During the pretreatment baseline period, 88% of patients experienced abdominal pain every day and 76% of patients had no CSBMs.

Figure 1

Patient flow through the study.
Table 1

Summary of patient demographic and baseline characteristics (ITT population)

Efficacy results

For all primary and secondary efficacy end points, the linaclotide 290-μg group demonstrated statistically significant improvement compared with the placebo group, controlling for multiplicity.

For the individual components of the FDA end point, a significantly greater percentage of linaclotide-treated patients, compared with placebo-treated patients, reported a reduction of ≥30% in abdominal pain for at least 6 out of the 12 weeks of the treatment period (50.1 vs. 37.5%, P=0.0003 (Figure 2)) or an increase of ≥1 CSBM from baseline for at least 6 out of the 12 weeks of the treatment period (48.6 vs. 29.6%, P<0.0001 (Figure 2)). A total of 136 of 405 patients (33.6%) receiving linaclotide compared with 83 of 395 patients (21.0%) receiving placebo (odds ratio: 1.9, 95% confidence interval: 1.4, 2.7; P<0.0001) met the FDA end point ( Table 2; Figure 2). A significantly greater percentage of linaclotide-treated patients than placebo-treated patients also met the responder requirements for the other three primary end points, which required improvement in abdominal pain (i.e., a reduction of ≥30% in abdominal pain), CSBM rate (i.e., ≥3 CSBMs and an increase of ≥1 CSBM), or both for at least 9 of the 12 weeks of the treatment period ( Table 2). The NNT (number needed to treat) for the primary end points ranged from 7.6 to 14.3.

Figure 2

FDA end point and components. FDA end point: ≥30% abdominal pain reduction and increase ≥1 CSBM from baseline in the same week for ≥6/12 weeks. ****P value <0.0001, ***<0.001
Table 2

Primary efficacy parameter results (ITT population)

Linaclotide-treated patients also experienced statistically significantly greater improvements compared with placebo-treated patients for the secondary and additional end points ( Table 3). During the first week of treatment and for each subsequent week of treatment, linaclotide-treated patients reported greater improvements in worst abdominal pain and CSBM frequency compared with placebo-treated patients (P<0.001; Figure 3). At week 12, the mean decrease from baseline in worst abdominal pain was 2.4% for linaclotide vs. 1.5% for placebo (P<0.0001), and the mean increase from baseline in the weekly CSBM rate was 2.4 and 0.9 for linaclotide and placebo, respectively (P<0.0001). At the end of the Treatment Period (week 12), 52% of linaclotide-treated patients were either “very satisfied” or “quite satisfied” with treatment compared with 23% of placebo-treated patients (P<0.0001).

Figure 3

Weekly results for complete spontaneous bowel movement (CSBM) frequency (a, *P<0.0001 for linaclotide patients compared with placebo patients for each of the 12 Treatment-Period weeks, **P<0.001 for linaclotide–linaclotide
Table 3

Other efficacy parameter results (ITT population)

During the 4-week RW Period, patients who were re-randomized from linaclotide to placebo showed an increase in worst abdominal pain and a decrease in CSBMs to levels similar to those observed in the placebo group during the Treatment Period. The patients who continued to take linaclotide showed sustained improvement in worst abdominal pain and CSBMs similar to that previously observed during the Treatment Period. These improvements were statistically significant compared to patients re-randomized to placebo for weeks 13–16 for CSBMs (P<0.001) and weeks 14–16 for worst abdominal pain (P<0.05). Patients who switched from placebo to linaclotide showed levels of improvement similar to those experienced by linaclotide-treated patients during the Treatment Period (Figure 3).


A total of 228 of 406 linaclotide-treated patients (56.2%) reported at least one treatment-emergent AE (TEAE) compared with 210 of 396 placebo-treated patients (53.0%) in the 12-week treatment period ( Table 4). Most TEAEs were mild or moderate in severity (93.8%, linaclotide; 98.1%, placebo). The incidences of diarrhea (P<0.0001), flatulence (P=0.0084), and abdominal pain (P=0.0462) TEAEs were significantly greater in the linaclotide-treated patients compared with placebo-treated patients. The most common TEAE in the 12-week treatment period was diarrhea, experienced by 19.5% of linaclotide-treated patients compared with 3.5% of placebo-treated patients. The occurrences of diarrhea were reported to be mild or moderate in 71 of 79 linaclotide-treated patients (89.9%) and 13 of 14 placebo-treated patients (92.9%) who experienced diarrhea. There were no SAEs of diarrhea reported during the trial. None of the patients who reported diarrhea experienced clinically significant sequelae (e.g., orthostatic hypotension or dehydration). More than half of linaclotide-treated patients who experienced diarrhea had onset within the first 2 weeks of treatment. Diarrhea was the most common AE resulting in treatment discontinuation in linaclotide-treated patients (5.7 vs. 0.3% in placebo-treated patients); overall, AEs resulted in the premature discontinuation of 32 patients (7.9%) and 11 patients (2.8%) taking linaclotide and placebo, respectively, in the treatment period.

Table 4

Treatment-emergent adverse events (safety population)

Rates of serious AEs (SAEs) did not differ between linaclotide and placebo groups (two patients in each group (0.5%)). In the linaclotide group, the SAEs consisted of one patient who experienced asthma and a second patient who experienced pericardial effusion and pericarditis leading to withdrawal from the trial. In the placebo group, the SAEs consisted of one patient who experienced chronic cholecystitis and a second patient who experienced duodenitis, gastroenteritis, hiatal hernia, esophagitis, renal cyst, and urinary tract infection. There were no deaths during the treatment period; one screened patient died as a result of cardiorespiratory arrest and ventricular fibrillation due to a possible drug overdose, but this patient died before randomization and did not receive trial medication.

There were no clinically significant differences between the linaclotide and placebo groups in the incidence of abnormal laboratory parameters, vital signs, or electrocardiogram parameters. Serum bicarbonate levels were below the lower limit of normal at the end of treatment in seven patients receiving linaclotide compared with one patient receiving placebo. None of these patients reported diarrhea as an AE or other AEs that were considered to be related to low bicarbonate levels.

In the subset of patients who were assessed for linaclotide exposure, no quantifiable plasma levels of linaclotide were detected following trial-medication dosing at the randomization and week 4 trial visits. All patients tested (72 placebo and 64 linaclotide) had levels lower than the limit of quantification for linaclotide (<0.2 ng/ml) and its primary metabolite, MM-419447 (<2.0 ng/ml).

During the RW period, TEAEs occurred in 22.2% of linaclotide–linaclotide patients, 22.1% of linaclotide–placebo patients, and 30.6% of placebo–linaclotide patients. With the exceptions of diarrhea and abdominal pain, the incidence of TEAEs was similar across the three treatment sequences. The incidence of diarrhea was 1.9, 0.6, and 11.7%, in linaclotide–linaclotide, linaclotide–placebo, and placebo–linaclotide patients, respectively. The incidence of abdominal pain was 1.3% in the linaclotide–linaclotide patients and 2.4% in the placebo–linaclotide patients; there were no TEAEs of abdominal pain in the linaclotide–placebo patients. There was no evidence of “rebound” (i.e., worsening in IBS-C symptoms compared with the baseline period in the linaclotide–placebo patients). No SAEs were reported during the RW period.


In this large phase 3 clinical trial, a greater percentage of IBS-C patients who were treated with linaclotide achieved statistically significant improvement in the key symptoms of IBS-C, including abdominal pain and constipation, compared with placebo. Four primary outcomes measures were assessed, including the FDA end point. This end point required that patients experience a benefit of at least 30% when compared with baseline in abdominal pain and an increase of ≥1 CSBM from baseline in the same week for at least 6 out of the 12 weeks of the treatment period. In spite of the rigor of this end point, 33.6% of linaclotide-treated patients were responders compared with 21.0% of placebo-treated patients (P<0.0001). Furthermore, statistically significant differences in responder rates were also demonstrated for the three other primary end points, which required (i) a decrease in abdominal pain of ≥30%, (ii) both an absolute value of ≥3 CSBMs and an increase of ≥1 CSBM from baseline, and (iii) both abdominal pain and CSBM criteria for at least 9 of the 12 weeks of the treatment period.

Although IBS is a disorder with multiple symptoms, abdominal pain is one of the cardinal manifestations and strongly correlates with IBS severity (22) and utilization of healthcare resources (23). Also, an improvement in abdominal pain of ≥30% has been shown to be clinically important in IBS patients (23), and in patients reporting pain relief in general (24). In this trial, more than half of linaclotide-treated patients reported an improvement in abdominal pain of ≥30% for at least 6 out of 12 weeks compared with 37.5% of placebo-treated patients, for an NNT of 7.9. Improvement in abdominal pain began within the first week of therapy, and once reaching maximum at 6–8 weeks, was sustained throughout the remainder of the treatment period. By the last week of the treatment period (week 12), linaclotide-treated patients reported a mean improvement of 43.2% in abdominal pain compared with 27.5% for placebo-treated patients. During the 4-week RW period, patients re-randomized to remain on linaclotide had continued relief of abdominal pain, showing durability of response, while those re-randomized from linaclotide to placebo showed a gradual worsening of abdominal pain symptoms to the level experienced by patients receiving placebo during the treatment period, but without signs of a “rebound” or worsening of symptoms relative to baseline.

In addition to abdominal pain, linaclotide improved several other important abdominal symptoms that are frequently reported by IBS-C patients, including abdominal bloating and abdominal discomfort, beginning during the first week of treatment and continuing throughout the 12-week treatment period. Linaclotide also improved bowel function, including SBM and CSBM frequency, straining, stool consistency, and constipation severity. However, in contrast to the gradual improvement in abdominal symptoms, improvement in bowel function occurred more rapidly. Most linaclotide-treated patients experienced an SBM within 24 h of the first dose of linaclotide (67.4 vs. 43.8% for placebo, P<0.0001); maximal improvement in bowel function usually occurred within the first week. Thus, improvement with linaclotide in abdominal (sensory) symptoms such as abdominal pain may be attributable to more than improvement in bowel function alone. Preclinical data suggest that cGMP, which is released intra- and extracellularly following GCC activation by linaclotide, can reduce the firing of pain-sensing visceral afferent fibers (13). Further studies are under way that may provide a better understanding of the mechanisms by which linaclotide exerts its beneficial effects directly on abdominal sensory symptoms.

Diarrhea was the most common TEAE in linaclotide-treated patients and appears to be an extension of linaclotide’s pharmacological effects. Although diarrhea was reported in 19.5% of linaclotide-treated patients, only 2% reported that they had severe diarrhea and only 5.7% discontinued the drug due to diarrhea. The incidence of SAEs was similar between linaclotide- and placebo-treated patients (n=2 patients in each group); diarrhea was not reported as an SAE.

In conclusion, linaclotide significantly improved abdominal and bowel symptoms in this phase 3 trial (12-week treatment period+4-week RW period).


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Object name is ajg2012255i1.jpg


Annie Neild, PhD, of Ironwood Pharmaceuticals, provided editorial assistance.


Guarantor of the article: Jeffrey M. Johnston, MD.

Specific author contributions: Wrote the initial draft of the manuscript, assisted in the interpretation of data, and provided critical revision: Satish Rao and Anthony J. Lembo; designed the trial: Jeffrey M. Johnston, Bernard J. Lavins, Harvey A. Schneier, and Steven J. Shiff; assisted in the interpretation of data and critical revision of the manuscript for important intellectual content: Jeffrey M. Johnston, Bernard J. Lavins, Caroline B. Kurtz, Mark G. Currie, Harvey A. Schneier, and Steven J. Shiff; provided statistical design, analyses, and interpretation: James E. MacDougall, Xinwei D. Jia, Kelvin Shi, and James Z. Shao; coordinated acquisition of data and trial supervision: Paul Eng and Susan M. Fox.

Financial support: This trial was funded by Forest Research Institute and Ironwood Pharmaceuticals, Inc.

Potential competing interests: Jeffrey M. Johnston, Caroline B. Kurtz, James E. MacDougall, James Z. Shao, Bernard J. Lavins, and Mark G. Currie are employees of Ironwood Pharmaceuticals and own stock/stock options in Ironwood Pharmaceuticals. Harvey A. Schneier, Steven J. Shiff, Paul Eng, Susan M. Fox, Xinwei D. Jia, and Kelvin Shi are employees of Forest Laboratories and own stock/stock options in Forest Laboratories. Anthony J. Lembo and Satish Rao are paid consultants to Ironwood Pharmaceuticals and Forest Research Institute.


Portions of this manuscript were presented as an oral presentation at Digestive Disease Week, May 2011, Chicago, IL.


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Childhood acquired heart diseases in Jos, north central Nigeria

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The patterns of childhood acquired heart diseases (AHD) vary in different parts of the world and may evolve over time. We aimed to compare the pattern of childhood AHD in our institution to the historical and contemporary patterns in other parts of the country, and to highlight possible regional differences and changes in trend.

Materials and Methods:

Pediatric echocardiography records spanning a period of 10 years were reviewed. Echocardiography records of children with echocardiographic or irrefutable clinical diagnoses of AHD were identified and relevant data extracted from their records.


One hundred and seventy five children were diagnosed with AHD during the period, including seven that had coexisting congenital heart disease (CHD). They were aged 4 weeks to 18 years (mean 9.84΁4.5 years) and comprised 80 (45.7%) males and 95 (54.3%) females. Rheumatic heart disease (RHD) was the cause of the AHD in 101 (58.0%) children, followed by dilated cardiomyopathy (33 cases, 18.9%) which was the most frequent AHD in younger (under 5 years) children. Other AHD encountered were cor pulmonale in 16 (9.1%), pericardial disease in 15 (8.6%), infective endocarditis in 8 (4.6%) and aortic aneurysms in 2 (1.1%) children. Only one case each of endomyocardial fibrosis (EMF) and Kawasaki Disease were seen during the period.


The majority of childhood acquired heart diseases in our environment are still of infectious aeitology, with RHD remaining the most frequent, particularly in older children. Community-based screening and multicenter collaborative studies will help to better describe the pattern of AHD in our country. More vigorous pursuit of the Millennium development goals will contribute to reducing the burden of childhood acquired heart diseases in the country.

Keywords: Acquired heart disease, dilated cardiomyopathy, Nigerian children, rheumatic heart disease


Acquired heart diseases (AHD) known to have their origins predominantly in childhood are still major public health problems in the developing world.1,2 The patterns of childhood AHD also vary in different parts of the world.3,4 Reports dating back three or four decades show that “idiopathic cardiomegaly,” endomyocardial fibrosis (EMF), rheumatic heart disease (RHD) and infective pericarditis were the most commonly encountered AHD among Nigerian children.58 More recent reports indicate that there may not only be geographical differences in patterns of disease within the country, but that some diseases, notably EMF, may be disappearing.911 The reports on childhood AHD from North-Central Nigeria have been preliminary.9,12 In this 10-year retrospective review of our echocardiography records, we compare the pattern of childhood AHD in our center in North-Central Nigeria to the historical and contemporary patterns reported from other parts of the country, and aim to highlight possible regional differences and changes in trend.


We reviewed our pediatric echocardiography records over a 10-year period from December 1999, when the service became available at our center, the Jos University Teaching Hospital (JUTH), Jos, Plateau State, until November 2009. The pediatric cardiology unit of JUTH receives referrals from several states in North-Central Nigeria, parts of North-Western and North-Eastern Nigeria, and also from the Federal Capital Territory. All children referred to the unit for management or for echocardiography (ECHO) undergo clinical, radiologic (chest radiograph), and electocardiographic (ECG) evaluation before an ECHO is performed.

During the period under review, three different ECHO machines were in use in the hospital. From December 1999 to July 2000, a Hewlett-Packard (HP) Sonos 1250 was used. The second and third machines, a HP Sonos 1500 and a Logic Expert GE (General Electrics) ultrasound system, were in use from July 2000 to February 2006 and from July 2007 to November 2009 respectively (no machine was available for a 16-month period). All three machines had facilities for two-dimensional (2D), M-mode and color flow Doppler imaging. The latter two also had facilities for pulsed and continuous wave Doppler.

Depending on the age and size of the child and the quality of image produced, 3.5 or 5 MHz frequency transducers were used for the majority of children examined. Occasionally a 2.5 MHz frequency transducer had to be used for an older child. The number of pediatric ECHO procedures performed was limited by factors such as the availability of skilled personnel, cost of the procedure, and periods of equipment breakdown.9 Multiple users (the same machines were used by various other services and departments in the hospital) and unstable power supplies were other factors that not only limited the access of pediatric patients to echocardiography but also contributed to recurrent breakdown of equipment.9

Over the 10-year period, up to four different pediatricians performed ECHO examinations at different times (each after a period of training and supervision) and after the first few years, at least two of them were usually present at each ECHO session. Echocardiographic diagnoses were based on standard guidelines and on the diagnostic criteria for each acquired heart disease (AHD).1317 Rheumatic heart disease (RHD) was defined by the presence of any definite evidence of valve regurgitation or stenosis seen in two planes on Doppler examination, and at least two morphologic abnormalities, such as restricted leaflet mobility, focal or generalized valvular thickening, and abnormal subvalvular thickening of the affected valve.14 In the presence of poor LV contractility (fractional shortening less than 28%), dilated cardiomyopathy (DCM), another frequently encountered lesion, was diagnosed if the left ventricular (LV) dimensions were above the upper limit of normal for age,[14] while nondilated cardiomyopathy (NDCM) was diagnosed if the LV dimensions were within normal limits for age.17 Information obtained from our records included age at the time of ECHO, gender, clinical indication for the ECHO, and the echocardiography findings and diagnosis. This paper is a retrospective review based primarily on ECHO diagnosis. Thus children with normal ECHO were excluded, except there was irrefutable clinical evidence of an acquired heart disease such as infective endocarditis or Kawasaki disease.18,19

The data were analyzed using the statistical software Epi Info® version 3.5.1 of the Centres for Disease Control (CDC) Atlanta, Georgia, USA. Descriptive statistics including means, standard deviations, and frequencies were generated and stratified by age, gender, and heart lesions as appropriate. Means of continuous variables were compared using Student’s t-test while proportions were compared using the chi-square test. The level of statistical significance was set at P<0.05. Permission to publish the data was obtained from the hospital ethical committee.


A total of 580 children aged 2 weeks to 18 years had echocardiographic examinations performed during the period covered by this report, of which 167 (28.8%) had various forms of acquired heart disease (AHD) as their primary diagnoses, 390 (67.2%) had congenital heart disease (CHD) only, 7 (1.2%) children had both AHD and CHD, while 16 (2.8%) had normal ECHO findings. One of the latter, a female infant, had irrefutable clinical features of Kawasaki disease. The seven children with coexisting CHD and AHD were RHD with atrial septal defect (ASD) – two cases; dilated cardiomyopathy (DCM) with ASD – two cases; and three cases of infective endocarditis associated with patent ductus arteriosus, congenital mitral incompetence and Fallot tetralogy respectively.

Thus a total of 175 children were diagnosed with AHD during this period. The commonest indications for ECHO in these children are displayed in Table 1. They comprised 80 (45.7%) males and 95 (54.3%) females and were aged between 4 weeks and 18 years (mean 9.84±4.5 years). There was no significant age difference between males (9.6 ± 4.5 years) and females (9.9±4.5 years) – P=0.31. The relative frequencies, sex distributions, and mean ages of children with different acquired heart lesions are displayed in Tables ​Tables224.

Table 1

Indications for echocardiography in 175 children with acquired heart disease
Table 2

Age at ECHO and sex distribution of 175 children with acquired heart disease
Table 4

Ages at ECHO diagnosis of the most frequently encountered AHD

Rheumatic heart disease

Rheumatic heart disease (RHD) was the most common AHD encountered. It was diagnosed in 101 (57.7%) children, including the two with coexistent atrial septal defect (ASD). No RHD patient was less than 5 years old and they were significantly older than those with the other acquired heart diseases (10.8±3.2 versus 7.7±5.4 years) – P < 0.001 [Tables ​[Tables22 and ​and4].4]. The mitral valve (MV) was the most commonly affected valve – in 95% (96 cases) of the 101 RHD patients and in 96 (47.5%) of a total of 202 diseased valves. The most common isolated valve lesion was mitral incompetence (MI) which was present in 34 (32.3%) of the 101 patients with RHD while the least common was tricuspid stenosis (TS), seen in only one patient (0.95%). Furthermore, regurgitant lesions predominated while mixed valvular lesions (incompetence plus stenosis) were more frequent than isolated stenosis [Table 5]. No patient had isolated pulmonary valve pathology. All four valves were diseased in 16 (15.5%) of patients [Figure 1]. All the mitral and aortic valve lesions as well as the isolated tricuspid stenosis were associated with leaflet or cusp thickening or deformities, while majority (64.8%) of the tricuspid and pulmonary incompetences were not associated with these abnormalities, suggesting they were predominantly functional, or secondary to other valve abnormalities.

Figure 1

Pattern of valvular involvement in 101 children with rheumatic heart disease
Table 5

Pattern of valve pathology in relation to gender in 101 children with rheumatic heart disease


Cardiomyopathy was present in 37 (21.1%) subjects. Those with dilated cardiomyopathy (DCM) were slightly younger (mean age 6.8±4.9 years) compared with other acquired heart diseases and accounted for 33 (89.2%) of all subjects with cardiomyopathy [Tables ​[Tables33 and ​and4].4]. Eight (21.6%) of the children with ECHO features of DCM (dilated and poorly contractile left ventricle) were thought to have possible viral myocarditis based on a history of fever and upper respiratory tract symptoms preceding the symptoms of cardiac failure.20 Human immunodeficiency virus (HIV) infection was retrospectively considered in one child who died of DCM and whose father later died of the acquired immune deficiency syndrome (AIDS). Earlier on, a familial form of DCM had been under consideration due to history of similar illness that led to the death (in infancy) of a younger sibling. Two (5.4%) subjects (aged 9 and 16 years respectively) had nondilated but poorly contractile left ventricles, consistent with nondilated cardiomyopathy (NDCM).17 There was one case each of EMF in a 5-year-old boy and arrhythmogenic right ventricular dysplasia (ARVD) in an 11-year-old boy. No case of hypertrophic cardiomyopathy was diagnosed. However, one of the children with cor pulmonale also had septal hypertrophy.

Table 3

Types and sex distribution of acquired heart disease in children

Other acquired heart diseases

Other AHD diagnosed included cor pulmonale and pericardial disease in 16 (9.1%) and 15 (8.6%) respectively. Infective endocarditis was diagnosed in eight (4.4%) subjects; it was associated with rheumatic heart disease in four children, congenital heart disease in three and dilated cardiomyopathy in one child. Rarer forms of AHD encountered were aortic aneurysm and nondilated cardiomyopathy (two subjects each), and one each of endomyocardial fibrosis, arrhythmogenic right ventricular dysplasia and Kawasaki disease – Table 3.

Cor pulmonale was secondary to pulmonary tuberculosis in four children (two of whom also had human immunodeficiency virus (HIV) infection), sickle cell anemia in two and to poorly treated bacterial pneumonia and suspected broncho-pulmonary dysplasia (the latter in a former preterm) in one case each. The aeitology in the other eight children could not be ascertained.

The 15 patients with pericardial disease included two (13.3%) cases each of constrictive pericarditis (with pulmonary tuberculosis), myo-pericarditis (massive effusions in association with poorly contractile ventricles) and possible pyogenic pericardial effusion (ECHO evidence of organization of the effusion). In the remaining nine children, no direct pointers (clinical or ECHO) to the possible etiologies were found. However, viral pericarditis was considered very likely in the absence of any other systemic disease manifestations.

Four of the eight children with infective endocarditis had visible vegetations. These were on the anterior mitral leaflets of a 12-year-old girl with multivalvular RHD, a 9-year-old boy with NDCM and a 2-year-old girl with DCM; the fourth was in the main pulmonary artery of a boy with a patent ductus arteriosus. The other four children with no vegetations had underlying congenital (two boys) or rheumatic (two girls) heart disease but with compelling clinical features of infective endocarditis. All four eventually responded to prolonged high dose intravenous broad-spectrum antibiotic therapy, but only one of them had a positive blood culture (this was a 9-year-old boy with Fallot tetralogy whose blood culture grew Staphylococcus aureus).


Although based only on patients that came to specialist medical attention and thus not representative of the community prevalence of the various acquired heart diseases (AHD) in the region, our data nevertheless provide insight into the types of AHD common among children in Jos, North Central Nigeria, and by extension the rest of the region. They also provide a basis for comparison with similar studies; for example, we found relatively fewer children with AHD than with congenital heart disease (CHD) – in tandem with recent similar studies from other parts of the country and older studies from some developed countries.10,11,21 It however contrasts with community-based data from Egypt as reported by Refat et al.,22 who screened 8,000 school children and found predominantly rheumatic heart disease (RHD). The difference highlights the afore-mentioned varying emphases of hospital-based studies such as ours (which largely reflect the healthcare seeking behavior of the population) compared with community-based ones that better reflect disease epidemiology. This conclusion may however not be as straightforward as might at first appear.

School-age children are recognized as having the highest risk and prevalence of RHD but only the symptomatic ones are likely to present in hospital. Thus milder cases may not be captured in a hospital-based study. Also, the natural history of CHD is such that its prevalence reduces with age since the most severe cases die early without intervention. Others develop dramatic symptoms at a young age, prompting their families to seek early medical attention. RHD on the other hand, may evolve rather insidiously, with many patients presenting to hospital only when the disease is relatively advanced or complications have set in.3,23 Finally, cases from a wide area (whether congenital or acquired) would tend to congregate, but in a random manner, in a referral center such as ours. All these underscore the fact that hospital and community-based studies both have their different uses, with the former providing useful information in terms of disease pattern while the latter may provide more reliable data for prevalence studies and estimation of disease burden.

Like Refat et al.,[22] we found more girls with AHD than boys, particularly rheumatic heart disease (RHD) in the age range 10–18 years. RHD has been reported by various other authors to be more severe and more likely to occur in females.22,24,25 In consonance with some other Nigerian authors, we found RHD to be the most frequent AHD in children in our center.[5,10] However, a report from Lagos cited effusive pericarditis as the dominant AHD among children and RHD as the second most frequent.[12] The trend in the present report is also similar to that from other parts of the developing world and is an indication of the persistence of the poor social conditions that favor transmission of the group A β haemolytic streptococcal pharyngitis that leads to rheumatic fever (RF) and RHD.3,4,22,24,25 By contrast, Kawasaki disease (KD) is now the most frequent AHD affecting children in developed countries such as the USA and Japan.26,27 Our clinical diagnosis of Kawasaki disease in only one child might be indicative either of a true rarity of the condition in our environment or of a very low index of suspicion among physicians and other health workers. Our patient presented to specialist attention at a very early stage of the disease and was treated vigorously with aspirin which resulted in rapid and complete resolution of all signs and symptoms. The clinical cardiovascular and echocardiography findings in this child were normal throughout the acute phase of the illness and for several months thereafter. Coronary aneurysms, the major ECHO feature of Kawasaki disease, are seen only in the later stages and are usually asymptomatic. Thus children diagnosed with Kawasaki disease must be consistently followed up for several months and screened thoroughly for coronary aneurysms because of the risk of sudden death from coronary thrombosis and myocardial infarction.26,27 Kawasaki disease however has its highest incidence in people of Asian ancestry.26,27

Majority (95%) of our patients with RHD had mitral valve (MV) involvement either in isolation or in combination with other valve pathology. Similar patterns have been reported from other parts of the country.[8,28] The reason for this predominance is not completely clearly but has been attributed by some researchers to the dominance of the left heart.[3] The aortic valve was involved in only 3.6% of our patients, all of whom were aged 6 years and above. In contrast, Jaiyesimi8 in the early 1980s reported about double that figure (7.0%) from Ibadan, including a 4.5-year-old boy with aortic stenosis (AS). Isolated AS has been shown to be rare in RHD. Roberts29 in a necropsy study of 400 patients aged 14 years and above and having functionally severe valvular heart disease demonstrated that AS is usually of nonrheumatic origin. None of his 105 patients with AS demonstrated the Aschoff bodies typically seen in RHD. Our finding of isolated severe tricuspid stenosis (TS) in one of our patients is unusual. In addition to the thickened and severely restricted valve leaflets, there was a previous history of acute rheumatic fever in this patient, which increased the possibility of RHD as opposed to a congenital cause. It is however possible that valve pathology patterns could have geographical or racial differences. This might be a subject for further research.

DCM was the second most frequent acquired heart disease (AHD) we encountered – similar to the report from Kano by Asani et al.10 but different from an earlier Ibadan report8 where it was the least common AHD and a more recent report from Lagos12 where it ranked third in frequency. These differences may reflect a geographic variation in the incidence of DCM within the country. Although the researchers in Lagos classified cases of myocarditis and DCM separately in their series, it is not clear whether they relied solely on ECHO to do this or also on clinical or other features. Both conditions have similar structural and functional features at ECHO and it is widely acknowledged that many of the cases of DCM in children are secondary to myocarditis.21 In most instances, especially in developing countries where there are limited diagnostic facilities, the precise cause of DCM may be difficult to elicit, but studies in developed countries suggest that majority of the cases are usually of viral aeitology.21 Eight of our patients with DCM had preceding symptoms of acute upper respiratory tract infection prior to the onset of congestive heart failure (CCF), suggesting the possibility of viral myocarditis.21 The significant family history in one of our patients and recent literature suggest that HIV infection is an increasingly significant etiologic factor that should be considered in African children with DCM.30,31 DCM is also known to have familial or genetic forms, while recent reports suggest that selenium deficiency is another possible etiologic factor.32,33 With our limited diagnostic facilities we were unable to establish any of these diagnoses. However, micronutrient deficiencies are common among children in sub-Saharan Africa.34 Public health measures aimed at promoting good nutrition in the community in general and children in particular will therefore be helpful in preventing nutritionally derived DCM. The present study also showed that DCM was more common in younger children, while RHD occurred more frequently in school-aged children and adolescents, a trend that is similar to reports from other parts of Nigeria and Africa.10,11,22 These however were the ages at the time of ECHO diagnosis and not at the onset of illness.

Cor pulmonale was present in 15 (8.7%) of our patients with AHD. Much fewer cases have been reported from other parts of Nigeria.8,11 This calls for further investigation, as it is possible that with the high altitude in our locality, the effects of relative hypoxia such as vasoconstriction may lead to an increase in pressure in the pulmonary vascular bed.35 The fact that we found no apparent cause in many of our subjects may support this theory. The few etiologic or associated factors found were poorly treated bacterial pneumonia, tuberculosis, and sickle cell anemia, all of which are recognized causes of cor pulmonale.36,37 Human immunodeficiency virus (HIV) infection is increasingly recognized as another important cause of cor pulmonale in children, either in isolation or in combination with tuberculosis.30 Two of our patients diagnosed with cor pulmonale secondary to pulmonary tuberculosis also had HIV infection. However, during the period under review, we did not routinely screen all our echocardiography or cardiac patients for HIV and so may have missed some other cases.

We saw relatively fewer children with pericardial disease (15 cases or 8.6% of all children with AHD) compared with Lagos where it was the most frequent AHD and Ibadan where it was the second most frequent.8,11,38 On the other hand, Asani et al.10 in Kano reported no cases of pericardial disease at all. These apparent differences may be random or related to geographical variations within the country. Tuberculosis was a predisposing illness in two of our children with pericardial disease. Two of the other cases had associated fever and echocardiographic features of an organizing effusion which would suggest a purulent bacterial aeitology. Although there were no bacterial growths on culture, antibiotic treatment resulted in remarkable improvement, supporting a bacterial infective process and in keeping with the other Nigerian literature.8,11 HIV infection, which we did not routinely screen for, is also an increasingly recognized cause of pericardial disease in African children.30,31

We found only one child with EMF, as did Okoromah et al.,11 while Asani et al,10 reported no such case. By contrast, Antia5 had in 1972 reported 15 cases from Ibadan, while Jaiyesimi[8] in 1982 reported 52 cases from the same institution. The rarity of EMF in this and the other recent reports, may lend credence to the observations of other recent researchers that EMF may be a disappearing disease in Nigeria.39 Reasons adduced for this apparent change include general improvements in nutrition and socioeconomic conditions. Deficiencies of the amino acids leucine, valine, and tryptophan had earlier been implicated in the aeitology of EMF in adults in East Africa.40 Also, basic sanitation has improved, while better education including health education may have effected some behavioral changes that might have led to a reduction in the incidence of parasitic infections suggested in the past to be associated with EMF.41

The relative rarity of endocarditis in our study is not surprising as very few cases have been reported from other parts of the country.11,42,43 This may be the result of a low index of suspicion coupled with the fact that vegetations are usually seen on echocardiography only in advanced cases. The overall incidence in Nigeria and other developing countries is not known. As with our study the reports from Ibadan and Zaria documented endocarditis mainly in children with underlying heart disease.41,42

The other AHD we encountered, namely aortic aneurysm, ARVD and NDCM are all said to be rare in children.21,44 Apart from reports of left ventricular aneurysms from Ibadan,[8,45] reports from other parts of Nigeria have not included any of these heart lesions, a reflection perhaps of their rarity.10,11


RHD is still the most common AHD among children in our center, particularly among older children, while DCM is most common among younger children. There is urgent need for an improvement in living conditions and also a well-planned primary prevention program aimed at prompt and appropriate treatment of streptococcal sore throat alongside secondary prevention of RHD.25,46 These will reduce the incidence of rheumatic fever and its cardiac sequel RHD, as well as arrest disease progression, thus reducing the number of children and young adults requiring expensive heart valve surgeries (which are virtually unavailable in the country) or dying prematurely from chronic heart failure.3,47 There is also a need for more vigorous implementation of the National Tuberculosis Control Programme as this will help to reduce the incidence of its cardiovascular complications such as cor pulmonale and tuberculous pericarditis. Vigorous pursuit of the millennium development goals and a general improvement of child health in the developing world will also have an impact on the incidence of acquired heart diseases in children as the majority of these are of infectious aeitology.48 We also recommend multicenter collaborative studies and community surveys of heart disease prevalence with a view to ascertaining the true burden, spectrum and epidemiology of heart diseases in Nigerian children and to more accurately assess regional differences and changes in trend.


Part of this work was presented at the 37th Annual General and Scientific Conference of the Paediatric Association of Nigeria, held in Jos, Nigeria, in January 2006.

All three authors have fulfilled the criteria for authorship, have read and approved the final manuscript and believe that all the data presented therein are true and represent their honest work.


Source of Support: Nil

Conflict of Interest: None declared.


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Articles from Nigerian Medical Journal : Journal of the Nigeria Medical Association are provided here courtesy of Medknow Publications

Unraveling the Genetic Etiology of Adult Antisocial Behavior: A Genome-Wide Association Study

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James Bennett Potash, Editor


Crime poses a major burden for society. The heterogeneous nature of criminal behavior makes it difficult to unravel its causes. Relatively little research has been conducted on the genetic influences of criminal behavior. The few twin and adoption studies that have been undertaken suggest that about half of the variance in antisocial behavior can be explained by genetic factors. In order to identify the specific common genetic variants underlying this behavior, we conduct the first genome-wide association study (GWAS) on adult antisocial behavior. Our sample comprised a community sample of 4816 individuals who had completed a self-report questionnaire. No genetic polymorphisms reached genome-wide significance for association with adult antisocial behavior. In addition, none of the traditional candidate genes can be confirmed in our study. While not genome-wide significant, the gene with the strongest association (p-value = 8.7×10−5) was DYRK1A, a gene previously related to abnormal brain development and mental retardation. Future studies should use larger, more homogeneous samples to disentangle the etiology of antisocial behavior. Biosocial criminological research allows a more empirically grounded understanding of criminal behavior, which could ultimately inform and improve current treatment strategies.


Historically, the explanation of crime has shifted from a devil-based interpretation in medieval times into a more scientific interpretation, that is theory driven and multidisciplinary. In spite of the multidisciplinary approach of criminology, the last few decades have seen an almost purely environmental approach [1]. Despite the tremendous progress in molecular and behavioral genetics, modern biological approaches have been neglected by most criminological scholars to date. Nonetheless, biological insights seem indispensable in unraveling the etiology of criminal behavior and their incorporation into the explanation of crime should increase the explanatory power of criminology [2]. By elucidating genetic influences on antisocial behavior, a more sophisticated understanding of how the genetic liability of an individual ultimately leads to antisocial behavior can be achieved. Moreover, biological research may reveal the key elements that play a role in the interaction between certain environmental factors and genetic predisposition which would force criminology to expand its theories concerning the underlying biological underpinnings of criminal behavior [1].

It is known that crime related constructs such as conduct disorder [3], aggressive behavior [4], [5], rule-breaking behavior [6] and antisocial behavior [7] are substantially familial and likely heritable. However, few studies have tried to identify the specific genetic variants underlying this heritability. The present study therefore aims to contribute to biosocial criminology by conducting a genome wide association study on antisocial behavior. Previously, Dick et al. (2011) performed a genome-wide association study on conduct disorder, an antisocial syndrome that occurs in childhood and adolescence [8]. We performed the first GWAS on adult antisocial behavior.

Adult antisocial behavior (AAB)

In the present study, we performed a genome-wide association test on a combined dataset, composed of phenotypic data from two cohorts. Adult antisocial behavior was measured by a diagnostic antisocial personality disorder (ASPD) and a non-diagnostic adult antisocial behavior questionnaire. Antisocial personality disorder (ASPD) is a mental health condition defined by the American Psychological Association (APA) as a disorder characterized by “…a pervasive pattern of disregard for, and violation of, the rights of others that begins in childhood or early adolescence and continues into adulthood” [9]. This definition emphatically includes an early start of maladaptive behavior and demands that the behavior is persistent. Evidence of conduct disorder with onset before the age of 15, is therefore stated as an essential condition for the diagnoses of ASPD. The prevalence of ASPD is higher in males (3%) than in females (1%) and shows a high co-morbidity with other psychiatric syndromes [10].

Research has shown that individual differences in antisocial behavior are due to both genetic and environmental influences [11], [12]. Ferguson et al. (2010) showed in a meta-analytic review of behavioral genetic studies, that genetic factors explain 56% of the variance in antisocial personality and behavior, while the remainder of the variance could be explained by unique environmental factors [13]. Moreover, a recent study by Tuvblad et al. (2011) suggested that the development of persistent antisocial behavior was primarily influenced by genetic factors, explaining 67% of the total variance [14]. These studies have highlighted the genetic propensity for displaying antisocial behavior. Candidate gene studies, looking at the association between specific genetic variants and a trait, have identified a number of genetic polymorphisms, such as dopaminergic (DAT1, DRD2, DRD4), serotonergic (5-HTTLPR) and enzymatic degradation (COMT, MAOA) genes related to a number of antisocial phenotypes [1]. Monoamine oxidase A (MAOA), for example, an enzyme that breaks down several monoamine neurotransmitters, has been associated with multiple antisocial phenotypes such as serious physical violence and gang membership [15]. Likewise, low serotonin concentrations (due to the short allele of 5-HTTLPR) have been linked to antisocial and violent behavior [16], [17]. However, candidate studies focusing on the genetic etiology of antisocial phenotypes have generally failed to replicate these genes, a phenomenon observed in genetic studies of other complex traits. For example, Verweij et al (2011), Bosker et al (2010), and Chabris et al (2011) were unable to replicate most of the candidate gene associations for cannabis use, depression, and intelligence [18][20]. Publication bias of candidate gene studies is one likely explanation [21].

Here, we use a hypothesis-free approach by scanning the entire genome to identify novel loci, rather than focusing on small candidate areas only. A previous study using a similar approach focused on the genetic variants underlying conduct disorder (CD), a childhood disorder that often precedes adult antisocial behavior. Dick et al. (2005) found four genome-wide significant (p<5*10−8) markers, two of which were located in a tumor necrosis factor-related gene (C1QTNF7) [8]. The authors state that it remains unclear whether this gene has a biologically relevant role in CD. To date, no genome-wide association study has been conducted on ASPD or any other adult antisocial phenotype. Therefore, we conducted the first GWAS in a large Australian sample of twins and their families to identify common genetic variants underlying variation in adult antisocial behavior.


2.1 participants

A large community sample of twin pairs born between 1964 and 1971 were registered with the Australian Twin Registry (ATR) in 1980–1982 in response to media appeals and systematic approaches through the school system. The present study makes use of ATR participants, drawn from two studies that examined the role of genetic and social factors in drinking habits and co-morbid psychopathology, including antisocial behavior.

Data for the first study were collected between 1996 and 2000, by a telephone psychiatric interview containing lifetime assessments of several psychiatric disorders including adult antisocial behavior. This study cohort includes 1649 (43% male) participants, age range 24–41 (M = 31.2, SD = 3.5) and makes use of a non-diagnostic construct to measure adult antisocial behavior. Subjects in the second cohort were drawn from a series of studies as part of a Tobacco and Alcohol project, of which data were collected between 1981 and 2000. Study cohort 2 includes 3167 (41% male) individuals, who were aged between 18 and 81 (M = 47.6 years, SD = 9.5), and utilizes a diagnostic measure of antisocial personality disorder as its construct. Phenotypic and genotypic data collection was approved by the Queensland Institute of Medical Research (QIMR) Ethics Committee and informed consent was obtained from all participants. Phenotypic data on antisocial behavior were collected retrospectively using a semi-structured interview, administered by telephone. The total sample comprised of all the individuals for whom we had both genotypic and phenotypic data. Yielding a final study sample comprised of 4816 individuals from 2227 independent families.

2.2 Measurement

Adult antisocial behavior was determined from either a diagnostic assessment of ASPD (study 2) or a non-diagnostic measure of antisocial behavior (study 1). Participants in study 2 completed the Semi-Structured Assessment for the Genetics of Alcoholism [22], which includes a diagnostic assessment of antisocial personality disorder based on the criteria in the Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM–IV]; [23]. The Tobacco and Alcohol project questionnaire yields scores on seven empirically derived syndrome scales, composed of 32 items that assessed antisocial behavior after the participant’s 15th birthday. Items include ‘Since age 15, have you been in physical fights?’ and ‘Have you often driven when you were high or drowsy on alcohol or drugs?’. Items were scored on a dichotomous scale (0 = no, 1 = yes). Responses were summed and clustered into the seven syndrome scales stated in the DSM–IV (such as deceitfulness, irresponsibility and aggressiveness). Case status was defined by the endorsement of three or more of the seven DSM–IV ASPD criteria as displayed under Criterion A in the statistical manual. Although we refer to this phenotype as ASPD case status throughout this article, full diagnostic criteria were not applied since Criterion D was not considered (the occurrence of antisocial behavior is not exclusively during the course of schizophrenia or a manic episode) in defining cases. Controls were specified as those who endorsed fewer than three symptoms for DSM-IV ASPD. In total, 122 subjects met these criteria for ASPD case status, while the control group consisted of 3045 individuals.

The non-diagnostic construct obtained from study 1, utilizes seven items related to antisocial behavior that also specifically address unlawful behavior, such as ‘Have you ever been arrested for anything?’ and ‘Have you ever spent time in jail?’. In this study, only those individuals who endorsed at least one of the DSM–IV criteria for conduct disorder were inquired about antisocial behavior. Case status was defined by the endorsement of three or more items, while controls were specified as those who endorsed fewer than three symptoms on antisocial behavior. In this study cohort, 176 subjects met criteria for case status, while the control group consisted of 1473 individuals.

For individuals who were present in both samples (n = 60) we retained the diagnostic criteria from Study 2. Missing items were replaced by the item sample mean and individuals with missing values on more than 25% of the items were removed from the dataset. The combined sample from the two studies comprised 298 cases and 4518 controls; the mean age of the cases was 33.3 years (SD = 8.9; range 18–74 years), while the mean age of the controls was 34.6 years (SD = 9.1; range 18–77 years).

2.3 Genotyping, quality control and imputation procedures

DNA samples were submitted for genotyping under a number of primary projects using different Illumina SNP platforms (Human610-Quad, HumanCNV370-Quadv3 and Human 317K). Standard quality control (QC) filters were applied to the genotyping in the different platforms. QC included checks for ancestry outliers, Mendelian errors, Hardy Weinberg Equilibrium, and Minor Allele Frequency (MAF) and was conducted separately for each of the projects. Thereafter, the combined dataset was screened for missingness within individuals, pedigree and sex errors, and Mendelian errors. Full details of the initial QC procedures for the Illumina and Affymetrix data can be found elsewhere [24]. Imputation to the European reference dataset (HapMap 1+2, Release 22 Build 36) was undertaken by means of MACH [25] using a set of Single Nucleotide Polymorphisms (SNPSs) common across all genotyping platforms. SNPs characterized by either a low minor allele frequency (MAF<.01) or a low imputation quality score (R2<0.3) were removed. Monozygotic twins that were not genotyped were assigned their co-twin’s genotype. The final dataset included ∼2.4 million imputed autosomal SNPs and 13,783 genotyped X-chromosomal SNPs available for association analysis.

2.4 Statistical analyses

Prior to the GWAS analyses, we tested for sex and age effects in our sample in a linear regression model with binary adult antisocial behavior as the dependent variable. We conducted genome-wide association analyses in three study designs using imputation dosage genotypes: 1) combined studies, logistic regression on case-control status with sex, age and study as covariates 2) combined studies, linear regression on symptom count, same covariates as 1), 3) repeated analyses 1 and 2 for the two studies separately with age and sex as covariates. This allowed us to determine consistency among the associations across the studies. Given our family based sample, Merlin offline [26] was used since it accounts for family relationships including MZ twins. Minx (as implemented in Merlin) was used to perform association analyses on the X-chromosome. Ancestry principal components were not significantly associated with the phenotypes and were not included as covariates.

Gene-based test and pathway analysis

We tested for association at the level of genes using the versatile gene-based test for genome-wide association studies (VEGAS) [27]. While accounting for linkage disequilibrium (LD) and number of SNPs per gene, VEGAS aims to identify genes that show a higher signal of association than expected by chance, by considering all the p-values of all SNPs within genes (including ±50 kb from the 5′ and 3′ UTR). The gene-based association test was undertaken for 17,707 autosomal genes, we considered a p-value below α = 2.8×10−6 (0.05/17,707) to be significant. Since the MAOA gene is located on the X chromosome and sex chromosomes are not taken into account in VEGAS, we specifically checked all the SNPs in the MAOA gene that were covered in our dataset, to test if we could replicate the previously reported association in this gene.

A pathway analysis was carried out to determine which potential biological pathways could play a role in antisocial behavior. Pathway analysis was performed in the Ingenuity Pathway analysis program (Ingenuity Systems, release IPA6.0) using genes with a p-value below 0.01. Based on scientific literature, the Ingenuity database contains large amounts of up-to-date information concerning the localization, structure and biological functions of proteins and their interaction. Results were corrected for multiple testing using the Benjamini-Hochberg multiple testing correction as implemented in Ingenuity.

An approximate power calculation [28] indicates that the combined sample provided 50%, 72% and 87% power to detect a genetic variant (with a minor allele frequency of 0.25) with a relative risk of 1.4, 1.5 and 1.6, respectively.

Genome-wide Complex Trait Analysis

Furthermore, we performed a Genome-wide Complex Trait Analysis (GCTA) to estimate the proportion of the heritability of liability to adult antisocial behavior that can be explained by testing the SNPs on the GWAS chips simultaneously [29], [30]. One individual per family was selected for the analysis. We used only genotyped SNPs. To reduce the potential for bias, SNPs that had a Hardy-Weinberg p-value<10−3, had >5% missingness in all samples, or showed evidence of differential missingness between cases and controls (p<0.01), were removed. In this way only good quality SNPs genotyped across all genotyping platforms were retained. A total of 278.570 SNPs remained after quality control. A stringent cut-off of 0.025 was used to remove pairs of individuals that show evidence of cryptic relatedness. The final sample comprised 160 cases and 2012 controls. Analysis was performed using the GCTA software and all 22 autosomes were fitted in the model simultaneously. The prevalence estimate was 0.035% as estimated in the phenotypic sample.


Table 1 provides the means and standard deviations for antisocial behavior of both symptom count and case status derived from the two questionnaires. Consistent with findings in the literature, males had a significantly higher mean score than females on antisocial behavior (p<.001). Similarly, an age (of measurement) effect on the mean score was found. The mean score on antisocial behavior decreased as a function of age in our sample (p<.001). In order to overcome potential bias, we therefore adjusted for age and sex effects by including these variables as covariates in the association analyses. Moreover, because we used multiple study designs to operationalize adult antisocial behavior, study was also used as a covariate in the combined GWAS.

Table 1

Descriptive statistics for antisocial personality disorder (ASPD) and antisocial behavior (ASB).

The results of the association analyses on case status are summarized in Figure 1, and ​and2,2, and Table S1 that show the Manhattan plot, Quantile-Quantile (Q-Q) plots and the SNPs most associated with ASPD, respectively. The Manhattan plot in Figure 1 provides a graphical presentation of the association analyses in the combined study design. The strongest associations were located on chromosomes 5,14,15 and 21. However, none of these associations were genome-wide significant (p<5.0×10−8). Likewise, no SNPs reached genome-wide significance in the association analysis on symptom count of adult antisocial behavior. The genetic power calculation indicates that individual common genetic variants with a relative risk of ∼1.5 or greater do not contribute to individual differences in adult antisocial behavior. Figure 2 shows the Q-Q plots for each of the study designs, allowing inspection of systematic bias and population stratification by comparing the distribution of observed p-values with their expected distribution. The Q-Q plot lambda values are close to 1, indicating that the residual population stratification effect is minimal [31].

Figure 1

Manhattan plot showing the GWAS results of the combined study design for adult antisocial behavior.
Figure 2

Quantile-Quantile plot showing the association between the observed and expected −log10 p-values.

Table S1 lists the top 50 genetic markers showing the strongest association with our phenotype. The top SNPs explained less than 1% of the phenotypic variance, suggesting a highly polymorphic genetic architecture. Using these GWAS results we ran a gene-based association test aimed at finding evidence for association on a per gene basis. Table S2 displays the results of VEGAS and lists the 20 genes that showed the highest signal of association in our sample.

No genes met the criteria for genome-wide significance (p<2.8*10−6), but the most associated gene was Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene (located at 21q22.13). Within the DYRK1A gene, 30 SNPs had a p-value below p<10−5 and there were an additional 96 SNPs that reached nominal significance (p<.05) in the gene, yielding converging evidence of association (see Figure S1). To see whether we could find independent evidence for involvement of this gene, we checked the associations in both study cohorts separately. The DYRK1A SNPs in the first study cohort yielded similar p-values as compared to the combined study design. In the second study cohort, no SNPs were significant at p<0.05.

We examined whether our top genes were more prevalent in any known biological or canonical pathway using genes associated with p-value<0.01. The pathway analyses showed that the top genes in our sample were not significantly more prevalent in any known pathway, although the biological pathway ‘Nervous System Development and Function’ showed the strongest association in our sample (p = .07, after correction for multiple testing).

We estimated the proportion of the heritability of liability to adult antisocial behavior explained by testing all the SNPs simultaneously using GCTA software. The estimated proportion of the phenotypic variance explained by the SNPs on the GWAS chips was 0.55 with a standard error of 0.41 and the estimate was not significantly different from zero (p = 0.07).

Finally, we checked whether the SNPs and genes that are previously associated with antisocial behavior could be replicated in our GWAS panel. Although several genetic polymorphisms related to antisocial phenotypes have been reported in the literature, follow-up studies attempting to replicate these findings reveal mixed results [32]. A list of candidate genes for antisocial phenotypes was gathered from published genetic association studies and gene expression studies. Table S3 contains an overview of the candidate genes that have been previously associated with antisocial phenotypes [33], displayed with their corresponding p-values as derived from our sample. Results indicate that none of the candidate genes reached nominal significance in our gene-based analyses, implicating that in contrast with these previous studies, we did not find evidence in our sample for involvement of these polymorphisms in adult antisocial behavior. Likewise, the genome-wide significant SNPs reported by Dick et al. (2011) did not reach nominal significance (p<0.05) in our sample. The MAOA gene is considered one of the most important candidate genes for antisocial phenotypes [33][39]. Since VEGAS does not take into account the X chromosome in its analyses, we tested all the SNPs across the MAOA gene that were covered by our GWAS panel. None of the seven MAOA SNPs yielded p-values below α = 0.05, implying no evidence for association of the MAOA gene in our sample (see Table S4).


Notwithstanding the enormous potential biology could offer criminology, there is still a relative paucity of biological research in the explanation of crime. The present study aims to contribute to biosocial criminology by performing the first genome-wide association analysis on adult antisocial behavior. Despite the substantial power to detect common genetic polymorphisms, no genome-wide significant SNPs were found. Nevertheless, the most associated gene DYRK1A (p = 8.70 * 10−5) reflected associations at three of our most associated SNPs (rs12106331, rs2835702 and rs2835771). The DYRK1A gene encodes for dual specificity tyrosine-phosphorylation-regulated kinase 1A, an enzyme that is thought to play a role in signaling pathway regulating cell proliferation and has been previously associated with synaptic plasticity and brain development [40], [41]. More specifically, DYRK1A is considered to be a strong candidate gene for mental retardation and is localized in the Down syndrome critical region of chromosome 21. Research has shown that early neuropsychological deficits might lead to poor cognitive functioning, emotional reactivity, and hyperactivity/impulsivity, all known as risk factors for antisocial behavior [42]. Terracciano et al. (2010) reported a nominal association (p = 3.0 * 10−5) of a SNP (rs2835731) within the DYRK1a gene with conscientiousness – a trait related to antisocial behavior [43]. Nevertheless, the associated SNP was not significant (p = 0.37) in our sample. We also tested for replication of the SNPs in the DYRK1a gene with conduct disorder in an American sample (N = 3963, 872 cases, 3091 controls, see Dick et al., 2010) [8]. None of the 99 tested SNPs reached significance after correcting for multiple testing, implying no evidence for replication.

Although several genetic polymorphisms related to antisocial phenotypes have been reported in the literature, follow-up studies attempting to replicate these findings have revealed mixed results [32], [44]. A list of candidate genes for antisocial phenotypes was gathered from published genetic association studies and gene expression studies. Results indicate that none of the candidate genes reached nominal significance in our sample, implicating that in contrast with these previous studies, we did not find evidence for involvement of these polymorphisms in adult antisocial behavior. However, since we did not test for gene environment interaction effects it is still possible that these genetic variants have relatively strong effects when linked with certain environmental factors. Previous studies have underscored the importance of taking into account the close interplay between genetic and environmental factors in the etiology of antisocial behavior. Caspi et al. (2002) showed for example that a functional polymorphism in the MAOA gene moderates the impact of childhood maltreatment on the development of antisocial behavior [45].

The discrepancy between the high heritability estimates in twin and adoption studies on the one hand, and the inability to identify genes involved in these behaviors on the other hand, has been often referred to as the problem of the ‘missing’ heritability [46]. While some genome-wide association studies have been successful in identifying common SNPs, the majority of genetic variants that contribute to disease susceptibility remain undiscovered [29]. Moreover, these associated genes typically explain only a small proportion (<1%) of the genetic variance underlying the trait. The power calculation shows that our sample is unable to detect common genetic variants of small effect sizes that contribute to the variance in antisocial behavior. Yang et al. (2010) showed that it is likely that the heritability is not ‘missing’, at least in part, but that the SNPs that tag certain genes have a very small effect individually and might therefore not be detected in the analyses [30], [47]. We estimated that the total proportion of phenotypic variance explained by genome-wide SNPs when considered together is 0.55, with a standard error of 0.41. The point estimate is non-significantly different from zero and larger sample sizes, enriched for cases, will be required to ensure sufficient power to accurately estimate the proportion of phenotypic variance in adult antisocial behavior explained by all the genome-wide SNPs. The application of this methodology to criminal behavior phenotypes is particularly relevant, a field in which a genetic contribution to the etiology remains contentious. Although the classical twin design for estimation of heritability is designed to separate out the common family environment effects from genetic effects in the familial relationship, some contamination with common environmental effects could remain [48]. The methods of Yang et al, estimate the contribution of genetic effects from such distantly relatives that contamination with family environmental effects is less likely.

Research has shown that it is likely that each gene associated with antisocial behavior affects many brain pathways (pleiotropy), while at the same time many genes affect each single brain pathway related to antisocial behavior (polygenicity) [1]. Hence, the genetic complexity of antisocial behavior makes it difficult to reveal causative genetic variants involved in this trait. Future research could therefore focus on functionally integrated brain networks, consisting of groups of genes, which are selected on the basis of their biological role. Functional gene group analyses are different from the pathway analysis conducted here, where we tested whether associated genetic variants are more prevalent in any known biological pathway. Instead, functional gene-group analysis tests whether the associated genes are more prevalent in any known functional gene-group (genes with a similar cellular function). As such, this analysis can deliver additional information to the field of criminology by complementing single SNP analysis [49]. Subsequently, genetic data combined with new biological techniques such as neuroimaging, could further explore the neurobiological underpinnings of criminal behavior by linking the genetic makeup of an individual to his neuroradiological features. Testing the hypothesis that there is a relationship between functional genetic networks, abnormalities in brain morphology and intra/inter-hemispheric connectivity related to antisocial phenotypes could be promising. Moreover, the neuroimaging data acquired can serve as an intermediate (endo-) phenotype and thus be used to form homogeneous groups of specific subtypes of antisocial behavior (such as aggression or conduct disorder), which improves biological interpretability as well as phenotypic differentiation under the assumption that different subtypes also have a different etiology [50].

Given the fact that criminology is in itself a highly multidisciplinary study, it is surprisingly that biological knowledge has been neglected by the majority of the criminological scholars the last few decades. There may be multiple reasons why criminologists have been cautious in applying biological theories to crime. The unpopularity of biosocial criminology is partly due to unfounded concerns regarding genetic determinism. Current biological approaches in criminology still suffer from the image of the Italian school of Cesare Lombroso in the nineteenth century [2]. In his most famous work ‘Criminal Man’ [51], Lombroso postulated that crime was caused by biological defects in inferior “atavistic” individuals who were “throwbacks” from an earlier evolutionary stage of human development. Although Lombroso published widely on the origins of delinquency, he is recognized and criticized most about his idea of physiognomy: the born criminal that could be distinguished by physical characteristics, such as large jaws and high cheekbones [52]. It is this reputation, a rather unsophisticated methodology used by early founders of biological theory that still puts biosocial criminology in a bad light. Nowadays the methodological tools have become one of the strengths of biology which is, as an exact discipline, characterized by empirical research and could therefore be of important value for criminology. Subsequently, the contemporary zeitgeist seems to be more receptive for further insights and the resistance against biology may gradually diminish [53].

Given the rise of modern biology in the explanation of crime, it is important to look ahead for the potential ethical implications that emanate with the emergence of neurobiological research. Crime is strongly related to our legal system and thereby impacts on typical legal concepts such as responsibility and free will, which explains why the use of biological techniques remains controversial [54]. Biosocial criminology urges a greater philosophical question whether an individual still has freedom to act if his behavior is biologically caused. Opponents argue that free will, as the foundation of our legal system, would be undermined if crime has genetic origins. It is clear that there are legal and ethical issues arising from behavioral genetics and neuroscience and these concerns should be taken into meticulous consideration [55]. In biosocial criminological circles it is widely acknowledged that there are ethical drawbacks to a strict biological approach and the large majority of these authors aim to have a biosocial perspective on crime rather than genetic determinism [1]. However, sometimes scientific findings are erroneously used by the uninitiated. Recently an Italian appeal court reduced the sentence of a murderer by one year, on the grounds of identifying the MAOA gene linked to violent behavior. It is exactly this type of events that shapes the fear of genetic research. Logically, behavioral geneticists from all over the world have challenged this ruling. Contemporary knowledge in genetics is surely not capable of predicting behavior at an individual level (as is clear from heritability estimates that are substantially less than one), but only in large population statistics [56].

Nevertheless, integrating biological research into the traditional sociological theories of crime, could be helpful in unraveling the complex etiology of criminal behavior. Ultimately, neuroscientific research could provide clues on which psychological or pharmacological interventions are suitable in improving the neurobiological pathways disrupted in antisocial individuals. To conclude, the study of crime has been eminently theoretical and lacks substantial empirical verification of those theories [57]. For these reasons, biological research could be of tremendous importance for criminology by incorporating empirical research into the traditional explanations of crime.

Supporting Information

Figure S1

Plot showing linkage disequilibrium and association of the SNPs in the DYRK1A region.


Table S1

50 strongest SNPs associated with adult antisocial behavior.


Table S2

Top 20 genes showing strongest association with adult antisocial behavior.


Table S3

Association results from the seven candidate genes previously found in antisocial phenotypes.


Table S4

Association results of the SNP p-values within the MAOA* gene in our sample.



We greatly thank the twins for their participation. Thanks also to Anna Vinkhuyzen for statistical assistance, and to Grant Montgomery for genotypic data collection. We are also very thankful to Danielle Dick and Fazil Aliev for providing us the list of SNPs that allowed us to check for signals in the DYRK1A gene in their cohort.

Funding Statement

This study was supported in part by grants AA013326, AA014041, AA13320, AA013321, and DA12854 from the National Institutes of Health, Bethesda, Maryland. KJHV is supported by The Australia and New Zealand Banking Group Limited (ANZ) Trustees PhD scholarship in Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


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Oncoplastic Technique Combining an Adipofascial Flap with an Extended Glandular Flap for the Breast-Conserving Reconstruction of Small Dense Breasts

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We introduce a method combining two oncoplastic techniques for breast-conserving reconstruction. The procedure is as follows: first, an extended glandular flap is made by undermining the breast from both the skin and the pectoralis fascia to the upper edge of the breast at the subclavicular area. After modeling the breast mound with the extended glandular flap, an inframammary adipofascial flap is made. The flap is reflected back to the breast area remodeled using the extended glandular flap. After reshaping the breast, the inframammary line is then re-shaped. This method is indicated for patients with breast cancer in the outer portion of the breast, who have small dense breasts, and have undergone a large excision of about 40% of their breast volume. We treated four patients, all of whom had either excellent or good cosmetic results with no fat necrosis.

Keywords: Mammaplasty, Segmental mastectomy, Surgical procedures


Using oncoplastic techniques can help maintain good cosmesis after large excisions exceeding 20% of the breast volume [1,2]. However, while many oncoplastic techniques are suitable for large breasts, many Japanese females have small and dense glandular breasts. We have therefore developed two oncoplastic techniques [3-5] for the breast-conserving reconstruction of small breasts.

If the excision will affect 20% to 30% of their breast volume, we propose that good cosmetic results can be obtained by using an extended glandular flap [5] or an adipofascial flap [3,4]. However, it is difficult to compensate with an extended glandular flap alone in cases where the defect includes about 40% of the breast volume. If the part of the breast that is excised is the lower portion, it may be possible to compensate for the defect with an inframammary adipofascial flap, even if the excision volume is about 40% of the breast volume. However, if the defect is in the outer portion of the breast, it is difficult to bring a large amount of tissue from the inframammary area.

Some volume replacement methods, such as the latissimus dorsi myocutaneous flap [6,7] and perforator flap [8,9], have been reported as oncoplastic techniques to repair defects in the outer portion of the breast affecting about 40% of the breast volume. These flaps are usually the best choice for defects that are too large to be corrected using local tissue. However, these techniques must be performed by plastic surgeons, and involve the loss of donor site muscle or lead to the formation of an additional donor-site scar. This often precludes the use of these techniques.

Therefore, we developed a method combining an adipofascial flap with an extended glandular flap for the reconstruction of a large breast partial resection comprising about 40% of the outer portion of the breast. The aim of this report is to describe the efficacy of the method combining these two oncoplastic techniques after a large excision of the breast volume for the breast-conserving reconstruction of small dense breasts.


Four females with breast cancer in the outer portion of the breast underwent remodeling using the method combining two oncoplastic techniques (an extended glandular flap [5] and an inframammary adipofascial flap [3,4]) after an excision of about 40% of their breast volume. The excision volume compared to the total breast volume was estimated by using a preoperative photograph of the markings made for the partial resection area by seven independent observers (breast surgeons). Summary of the patient characteristics is shown in Table 1. In all patients, the size of the bra was an A cup, and the breast density on mammography was heterogeneously dense in all four cases. All patients had undergone a sentinel lymph node biopsy. Three patients had no metastasis in the sentinel lymph nodes, allowing them to avoid an axillary lymph node dissection. One patient with metastasis in the sentinel lymph nodes underwent an axillary lymph node dissection. The operations were performed by breast surgeons without the help of plastic surgeons.

Table 1

Summary of the patient characteristics

After marking the partial resection area with the patient in the supine position, the upper edge of the breast at the subclavicular area is drawn on the skin with the patient in the standing position (Figure 1). This marking is for the extended glandular flap. The extended glandular flap is perfused through the 2nd and/or 3rd internal mammary artery perforators. So a preoperative Doppler examination was performed to confirm the location of perforators from the internal mammary artery.

Figure 1

The design before the operation. Marking the partial resection area, the upper edge of the breast at the subclavicular area, and the position of the nipple in the standing position, as well as the inframammary groove, the area of the adipofascial flap,

The inframammary groove and the area of the adipofascial flap are also drawn on the skin. At that moment, it is important to confirm the location of the perforators by Doppler sonography (Figure 1, x mark).

After a partial resection of the breast is performed, the extended glandular flap is made by freeing the breast from both the skin and the pectoralis fascia up to the subclavicular area that was marked before surgery. While making the flap, it is important to undermine the skin of the subclavicular area so that the subcutaneous fat might remain thick and taper gradually toward the head side. It is important to keep the perforators of the internal mammary artery intact as well. This flap is moved to the breast area where the tumor has been removed (Figure 2). After the flap is inserted, it is secured to the surrounding breast tissue with absorbable sutures.

Figure 2

The extended glandular flap. The extended glandular flap is made by freeing the breast from both the skin and the pectoralis fascia. The flap is moved into the defect in the direction of arrows, and the breast mound is remodeled.

The skin of the inframammary area is undermined by subcutaneous fat. The subcutaneous fat, together with the fascia of the external oblique muscle and anterior sheath of the rectus abdominis muscle, is dissected semicircularly, resulting in the formation of an adipofascial flap. The flap is reflected back to the breast area remodeled using the extended glandular flap, and then is secured to the surrounding breast tissue with absorbable sutures (Figure 3). While making the breast mound, it is important to keep the perforators intact. In order to make a new inframammary line, the subcutaneous tissue of the skin is fixed to the muscle with absorbable sutures. While making the breast mound and re-shaping the inframammary line, the shape of the breast is checked when putting pressure from the upper side until the nipple is set at the position that had been marked before surgery when the patient was in the standing position (Figure 4). Finally, a suction tube was placed, and the skin was sutured.

Figure 3

The inframammary adipofascial flap. The inframammary adipofascial flap is reflected back to the breast area (arrow) that was remodeled by using the extended glandular flap.
Figure 4

Checking the shape of the breast. The nipple position is set at the position that had been marked before surgery with the patient in the standing position while applying pressure from the upper side (arrow).

The cosmetic assessment of four patients was performed based on photographs taken more than 1 year after the operation. The photographs for case 1 was taken 6.6 years after the operation (Figure 5), the photographs for case 2 were taken 3.1 years after the operation (Figure 6), those for case 3 were taken 2.4 years after the operation (Figure 7), and the photographs for case 4 was taken 1.3 years after the operation (Figure 8). Photographs of the patients’ breasts were then taken using frontal, left oblique and right oblique views without any identifying features. The cosmetic results were evaluated by seven independent observers (breast surgeons) as “excellent”, “good”, “fair”, or “poor” using the Harvard Scale established by Harris et al. [10]. An excellent result was reported when the treated breast was almost identical to the untreated one, a good result was reported when the treated breast was slightly different from the untreated breast, a fair result when there was an obvious difference between the two sides without major distortion, and a poor result when the treated breast was seriously distorted. The observers were ‘blinded’ to the identity of the patients.

Figure 5

Photographs of case 1, showing the good cosmetic results. (A, B) Preoperative photographs: (A) frontal view, (B) oblique view. (C, D) Postoperative photographs taken 6.6 years after the operation: (C) frontal view, (D) oblique view.
Figure 6

Photographs of case 2, showing the excellent cosmetic results. (A, B) Preoperative photographs: (A) frontal view, (B) oblique view. (C, D) Postoperative photographs taken 3.1 years after the operation: (C) frontal view, (D) oblique view.
Figure 7

Photographs of case 3, showing the excellent cosmetic results. (A, B) Preoperative photographs: (A) frontal view, (B) oblique view. (C, D) Postoperative photographs taken 2.4 years after the operation: (C) frontal view, (D) oblique view.
Figure 8

Photographs of case 4, showing the good cosmetic results. (A, B) Preoperative photographs: (A) frontal view, (B) oblique view. (C, D) Postoperative photographs taken 1.3 years after the operation: (C) frontal view, (D) oblique view.

The blood loss and the length of the operation ranged from 31 to 186 g (average, 93.8 g) and from 116 to 168 minutes (average, 138.3 minutes), respectively. There was one case of invasive ductal carcinoma and three cases of noninvasive ductal carcinoma. None of the patients in this study complained of upper abdominal asymmetry. One patient had delayed wound healing, but eventually healed within 2 months. One patient refused radiation therapy. The other three patients received radiation therapy to the breast after wound healing, as usual. There was no fat necrosis of the flap and no dystrophic calcification on mammography in any of the patients. Depression on the donor area of the extended glandular flap was not noticeable, and furthermore, clothing that shows the décolletage is not popular in Japan, so there were no patient complaints. All of the patients are still alive without recurrence at time of the writing of this manuscript.

The cosmetic results of the four patients were assessed using photographs. The results were found to be excellent (Figures 6, ​,7)7) in two cases and good in 2 cases (Figures 5, ​,8).8). No unacceptable outcome (either fair or poor) was observed.


In European countries, oncoplastic techniques for the breast-conserving reconstruction have been popular for more than 20 years, and many oncoplastic techniques have been reported [2,11,12]. However, most of the reported oncoplastic techniques are suitable only for large breasts. Many Japanese patients have small breasts, therefore, it is necessary to develop new oncoplastic methods suitable for small breasts.

We have previously reported two oncoplastic techniques [3-5] for the breast-conserving reconstruction of small breasts. One technique employs an extended glandular flap [5], and the other uses an inframammary adipofascial flap [3,4]. The extended glandular flap comprises the mammary gland, including the fat in the subclavicular area, which is used for volume displacement for breast-conserving reconstruction in the upper portion of a dense breast. A dense glandular breast can be easily mobilized by advancing the breast tissue into the excision cavity, without a risk of fat necrosis. Thus, this procedure is suitable for small dense breasts. The inframammary adipofascial flap is used by inverting a tongue-shaped adipofascial flap in the upper abdominal area, which is used for volume replacement for breast-conserving reconstruction in the lower portion of the breast. These two techniques can be used for defects where it is often difficult to reshape the breast following large excisions exceeding 20% of the breast volume. However, it is difficult to fill up a defect comprising about 40% of the breast volume using an extended glandular flap alone. Since the inframammary adipofascial flap is a commonly used volume replacement technique, it could thus be used to replace a defect of about 40% of the breast volume if the tumor location is in the lower portion of the breast. However, if the tumor is in the outer portion of the breast, it is difficult to bring a sufficiently large amount of tissue from the inframammary area. For the tumors in the outer portion of the breast, other procedures for breast reshaping using a tissue flap, such as the latissimus dorsi myocutaneous flap [6,7] and perforator flap [8,9] have been reported. These flaps can be filled up for a large defect. However, these techniques must be performed by plastic surgeons and involve the loss of donor site muscle or the formation of an additional donor-site scar.

Using our new technique, we were able to fill up a defect of about 40% of the breast volume by using a method combining an adipofascial flap with an extended glandular flap. The advantages of this method are as follows: 1) It is not necessary to make an additional scar, since both an extended glandular flap and adipofascial flap can be created through the same skin incision; 2) If mastectomy is required due to the presence of a positive margin, it is possible to use a latissimus dorsi flap for reconstructive surgery; 3) Since not much tissue is taken from the inframammary area, deformation of the donor site is unlikely to occur; 4) This method can be performed by breast surgeons, without the help of a plastic surgeon. However, this method has limited indications for patients with a tumor located in the outer portion of a small dense breast. This is the greatest disadvantage.

We treated four patients with breast cancer in the outer portion of a small dense breast who underwent remodeling using a method combining the extended glandular flap and the inframammary adipofascial flap after an excision of about 40% of their breast volume. Even though more than 6 years had passed since the surgery in one case, there was no fat necrosis. In addition, no dystrophic calcification was observed by the mammography. This oncoplastic technique combining an adipofascial flap with an extended glandular flap has limited indications. However, this method is useful after a large excision of the breast volume for performing the breast-conserving reconstruction of small dense breasts.


The authors declare that they have no competing interests.


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