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Gentamicin has been used for the treatment of gonorrhea in Malawi since 1993. However, declining clinical cure rates have been suspected. We evaluated current Neisseria gonorrhoeae susceptibility to gentamicin in vitro and clinically.Men with acute urethritis were recruited at the Bwaila District Hospital STI Clinic in Lilongwe, Malawi, between January 2017 and August 2019. All men provided urethral swabs for etiological testing at enrollment and test of cure (TOC), 1 week later, using Gram-stained microscopy and culture. We used Etest to determine minimum inhibitory concentrations (MICs) of gentamicin, azithromycin, cefixime, ceftriaxone, ciprofloxacin, and spectinomycin; disc diffusion for tetracycline susceptibility; and whole-genome sequencing (WGS) to verify/refute treatment failure.Among 183 N. gonorrhoeae culture-positive men enrolled, 151 (82.5%) had a swab taken for TOC. Of these 151 men, 16 (10.6%) had a positive culture at TOC. One hundred forty-one baseline isolates were tested for gentamicin susceptibility using Etest: 2 (1.4%), MIC = 2 μg/mL; 111 (78.7%), MIC = 4 μg/mL; and 28 (19.9%), MIC = 8 μg/mL. All isolates were susceptible to azithromycin, cefixime, ceftriaxone, and spectinomycin, whereas 63.1% had intermediate susceptibility or resistance to ciprofloxacin. Almost all (96.1%) isolates were resistant to tetracycline. All examined isolates cultured at TOC (n = 13) had gentamicin MICs ≤8 μg/mL. Ten men had pretreatment and posttreatment isolates examined by whole-genome sequencing; 2 (20%) were verified new infections (4119 and 1272 single-nucleotide polymorphisms), whereas 8 (80%) were confirmed treatment failures (0-1 single-nucleotide polymorphism).Gentamicin MICs poorly predict gonorrhea treatment outcome with gentamicin, and treatment failures are verified with gonococcal strains with in vitro susceptibility to gentamicin. The first-line treatment of gonorrhea in Malawi should be reassessed.

To assess the craniofacial morphology in children with sleep-disordered breathing (SDB) using nonradiation and readily accessible photogrammetry technique.Included children aged 3-18 years with SDB-related symptoms from April 2019 to February 2020 in a tertiary center. All participants underwent craniofacial photogrammetry and overnight polysomnography (PSG). Participants were stratified into 2 groups (obstructive sleep apnea [OSA] group: apnea-hypopnea index [AHI] ≥ 1 and non-OSA group: AHI1). Craniofacial photogrammetry was performed to derive variables of craniofacial features in standardized frontal and profile views. The 2 groups were propensity score matched based on age, sex, and body mass index (BMI) percentiles. Associations between craniofacial feature variables and OSA (AHI ≥1) likelihood were examined using logistic regression test. intraclass correlation coefficient (ICC) was used to evaluate the intrarater and interrater reliability.In total, 58 children were enrolled for the analysis after matching. All 3 variables representing the mandibular plane angle in the profile view were increased in the OSA group (mego-tn: 34.85 ± 5.99 vs 31.65 ± 5.96°, odds ratio [OR]: 1.10, 95% CI:1.02 to 1.18, P = .01; tn-gogn: 28.65 ± 6.38 vs 25.91 ± 5.38°, OR: 1.08, 95% CI:1.02 to 1.15, P = .012; and gome-tsup: 26.71 ± 6.13 vs 22.20 ± 5.89°, OR: 1.13, 95% CI:1.04 to 1.23, P = .003).Craniofacial photogrammetry revealed increased mandibular inclination in children with OSA. A steep mandibular plane with craniofacial photogrammetry is considered a potential predictor of pediatric OSA. Further investigation with a large sample size is required to clarify the validity of photogrammetry in evaluating pediatric OSA.

Diamond-Blackfan anemia (DBA) is a congenital erythroblastopenia that is characterized by a blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified 2 in vitro erythroid cell growth phenotypes for primary CD34+ cells from DBA patients and following short hairpin RNA knockdown of RPS19, RPL5, and RPL11 expression in normal human CD34+ cells. The haploinsufficient RPS19 in vitro phenotype is less severe than that of 2 other ribosomal protein (RP) mutant genes. We further documented that proteasomal degradation of HSP70, the chaperone of GATA1, is a major contributor to the defect in erythroid proliferation, delayed erythroid differentiation, increased apoptosis, and decreased globin expression, which are all features of the RPL5 or RPL11 DBA phenotype. In the present study, we explored the hypothesis that an imbalance between globin and heme synthesis may be involved in pure red cell aplasia of DBA. We identified disequilibrium between the globin chain and the heme synthesis in erythroid cells of DBA patients. This imbalance led to accumulation of excess free heme and increased reactive oxygen species production that was more pronounced in cells of the RPL5 or RPL11 phenotype. Strikingly, rescue experiments with wild-type HSP70 restored GATA1 expression levels, increased globin synthesis thereby reducing free heme excess and resulting in decreased apoptosis of DBA erythroid cells. These results demonstrate the involvement of heme in DBA pathophysiology and a major role of HSP70 in the control of balanced heme/globin synthesis.

This study aimed to investigate alveolar bone change around mandibular anterior teeth during orthodontic decompensation in patients with skeletal Class III malocclusion and different vertical facial patterns. The records of 29 consecutive Class III patients selected from those pending two-jaw orthognathic surgery were divided into low (≤ 28°), average (30°–37°), and high (≥ 39°) mandibular plane angle (MPA) groups. The DICOM files of CBCT scans and STL files of digital dental models, taken before (T1) and after (T2) presurgical orthodontic treatment, were imported into Dolphin imaging software to reconstruct dentoskeletal images. T1 and T2 images were superimposed and analyzed for bone thickness and height at the level of root apex on each mid-sagittal slice of six mandibular anterior teeth. Differences between T1 and T2 were analyzed by non-parametric tests and mixed-effect model analysis. The results showed that the measurements of alveolar bone height generally decreased after treatment, regardless of MPA. The facial divergence, incisor irregularity, tooth site, treatment time, and change in proclination were identified as the significant factors affecting alveolar bone thickness and height during treatment. The presurgical orthodontic treatment to decompensate mandibular anterior teeth should be very careful in all MPA groups.

OBJECTIVE Cone-beam computed tomography (CBCT) offers three-dimensional structures in assessing upper airway of patients. This study aims to compare the cone-beam computerized tomography scan measurements between children with obstructive sleep apnea (OSA) and primary snoring. STUDY DESIGN Case-control study. METHODS This prospective study was conducted in a tertiary referral center. Thirty-six children with moderate-to-severe OSA (with apnea-hypopnea index [AHI] > 5 events/hour) and 36 age-, gender-, and obesity-matched children with primary snoring (AHI

Early orthodontic tooth movement following regenerative surgery is controversial. In this case, during protraction of the maxillary right first premolar to substitute for the long-term missing maxillary right canine, Bio-Oss and Bio-Gide were used for lateral ridge augmentation at the area of the maxillary right lateral incisor and to cover the denuded surface at the buccal side of the first premolar. Orthodontic tooth movement (OTM) commenced 2 weeks after regenerative surgery. After 8 months, new bone formation was observed on the root surface of the first premolar during implant surgery. A cone beam computed tomography scan taken 1.5 years postsurgery revealed good maintenance of regenerative bone at the same site. This satisfactory outcome of early OTM following regenerative surgery suggests biomechanical stimulation may not jeopardize the regenerative effect.

Background/Purpose The aim of this study is to comprehensively analyze the potential factors affecting the failure rates of three types of mini-implants used for orthodontic anchorage. Methods Data were collected on 727 mini-implants (miniplates, predrilled titanium miniscrews, and self-drilling stainless steel miniscrews) in 220 patients. The factors related to mini-implant failure were investigated using a Chi-square test for univariate analysis and a generalized estimating equation model for multivariate analysis. Results The failure rate for miniplates was significantly lower than for miniscrews. All types of mini-implants, especially the self-drilling stainless steel miniscrews, showed decreased stability if the previous implantation had failed. The stability of predrilled titanium miniscrews and self-drilling stainless steel miniscrews were comparable at the first implantation. However, the failure rate of stainless steel miniscrews increased at the second implantation. The univariate analysis showed that the following variables had a significant influence on the failure rates of mini-implants: age of patient, type of mini-implant, site of implantation, and characteristics of the soft tissue around the mini-implants. The generalized estimating equation analysis revealed that mini-implants with miniscrews used in patients younger than 35 years, subjected to orthodontic loading after 30 days and implanted on the alveolar bone ridge, have a significantly higher risk of failure. Conclusion This study revealed that once the dental surgeon becomes familiar with the procedure, the stability of orthodontic mini-implants depends on the type of mini-implant, age of the patient, implantation site, and the healing time of the mini-implant. Miniplates are a more feasible anchorage system when miniscrews fail repeatedly.

OBJECTIVE The aim of this study was to analyse morphological changes in the upper airways in patients with anterior open bite treated with temporary anchorage devices for intrusion of upper posterior teeth. MATERIALS AND METHODS Twelve nonobese (body mass index

Introduction The aim of this retrospective study on dental models was to compare the orthodontic outcomes of maxillary dentoalveolar protrusion treated with headgear, miniscrews, or miniplates for maximum anchorage. Methods The 40 subjects were diagnosed as having either Angle Class II malocclusion or Class I bimaxillary dentoalveolar protrusion. All patients were treated to retract the maxillary dentoalveolar process by using the extraction space of the bilateral maxillary first premolars. They were divided into 3 groups according to the type of anchorage used. Group 1 (n = 16) received traditional anchorage preparation with a transpalatal arch and headgear, group 2 (n = 15) received miniscrews, and group 3 (n = 9) received miniplates for skeletal anchorage. To investigate the movement of the maxillary teeth during dentoalveolar retraction, we used a 3-dimensional (3D) digitizer to assess the positional changes of the maxillary teeth relative to the stable palatal rugose structures on the serial dental models. The 3D coordinates representing pretreatment and posttreatment maxillary dental casts were superimposed to determine the movement of individual teeth from the positional changes of 18 landmarks of the central incisor, canine, second premolar, and first molar. Results Three-dimensional analysis of the maxillary dental models in the buccopalatal, anteroposterior, and vertical directions showed significant differences in tooth movements between the headgear and the mini-implant (miniscrew or miniplate) groups. Both skeletal anchorage groups had greater incisor retraction (6.9 mm for the miniscrew, 7.3 mm for the miniplate) than did the headgear group (5.5 mm). Mesialization of occlusal centroid of the maxillary molar in the skeletal anchorage groups was less than that in the headgear group (1.3 mm for the miniscrew, 1.4 mm for the miniplate, 2.5 mm for the headgear). Tooth movements in the anteroposterior and buccopalatal directions did not reach a statistically significant difference between the miniscrew and miniplate groups, but the maxillary posterior teeth of the subjects receiving miniplates showed greater intrusion than those receiving miniscrews anchorage. Conclusions This 3D analysis of serial dental models demonstrated that, compared with headgear, skeletal anchorage achieved better results in the treatment of maxillary dentoalveolar protrusion. Significant intrusion of the maxillary posterior teeth was noted in the miniplate group but not in the miniscrew and headgear groups. Greater retraction of the maxillary anterior teeth, less anchorage loss of the maxillary posterior teeth, and the possibility of maxillary molar intrusion all facilitated correction of the Class II malocclusion, especially for patients with a hyperdivergent face.

Objectives: The aim of this retrospective study was to evaluate systematically the potential factors that influence failure rates of temporary anchorage devices (TADs) used for orthodontic anchorage. Materials and methods: Data on 492 TADs (miniplates, pre-drilling miniscrews, and self-drilling miniscrews) in 194 patients were collected. The factors related to TAD failure were evaluated using univariate analysis and multivariate forward stepwise logistic regression analysis. Results: There were no significant differences in failure rates among the TADs for the following variables: gender, type of malocclusion, facial divergency, implantation site (buccal, lingual, or crestal/midpalatal), location (anterior or posterior), method of force application (power chain or Ni–Ti coil spring), arch (upper or lower), type of soft tissue (attached gingiva or removable mucosa), and most of the cephalometric measurements that reflect dento-cranio-facial characteristics. An increased failure rate was noted for the self-drilling miniscrew type of TAD, TADs used for tooth uprighting, those inserted on bone with lower density, those associated with local inflammation of the surrounding soft tissue, those loaded within 3 weeks after insertion, and those placed in patients with greater mandibular retrusion. Failure rates of the self-drilling miniscrews installed by an oral surgeon and by an orthodontist did not differ significantly. Conclusions: Inflammation of soft tissue surrounding a TAD and early loading within 3 weeks after insertion were the most significant factors predicting TAD failure. Both orthodontists and oral surgeons who install orthodontic TADs must undergo sufficient training to achieve clinical excellence.

Introduction The goal of this retrospective cephalometric study was to compare orthodontic outcomes in patients with maxillary dentoalveolar protrusion malocclusion treated with extraoral headgear or mini-implants for maximum anchorage. Materials Forty-seven subjects with Angle Class II malocclusion or Class I bimaxillary dentoalveolar protrusion were treated by retracting the maxillary dentoalveolar process by using the extraction space of the bilateral maxillary first premolars. Two anchorage systems were used. Group 1 (n = 22) received traditional anchorage preparation with a transpalatal arch and headgear; group 2 (n = 25) received mini-implants (miniplates, miniscrews, or microscrews) for bony anchorage. Pretreatment and posttreatment lateral cephalograms were superimposed to compare the following parameters between groups: (1) amount of maxillary central incisor retraction, (2) reduction in maxillary central incisor angulation, (3) anchorage loss of the maxillary first molar, (4) movements of the maxillary central incisor and first molar in the vertical direction, and (5) changes in skeletal measurements representing the anteroposterior and vertical jaw relationships. Results The skeletal anchorage group had greater anterior tooth retraction (8.17 vs 6.73 mm) and less maxillary molar mesialization (0.88 vs 2.07 mm) than did the headgear group, with a shorter treatment duration (29.81 vs 32.29 months). Translational movement of the incisors was more common than tipping movement, and intrusion of the maxillary dentition was greater, in patients receiving miniplates than in those receiving screw-type bony anchorage, resulting in counterclockwise rotation of the mandible and a statistically significant decrease in the mandibular plane angle. Cephalometric analysis of skeletal measurements in patients with low to average mandibular plane angles showed no significant difference between groups, although greater maxillary incisor retraction and less mesial movement of the first molar were noted in the mini-implant group. In patients with a high mandibular plane angle, those receiving skeletal anchorage had genuine intrusion of the maxillary first molar and reduction in the mandibular plane angle, whereas those receiving headgear anchorage had extrusion of the maxillary first molar and an increase of mandibular plane angle. In contrast to the posterior movement in the headgear group, anterior movement of Point A was noted in the mini-implant group. Conclusions In both the anteroposterior and vertical directions, skeletal anchorage achieved better control than did the traditional headgear appliance during the treatment of maxillary dentoalveolar protrusion. Greater retraction of the maxillary incisor, less anchorage loss of the maxillary first molar, and the possibility of counterclockwise mandibular rotation all facilitated the correction of the Class II malocclusion.

Background/Purpose The age at menarche reflects a pubertal girl's physiologic maturity. The aims of this study were to evaluate the relationship between the age at menarche and skeletal maturation in female orthodontic patients. Methods Hand-wrist radiographs and lateral cephalometric radiographs from 304 adolescent female subjects (age, 8–18.9 years) were selected from the files of the Department of Orthodontics, National Taiwan University Hospital (NTUH). Hand-wrist bone maturation stages were assessed using the NTUH Skeletal Maturation Index (NTUH-SMI). Cervical vertebral maturation stages (CVMS) were determined using the latest CVMS Index. Menarcheal ages were self-reported by the patients and verified by the patients' mothers. The relationships between the NTUH-SMI or CVM stages and menarcheal status were investigated. Results More than 90% of the 148 subjects who had already attained menstruation had skeletal maturation beyond the NTUH-SMI stage four or CVMS III. However, the subjects who had never experienced menarche mostly had skeletal maturation before NTUH-SMI stage five or CVMS IV. During the period of orthodontic treatment, 19 females experienced their menarche. The mean age at menarche for the 167 female patients in total was 11.97 years. In average, menarche occurred between NTUH-SMI stages four and five or between CVM stages III and IV. The percentage of girls with menses increased from 1.2% at age 9 to 6.6% at age 10, 39.5% at age 11, 81.4% at age 12, 97% at age 13, and 100% at age 14. Compared with the results obtained 20 years previously, we found a downward shift of 0.47 years per decade for the mean age at menarche in female orthodontic patients. Conclusion The majority of female orthodontic patients have passed the pubertal growth spurt when they experience their menarche. Menarche usually follows the pubertal growth spurt by about 1 year and occurs after NTUH-SMI stage four or CVMS III.

Background/Purpose This study aimed at comparing the transverse and sagittal angulations of proximal segment after sagittal split ramus osteotomy (SSRO) and intraoral vertical ramus osteotomy (IVRO), and examining their influences on the stability of distal segment. Methods Patients who received SSRO (n = 21) or IVRO (n = 11) for mandibular setback were included. Lateral and posteroanterior cephalograms taken within 1 month before surgery (T1), within 1 week after surgery (T2), and at least 6 months after surgery (T3) were analyzed. The angulation of each proximal segment relative to the upper orbital margin line was measured on posteroanterior cephalogram and the sum of both angles (total ramus angle, TRA) was obtained. On lateral radiograph, ramus inclination angle (RIA) relative to a horizontal reference line 7° to the sella–nasion was assessed and B-point position was measured. Results From T1 to T2, more increases in TRA and RIA were noted after IVRO than after SSRO. From T2 to T3, TRA and RIA significantly decreased in IVRO group but remained relatively stable in SSRO group. ΔTRAT1–T2 positively related to upward rotation of distal segment for SSRO and downward rotation for IVRO from T2 to T3. For SSRO only, ΔRIAT1–T2 significantly related to forward movement of distal segment during remodeling. Conclusion TRA and RIA increase significantly after IVRO and then regress, whereas they increase mildly after SSRO and remain stable. Increase in TRA significantly relates to distal segment rotation during remodeling for both surgeries, but increase in RIA relates to forward relapse of the distal segment only for SSRO. The reasons underlying the correlations are not certain and deserve future investigations.

Sudden cardiac death due to ventricular tachycardia (VT) is a major health issue worldwide. Efforts to identify patients at risk, determine VT mechanisms, and effectively prevent and treat VT with a mechanism-based approach would benefit from continuous noninvasive imaging of the arrhythmia over the entire heart. This paper presents the first noninvasive images of human ventricular arrhythmias using electrocardiographic imaging (ECGI), highlighting the large diversity of human VT in terms of activation patterns, mechanisms, and sites of initiation. Based on comparison with catheter mapping, ECGI provided high spatial resolution; a property that overcomes a limitation of the body surface electrocardiogram, which provides only global information. The spatial resolution and ability to image the activation sequences over the entire ventricular surfaces in a single beat allowed us to make observations regarding VT initiation and continuation, and regarding relationships to ventricular substrates, including anatomical scars and abnormal electrophysiological substrate. The ability of ECGI to provide patient-specific physiologic insights, to map the VT activation sequence and to identify the location and depth of VT origin from a single beat has important clinical implications in treating patients with ventricular arrhythmias.

Objectives: The aim of this retrospective study was to assess systematically the case distribution among three types of mini-implants and to evaluate the clinical factors that influence the failure rates of mini-implants used as an orthodontic anchorage. Material and methods: Data for 359 mini-implants (miniplates, miniscrews, and microscrews) in 129 patients were collected. The factors related to mini-implant failure were evaluated using univariate analysis and multivariate stepwise logistic regression analysis. Results: Among these three different types of skeletal anchorage, there was a significant difference between the failure rates of these mini-implants, with the miniscrews and microscrews showing much higher failure rates. There were no significant differences in failure rates among the mini-implants for the following variables: gender, type of malocclusion, local or full-arch treatment, whether on the buccal or lingual side, length of the screw, loading pattern, or the duration of the healing phase. Greater risks for failure were found in younger patients, when an implant was placed for retraction/protraction, when it was placed on the mandibular arch, when it was placed anterior to the second premolars, or when using the miniscrew/microscrew systems. After adjusting for potential confounding effects, only three factors (type of mini-implant, placement on the mandibular arch, and age) were found to be statistically significant in predicting mini-implant failures (P

Implant anchors such as miniscrews and miniplates have been loaded immediately for anchorage during orthodontic treatment. The purpose of this study was to measure the removal torque of immediately loaded miniscrews after clinical usage and to determine the possible factors associated with this value.From 29 patients with malocclusions, 46 miniscrews were removed, and removal torque was measured with a torque gauge. Removal torque values were subjected to statistical analysis for possible association of different clinical characteristics.The mean removal torque value was 1.10 kg x cm, and removal torques for 50% of the implants were greater than 0.89 kg x cm (8.7 N x cm). Removal torque values were significantly higher in the mandible than in the maxilla. The removal torques of 15-mm and 17-mm miniscrews were significantly higher than those of 13-mm miniscrews. Therefore, the site of implantation and miniscrew length were important factors associated with removal torque. However, there was no significant correlation between the removal torque value and age, gender, healing time, or time in function.When miniscrews are used as anchorage for uprighting tipped molars, excessive torque in a counterclockwise direction may loosen them. From the measurements obtained in this investigation, miniscrews can sufficiently sustain an uprighting moment.The removal torque values of the majority of miniscrews in this study population when loaded immediately as orthodontic anchorage were greater than 0.89 kg x cm, and this was sufficient for these implants to fulfill their purpose as anchors in 3-dimensional tooth movements.

The intrusion of an overerupted maxillary molar using traditional orthodontic treatment is a real challenge. The aim of this study was to investigate the envelope of intrusive movements of a maxillary molar in cases using mini-implants as anchorage with partial or full-mouth fixed edgewise appliances. The cusp tips of the pretreatment and postintrusion dental casts were recorded by a three-dimensional (3D) digitizer. The 3D data of the serial dental casts were analyzed to distinguish the direction and magnitude of individual tooth movement. The mean intrusive movement of the maxillary first molars was three to four mm, with a maximum of over eight mm. For the adjacent maxillary second molars and second premolars, the amount of intrusion was two mm and 1-2 mm, respectively. This study demonstrated that significant true intrusion of maxillary molars could be obtained in a well-controlled manner by using fixed appliances with titanium mini-implants as bony anchorage.

Overeruption of maxillary molar(s) because of loss of the opposing teeth creates occlusal interference and functional disturbances. To restore proper occlusion, intrusion of the overerupted molars becomes essential before reconstruction can be initiated. A plausible procedure is orthodontic intrusion, which demands calibrated anchorage support from intraoral multiunit teeth and from headgear wear. In this report, we present a simplified and localized version of the orthodontic appliances in conjunction with mini-implants to intrude the overerupted molars. The purpose of using implants as skeletal anchorage was to eliminate the need for patient compliance for headgear wear and to overcome the difficulty resulting from the shortage of anchor teeth. The results showed that the biological responses of the teeth and the surrounding bony structures to the intrusion appeared normal and acceptable. Furthermore, the periodontal health and vitality of the teeth were well maintained even after a one-year follow-up.

Background/Purpose: The skeletal maturation status of a growing patient can influence the selection of orthodontic treatment procedures. Either lateral cephalometric or hand-wrist radiography can be used to assess skeletal development. In this study, we examined the correlation between the maturation stages of cervical vertebrae and hand-wrist bones in Taiwanese individuals. Methods: The study group consisted of 330 male and 379 female subjects ranging in age from 8 to 18 years. A total of 709 hand-wrist and 709 lateral cephalometric radiographs were analyzed. Hand-wrist maturation stages were assessed using National Taiwan University Hospital Skeletal Maturation Index (NTUH-SMI). Cervical vertebral maturation stages were determined by the latest Cervical Vertebral Maturation Stage (CVMS) Index. Spearman’s rank correlation was used to correlate the respective maturation stages assessed from the hand-wrist bones and the cervical vertebrae. Results: The values of Spearman’s rank correlation were 0.910 for males and 0.937 for females, respectively. These data confirmed a strong and significant correlation between CVMS and NTUH-SMI systems (p < 0.001). After comparison of the mean ages of subjects in different stages of CVMS and NTU-SMI systems, we found that CVMS I corresponded to NTUH-SMI stages 1 and 2, CVMS II to NTUH-SMI stage 3, CVMS III to NTUHSMI stage 4, CVMS IV to NTUH-SMI stage 5, CVMS V to NTUH-SMI stages 6, 7 and 8, and CVMS VI to NTUH-SMI stage 9. Conclusion: Our results indicate that cervical vertebral maturation stages can be used to replace hand-wrist bone maturation stages for evaluation of skeletal maturity in Taiwanese individuals. [J Formos Med Assoc 2008;107(4):316–325]

Anemia of β-thalassemia is caused by ineffective erythropoiesis and reduced red cell survival. Several lines of evidence indicate that iron/heme restriction is a potential therapeutic strategy for the disease. Glycine is a key initial substrate for heme and globin synthesis. We provide evidence that bitopertin, a glycine transport inhibitor administered orally, improves anemia, reduces hemolysis, diminishes ineffective erythropoiesis, and increases red cell survival in a mouse model of β-thalassemia (Hbb(th3/+) mice). Bitopertin ameliorates erythroid oxidant damage, as indicated by a reduction in membrane-associated free α-globin chain aggregates, in reactive oxygen species cellular content, in membrane-bound hemichromes, and in heme-regulated inhibitor activation and eIF2α phosphorylation. The improvement of β-thalassemic ineffective erythropoiesis is associated with diminished mTOR activation and Rab5, Lamp1, and p62 accumulation, indicating an improved autophagy. Bitopertin also upregulates liver hepcidin and diminishes liver iron overload. The hematologic improvements achieved by bitopertin are blunted by the concomitant administration of the iron chelator deferiprone, suggesting that an excessive restriction of iron availability might negate the beneficial effects of bitopertin. These data provide important and clinically relevant insights into glycine restriction and reduced heme synthesis strategies for the treatment of β-thalassemia.