Application of Innovative 3D Pathological Tactic for Diagnosis of Organizing Pneumonia.

BACKGROUND/AIM: The pathological diagnosis of organizing pneumonia (OP) relies on conventional traditional histopathological analysis, which involves examining stained thin slices of tissue. However, this method often results in suboptimal diagnostic objectivity due to low tissue sampling rates. This study aimed to assess the efficacy of tissue-clearing and infiltration-enhanced 3D spatial imaging techniques for elucidating the tissue architecture of OP. MATERIALS AND METHODS: H&E staining, 3D imaging technology, and AI-assisted analysis were employed to facilitate the construction of a multidimensional tissue architecture using six OP patient specimens procured from Taichung Veterans General Hospital, enabling a comprehensive morphological assessment. RESULTS: Specimens underwent H&E staining and exhibited Masson bodies and varying degrees of interstitial fibrosis. Furthermore, we conducted a comprehensive study of 3D images of the pulmonary histology reconstructed through an in-depth pathology analysis, and uncovered heterogenous distributions of fibrosis and Masson bodies across different depths of the OP specimens. CONCLUSION: Integrating 3D imaging for OP with AI-assisted analysis permits a substantially enhanced visualization and delineation of complex histological pulmonary disorders such as OP. The synergistic application of conventional histopathology with novel 3D imaging elucidated the sophisticated spatial configuration of OP, revealing the presence of Masson bodies and interstitial fibrosis. This methodology transcends conventional pathology constraints and paves the way for advanced algorithmic approaches to enhance precision in the detection, classification, and clinical management of lung pathologies.

'Unable to have a proper conversation over the phone about my concerns': a multimethods evaluation of the impact of COVID-19 on routine childhood vaccination services in London, UK.

OBJECTIVES: Investigating the completion rate of 12-month vaccinations and parental perspectives on vaccine services during COVID-19. STUDY-DESIGN: Service evaluation including parental questionnaire. METHODS: Uptake of 12-month vaccinations in three London general practices during three periods: pre-COVID (1/3/2018-28/2/2019, n = 826), during COVID (1/3/2019-28/2/2020, n = 775) and post-COVID first wave (1/8/2020-31/1/2021, n = 419). Questionnaire of parents whose children were registered at the practices (1/4/2019-1/22/2021, n = 1350). RESULTS: Comparing pre-COVID and both COVID cohorts, the completion rates of 12-month vaccines were lower. Haemophilus influenzae type B/meningococcal group C (Hib/MenC) vaccination uptake was 5.6% lower (89.0% vs 83.4%, P=<0.001), meningococcal group B (MenB) booster uptake was 4.4% lower (87.3% vs 82.9%, P = 0.006), pneumococcal conjugate vaccine (PCV) booster uptake was 6% lower (88.0% vs 82.0%, P < 0.001) and measles, mumps and rubella (MMR) vaccine uptake was 5.2% lower (89.1% vs 83.9%, P = 0.003). Black/Black-British ethnicity children had increased odds of missing their 12-month vaccinations compared to White ethnicity children (adjusted odds ratio 0.43 [95% confidence interval 0.24-0.79, P = 0.005; 0.36 [0.20-0.65], P < 0.001; 0.48 [0.27-0.87], P = 0.01; 0.40 [0.22-0.73], P = 0.002; for Hib/MenC, MenB booster, PCV booster and MMR. Comparing pre-COVID and COVID periods, vaccinations coded as not booked increased for MMR (10%), MenB (7%) and PCV booster (8%). Parents reported changes to vaccination services during COVID-19, including difficulties booking and attending appointments and lack of vaccination reminders. CONCLUSION: A sustained decrease in 12-month childhood vaccination uptake disproportionally affected Black/Black British ethnicity infants during the first wave of the pandemic. Vaccination reminders and availability of healthcare professionals to discuss parental vaccine queries are vital to maintaining uptake.

The Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Outcomes of Patients Treated with Immune Checkpoint Inhibitors: a Retrospective Cohort Study.

AIMS: Renin-angiotensin-aldosterone system inhibitors (RAASi) are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the data on the response to treatment and tumour-based endpoints across different tumour types are unknown. MATERIALS AND METHODS: We carried out a retrospective study at two tertiary referral centres in Taiwan. All adult patients treated with ICIs between January 2015 and December 2021 were included. The primary outcome was overall survival and the secondary outcomes were progression-free survival (PFS) and clinical benefit rates. RESULTS: In total, 734 patients were enrolled in our study, of which 171 were RAASi users and 563 were non-users. Compared with non-users, RAASi users had a longer median overall survival [26.8 (interquartile range 11.3-not reached) versus 15.2 (interquartile range 5.1-58.4) months, P < 0.001] and PFS [12.2 (interquartile range 3.9-34.5) versus 5.0 (interquartile range 2.2-15.2) months, P < 0.001]. In univariate Cox proportional hazard analyses, the use of RAASi was associated with a 40% reduction in the risk of mortality [hazard ratio 0.58 (95% confidence interval 0.44-0.76), P < 0.001] and disease progression [hazard ratio 0.62 (95% confidence interval 0.50-0.77), P < 0.001]. The association remained significant after adjusting for underlying comorbidities and cancer therapy in multivariate Cox analyses. A similar trend was observed for PFS. Furthermore, RAASi users experienced a greater clinical benefit rate than non-users (69% versus 57%, P = 0.006). Importantly, the use of RAASi before ICI initiation was not associated with improved overall survival and PFS. RAASi were not associated with an increased risk of adverse events. CONCLUSION: The use of RAASi is associated with improved survival outcomes, treatment response and tumour-based endpoints in patients undergoing immunotherapy.

Effectiveness of an enhanced antibiotic stewardship programme among paediatric patients in a tertiary hospital in Vietnam.

BACKGROUND: In 2016, the Vietnamese Ministry of Health promoted development of antimicrobial stewardship for hospitals. AIM: To evaluate the effectiveness and safety of the enhanced antibiotic stewardship programme (ASP) compared to the original ASP among paediatric patients at a tertiary hospital for infectious diseases in Vietnam. METHODS: An interrupted time-series analysis was conducted to examine antibiotic use in paediatric patients aged 0-17 years admitted to the Hospital for Tropical Diseases in Ho Chi Minh City from April 2016 to March 2020. Outcomes measured were defined daily doses (DDDs) per 1000 patient-days; antibiotic days of therapy (DOT) per 1000 patient-days; percentage of antibiotic use by the World Health Organization Access, Watch, and Reserve (AWaRe) system; Access-to-Watch ratio; and worse clinical outcomes at discharge. FINDINGS: Of 60,172 admissions during the study period, 28,019 received at least one antibiotic (46.6%) during hospital stay. The Watch antibiotics were the most frequently prescribed (78.1% of total antibiotic courses). The enhanced ASP did not improve antibiotic prescribing by DDDs per 1000 patient-days (risk ratio: 1.05; 95% confidence interval: 0.94-1.17) and DOT per 1000 patient-days (1.11; 0.99-1.25) compared to the original ASP. However, the percentage of Access antibiotics prescribed, and the Access-to-Watch ratio increased after the enhanced ASP (1.73; 1.38-2.17). There was no significant difference in worse clinical outcomes at discharge between the original and enhanced ASP (1.25; 0.78-2.00). CONCLUSION: The enhanced ASP had modest impact on antibiotic consumption in the paediatric population despite the improvement of Access antibiotic use and the Access-to-Watch ratio.

Computational design of mechanically coupled axle-rotor protein assemblies.

Natural molecular machines contain protein components that undergo motion relative to each other. Designing such mechanically constrained nanoscale protein architectures with internal degrees of freedom is an outstanding challenge for computational protein design. Here we explore the de novo construction of protein machinery from designed axle and rotor components with internal cyclic or dihedral symmetry. We find that the axle-rotor systems assemble in vitro and in vivo as designed. Using cryo-electron microscopy, we find that these systems populate conformationally variable relative orientations reflecting the symmetry of the coupled components and the computationally designed interface energy landscape. These mechanical systems with internal degrees of freedom are a step toward the design of genetically encodable nanomachines.

Three-dimensional measurement of radiographic bone-implant contact lengths of zygomatic implants in zygomatic bone: a retrospective study of 66 implants in 28 patients.

Zygomatic implant treatment is widely applied for severe maxillary atrophy to help rehabilitate the maxillary dentition. This retrospective study was performed to evaluate the actual radiographic bone-implant contact (rBIC) lengths of zygomatic implants. The records of 28 patients who underwent zygomatic implant surgery and subsequent follow-up examinations between August 2013 and September 2018 in the Department of Oral and Maxillofacial Surgery, Taipei Tzu Chi Hospital were reviewed. The surgeries were performed by a single surgeon using the same treatment protocol. All patients had a computed tomography scan at 1year after the surgery. Using three-dimensional imaging software, an investigator measured the rBIC lengths of 66 implants and documented their clinical status. The implant survival rate was 100%. The mean rBIC length was significantly longer in male patients than in female patients (20.80±5.88mm versus 17.79±6.34mm; P=0.028). The mean rBIC length of double zygomatic implants was significantly longer when compared to that of single implants (21.11±6.23mm versus 17.75±5.85mm; P=0.027). This article is novel in reporting the exact rBIC lengths of zygomatic implants in a clinical setting. The results showed that zygomatic implants are a viable treatment modality for full-mouth rehabilitation.

Antibiotic treatment and antimicrobial resistance in children with urinary tract infections.

OBJECTIVES: The aim of this study was to describe antibiotic prescribing patterns and antimicrobial resistance rates in hospitalised children with febrile and afebrile urinary tract infections (UTIs). METHODS: Antibiotic prescriptions and antibiograms for neonates, infants and older children with UTI admitted to a general district hospital in Central Greece were evaluated. Data covering a 5-year period were collected retrospectively from the Paediatric Department's Electronic Clinical Archive. Patients were included based on clinical and microbiological criteria. Antimicrobial susceptibility was determined by the Kirby-Bauer disk diffusion method. RESULTS: A total of 230 patients were included in the study. Among 459 prescriptions identified, amikacin (31.2%) was the most common antibiotic prescribed in this population, followed by amoxicillin/clavulanic acid (17.4%) and ampicillin (13.5%). Children received prolonged intravenous (i.v.) treatments for febrile (mean ± S.D., 5.4 ± 1.45 days) and afebrile UTIs (mean ± S.D., 4.4 ± 1.64 days). A total of 236 pathogens were isolated. The main causative organism was Escherichia coli (79.2%) with high reported resistance rates to ampicillin (42.0%), trimethoprim/sulfamethoxazole (26.5%) and amoxicillin/clavulanic acid (12.2%); lower resistance rates were identified for third-generation cephalosporins (1.7%), nitrofurantoin (2.3%), ciprofloxacin (1.4%) and amikacin (0.9%). Klebsiella spp. isolates were highly resistant to cefaclor (27.3%). CONCLUSION: High prescribing rates for amikacin and penicillins (± ß-lactamase inhibitors) and prolonged i.v. treatments were observed. Escherichia coli was highly resistant to ampicillin, whilst third-generation cephalosporins exhibited greater in vitro efficacy. Establishment of antimicrobial stewardship programmes and regular monitoring of antimicrobial resistance could help to minimise inappropriate prescribing for UTIs.

Treatment efficiency and stability of skeletal Class III malocclusion with a surgery-first approach.

OBJECTIVES: To compare treatment duration in skeletal Class III malocclusion patients managed with a 2-step treatment (surgery-first approach, SFA) and conventional 3-step treatment, and to compare stability of surgical outcomes between segmentation and non-segmentation in the 2-step treatment group. SETTING AND SAMPLE POPULATION: The sample population consisted of 37 patients who completed orthognathic surgery (OGS) and orthodontic correction at the Charm Aesthetic Surgery Clinic (Taipei, Taiwan) between 2012 and 2015. Of these, 26 received 2-step treatment and 11 received 3-step treatment. MATERIALS AND METHODS: To compare treatment efficiency and stability, three time points were analysed: T0 , before treatment (before OGS in the 2-step group and before orthodontic treatment in the 3-step group); T1 , after OGS but before orthodontic correction (cone beam computed tomography (CBCT) was obtained within 2 weeks of OGS); and T2 , after orthodontic correction (CBCT was obtained on the day of bracket removal). The post-OGS (T1 ) CBCT items were individually superimposed on the pre-treatment (T0 ) CBCT items to determine the distance of B point migration. RESULTS: A significant difference was found in treatment times between 2-step treatment and conventional 3-step treatment. In addition, no significant difference was found when comparing B-X (mm) and B-Y (mm) at T2 -T1 for the segmentation and non-segmentation groups. CONCLUSIONS: Using SFA for skeletal Class III malocclusions saves approximately 6 months of treatment time over 3-step treatment; the stability of the segmentation group was comparable to that of the non-segmentation group, a result that is possibly associated with the fixation of 2 miniplates.

The relationship between Gram-negative colonization and bloodstream infections in neonates: a systematic review and meta-analysis.

OBJECTIVES: Neonates admitted to neonatal intensive care units (NICU) are at significant risk of developing bloodstream infections (BSIs). Gram-negative bacteria (GNB) both colonize and infect, but the association between these entities is unclear. By conducting a systematic literature review, we aimed to explore the impact of factors on the association between GN colonization and GN-BSI at both baby-level and unit-level. METHODS: We searched Medline, Embase, and Cochrane Library. Observational cohort studies published after 2000 up to June 2016 reporting data on the total number of neonates (0-28 days) colonized with GNB assessed by rectal/skin swab culture and the total number of neonates with GN-BSI (same bacteria) were included. Studies were excluded if data on skin/rectal colonization, neonates, and GNB could not be identified separately. Meta-analyses along with multivariate meta-regression with a random-effect model were performed to investigate factors associated with the GN colonization and GN-BSI at baby-level and unit-level. RESULTS: Twenty-seven studies fulfilled our inclusion criteria, 15 for the baby-level and 12 for the unit-level analysis. Study heterogeneity was high, with suboptimal overall quality of reporting assessed by the STROBE-NI statement (44.8% of items adequately reported). In 1984 colonized neonates, 157 (7.9%) developed GN-BSI compared with 85 of 3583 (2.4%) non-colonized neonates. Considerable heterogeneity was observed across studies. Four factors were included in the meta-regression model: gross domestic product (GDP), pathogen, outbreak, and frequency of screening. There was no statistically significant impact of these factors on GN colonization and GN-BSI in baby-level. We were unable to perform the multivariate meta-regression because of insufficient reported data for unit-level. CONCLUSIONS: Study limitations include the small number and the high heterogeneity of the included studies. While this report shows a correlation between colonization and BSI risk, these data currently do not support routine screening for GNB. Analysis of large cohorts of colonized neonates with clinical outcomes is still needed to define the major determinants leading from colonization to infection.

Nasopharyngeal carcinoma metastatic to the mandible.

Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in the head and neck region, especially among those of Chinese origin. NPC has multifactorial aetiologies including genetic susceptibility, consumption of food with high salt content, and the Epstein-Barr virus. The primary tumour usually arises from the lateral walls of the nasopharynx and is characterized by a rich sub-mucosal lymphatic structure, often leading to cervical lymph node metastasis. Distant metastasis has been recognized to be a major cause of treatment failure in patients with nasopharyngeal carcinoma. Bone, liver and lung are the most frequent sites of NPC metastases.

Efficacy and safety of anti-obesity drugs in children and adolescents: systematic review and meta-analysis.

We undertook a meta-analysis of randomized controlled trials to summarize the efficacy of anti-obesity drugs in reducing BMI and improving health in children and adolescents. Data sources included Medline, Embase, the Cochrane controlled trials register and other registers of controlled trials, together with reference lists of identified articles. All data sources were searched from January 1996 to July 2008. We searched for double blind randomized placebo controlled trials of approved anti-obesity drugs used in children and adolescents (age < 20) with primary obesity for > or = 6 months. Six trials, 4 of sibutramine (total patients = 686) and 2 of orlistat (n = 573) met inclusion criteria. No trials of rimonabant were identified. Compared with placebo, sibutramine together with behavioural support reduced BMI by 2.20 kg/m(2) (95% CI: 1.57 to 2.83) and orlistat together with behavioural support reduced BMI by 0.83 kg/m(2) (95% CI 0.47 to 1.19). Sibutramine improved waist circumference, triglycerides and high density lipoprotein (HDL)-cholesterol, but raised systolic and diastolic blood pressure and pulse. Orlistat increased rates of gastrointestinal side-effects. We conclude that sibutramine in adolescents produces clinically meaningful reductions in BMI and waist circumference of approximately 0.63 SD, with improvements in cardiometabolic risk. Orlistat modestly reduces BMI (effect size approximately 0.24 SD) with a high prevalence of gastrointestinal adverse effects.

Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo.

Mitochondrial complex I inhibition has been implicated in the degeneration of midbrain dopaminergic (DA) neurons in Parkinson's disease. However, the mechanisms and pathways that determine the cellular fate of DA neurons downstream of the mitochondrial dysfunction have not been fully identified. We conducted cell-type specific gene array experiments with nigral DA neurons from rats treated with the complex I inhibitor, rotenone, at a dose that does not induce cell death. The genome wide screen identified transcriptional changes in multiple cell death related pathways that are indicative of a simultaneous activation of both degenerative and protective mechanisms. Quantitative PCR analyses of a subset of these genes in different neuronal populations of the basal ganglia revealed that some of the changes are specific for DA neurons, suggesting that these neurons are highly sensitive to rotenone. Our data provide insight into potentially defensive strategies of DA neurons against disease relevant insults.

HLA class I (A, B, C) and class II (DRB1, DQA1, DQB1, DPB1) alleles and haplotypes in the Han from southern China.

In this study, polymerase chain reaction-sequence-specific oligonucleotide prode (SSOP) typing results for the human leukocyte antigen (HLA) class I (A, B, and C) and class II (DRB1, DQA1, DQB1, and DPB1) loci in 264 individuals of the Han ethnic group from the Canton region of southern China are presented. The data are examined at the allele, genotype, and haplotype level. Common alleles at each of the loci are in keeping with those observed in similar populations, while the high-resolution typing methods used give additional details about allele frequency distributions not shown in previous studies. Twenty distinct alleles are seen at HLA-A in this population. The locus is dominated by the A*1101 allele, which is found here at a frequency of 0.266. The next three most common alleles, A*2402, A*3303, and A*0203, are each seen at frequencies of greater than 10%, and together, these four alleles account for roughly two-thirds of the total for HLA-A in this population. Fifty alleles are observed for HLA-B, 21 of which are singleton copies. The most common HLA-B alleles are B*4001 (f= 0.144), B*4601 (f= 0.119), B*5801 (f= 0.089), B*1301 (f= 0.068), B*1502 (f= 0.073), and B*3802 (f= 0.070). At the HLA-C locus, there are a total of 20 alleles. Four alleles (Cw*0702, Cw*0102, Cw*0801, and Cw*0304) are found at frequencies of greater than 10%, and together, these alleles comprise over 60% of the total. Overall, the class II loci are somewhat less diverse than class I. Twenty-eight distinct alleles are seen at DRB1, and the most common three, DRB1*0901, *1202, and *1501, are each seen at frequencies of greater than 10%. The DR4 lineage also shows extensive expansion in this population, with seven subtypes, representing one quarter of the diversity at this locus. Eight alleles are observed at DQA1; DQA1*0301 and 0102 are the most common alleles, with frequencies over 20%. The DQB1 locus is dominated by four alleles of the 03 lineage, which make up nearly half of the total. The two most common DQB1 alleles in this population are DQB1*0301 (f= 0.242) and DQB1*0303 (f= 0.15). Eighteen alleles are observed at DPB1; DPB1*0501 is the most common allele, with a frequency of 37%. The class I allele frequency distributions, expressed in terms of Watterson's (homozygosity) F-statistic, are all within expectations under neutrality, while there is evidence for balancing selection at DRB1, DQA1, and DQB1. Departures from Hardy-Weinberg expectations are observed for HLA-C and DRB1 in this population. Strong individual haplotypic associations are seen for all pairs of loci, and many of these occur at frequencies greater than 5%. In the class I region, several examples of HLA-B and -C loci in complete or near complete linkage disequilibrium (LD) are present, and the two most common, B*4601-Cw*0102 and B*5801-Cw*0302 account for more than 20% of the B-C haplotypes. Similarly, at class II, nearly all of the most common DR-DQ haplotypes are in nearly complete LD. The most common DRB1-DQB1 haplotypes are DRB1*0901-DQB1*0303 (f= 0.144) and DRB1*1202-DQB1*0301 (f= 0.131). The most common four locus class I and class II combined haplotypes are A*3303-B*5801-DRB1*0301-DPB1*0401 (f= 0.028) and A*0207-B*4601-DRB1*0901-DPB1*0501 (f= 0.026). The presentation of complete DNA typing for the class I loci and haplotype analysis in a large sample such as this can provide insights into the population history of the region and give useful data for HLA matching in transplantation and disease association studies in the Chinese population.

Up-regulation of a serine-threonine kinase proto-oncogene Pim-1 in oral squamous cell carcinoma.

The Pim-1 proto-oncogene, encoding a serine-threonine kinase, has been found to play an important role in regulating apoptosis, differentiation, proliferation and tumourigenesis. The present study was conducted to assess the importance of Pim-1 in oral tumourigenesis in vivo. Reverse transcriptase-polymerase chain reaction and immunohistochemistry were used to study the expression of Pim-1 in oral squamous cell carcinoma (OSCC) and non-cancerous match tissue (NCMT) sampled from the periphery of the tumours. Pim-1 mRNA expression in OSCC was significantly higher than that in NCMT in 36 tissue pairs (1.33+/-0.41 versus 0.97+/-0.29, P=0.03). The percentage of OSCCs exhibiting strong cytoplasmic Pim-1 immunoreactivity was significantly higher than that of NCMT (60% versus 19%, P=0.007). Pim-1 immunoreactivity is higher in the more differentiated components of a tumour. In around 10% of OSCC cases, Pim-1 immunoreactivity was found in the nucleus as well. These results show novel findings of the up-regulation of Pim-1 expression from NCMT to OSCC. The pathogenetic role of Pim-1 expression in oral tumourigenesis deserves further investigation.

Dyggve-Melchior-Clausen syndrome: report of seven patients with the Smith-McCort variant and review of the literature.

Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive disorder affecting skeletal development. The patients have a striking "barrel-shape" chest, shortened trunk, and various distal deformities, including genu valgum or varum, and minimal decrease in joint mobility. The most notable radiographic findings are a lacy iliac crest apophysis, hip dysplasia, double vertebral hump, and odontoid hypoplasia with atlanto-axial instability. Patients may require orthopedic femoral osteotomy, total hip arthroplasty, early meniscectomy, realignment osteotomy, or posterior cervical spine fusion. Patients with the Smith McCort variant have similar orthopaedic manifestations but are not mentally retarded. The diagnosis may be confirmed histologically, but no biochemical or developmental defect has been defined as yet. The authors report seven affected members of two families from Guam and describe their orthopaedic treatment. The authors review the historical reports, clinical findings, and diagnostic radiographic features in DMC syndrome.

Orthopaedic manifestations of Marinesco-Sjögren syndrome.

Two patients with Marinesco-Sjögren syndrome had striking orthopaedic abnormalities that seemed to arise from multiple areas of physeal growth arrest. Major involvement was seen in the distal femora, where bilateral hypoplasia of the lateral condyles resulted in progressive valgus, patellar dislocation, and quadriceps dysfunction. Marinesco-Sjögren syndrome seems to arise from an error in lysosomal handling of lipids. Timely orthopaedic intervention may be helpful in prolonging ambulation in these patients.

Determination of the breakpoint of the common alpha-thalassaemia deletion in Filipinos in Hawaii.

The region of the crossover causing the Filipino type of alpha thalassaemia has been determined by examining similarity between the regions which had been indicated as involved in the crossover points by restriction mapping, using the published alpha-globin region DNA sequence. The crossover point was found in 21 base pairs between two Alu sequences using PCR primers flanking these Alu sequences. A simple PCR multiplex assay has been devised to detect heterozygotes and homozygotes.

Near-total intestinal aganglionosis in the Waardenburg-Shah syndrome.

Both pigmentation and otic defects of Waardenburg Syndrome and Hirschsprung's disease have a common origin in neural crest cells and were described in 1951 and 1887, respectively. The clinical manifestations of both in the same patient were described in 1981 in 12 infants so afflicted. The authors present such a case of long segment aganglionosis in a 15-day-old Marshallese girl with Waardenburg-Shah syndrome and discuss diagnosis, treatment, and prognosis.

Microchimerism and tolerance following intrauterine transplantation and transfusion for alpha-thalassemia-1.

A fetus homozygous for alpha-thalassemia-1 was given haploidentical paternal CD34 cells at 13, 19 and 24 weeks' gestation and supported through pregnancy by blood transfusion. The fetal hematocrit ranged between 27 and 47% and between one half and three quarters of this hemoglobin was of recipient (Bart's) type. Intrauterine growth proceeded normally and no significant fetal hydrops was detected. Tests for donor HLA antigens, and alpha-globin DNA, were negative on fetal blood samples drawn before birth. A positive signal for alpha-globin DNA was obtained from cord blood and from marrow obtained at 3 months of age, suggesting that some donor stem cells had persisted in the recipient. The infant's blood mononuclear cells showed little proliferative and no cytotoxic response to the donor while responses to a third party were present. Additional paternal CD34 cells given at 3 months age did not reduce transfusion dependency in the subsequent 6 months. Our results show that repeated transfusions can support an alpha-thalassemia-1 fetus through pregnancy, in this instance without significant birth defects or apparent hypoxic tissue injury. The donor stem cells did not have a survival advantage compared with endogenous stem cells, but appeared to survive in the recipient as judged by the persistence of an alpha-globin DNA signal. In vitro studies of alloreactivity suggest tolerization of the host to the donor's MHC disparity. Future efforts will focus on exploiting this tolerance to improve the level of donor chimerism.