The ratio of bone marrow myeloid progenitor cell proportion to mature lymphocytes proportion can effectively differentiate aplastic anemia and hypoplastic myelodysplastic syndrome and evaluate the quality of bone marrow aspirates.

INTRODUCTION: Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (MDS-h) are bone marrow failure disease and difficult to distinguish merely by morphological analysis. In this study, we investigated the value of flow cytometry (FCM) in the differential diagnosis of AA and MDS-h. METHODS: We included 822 patients (626 control, 69 AA, 22 MDS-h and 105 dilution patients) from January 2017 to December 2022 for a retrospective study. Bone marrow myeloid progenitor (MP) cell and mature lymphocytes proportions were analyzed by FCM. The ratio of MP cell proportion and mature lymphocytes proportion, MPLR, was calculated. Data were compared by Kruskal-Wallis test. Differential diagnostic efficacy was evaluated by receiver operating characteristic (ROC) curve. Cutoff value was determined by the maximum Youden index. RESULTS: Bone marrow MP cell proportion and MPLR of MDS-h patients were higher than AA patients. Mature lymphocytes proportion of MDS-h patients was lower than AA patients. Area under ROC curve (AUC of ROC) of MP cell proportion, MPLR and mature lymphocytes proportion to distinguish AA from MDS-h were 0.992, 0.988, and 0.850, respectively. Moreover, MPLR of dilution patients was higher than AA patients but lower than MDS-h patients. The AUC of ROC curves of MPLR to distinguish MDS-h and AA from dilution were 0.854 and 0.871, respectively. CONCLUSION: Bone marrow MP cell proportion and MPLR can effectively discriminate AA from MDS-h with similar differential efficacy, which is higher than mature lymphocytes proportion. Moreover, MPLR can evaluate the quality of bone marrow aspirates, which would interfere with the differential diagnosis.

[Clinical phenotype and genetic analysis of a fetus with recombinant chromosome 8 syndrome].

OBJECTIVE: To explore the clinical characteristics and molecular genetic mechanism of a fetus with recombinant chromosome 8 (Rec8) syndrome. METHODS: A fetus who was diagnosed with Rec8 syndrome at the Provincial Hospital Affiliated to Shandong First Medical University on July 20, 2021 due to high risk for sex chromosomal aneuploidy indicated by non-invasive prenatal testing (NIPT) (at 21st gestational week) was selected as the study subject. Clinical data of the fetus was collected. G-banded karyotyping and chromosomal microarray analysis (CMA) were carried out on the amniotic fluid sample. Peripheral blood samples of the couple were also subjected to G banded karyotyping analysis. RESULTS: Prenatal ultrasonography at 23rd gestational week revealed hypertelorism, thick lips, renal pelvis separation, intrahepatic echogenic foci, and ventricular septal defect. The karyotype of amniotic fluid was 46,XX,rec(8)(qter→q22.3::p23.1→qter), and CMA was arr[GRCh37]8p23.3p23.1(158049_6793322)×1, 8q22.3q24.3(101712402_146295771)×3. The karyotype of the pregnant woman was 46,XX,inv(8)(p23.1q22.3), whilst that of her husband was normal. CONCLUSION: The Rec8 syndrome in the fetus may be attributed to the pericentric inversion of chromosome 8 in its mother. Molecular testing revealed that the breakpoints of this Rec8 have differed from previously reported ones.

Voxel-based morphometry reveals the correlation between gray matter volume and serum P-tau-181 in type 2 diabetes mellitus patients with different HbA1c levels.

Introduction: Emerging evidence suggested widespread decreased gray matter volume (GMV) and tau hyperphosphorylation were associated with type 2 diabetes mellitus (T2DM). Insulin resistance is one of the mechanisms of neuron degeneration in T2DM; it can decrease the activity of protein kinase B and increase the activity of glycogen synthesis kinase-3ß, thus promoting the hyperphosphorylation of tau protein and finally leading to neuronal degeneration. However, the association between GMV and serum tau protein phosphorylated at threonine 181 (P-tau-181) in T2DM patients lacks neuroimaging evidence. We aimed to investigate the difference in brain GMV between T2DM patients with different glycated hemoglobin A1c (HbA1c) levels and healthy control (HC) subjects and the correlation between serum P-tau-181 and GMV in T2DM patients. Methods: Clinical parameters, biochemical indicators, and MRI data were collected for 41 T2DM patients with high glycosylated hemoglobin level (HGL), 17 T2DM patients with normal glycosylated hemoglobin level (NGL), and 42 HC subjects. Voxel-based morphometry (VBM) method was applied to investigate GMV differences among groups, and multiple regression analysis was used to examine the correlation between serum P-tau-181 and GMV. Results: Compared with HC subjects, the T2DM patients with HGL or NGL all showed significantly decreased GMV. Briefly, the GMV decreased in T2DM patients with HGL was mainly in the bilateral parahippocampal gyrus (PHG), right middle temporal gyrus (MTG), temporal pole (TPOmid), hippocampus (HIP), and left lingual gyrus. The GMV reduction in T2DM patients with NGL was in the right superior temporal gyrus (STG), and there was no significant difference in GMV between the two diabetic groups. The GMV values of bilateral PHG, right MTG, TPOmid, HIP, and STG can significantly (p < 0.0001) distinguish T2DM patients from HC subjects in ROC curve analysis. In addition, we found that serum P-tau-181 levels were positively correlated with GMV in the right superior and middle occipital gyrus and cuneus, and negatively correlated with GMV in the right inferior temporal gyrus in T2DM patients. Conclusion: Our study shows that GMV atrophy can be used as a potential biological indicator of T2DM and also emphasizes the important role of P-tau-181 in diabetic brain injury, providing new insights into the neuropathological mechanism of diabetic encephalopathy.

Altered Brain Morphometry in Cerebral Small Vessel Disease With Cerebral Microbleeds: An Investigation Combining Univariate and Multivariate Pattern Analyses.

Purpose: The objective of this study was to evaluate whether altered gray matter volume (GMV) and white matter volume (WMV) are associated with the presence of cerebral microbleeds (CMBs) in cerebral small vessel disease (CSVD). Materials and Methods: In this study, we included 26 CSVD patients with CMBs (CSVD-c), 43 CSVD patients without CMBs (CSVD-n) and 39 healthy controls. All participants underwent cognitive assessment testing. Both univariate analysis and multivariate pattern analysis (MVPA) approaches were applied to investigate differences in brain morphometry among groups. Results: In univariate analysis, GMV and WMV differences were compared among groups using voxel-based morphometry (VBM) with diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL). Compared to healthy controls, the CSVD-c group and CSVD-n group showed significantly lower GMV than the control group in similar brain clusters, mainly including the right superior frontal gyrus (medial orbital), left anterior cingulate gyrus, right inferior frontal gyrus (triangular part) and left superior frontal gyrus (medial), while the CSVD-n group also showed significantly lower WMV in the cluster of the left superior frontal gyrus (medial). No significant GMV or WMV differences were found between the CSVD-c group and the CSVD-n group. Specifically, we applied the multiple kernel learning (MKL) technique in MVPA to combine GMV and WMV features, yielding an average of >80% accuracy for three binary classification problems, which was a considerable improvement over the individual modality approach. Consistent with the univariate analysis, the MKL weight maps revealed default mode network and subcortical region damage associated with CSVD compared to controls. On the other hand, when classifying the CSVD-c group and CSVD-n group in the MVPA analysis, we found that some WMVs were highly weighted regions (left olfactory cortex and right middle frontal gyrus), which hinted at the presence of different white matter alterations in the CSVD-c group. Conclusion: Our findings not only suggested that the localized alterations in GMV and WMV appeared to be associated with the pathophysiology of CSVD but also indicated that altered brain morphometry could be a potential discriminative pattern to detect CSVD at the individual level.

Iron Deposition Characteristics of Deep Gray Matter in Elderly Individuals in the Community Revealed by Quantitative Susceptibility Mapping and Multiple Factor Analysis.

PURPOSE: The objective of this study was to determine which factors influence brain iron concentrations in deep gray matter in elderly individuals and how these factors influence regional brain iron concentrations. METHODS: A total of 105 elderly individuals were enrolled in this study. All participants underwent detailed magnetic resonance imaging (MRI) examinations from October 2018 to August 2019. Among them, 44 individuals had undergone a previous MRI examination from July 2010 to August 2011. Quantitative susceptibility mapping (QSM) was utilized as an indirect quantitative marker of brain iron, and the susceptibility values of deep gray matter structures were obtained. Univariate analysis and multiple linear regression analysis were used to investigate 11 possible determinants for cerebral iron deposition. RESULTS: Our results showed no sex- or hemisphere-related differences in susceptibility values in any of the regions studied. Aging was significantly correlated with increased insusceptibility values in almost all analyzed brain regions (except for the thalamus) when we compared the susceptibility values at the two time points. In a cross-sectional analysis, the relationship between gray matter nucleus susceptibility values and age was conducted using Pearson's linear regression. Aging was significantly correlated with the susceptibility values of the globus pallidus (GP), putamen (Put), and caudate nucleus (CN), with the Put having the strongest correlations. In multiple linear regression models, associations with increased susceptibility values were found in the CN, Put, red nucleus, and dentate nucleus for individuals with a history of type 2 diabetes mellitus (T2DM). However, the patients with hypertension showed significantly reduced susceptibility values in the red nucleus and dentate nucleus. Our data suggested that smokers had increased susceptibility values in the thalamus. No significant associations were found for individuals with a history of hypercholesterolemia and Apolipoprotein E4 carrier status. CONCLUSION: Our data revealed that aging, T2DM, and smoking could increase iron deposition in some deep gray matter structures. However, hypertension had the opposite effects in the red nuclei and dentate nuclei. Brain iron metabolism could be influenced by many factors in different modes. In future studies, we should strictly control for confounding factors.

Bainbridge-ropers syndrome caused by loss-of-function variants in ASXL3: Clinical abnormalities, medical imaging features, and gene variation in infancy of case report.

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the Additional sex combs-like 3 (ASXL3) gene. Only four cases have been reported in China and are limited to the analysis of its clinical abnormalities, medical imaging features and gene variation. The aim of this study was to investigate the clinical phenotype, imaging manifestations and genetic characteristics of BPRS syndrome caused by ASXL3 gene mutation. Clinical data, medical imaging data and gene test results of BRPS in infant patients were retrospectively analyzed, and related literature was summarized. CASE PRESENTATION: At the age of 8 months, brain MRI showed that the subarachnoid space of the forehead was widened, part of the sulci was deepened, and the corpus callosum was thin. The development quotient (DQ) was determined using the 0~6-year-old pediatric examination table of neuropsychological development at 6 months and 8 months. The DQ of both tests was less than 69. Whole-exome sequencing revealed a heterozygous frameshift mutation c.3493_3494deTG in exon 12 of the ASXL3 gene, resulting in the amino acid change p. (Cys1165Ter). No variation was present at this site in her parents. Sanger sequencing of family members validated this analysis, suggesting a de novo mutation. The de novo ASXL3 mutations generated stop codons and were predicted, in silico, to generate a truncated ASXL3. CONCLUSIONS: The main clinical features of the patient included psychomotor development retardation, difficulty in feeding, hypotonia, and special facial features. MRI features showed that brain development lagged behind that of normal children. Genetic testing is helpful in the early diagnosis of BRPS.

The Higher Response of Vascular Endothelial Growth Factor and Angiotensin-II to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome.

BACKGROUND: This research investigated the response of vascular active factors, vascular endothelial growth factor (VEGF) and angiotensin-II (AT-II) to ovarian stimulation during 24 hours in patients with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: In this clinical trial study, 52 patients with PCOS and 8 control cases were stimulated with human chorionic gonadotropin (HCG) on the 4(th) to 7(th) day of the patients' natural or induced menstrual cycles. We measured VEGF and AT-II by radioimmunoassay before the injection (0 hour) and 3, 8, 12, 18 and 24 hours after the stimulation. RESULTS: After ovarian stimulation, there was substantially higher level of VEGF in typical PCOS patients than the other three groups at the 3 hour time point (p<0.05), while there were no significant differences in VEGF at all the other time points among the four groups. As for AT-II, before and at all time points after the ovarian stimulation, it seemed that the AT-II levels in patients' sera with different phenotypes of PCOS by the Rotterdam criteria were all higher than in the control group although the differences were not statistically significant. The level of AT-II in typical PCOS patients was also significantly higher than the other three groups at the 3 hour time point (p<0.05), while no significant differences at all the other time points among the four groups were observed. CONCLUSION: The response to the stimulation varied among patients with different phenotypes of PCOS according to the Rotterdam criteria. Serum VEGF and AT-II were possible contributors to an increased risk of developing ovarian hyperstimulation syndrome (OHSS) in patients with typical PCOS during the early follicular phase (3 hours) after ovarian stimulation ( REGISTRATION NUMBER: NCT02265861).

Microsatellite polymorphism in the fibrillin 3 gene and susceptibility to PCOS: a case-control study and meta-analysis.

The D19S884 marker at the fibrillin 3 gene has been analysed as a candidate location for polycystic ovary syndrome (PCOS) mainly in Caucasian descendants. A case-control study was performed with 272 PCOS women and 271 controls to test the hypothesis that variants in the D19S884 marker increase susceptibility to PCOS in Chinese women and a meta-analysis was undertaken to clarify whether there is an allele consistently contributing to the susceptibility. The association analysis showed that PCOS women were significantly different from controls in the distribution of D19S884 allele frequencies. Instead of the well-known A8 allele, the most common allele in Chinese population was proved to be A7, and the allele frequencies of A7 were statistically different between cases and controls (P=0.037). The meta-analysis of A8 and A7 only identified A8 as a significant allelic association at the D19S884 marker in all combined samples (A8: OR 1.391, 95% CI 1.169-1.654; A7: OR 1.154, 95% CI 0.894-1.490). In conclusion, the association study showed a potential association of the D19S884 marker with PCOS in Chinese Han women and the meta-analysis identified that A8 may increase susceptibility to PCOS. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, and it affects an estimated 15% of women worldwide based on the Rotterdam criteria. Many studies in Caucasian descendants suggested that variants of the D19S884 marker at the fibrillin 3 gene are associated with the risk of this syndrome. Here we performed a case-control study with 272 PCOS women and 271 controls to investigate whether variants in the D19S884 marker increase susceptibility to PCOS in Chinese women. We also carried out a meta-analysis of some relevant studies to find a more reliable result. Our association analysis showed that PCOS women were significantly different from controls in the distribution of D19S884 allele frequencies, and instead of the well-known A8 (the letter 'A' represents 'allele'), the most common allele in Chinese population was proved to be A7, whose allele frequencies were statistically different between cases and controls. The meta-analysis of A8 and A7 only identified A8 as a significant allelic association at the D19S884 marker in all combined samples. In conclusion, our association study showed a potential association of the D19S884 marker with PCOS in Chinese Han women and the meta-analysis identified that A8 may increase susceptibility to PCOS.

Association between polymorphisms of the CYP11A1 gene and polycystic ovary syndrome in Chinese women.

The cholesterol side chain cleavage enzyme (CYP11A1) gene plays an important part in the synthesis of sex hormones and has been reported to be involved in the pathogenesis of polycystic ovary syndrome. A case-control study including 314 PCOS patients and 314 controls was conducted to assess the association of the SNPs rs4077582 and rs11632698 in CYP11A1 with PCOS using the polymerase chain reaction-restriction fragment length polymorphism method. Thereafter, 100 DNA samples were re-genotyped by direct sequencing for confirmation. The genotypic distribution of rs4077582 in women with PCOS differed from that in controls (P = 0.002). No such distributional difference was found in rs11632698 (P = 0.912). Data from our previous study of these two SNPs in another population including 290 PCOS patients and 344 controls was combined with the current data. Combined analysis (a total of 1262 participants, including 604 PCOS patients and 658 control women) showed a much more significant difference in the genotypic distribution of rs4077582 between PCOS and controls (P < 0.001). The T allele was more prevalent in PCOS patients (Odds ratio = 1.314; 95 % CI 1.122-1.540). The testosterone levels among the three genotypes for rs4077582 were different in the control group, as were the LH levels and the LH/FSH ratio. Therefore, SNP rs4077582 in CYP11A1 is strongly associated with susceptibility to PCOS and may alter the testosterone levels by the regulation of LH in different genotypes. No association was observed in rs11632698.

Polymorphic CAG repeat in the androgen receptor gene in polycystic ovary syndrome patients.

Human androgen receptor (AR) contains a highly polymorphic polyglutamine tract encoded by CAG repeats [(CAG)n] in exon 1 of the AR gene. The CAG repeats, ranging from 11 to 38, have been reported to be inversely correlated with AR activity. A case-control study involving 261 polycystic ovary syndrome (PCOS) patients and 278 healthy controls was conducted. Fluorescently labeled DNA fragments containing (CAG)n were obtained by PCR and genotyped via capillary electrophoresis. AR (CAG)n ranges were 6, 12-28 in PCOS cases and 9, 10, 12-32 in controls. In the PCOS group, a higher frequency of short (CAG)n alleles was found compared with that of controls (P=0.007). Similarly, CAG biallelic mean distributions also showed statistical difference between the two groups (P=0.025). In conclusion, shorter alleles of the (CAG)n in exon 1 of the AR gene enhanced the susceptibility to PCOS, either by upregulating AR activity or by causing hyperandrogenism.

SNP rs2470152 in CYP19 is correlated to aromatase activity in Chinese polycystic ovary syndrome patients.

CYP19 encodes aromatase, a key enzyme essential for estrogen biosynthesis. Single nucleotide polymorphism (SNP) rs2470152 in CYP19 is associated with serum estradiol (E2) level and the E2/T (estradiol/testosterone) ratio. A case­control study including 661 individuals [364 polycystic ovary syndrome (PCOS) patients and 297 controls] was conducted to assess the association of SNP rs2470152 with PCOS. The subjects were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. Hormone levels were analyzed among various genotypes. The genotypic distributions of rs2470152 did not differ in PCOS patients when compared to the controls. However, differences in the E2/T ratio were detected, exhibiting a lower ratio in the heterozygous TC genotype in PCOS patients (p=0.01036) and controls (p=0.000). Testosterone levels also differed between the three genotypes of PCOS patients (p=0.00625), with a higher level in the TC genotype. Therefore, rs2470152 in CYP19 was not a major etiological factor for PCOS; however, the heterozygous TC genotype may inhibit aromatase activity, resulting in hyperandrogenism, particularly in PCOS patients.

Polymorphisms of the HSD17B6 and HSD17B5 genes in Chinese women with polycystic ovary syndrome.

OBJECTIVES: To investigate the polymorphisms of the 17ß-hydroxysteroid dehydrogenase type 5 and type 6 (HSD17B5 and HSD17B6) genes in Chinese women with polycystic ovary syndrome (PCOS). METHODS: Two hundred twenty-two PCOS patients and 283 controls were studied. Menarche age was recorded. Body mass indices (BMI) were calculated. Blood samples were obtained for single nucleotide polymorphism (SNP) analyses and hormone measurements. Genotyping of HSD17B6 and HSD17B5 in cases and controls was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The SNP rs898611 of the HSD17B6 gene (TT, CT, CC) in women with PCOS (0.680, 0.270, 0.050, respectively) did not differ from those in controls (0.700, 0.258, 0.042, respectively), and the SNP rs3763676 of the HSD17B5 gene (AA, AG, GG) was rare in Chinese women. Total testosterone and other reproductive hormones, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH/FSH, and estradiol (E(2)), were also similar among the different genotypes of the HSD17B6 in the PCOS subjects and the controls, whereas BMI was different in the three genotypes of the HSD17B6 in PCOS subjects. CONCLUSIONS: Our data suggest that there is no association of HSD17B6 and HSD17B5 variants with the occurrence of PCOS in the Chinese population, but the polymorphism of SNP rs898611 is associated with BMI in PCOS patients.

Polymorphisms of TCF7L2 and HHEX genes in Chinese women with polycystic ovary syndrome.

PURPOSE: This study was to evaluate whether polymorphisms of TCF7L2 (rs7903146) and HHEX (rs1111875) genes responsible for insulin secretion are associated with the polycystic ovary syndrome (PCOS) in Chinese people. METHODS: 326 PCOS patients and 290 healthy individuals as controls were studied. Blood samples were obtained for DNA analyses and hormone measurements. Genotyping of the TCF7L2 (rs7903146) and HHEX (rs1111875) genes was carried out by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: We did not find statistically significant differences in the distribution of the TCF7L2 rs7903146 and HHEX rs1111875 polymorphisms between the Chinese women with PCOS and the controls. Levels of hormones such as insulin, FSH, LH, LH/FSH, P, T and E2 were also similar between the different genotypes of the genes TCF7L2 and HHEX, respectively, which was confirmed within either the PCOS subjects or controls. CONCLUSIONS: There was no association of either of the two variants, rs7903146 of TCF7L2 and rs1111875 of HHEX, with the occurrence of PCOS in the Chinese population.

Association between ACE gene I/D polymorphisms and hyperandrogenism in women with polycystic ovary syndrome (PCOS) and controls.

BACKGROUND: I/D polymorphisms of ACE are associated with the plasma ACE concentration. The ACE is associated with the angiogenesis of ovarian endothelium in vitro as well as steroidogenesis and follicular growth in cattle. Since ACE induces a high blood supply and hypersteroidogenesis in the ovary, it may be associated with polycystic ovary syndrome (PCOS) which exhibits hyperplasia, hypervascularity of the ovarian theca interna and stroma, as well as disorderd steroidogenesis. Therefore, we hypothesized that the ACE plays some roles in the human ovary. To investigate whether the ACE I/D polymorphisms are associated with the steroidogenesis disorder in PCOS and contribute to the susceptibility of PCOS in Chinese women, we designed a case-controlled association study in 582 individuals. METHODS: The ACE I/D polymorphisms were assessed in 582 reproductive-age women. Genotyping and frequency of ACE I/D polymorphisms were obtained by PCR amplification that was performed on genomic DNA isolated from blood leucocytes. Results were analyzed in respect to clinical test results. RESULTS: The frequencies of the D allele and the genotypic distributions (DD, ID and II) in the women with PCOS did not differ from those in controls (P = 0.458). However, there were significant differences in the concentrations of testosterone among three genotypes both in the PCOS patients and controls (P = 0.0045, P = 0.0052, respectively). Differences were also found between these groups with distinct genotypes: DD versus II and DI versus II in the PCOS patients as well as DD versus DI and DD versus II in the controls. There were significant differences in the ratio of LH/FSH among three genotypes in the patients (P = 0.01). However, there were no statistical differences in the BMI, AAM, E2 concentrations and other serum hormone concentrations among the three genotypes both in the PCOS patients and controls. CONCLUSION: The ACE I/D polymorphisms were not associated with the pathogenesis of PCOS. However, the polymorphisms were associated with the steroidogenesis in the ovary. The observation indicated that the ACE I/D polymorphisms were not the key etiological factor, which in stead may be associated with the aggravated clinical manifestations of PCOS.