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Four clinical cases are presented: (a) cured systemic lupus erythematosus, fracture of the odontoid process of the axis; (b) renovascular stenosis following renal transplant; dissecting aneurysm of aorta, consolidated for the last 3 years; (c) rejection glomerulonephritis following renal transplant; (d) unusual complications in a patient of intermittent hemodialysis for the last 8 years.
BACKGROUND: Human heart failure involves multicellular transcriptional remodeling, but public transcriptomic studies often remain disconnected from cell-type localization and perturbational interpretation. METHODS: We developed a reproducible computational workflow integrating human left-ventricular bulk transcriptomes, donor-level cell-type pseudobulk results from a human heart-failure single-cell/single-nucleus atlas, external snRNA-seq support, curated module scoring, focused ligand-receptor prioritization and LINCS/L1000 perturbational matching. RESULTS: Cross-cohort analysis identified 14,358 same-direction HF-associated genes, including 1633 replicated HF-up and 785 replicated HF-down genes. Donor-level pseudobulk analysis localized disease remodeling to cardiomyocyte, fibroblast and myeloid compartments. Activated fibroblast and inflammatory myeloid programs defined a fibroinflammatory remodeling axis connected to context-dependent AKT-associated transcriptional shifts. External snRNA-seq support was strongest for fibroblast activation and AKT-associated remodeling, with etiology-dependent heterogeneity across validation resources. L1000FWD screening prioritized safety-aware perturbational hypotheses, including glimepiride and simvastatin as interpretable candidates requiring experimental validation. CONCLUSIONS: This study provides a computational transcriptomic framework linking reproducible human HF signatures, cell-type-resolved fibroinflammatory remodeling and perturbational genomic prioritization without claiming drug efficacy or AKT causality.
A 21-year-old Japanese man with basilar impression with an anomalous configuration of the odontoid process and many other vertebral anomalies is reported. We thought that posterior decompression alone would be hazardous; therefore, in one session, the odontoid tip and anterior arch of the atlas were removed transorally, and posterior fixation between the occipital squama and the lamina of C-3 using acrylic plastic was performed. This treatment resulted in marked clinical improvement and required only a short hospital stay.
Three-dimensional organoids of the gut, liver, and lung have become mainstream models of human development, disease, and therapy. These organs share an embryonic endodermal origin, yet the field measures their progress inconsistently because the word "maturity" carries two unrelated meanings. Herein, we review the organoid work across all three organs and propose that the two orthogonal axes of advancement be analyzed separately. The first axis is single-organ fidelity. Adult stem cell organoids are faithful but partial, reproducing the adult epithelium of their source tissue with genomic stability yet lacking stromal, vascular, immune, and neural compartments. Human pluripotent stem cell organoids are complete but immature, co-emerging with multiple lineages yet arrested in a fetal-like state. The cost of each limitation is organ-dependent, smallest in the intestine, largest for hepatic drug metabolism, and most spatially defined across the proximal and distal lungs. The second axis is inter-organ reconstruction, where progress is strongly asymmetric. The gut-liver axis is comparatively advanced and sustained by linked organoid and microphysiological systems. The gut-lung axis, by contrast, remains the least-developed frontier, and no such linked organoid has yet been built. We therefore frame it as a proposal, using in vivo and correlative evidence to outline the design principles for such a model. Four bottlenecks recur across both axes: limited vascularization; batch-to-batch variability; organ-skewed immune, microbial, and stromal microenvironments; and unidirectional signaling. We argue that benchmarking models against single-cell developmental atlases and prioritizing construction of the gut-lung frontier should guide the field over the next decade.
The somatotropic axis encompassing growth hormone (GH), insulin-like growth factor (IGF), myostatin (MSTN), and prolactin (PRL) signalling cascades is the master regulator of somatic growth, metabolism, and development in vertebrates. African catfish (Clarias gariepinus), a commercially pivotal aquaculture species, now possesses a chromosome-level reference genome (CGAR_prim_01v2); however, a systematic, genome-wide characterization spanning all five interconnected growth-related gene families has not previously been undertaken in this species. Here, we identified and characterized 15 growth-related genes spanning gh1, ghra, ghrb, Igf1, Igf2a, Igf2b, igf1ra, Igf1rb, Igf2r, Mstna, Mstnb, prl, prlra, prlrb, and smtlb distributed across 13 chromosomes. Complete one-to-one orthology with zebrafish confirmed strong dosage-balance conservation across >120 million years of teleost divergence. Physicochemical analysis resolved a clear biochemical dichotomy between compact, basic secreted ligands (19.88-45.81 kDa; pI up to 10.02) and large, acidic, heavily glycosylated membrane receptors (56.82-270.80 kDa; pI 4.85-5.97). Phylogenetic analysis confirmed 3R whole-genome duplication origins for all paralog pairs, while synteny analysis revealed a disruption of the ancestral gh1-prl chromosomal block in C. gariepinus, a finding that warrants further comparative and functional investigation. This genomic atlas provides the sequence and structural information including exon-intron boundaries, domain architecture, and chromosomal coordinates needed as a prerequisite for future marker-assisted selection and CRISPR-based myostatin-editing efforts in African catfish aquaculture, though translation into applied breeding outcomes will require subsequent functional and expression studies.
Diabetic retinopathy (DR) is a major cause of vision loss worldwide. Here, we conduct single-cell RNA sequencing of twenty human retina samples (from living and post-mortem donors) across non-diabetic, diabetic, and DR states to create a comprehensive transcriptomic atlas. We identify two stable microglial populations-homeostatic and inflammatory-that exist along a functional continuum, plus a neutrophil cluster within C1QA+ myeloid cells with dynamic transitions occurring throughout disease progression. Module-level analysis reveals divergent transcriptional trajectories: homeostatic microglia maintain energetic programs while selectively upregulating stress elements, whereas inflammatory microglia layer additional pro-inflammatory programs onto preserved biosynthetic foundations. Eleven co-expression modules organize into two major axes: an inflammatory-stress axis, and a regulatory/metabolic-motility axis, with a stable translation module persisting across disease stages. Cell communication analysis further highlights sophisticated neural-immune interactions, particularly between photoreceptors and microglia. Our findings provide insights into the complex cellular dynamics of DR progression and suggest potential therapeutic targets for early intervention.
The usefulness of microrecording guidance to adequately place pallidotomy lesions is not thoroughly accepted. We have analysed in 23 consecutive Parkinsonian patients the deviation of the first recording track (FRT), which was directed to the theoretical stereotactic target, from the sensorimotor area of the internal pallidum, the internal capsule and the center of the lesion. Standard stereotactic co-ordinates were calculated applying a digitized brain atlas adapted to neuro-imaging techniques. The first recording track (FRT) was located out of the sensorimotor area of the pallidum in 13 cases and out of the internal pallidum in 11 cases. In four of these cases the FRT was within the fibers of the internal capsule. The FRT was displaced posteriorly in 9 patients, anteriorly in 11, medially in 9 and laterally in 9. The mean deviation was 1.8 mm (+/- 1.5) in the medial-lateral axis, and 2.5 mm (+/- 1.9) in the antero-posterior plane. In none of the patients the center of the lesion was co-incident with the theoretical anatomical target. The center of the lesion presented a mean deviation from the theoretical anatomical target of 1,4 mm (+/- 1,1) in the medial-lateral, plane, and 2.5 mm (+/- 1.3) in the antero-posterior plane. In addition, 8 patients presented a deviation from the theoretical anatomical target of more than 3 mm in the antero-posterior plane (mean 4.2+/-0.7 mm) and 4 patients presented deviation in the medial-lateral plane of more than 3 mm (mean 3,4+/-0,2 mm). Lesion location was checked by magnetic resonance imaging. All patients improved to a similar extent to that previously reported by the other groups performing pallidotomy under neurophysiological guidance. At 3 months follow-up, pallidotomy ameliorated contralateral bradykinesia in the off condition by 41%, rigidity by 38%, tremor by 52% and dyskinesias by 92%. No major side effects were noted. We conclude that microrecording guidance is a useful tool for avoiding damage to adjacent structures and to precisely localize the sensorimotor area of the internal pallidum in order to obtain optimal clinical results.
Insulin-like growth factor 1 (IGF-1) is the major factor that affects linear bone growth. Also, androgens and estrogens are necessary for increasing longitudinal bone growth during sexual maturation. The aim of this study was to investigate the relationships among IGF-1 axis and sex steroids during pubertal development in healthy adolescents. In this cross-sectional study, IGF-1, IGF binding protein-3 (IGFBP-3) and sex steroid levels (estradiol in girls, testosterone in boys) of 205 healthy adolescents (101 female, 104 male) aged 9-17 years were measured. All subjects were apparently healthy, with no growth retardation and with skeletal ages appropriate for chronological ages, and none were taking medications known to influence calcium homeostasis. Greulich and Pyle's Radiographic Atlas of Skeletal Development of the Hand and Wrist was used for determination of skeletal ages. Tanner's classification was used to determine the pubertal developmental stage. Fasting blood samples were obtained from subjects between 09:00-10:00 h. Serum IGF-1 and IGFBP-3 levels differed significantly between pubertal developmental stages. Serum IGF-1 levels and IGF-1/IGFBP-3 ratios increased with proceeding stages and maximum mean values were found at stages III-IV in girls and at stage IV in boys. Estradiol levels of girls and testosterone levels of boys differed significantly between stages, and in both sexes, serum IGF-1 levels and IGF-1/IGFBP-3 ratios were significantly correlated with sex steroid levels. Increase in growth hormone secretion increases IGF-1 levels. Furthermore, increasing sex steroids with pubertal development increase the IGF-1 levels and IGF-1/IGFBP-3 ratios that affect bone growth.
Hub genes associated with non-small cell lung cancer (NSCLC) were identified through bioinformatics screening. In vitro experiments analyzed the potential mechanisms by which these genes regulate tumor malignant phenotypes and macrophage polarization. Differentially expressed genes were identified from The Cancer Genome Atlas (TCGA)-NSCLC and GSE32175 datasets, followed by protein-protein interaction (PPI) network analysis to screen hub genes. The effects of MYB Proto-Oncogene Like 2 (MYBL2) on NSCLC progression and macrophage polarization were evaluated using in vitro models. The regulatory relationship between MYBL2 and C-C motif chemokine ligand 2 (CCL2) was investigated by Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays, and rescue experiments were performed to validate the role of the MYBL2-CCL2 axis. Bioinformatics screening identified BUB1B, CDCA2 and MYBL2 as key hub genes with high expression in NSCLC, among which MYBL2 was significantly upregulated in NSCLC cells. Functional experiments confirmed that MYBL2 silencing markedly inhibited the malignant proliferation, migration and invasion of NSCLC cells. Tumor cell MYBL2 knockdown effectively reversed M2-like polarization and promoted M1-like polarization in the co-culture system. Mechanistically, MYBL2 directly bound to the CCL2 promoter region to enhance CCL2 transcriptional activity and upregulate CCL2 expression in NSCLC cells. Exogenous CCL2 supplementation significantly rescued the inhibitory effect of MYBL2 knockdown on macrophage M2-like polarization, verifying the mediating role of CCL2 in this regulatory axis. MYBL2 is strongly expressed in NSCLC cells and is associated with enhanced malignant phenotypes. It may affect macrophage M2-like polarization by upregulating CCL2, thus participating in NSCLC immune microenvironment remodeling.
BACKGROUND: To investigate the role of nucleoside diphosphate kinase 2 (NME2) in HCC progression, assessing its therapeutic potential. METHODS: Utilizing transcriptome sequencing data from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of tissue microarrays, we analyzed NME2 expression in HCC tumor tissues. The effects of NME2 on HCC cell proliferation and autophagy flux were assessed through knockdown and overexpression experiments. Additionally, the relationship between NME2 and 4EBP1 phosphorylation was explored through specific site mutation analysis. RESULTS: NME2 overexpression in HCC correlated with poor prognosis. NME2 knockdown significantly hindered HCC cell proliferation and induced autophagy flux. Notably, NME2 modulates 4EBP1 phosphorylation (Thr37/46) independently of mTOR, unveiling a novel axis in HCC pathogenesis. Additionally, NME2 modulates eukaryotic translation initiation factor 4F (eIF4F) complex formation and autophagy flux. CONCLUSIONS: NME2 plays a crucial role in HCC development by modulating 4EBP1 phosphorylation and autophagy through an mTOR-independent pathway. Our research underscores NME2's significance as a potential therapeutic target in HCC, meriting further exploration of its underlying mechanisms and clinical applicability.
We present operative procedures for the stabilization of fractures of C1 and C2. As is the case for fractures of the extremities, a direct approach to the injury should be attempted in order to avoid the inclusion of intact segments in the spondylodesis. The aim of the three presented techniques - direct screw fixation of fracture of the dens axis and traumatic lysis of C2 - is to active anatomical reconstruction by optimal stabilization. The new technique of transarticular screw fixation of C1-2 developed by Magerl allows unisegmental three-dimensional stabilization in cases in which at least a three-level fusion would have previously been considered necessary.
Gonadotropin-releasing hormone (GnRH) analogues are used for the treatment of breast, prostate, and ovarian cancer. These analogues exert their antitumor effects indirectly by inhibiting the pituitary-gonadal axis, as well as by direct inhibition of proliferation of human breast cancer cells. However, the molecular mechanisms mediating these direct antiproliferative effects are not fully understood. We found that normal and malignant human breast tissue express two forms of the neuropeptide GnRH. Quantitative reverse transcription-PCR shows that mRNA encoding the GnRH-I and GnRH-II peptides are overexpressed in cancerous versus normal tissues obtained from the same patients. To elucidate the function of these peptides in breast cancer cells, we used the atlas human cDNA expression arrays technology and studied the differentially regulated genes after GnRH treatment of MCF-7 cells. We found that a wide range of GnRH-I or GnRH-II concentrations (0.1-10 nM) inhibit the expression of mRNA encoding the 60S acidic ribosomal phosphoproteins, P1 and P2. These results were confirmed by quantitative reverse transcription-PCR, as well as Western blot analysis and immunofluorescence staining. The P1 and P2 proteins interact with elongation factors EF1 and EF2, and the level of their phosphorylation is one of the regulatory mechanisms for the overall rate of protein elongation. Thus, reduced expression of P1 and P2 proteins can affect the rate of protein translation, thereby decreasing proliferation rate of cells. Our studies may therefore suggest a putative mechanism for the direct antiproliferative effect of GnRH in breast cancer cells.
Intersubject variability of striate and extrastriate areas was mapped by conjoined use of positron emission tomography (PET) and magnetic resonance imaging (MRI). We used two dynamic bowtie-shaped random-dot patterns centered symmetrically around the vertical- and horizontal-meridian, respectively, presented during sequential PET scans in 11 subjects. Control condition was simple fixation on a central dot in absence of a surrounding random dot pattern. V1, V2, VP, V3, V3a, V4, V5, and "wordform" areas were identified. After spatial normalization to Talairach atlas space, mean locations and standard deviations about these mean locations for x-, y-, and z-axes were calculated for each area in both hemispheres and compared for differences. The mean standard deviation for all axes across all areas tested was found to be small (4.9 mm). No significant differences were found in the mean standard deviations for the x-, y-, and z-axes in the left hemisphere vs. their counterparts in the right hemisphere. However, when mean standard deviations in both hemispheres were polled together by axis, the mean standard deviation for the y-axis (5.3 mm) was found to be significantly different from the mean standard deviation for the x-axis (4.3 mm). Furthermore, in the left hemisphere, the mean standard deviation for the z-axis (5.7 mm) was significantly greater than the mean standard deviation for the x-axis (3.9 mm). The values reported in this study for mean location and standard deviation of visual areas can be used to establish confidence intervals for distinguishing normal variations from pathology and consequent brain reorganization.
The so-called "peridentale aureole" ("crowned odontoid"), a horseshoe-like calcification around the odontoid process, can occasionally be shown on transbuccal views of the occipito-atlantoaxial region, but is commonly only seen on a.p. tomography in patients with osteoarthrosis of the anterior atlantoaxial joint. Tomographic examinations reveal that these irregular horseshoe-like calcifications around the odontoid peg represent mainly the osteophyte formation on the superior border of the anterior arch of the atlas. These calcifications are often surrounding a smaller calcification on the tip of the odontoid process. The peridentale aureole or crowned odontoid process is easily overlooked unless tomography is performed, and misinterpretations are possible if the radiologist is not familiar with this appearance of osteoarthrosis and some other joint diseases of the anterior atlantoaxial joint.
Rotational motion of the normal upper cervical spine was analyzed in 20 men using biplanar roentgenograms, a system digitizer, and a personal computer. To detect the bony landmarks of the atlas, the subjects' heads were fixed and their trunks rotated in the reference frame while these biplanar studies were obtained. Coupling motions observed included 10 degrees extension at C0-C1, with 11 degrees of lateral bending between C1-C2. Almost all (80%) cervical axial rotation took place at C1-C2, whereas only 4 degrees of rotation occurred at C0-C1. Furthermore, as C1-C2 axial rotation increased, so did rotation in the opposite direction at C0-C1 while less rotation was noted below C2. The instantaneous axis of rotation was located anterior to the foramen magnum at the C0-C1 level, in the central portion of the dens at C1-C2.
Morphological and morphometric examinations were conducted on skeletons of knotty-tail (knt/knt) mouse, a new autosomal recessive mutant. The knt/knt mice have short and knotty tails. The number of caudal vertebrae is reduced and their deformed caudal vertebrae show no parallelism between the epiphyseal planes and no osseous fusions. Morphological changes, except for the caudal vertebrae, are confined to the neural arches of the axis in knt/knt mice. As for the tail anomaly, the knt gene seems to have the same action as the tk gene, but knt/knt mice differ from other strains with respect to cervical morphology. The morphometry of the caudal vertebrae revealed that knt/knt mice have a discontinuous and lower ratio of width to length after their 6th caudal vertebra. The morphometry also revealed that knt/knt mice have 1) broadened cervical vertebrae in the transverse direction, 2) thickened ventral lamina of the 6th cervical vertebra and 3) shortened and broadened ventral tuberculum of the atlas. From these results, the knt/knt mouse was considered to be a new pleomorphic mutant.
BACKGROUND AND PURPOSE: Some investigators have proposed that either calculated diffusion trace images or apparent diffusion coefficient (ADC) maps, which require imaging with multiple diffusion sensitivities and/or postacquisition image processing, are essential for the accurate interpretation of diffusion-weighted images in acute stroke because of the possible pitfalls of regional diffusion anisotropy, magnetic susceptibility artifacts, and confounding T2 effects, all of which alter signal on diffusion-weighted MR images. The purpose of our study was to compare the sensitivity, specificity, and accuracy of simple, orthogonal-axis diffusion-weighted imaging for the diagnosis of early cerebral infarction with three other sets of postacquisition-processed images: isotropic diffusion-weighted, diffusion trace-weighted, and diffusion trace images. METHODS: Twenty-six consecutive adult patients with signs and symptoms consistent with a clinical diagnosis of early cortical and/or subcortical cerebral infarction and 17 control subjects were studied with multisection, single-shot, spin-echo echo-planar diffusion-weighted imaging at 1.5 T to generate a set of three orthogonal-axis diffusion-weighted images. Isotropic diffusion-weighted, diffusion trace-weighted, and diffusion trace (mean ADC) images were then generated off-line and all four sets of images were interpreted blindly by two neuroradiologists. RESULTS: The average sensitivity, specificity, and accuracy for the orthogonal-axis diffusion-weighted images were 98.1%, 97.1%, and 97.7%, respectively. The average sensitivity, specificity, and accuracy for isotropic diffusion-weighted images were 88.5%, 100%, and 93% respectively. The average sensitivity, specificity, and accuracy for diffusion trace-weighted images were 82.7%, 73.6%, and 79.1%, respectively. The average sensitivity, specificity, and accuracy for diffusion trace images were 50.0%, 85.3%, and 64.0%, respectively. CONCLUSION: Orthogonal-axis diffusion-weighted images have the highest sensitivity and accuracy and very high specificity for early cerebral infarction. Our data contradict the contention that quantitative diffusion maps, requiring imaging with multiple diffusion sensitivities and/or subsequent image processing, are necessary for clinical stroke imaging.
PURPOSE: Empirical soft toric contact lens fitting based on manifest refraction and keratometry often presents unanticipated fitting and power errors upon initial lens dispensing. However, corneal topography may provide features that influence soft toric lens performance, flexure, and back vertex power in situ, which may assist in improved fitting guidelines. In this study, quantitative topographic descriptors were generated and analyzed as potential variables in predicting soft toric fitting success. METHODS: One hundred five eyes of 54 patients were empirically fit with back surface toric, prism ballasted, soft contact lenses after videokeratography was performed with the EyeSys 2000 (v. 4.0) or Humphrey Atlas (v. A6) instrument. Custom software was written to generate 54 separate quantitative descriptors of shape and astigmatism from the raw data files. A logistic regression was used to determine which variables significantly contributed to a successful or failed fit. RESULTS: Two types of empirical fitting failures were identified: loose fit (n = 15) and power errors (n = 17). The following variables were associated with a fitting failure: flat simulated keratometry (SimKf2b) within the central 3 mm zone, steep simulated keratometry (SimKs2b) within the central 3 mm zone, a difference between central and peripheral flat meridian axis (DIFFAXIS), and a difference between central and peripheral astigmatism (DIFFASTIG). For fitting failures caused by power errors, a larger steep SimKs2b (p< 0.01) and smaller DIFFAXIS (p< 0.05) were associated with a failed fit. For failures caused by physical fit of a selected base curve, a smaller DIFFAXIS (p< 0.05), larger steep SimKs2b (p< 0.05), and larger DIFFASTIG (p< 0.01) were associated with a failed fit. CONCLUSIONS: Novel quantitative descriptors of corneal shape and toricity derived from topography are associated with empirical soft toric contact lens fitting failures. Future algorithms or recommendations for improved soft toric lens selection may be derived from such indices to develop a predictive model for successful soft toric lens fitting using corneal topography data.