PURPOSE: The secondary damage of spinal cord injury (SCI) starts from the collapse of the blood spinal cord barrier (BSCB) to chronic and devastating neurological deficits. Thereby, the retention of the integrity and permeability of BSCB is well-recognized as one of the major therapies to promote functional recovery after SCI. Previous studies have demonstrated that activation of hypoxia inducible factor-1α (HIF-1α) provides anti-apoptosis and neuroprotection in SCI. Endogenous HIF-1α, rapidly degraded by prolylhydroxylase, is insufficient for promoting functional recovery. Dimethyloxalylglycine (DMOG), a highly selective inhibitor of prolylhydroxylase, has been reported to have a positive effect on axon regeneration. However, the roles and underlying mechanisms of DMOG in BSCB restoration remain unclear. Herein, we aim to investigate pathological changes of BSCB restoration in rats with SCI treated by DOMG and evaluate the therapeutic effects of DMOG. METHODS: The work was performed from 2022 to 2023. In this study, Allen's impact model and human umbilical vein endothelial cells were employed to explore the mechanism of DMOG. In the phenotypic validation experiment, the rats were randomly divided into 3 groups: sham group, SCI group, and SCI + DMOG group (10 rats for each). Histological analysis via Nissl staining, Basso-Beattie-Bresnahan scale, and footprint analysis was used to evaluate the functional recovery after SCI. Western blotting, TUNEL assay, and immunofluorescence staining were employed to exhibit levels of tight junction and adhesion junction of BSCB, HIF-1α, cell apoptosis, and endoplasmic reticulum (ER) stress. The one-way ANOVA test was used for statistical analysis. The difference was considered statistically significant at p < 0.05. RESULTS: In this study, we observed the expression of HIF-1α reduced in the SCI model. DMOG treatment remarkably augmented HIF-1α level, alleviated endothelial cells apoptosis and disruption of BSCB, and enhanced functional recovery post-SCI. Besides, the administration of DMOG offset the activation of ER stress induced by SCI, but this phenomenon was blocked by tunicamycin (an ER stress activator). Finally, we disclosed that DMOG maintained the integrity and permeability of BSCB by inhibiting ER stress, and inhibition of HIF-1α erased the protection from DMOG. CONCLUSIONS Our findings illustrate that the administration of DMOG alleviates the devastation of BSCB and HIF-1α-induced inhibition of ER stress.
Spinal Cord Injuries/pathology* ; Animals ; Apoptosis/drug effects* ; Amino Acids, Dicarboxylic/therapeutic use* ; Recovery of Function/drug effects* ; Rats ; Rats, Sprague-Dawley ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Male ; Spinal Cord/blood supply*

PURPOSE: End-stage knee osteoarthritis (OA) patients are the primary candidates for total knee arthroplasty (TKA). However, most morphological refinements of TKA prosthesis are based on anatomical data from the knees of healthy individuals. This study aimed to determine whether differences exist in key bony morphological characteristics of the distal femur and proximal tibia between osteoarthritic knees and healthy knees. METHODS: This was a retrospective cross-sectional observational study with a case-control design. Patients who were aged ≥ 50 years, had no history of trauma, fracture, or surgery in the studied knee, and had no obvious knee flexion contracture were included in this study by CT scans. Patients who met the American College of Rheumatology clinical criteria for knee OA were included in the study group. Kellgren-Lawrence grade III or IV knees were studied (for bilateral cases, the more severely affected knee was chosen). Patients who presented with unilateral knee pain or trauma were included in the control group, with CT scans from the opposite (asymptomatic) knee used for analyzing. The studied knee had a Kellgren-Lawrence grade of 0 or I and showed no abnormalities upon physical examination. Archived knee CT scans from 160 patients were divided into 2 groups: the study group (80 moderate-to-severe OA knees) and the control group (80 healthy knees). After 3-dimensional reconstruction and virtual cutting using a CT workstation, 13 morphological parameters of the distal femur and proximal tibia were compared between the 2 groups using independent-samples t-tests. RESULTS: No significant group differences in the femoral anteroposterior dimension (p = 0.797), height of the lateral femoral condyle (p = 0.268), posterior condylar angle (p = 0.240), tibial anteroposterior dimension (p = 0.536), or tibial lateral anteroposterior dimension (p = 0.702) were observed. However, the femoral mediolateral dimension (p = 0.002), distal femoral aspect ratio (femoral mediolateral dimension/femoral anteroposterior dimension) (p < 0.001), height of the femoral trochlear groove (p < 0.001), height of the medial femoral condyle (p < 0.001), tibial mediolateral dimension (p = 0.001), proximal tibial aspect ratio (tibial mediolateral dimension/tibial anteroposterior dimension) (p = 0.004), tibial medial anteroposterior dimension (p = 0.005), and tibial asymmetry ratio (tibial medial anteroposterior dimension/tibial lateral anteroposterior dimension) (p = 0.006) were all significantly greater in the study group. CONCLUSION Knees with moderate-to-severe OA are significantly wider than healthy knees, and OA is a risk factor for increased tibial platform asymmetry. When refining the morphological parameters of TKA prostheses, the specific bony morphological characteristics of OA knees should be taken into account to reduce the potential risk of femoral or tibial component underhang and facilitate optimal balance between tibial component fit and rotational alignment.
Humans ; Osteoarthritis, Knee/pathology* ; Male ; Female ; Cross-Sectional Studies ; Retrospective Studies ; Arthroplasty, Replacement, Knee ; Middle Aged ; Aged ; Case-Control Studies ; Prosthesis Design ; Knee Prosthesis ; Femur/anatomy & histology* ; Tibia/anatomy & histology* ; Tomography, X-Ray Computed ; Knee Joint/diagnostic imaging*

In most types of erectile dysfunction, particularly in advanced stages, typical pathological features observed are reduced parenchymal cells coupled with increased tissue fibrosis. However, the current treatment methods have shown limited success in reversing these pathologic changes. Recent research has revealed that changes in autophagy levels, along with alterations in apoptosis and fibrosis-related proteins, are linked to the progression of erectile dysfunction, suggesting a significant association. Autophagy, known to significantly affect cell fate and tissue fibrosis, is currently being explored as a potential treatment modality for erectile dysfunction. However, these present studies are still in their nascent stage, and there are limited experimental data available. This review analyzes erectile dysfunction from a pathological perspective. It provides an in-depth overview of how autophagy is involved in the apoptotic processes of smooth muscle and endothelial cells and its role in the fibrotic processes occurring in the cavernosum. This study aimed to develop a theoretical framework for the potential effectiveness of autophagy in preventing and treating erectile dysfunction, thus encouraging further investigation among researchers in this area.
Male ; Humans ; Autophagy/physiology* ; Apoptosis/physiology* ; Erectile Dysfunction/physiopathology* ; Fibrosis ; Penis/pathology* ; Animals ; Endothelial Cells/pathology* ; Myocytes, Smooth Muscle/pathology*

Nonobstructive azoospermia (NOA) is the most challenging and complex clinical scenario for infertile men. Besides circumstances such as hypogonadotropic hypogonadism, surgical sperm retrieval is typically necessary, and microdissection testicular sperm extraction (micro-TESE) is the procedure of choice for men with NOA desiring to father children with their own gametes. Micro-TESE results in the highest numbers of sperm cells retrieved for use with in vitro fertilization/intracytoplasmic sperm injection (ICSI) in comparison to all other techniques for surgical sperm retrieval in men with NOA. Several factors may affect sperm retrieval rate and ICSI outcomes, including the patient's age, testicular volume, histopathological and genetic profile, and serum hormone levels. This article aims to review the medical literature describing predictors of successful micro-TESE and the outcomes of ICSI in men with NOA.
Humans ; Azoospermia/surgery* ; Male ; Sperm Injections, Intracytoplasmic ; Sperm Retrieval ; Treatment Outcome ; Testis/pathology* ; Female ; Microdissection

One major challenge in male factor infertility is nonobstructive azoospermia (NOA), which is characterized by spermatozoa-deficient semen without physical duct blockage. This review offers a thorough overview of the histopathology of the testes in NOA cases, clarifying its complex etiology and emphasizing the possible value of histopathology inspection for both diagnosis and treatment. Variable histopathological findings have been linked to NOA, such as tubular hyalinization, Sertoli cell-only syndrome, hypospermatogenesis, and germ cell arrest. Understanding the pathophysiology and forecasting the effectiveness of treatment are further enhanced by both morphometric and ultrastructural analyses. The potential significance of testicular biopsy in forecasting reproductive outcomes is assessed, especially concerning assisted reproductive technologies like intracytoplasmic sperm injection (ICSI). Besides, testicular microlithiasis, serum hormone profiles, and testicular size are investigated concerning NOA histopathology. It is concluded that understanding the histopathological patterns in NOA is crucial for its accurate diagnosis and appropriate management. Further research is still warranted to improve understanding of the complex pathophysiology underlying NOA.
Humans ; Azoospermia/etiology* ; Male ; Testis/pathology* ; Sertoli Cell-Only Syndrome/pathology* ; Sperm Injections, Intracytoplasmic

Azoospermia is the complete absence of spermatozoa in the ejaculate in two or more semen analyses after centrifugation. Nonobstructive azoospermia (NOA) represents the most severe form of male factor infertility accounting for 10%-15% of cases and stems from an impairment to spermatogenesis. Understanding of the hypothalamic-pituitary-testicular axis has allowed NOA to be subcategorized by anatomic and/or pathophysiologic level. The etiologies of NOA, and therefore, the differential diagnoses when considering NOA as a cause of male factor infertility, can be subcategorized and condensed into several distinct classifications. Etiologies of NOA include primary hypogonadism, secondary hypogonadism, defects in androgen synthesis and/or response, defective spermatogenesis and sperm maturation, or a mixed picture thereof. This review includes up-to-date clinical, diagnostic, cellular, and histologic features pertaining to the multitude of NOA etiologies. This in turn will provide a framework by which physicians practicing infertility can augment their clinical decision-making, patient counseling, thereby improving upon the management of men with NOA.
Humans ; Azoospermia/diagnosis* ; Male ; Spermatogenesis/physiology* ; Hypogonadism/complications* ; Infertility, Male/etiology* ; Testis/pathology*

Multiple morphological abnormalities of the flagella (MMAF) represent a severe form of sperm defects leading to asthenozoospermia and male infertility. In this study, we identified a novel homozygous splicing mutation (c.871-4 ACA>A) in the adenylate kinase 7 (AK7) gene by whole-exome sequencing in infertile individuals. Spermatozoa from affected individuals exhibited typical MMAF characteristics, including coiled, bent, short, absent, and irregular flagella. Transmission electron microscopy analysis showed disorganized axonemal structure and abnormal mitochondrial sheets in sperm flagella. Immunofluorescence staining confirmed the absence of AK7 protein from the patients' spermatozoa, validating the pathogenic nature of the mutation. This study provides direct evidence linking the AK7 gene to MMAF-associated asthenozoospermia in humans, expanding the mutational spectrum of AK7 and enhancing our understanding of the genetic basis of male infertility.
Humans ; Male ; Sperm Tail/ultrastructure* ; Homozygote ; Consanguinity ; Asthenozoospermia/pathology* ; Infertility, Male/genetics* ; Mutation ; Pakistan ; Adenylate Kinase/genetics* ; Adult ; Pedigree ; RNA Splicing ; Exome Sequencing ; Spermatozoa

Testicular histology based on testicular biopsy is an important factor for determining appropriate testicular sperm extraction surgery and predicting sperm retrieval outcomes in patients with azoospermia. Therefore, we developed a deep learning (DL) model to establish the associations between testicular grayscale ultrasound images and testicular histology. We retrospectively included two-dimensional testicular grayscale ultrasound from patients with azoospermia (353 men with 4357 images between July 2017 and December 2021 in The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China) to develop a DL model. We obtained testicular histology during conventional testicular sperm extraction. Our DL model was trained based on ultrasound images or fusion data (ultrasound images fused with the corresponding testicular volume) to distinguish spermatozoa presence in pathology (SPP) and spermatozoa absence in pathology (SAP) and to classify maturation arrest (MA) and Sertoli cell-only syndrome (SCOS) in patients with SAP. Areas under the receiver operating characteristic curve (AUCs), accuracy, sensitivity, and specificity were used to analyze model performance. DL based on images achieved an AUC of 0.922 (95% confidence interval [CI]: 0.908-0.935), a sensitivity of 80.9%, a specificity of 84.6%, and an accuracy of 83.5% in predicting SPP (including normal spermatogenesis and hypospermatogenesis) and SAP (including MA and SCOS). In the identification of SCOS and MA, DL on fusion data yielded better diagnostic performance with an AUC of 0.979 (95% CI: 0.969-0.989), a sensitivity of 89.7%, a specificity of 97.1%, and an accuracy of 92.1%. Our study provides a noninvasive method to predict testicular histology for patients with azoospermia, which would avoid unnecessary testicular biopsy.
Humans ; Male ; Azoospermia/diagnostic imaging* ; Deep Learning ; Testis/pathology* ; Retrospective Studies ; Adult ; Ultrasonography/methods* ; Sperm Retrieval ; Sertoli Cell-Only Syndrome/diagnostic imaging*

Male infertility can result from impaired sperm motility caused by multiple morphological abnormalities of the flagella (MMAF). Distinct projections encircling the central microtubules of the spermatozoal axoneme play pivotal roles in flagellar bending and spermatozoal movement. Mammalian sperm-associated antigen 17 ( SPAG17 ) encodes a conserved axonemal protein of cilia and flagella, forming part of the C1a projection of the central apparatus, with functions related to ciliary/flagellar motility, skeletal growth, and male fertility. This study investigated two novel homozygous SPAG17 mutations (M1: NM_206996.2, c.829+1G>T, p.Asp212_Glu276del; and M2: c.2120del, p.Leu707*) identified in four infertile patients from two consanguineous Pakistani families. These patients displayed the MMAF phenotype confirmed by Papanicolaou staining and scanning electron microscopy assays of spermatozoa. Quantitative real-time polymerase chain reaction (PCR) of patients' spermatozoa also revealed a significant decrease in SPAG17 mRNA expression, and immunofluorescence staining showed the absence of SPAG17 protein signals along the flagella. However, no apparent ciliary-related symptoms or skeletal malformations were observed in the chest X-rays of any of the patients. Transmission electron microscopy of axoneme cross-sections from the patients showed incomplete C1a projection and a higher frequency of missing microtubule doublets 1 and 9 compared with those from fertile controls. Immunofluorescence staining and Western blot analyses of spermatogenesis-associated protein 17 (SPATA17), a component of the C1a projection, and sperm-associated antigen 6 (SPAG6), a marker of the spring layer, revealed disrupted expression of both proteins in the patients' spermatozoa. Altogether, these findings demonstrated that SPAG17 maintains the integrity of spermatozoal flagellar axoneme, expanding the phenotypic spectrum of SPAG17 mutations in humans.
Humans ; Male ; Infertility, Male/pathology* ; Sperm Tail/ultrastructure* ; Homozygote ; Microtubule-Associated Proteins/genetics* ; Axoneme/genetics* ; Spermatozoa/ultrastructure* ; Adult ; Mutation ; Sperm Motility/genetics* ; Pedigree ; Microtubules ; Microtubule Proteins/genetics*

To investigate the impact of preoperative serum follicle-stimulating hormone (FSH) levels on the probability of testicular sperm retrieval, we conducted a study of nonobstructive azoospermic (NOA) men with different testicular volumes (TVs) who underwent microdissection testicular sperm extraction (micro-TESE). A total of 177 NOA patients undergoing micro-TESE for the first time from April 2019 to November 2022 in Shenzhen Zhongshan Obstetrics and Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital, Shenzhen, China) were retrospectively reviewed. The subjects were divided into four groups based on average TV quartiles. Serum hormone levels in each TV group were compared between positive and negative sperm retrieval subgroups. Overall sperm retrieval rate was 57.6%. FSH levels (median [interquartile range]) were higher in the positive sperm retrieval subgroup compared with the negative outcome subgroup when average TV was <5 ml (first quartile [Q1: TV <3 ml]: 43.32 [17.92] IU l -1 vs 32.95 [18.56] IU l -1 , P = 0.048; second quartile [Q2: 3 ml ≤ TV <5 ml]: 31.31 [15.37] IU l -1 vs 25.59 [18.40] IU l -1 , P = 0.042). Elevated serum FSH levels were associated with successful micro-TESE sperm retrieval in NOA men whose average TVs were <5 ml (adjusted odds ratio [OR]: 1.06 per unit increase; 95% confidence interval [CI]: 1.01-1.11; P = 0.011). In men with TVs ≥5 ml, larger TVs were associated with lower odds of sperm retrieval (adjusted OR: 0.84 per 1 ml increase; 95% CI: 0.71-0.98; P = 0.029). In conclusion, elevated serum FSH levels were associated with positive sperm retrieval in micro-TESE in NOA men with TVs <5 ml. In men with TV ≥5 ml, increases in average TVs were associated with lower odds of sperm retrieval.
Humans ; Male ; Azoospermia/surgery* ; Sperm Retrieval/statistics & numerical data* ; Adult ; Follicle Stimulating Hormone/blood* ; Retrospective Studies ; Testis/pathology* ; Microdissection ; Organ Size