Denosumab Can Prevent Collapse in Patients with Early-Stage Steroid-Induced Osteonecrosis of the Femoral Head by Inhibiting Osteoclasts and Autophagy.

OBJECTIVE: The osteoclastic bone resorption inhibitors might have positive effect in preventing femoral head collapse in patients with osteonecrosis of the femoral head (ONFH). However, as a novel osteoclastic inhibitor, whether denosumab can prevent collapse in steroid-induced ONFH remains unknown. This study aims to evaluate the treatment effect of denosumab and the potential protective mechanism. METHODS: This was a retrospective study. A total of 161 patients with steroid-induced ONFH who underwent denosumab treatment were reviewed, and 209 untreated patients were selected as controls. Their clinical characteristics and radiological exam results were obtained. Patients were treated with 60 mg denosumab every 6 months for 2 years. The primary outcome was the incidence of femoral head collapse at 2 years after the initial diagnosis of ONFH. Secondary outcomes included the Harris hip score, progression of osteosclerosis, increase in necrotic area, bone marrow oedema relief, and bone mineral density increase in the femoral head. The Mann-Whitney U test and chi-square tests were performed to identify the differences between the continuous and categorical variables, respectively. A multivariate logistic regression model was built to identify the factors associated with the treatment effect of denosumab. RESULTS: The incidence of femoral head collapse was 42.24% (68/161) in the denosumab group and 54.07% (113/209) in the control group (χ2  = 5.094, p = 0.024; relative risk = 0.787, 95% CI = 0.627-0.973). The excellent-good rates of the Harris hip score were 63.98% (103/161) in the denosumab group and 44.98% (94/209) in the control group (χ2  = 13.186, p < 0.001). The incidence of osteosclerosis progression in the denosumab group was 55.28% (89/161), which was significantly higher than that in the control group (43.54%, 91/209, χ2  = 5.016, p = 0.025). Meanwhile, a significant increase in bone mineral density was identified in 29.19% (47/161) and 7.18% (15/209) of patients in the denosumab and control groups, respectively (χ2  = 31.600, p < 0.001). The osteoclastic cytoplasm expression of LC3-II was more positive in the control group than in the denosumab group (immunohistochemistry scoring: 3.58 ± 2.27 vs 6.33 ± 2.64, Z = -2.684, p = 0.007). A total of three independent factors were considered to be associated with the positive treatment effect of denosumab, the time of first denosumab administration (OR = 2.010, 95% CI = 1.272-3.177), osteosclerosis (OR = 1.583, 95% CI = 1.024-2.445), and the necrotic area before denosumab administration (medium necrotic area: OR = 2.084, 95% CI = 1.245-3.487; large necrotic area: OR = 2.211, 95% CI = 1.255-3.893). CONCLUSIONS: The current study demonstrated that denosumab had a positive effect on preventing femoral head collapse in patients with steroid ONFH. This effect might be closely associated with the inhibition of osteoclasts and their autophagy.

Comparing the blood oxygen level-dependent fluctuation power of benign and malignant musculoskeletal tumors using functional magnetic resonance imaging.

Purpose: The aim of this study is to compare the blood oxygen level-dependent (BOLD) fluctuation power in 96 frequency points ranging from 0 to 0.25 Hz between benign and malignant musculoskeletal (MSK) tumors via power spectrum analyses using functional magnetic resonance imaging (fMRI). Materials and methods: BOLD-fMRI and T1-weighted imaging (T1WI) of 92 patients with benign or malignant MSK tumors were acquired by 1.5-T magnetic resonance scanner. For each patient, the tumor-related BOLD time series were extracted, and then, the power spectrum of BOLD time series was calculated and was then divided into 96 frequency points. A two-sample t-test was used to assess whether there was a significant difference in the powers (the "power" is the square of the BOLD fluctuation amplitude with arbitrary unit) of each frequency point between benign and malignant MSK tumors. The receiver operator characteristic (ROC) analysis was used to assess the diagnostic capability of distinguishing between benign and malignant MSK tumors. Results: The result of the two-sample t-test showed that there was significant difference in the power between benign and malignant MSK tumor at frequency points of 58 (0.1508 Hz, P = 0.036), 59 (0.1534 Hz, P = 0.032), and 95 (0.247 Hz, P = 0.014), respectively. The ROC analysis of mean power of three frequency points showed that the area of under curve is 0.706 (P = 0.009), and the cutoff value is 0.73130. If the power of the tumor greater than or equal to 0.73130 is considered the possibility of benign tumor, then the diagnostic sensitivity and specificity values are 83% and 59%, respectively. The post hoc analysis showed that the merged power of 0.1508 and 0.1534 Hz in benign MSK tumors was significantly higher than that in malignant ones (P = 0.014). The ROC analysis showed that, if the benign MSK tumor was diagnosed with the power greater than or equal to the cutoff value of 1.41241, then the sensitivity and specificity were 67% and 68%, respectively. Conclusion: The mean power of three frequency points at 0.1508, 0.1534, and 0.247 Hz may potentially be a biomarker to differentiate benign from malignant MSK tumors. By combining the power of 0.1508 and 0.1534 Hz, we could better detect the difference between benign and malignant MSK tumors with higher specificity.

Ultrasonographic Diagnosis of Lipomatosis of Nerve: A Review of Ultrasonographic Finding for 8 Cases.

OBJECTIVE: Lipomatosis of nerve (LN) is a rare tumor-like condition with epineural and perineural infiltration by adipose and fibrous tissue. The purpose was to analyze the ultrasonographic findings of LN involving upper limb peripheral nerves. METHODS: This was a retrospective analysis of a series of 8 patients with LN involving upper-limb peripheral nerves between 2013 and 2019. All patients underwent preoperative ultrasonography for the upper-extremity nerves and were diagnosed as LN by surgery. The clinical manifestations, ultrasonography characteristics, and accuracy were analyzed. RESULTS: In this series, LN was involved in 10 peripheral nerves from 8 patients. The median nerve was the most commonly affected nerve (60%). Four cases presented macrodactyly combined with masses from distal forearm and extending to wrist and palm areas. Among 8 patients, 5 cases were diagnosed with LN by preoperative ultrasonography, an accuracy of 62.5%. Axial ultrasonic imaging showed the punctate hypoechoic fascicles was embedded in hyperechoic adipose tissue in the "lotus root-like" appearance; longitudinal ultrasonic imaging showed the strip hypoechoic fascicles alternates with hyperechoic adipose tissue in the "cable-like" appearance. Meanwhile, ultrasonic imaging showed the thickened of adipose tissue around the affected nerve and the enlargement of flexor tendons in some patients. CONCLUSIONS: Ultrasonography has the potential to be a useful tool for the noninvasive examination of LN. The possibility of LN should be considered in patients with a mass in wrist and palm, macrodactyly, or syndactyly. Our finding may benefit the preoperative differential diagnosis with common nerve tumors.

Systematic Genetic Analysis of the SMPD1 Gene in Chinese Patients with Parkinson's Disease.

To examine the association between the sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1) gene, and Parkinson's disease (PD) in Han Chinese from Central South part of Mainland China, we performed systematic genetic analysis in 502 Chinese Han patients with PD and 637 gender-, age-, and ethnicity-matched normal controls from Central South part of the Mainland China. We identified 11 single nucleotide variants and Leu-Ala (Val) repeat variants in the SMPD1 gene in our large cohort. Two novel missense variants, c.638A > C (p.H213P) and c.1673T > C (p.L558P), and a rare known missense variant, c.1805G > A (p.R602H, rs370129081), were identified in three sporadic PD cases. None of these three variants were observed in controls. Additionally, case-control analysis showed association between Leu-Ala (Val) repeat variants in SMPD1 and Chinese Han patients with PD (P = 0.015, χ (2) = 8.451). Our data provide supportive evidence that some genetic variants in SMPD1 increase the risk of PD in the Chinese Han population.

Genetic convergence of Parkinson's disease and lysosomal storage disorders.

Parkinson's disease is a common progressive neurodegenerative disorder characterized by predominant degeneration of the dopaminergic neurons in the substantia nigra pars compacta and the presence of intracellular inclusions enriched in α-synuclein, resulting in a variety motor and nonmotor symptoms. Lysosomal storage disorders are a group of disorders including Gaucher disease, Niemann-Pick disease, and neuronal ceroid lipofuscinoses caused by the defective activity of lysosomal and nonlysosomal proteins. In addition to an overlap in some clinical features between lysosomal storage disorders and Parkinson's disease, the two disorders may be also linked pathogenically. There is growing support for the notion that mutations in genes causing lysosomal storage disorders including the glucocerebrosidase gene, the sphingomyelin phosphodiesterase 1 gene, and the NPC1 gene may increase risk for developing Parkinson's disease. In this review, we discuss the recent advances in the genetic convergence of Parkinson's disease and lysosomal storage disorders, shedding new light on the understanding of shared pathogenic pathways.

A novel COL4A5 mutation identified in a Chinese Han family using exome sequencing.

Alport syndrome (AS) is a monogenic disease of the basement membrane (BM), resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and ocular anomalies. It is caused by mutations in the collagen type IV alpha-3 gene (COL4A3), the collagen type IV alpha-4 gene (COL4A4), and the collagen type IV alpha-5 gene (COL4A5), which encodes type IV collagen α3, α4, and α5 chains, respectively. To explore the disease-related gene in a four-generation Chinese Han pedigree of AS, exome sequencing was conducted on the proband, and a novel deletion mutation c.499delC (p.Pro167Glnfs*36) in the COL4A5 gene was identified. This mutation, absent in 1,000 genomes project, HapMap, dbSNP132, YH1 databases, and 100 normal controls, cosegregated with patients in the family. Neither sensorineural hearing loss nor typical COL4A5-related ocular abnormalities (dot-and-fleck retinopathy, anterior lenticonus, and the rare posterior polymorphous corneal dystrophy) were present in patients of this family. The phenotypes of patients in this AS family were characterized by early onset-age and rapidly developing into end-stage renal disease (ESRD). Our discovery broadens the mutation spectrum in the COL4A5 gene associated with AS, which may also shed new light on genetic counseling for AS.

The molecular biology of genetic-based epilepsies.

Epilepsy is one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system. The clinical features of this disorder are recurrent seizures, difference in age onset, type, and frequency, leading to motor, sensory, cognitive, psychic, or autonomic disturbances. Since the discovery of the first monogenic gene mutation in 1995, it is proposed that genetic factor plays an important role in the mechanism of epilepsy. Genes discovered in idiopathic epilepsies encode for ion channel or neurotransmitter receptor proteins, whereas syndromes with epilepsy as a main feature are caused by genes that are involved in functions such as cortical development, mitochondrial function, and cell metabolism. The identification of these monogenic epilepsy-causing genes provides new insight into the pathogenesis of epilepsies. Although most of the identified gene mutations present a monogenic inheritance, most of idiopathic epilepsies are complex genetic diseases exhibiting a polygenic or oligogenic inheritance. This article reviews recent genetic and molecular progresses in exploring the pathogenesis of epilepsy, with special emphasis on monogenic epilepsy-causing genes, including voltage-gated channels (Na(+), K(+), Ca(2+), Cl(-), and HCN), ligand-gated channels (nicotinic acetylcholine and GABAA receptors), non-ion channel genes as well as the mitochondrial DNA genes. These progresses have improved our understanding of the complex neurological disorder.

Genetic analysis of the FBXO42 gene in Chinese Han patients with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD), the second most common neurodegenerative disease, is characterized by loss of dopaminergic neurons in the substantia nigra. The clinical manifestations of PD encompass a variety of motor and non-motor symptoms. Mutations in the F-box protein 7 gene (FBXO7) have been identified to cause Parkinsonian-pyramidal syndrome, an autosomal recessive form of Parkinsonism. The F-box protein 42 gene (FBXO42), a paralog of the FBXO7 gene, is involved in the ubiquitin-proteasome system that may play a role in the pathogenesis of PD. METHODS: To determine whether the FBXO42 gene is associated with PD, we performed a systematic genetic analysis of the FBXO42 gene in 316 PD patients and 295 gender-, age-, and ethnicity-matched normal controls. RESULTS: We identified a novel variant c.1407T>C (p.S469S) and three known single nucleotide variants, including rs2273311, rs12069239 and rs35196193 in the FBXO42 gene in PD patient group. None of the three known variants displayed statistically significant difference in either genotypic or allelic distributions between patient and control groups (all P > 0.05). Haplotype analysis showed that a common haplotype (G-C-G) for the three single nucleotide variants conferred a 1.69-fold increased risk for PD (P = 0.008 after Bonferroni correction, OR = 1.69, 95% CI = 1.06-2.71). CONCLUSIONS: Our findings suggest that a haplotype of the FBXO42 gene might be associated with a higher susceptibility to PD.

Genetic analysis of the FBXO48 gene in Chinese Han patients with Parkinson disease.

The F-box only protein 48 gene (FBXO48) is located in 2p13.3, the disease gene locus of Parkinson disease type 3 (PARK3), and it is one of the paralogs of the F-box only protein 7 gene (FBXO7), which is a causative gene of the Parkinson disease type 15 (PARK15; also known as Parkinsonian-pyramidal disease, PPD). To determine whether genetic mutation in the coding region of the FBXO48 gene plays a role in the etiology of PD, we screened DNA samples from 350 Chinese Han patients with PD. No mutation in the coding region of the FBXO48 gene was identified in our PD cohort, suggesting that mutations in the coding region of the FBXO48 gene play little or no role in the development of PD.