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2.
Nutrients ; 16(18)2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39339650

RESUMO

Nutritional supplementation enriched with protein and antioxidants has been demonstrated to effectively strengthen skeletal muscle function and mitigate the risk of sarcopenia. Dietary protein has also been a common carrier to establish bioactive delivery system. Therefore, in this study, a Pickering emulsion delivery system for rutin was constructed with whey protein, and its structural characteristics, bioaccessibility, and molecular interactions were investigated. In the in vivo study, zebrafish (n = 10 in each group), which have a high genetic homology to humans, were treated with dexamethasone to induce sarcopenia symptoms and were administered with rutin, whey protein and the Pickering emulsion, respectively, for muscle movement ability evaluation, and zebrafish treated with or without dexamethasone was used as the model and the control groups, respectively. Results showed that the Pickering emulsion was homogeneous in particle size with a rutin encapsulation rate of 71.16 ± 0.15% and loading efficiency of 44.48 ± 0.11%. Rutin in the Pickering emulsion exhibited a significantly higher bioaccessibility than the free form. The interaction forces between rutin and the two components of whey proteins (α-LA and ß-LG) were mainly van der Waals forces and hydrogen bonds. After treatment for 96 h, the zebrafish in Picking emulsion groups showed a significantly increased high-speed movement time and frequency, an increased level of ATP, prolonged peripheral motor nerve length, and normalized muscular histological structure compared with those of the model group (p < 0.05). The results of this study developed a new strategy for rutin utilization and provide scientific evidence for sarcopenia prevention with a food-derived resource.


Assuntos
Emulsões , Músculo Esquelético , Rutina , Proteínas do Soro do Leite , Peixe-Zebra , Animais , Rutina/farmacologia , Proteínas do Soro do Leite/química , Proteínas do Soro do Leite/farmacologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Sarcopenia/prevenção & controle , Suplementos Nutricionais , Tamanho da Partícula , Dexametasona/farmacologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-39148418

RESUMO

CONTEXT: Hereditary distal renal tubular acidosis caused by SLC4A1 gene mutation (SLC4A1-dRTA) is a rare hereditary form of renal tubular acidosis. Rickets or osteomalacia is a common complication of SLC4A1-dRTA, and seriously affects patients' daily life. However, studies on the bone microstructure in SLC4A1-dRTA are limited. OBJECTIVE: This work aimed to evaluate the bone microstructure of SLC4A1-dRTA patients, compared to age- and sex-matched healthy controls and X-linked hypophosphatemic rickets (XLH) patients. METHODS: This was a retrospective study on eleven SLC4A1-dRTA patients. Clinical manifestations, biochemical and radiographical examinations were characterized. Bone microstructure was examined in seven SLC4A1-dRTA patients, seven healthy controls and twenty-one XLH patients using high-resolution peripheral quantitative computed tomography (HR-pQCT). RESULTS: Skeletal symptoms, including fracture, bone pain, and lower limb deformity, were presented in 72.7% of SLC4A1-dRTA patients. Short stature was presented in 63.6% of the patients. SLC4A1-dRTA patients had significantly lower volumetric BMD in the distal tibia, and more severe deteriorated trabecular bone in the distal radius and tibia than healthy controls. SLC4A1-dRTA patients had significantly more severe deteriorated trabecular bone in the distal radius and distal tibia compared to XLH patients. With long-term alkaline therapy, SLC4A1-dRTA patients had alleviation in bone pain, increase in height. CONCLUSIONS: Skeletal lesions were common clinical manifestations in SLC4A1-dRTA patients. Compared with XLH, another common type of rickets, SLC4A1-dRTA patients had more severe trabecular bone microstructure damage, further supporting the necessity of early diagnosis and timely treatment of the disease.

4.
Front Genet ; 15: 1421565, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39130747

RESUMO

Accurate haplotyping facilitates distinguishing allele-specific expression, identifying cis-regulatory elements, and characterizing genomic variations, which enables more precise investigations into the relationship between genotype and phenotype. Recent advances in third-generation single-molecule long read and synthetic co-barcoded read sequencing techniques have harnessed long-range information to simplify the assembly graph and improve assembly genomic sequence. However, it remains methodologically challenging to reconstruct the complete haplotypes due to high sequencing error rates of long reads and limited capturing efficiency of co-barcoded reads. We here present a pipeline, AsmMix, for generating both contiguous and accurate diploid genomes. It first assembles co-barcoded reads to generate accurate haplotype-resolved assemblies that may contain many gaps, while the long-read assembly is contiguous but susceptible to errors. Then two assembly sets are integrated into haplotype-resolved assemblies with reduced misassembles. Through extensive evaluation on multiple synthetic datasets, AsmMix consistently demonstrates high precision and recall rates for haplotyping across diverse sequencing platforms, coverage depths, read lengths, and read accuracies, significantly outperforming other existing tools in the field. Furthermore, we validate the effectiveness of our pipeline using a human whole genome dataset (HG002), and produce highly contiguous, accurate, and haplotype-resolved assemblies. These assemblies are evaluated using the GIAB benchmarks, confirming the accuracy of variant calling. Our results demonstrate that AsmMix offers a straightforward yet highly efficient approach that effectively leverages both long reads and co-barcoded reads for haplotype-resolved assembly.

5.
Osteoporos Int ; 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093437

RESUMO

Vertebral tumors in patients with tumor-induced osteomalacia (TIO) have a low diagnostic rate and poor postoperative outcomes. The application of 68 Ga-DOTATATE-PET/CT significantly increased the detection rate. Compared with tumor curettage, segmental resection was recommended as the preferred surgical type due to its high recovery rate. PURPOSE: Tumor-induced osteomalacia (TIO) is an acquired hypophosphatemic osteomalacia, and surgery is the first-line therapy. Most TIO tumors are found in the bones of the appendicular skeleton, cranium, and paranasal sinuses but rarely in the vertebrae. Tumor curettage and segmental resection are the two main surgical options for vertebral TIO patients. However, research on the clinical characteristics and surgical prognosis of vertebral TIO patients is rare. In the present study, for the first time, we investigated the clinical characteristics of 16 vertebral TIO patients and compared the surgical outcomes of patients who underwent surgery via two different surgical methods. METHODS: This was a retrospective cohort study. In this study, we included 16 adult TIO patients with lesions in vertebrae from Peking Union Medical College Hospital (PUMCH), all of whom underwent surgery. Baseline laboratory data were collected through medical records review. Technetium-99 m octreotide scintigraphy (99Tcm-OCT) and 68gallium-DOTA-TATE-positron emission tomography/computed tomography (68 Ga-DOTATATE-PET/CT) were conducted at the Department of Nuclear Medicine of PUMCH. The tumor histopathology was confirmed by a senior pathologist at our center. RESULTS: Vertebral TIO patients had lower serum phosphorus and TmP/GFR and higher serum alkaline phosphatase (ALP), serum parathyroid hormone (PTH), and serum C-terminal cross-linked telopeptide of type I collagen (ß-CTX) levels than the normal range. The sensitivity of 68 Ga‒DOTATATE PET/CT was 100%, significantly greater than that of 99Tcm-OCT (40%). After comparing the outcomes between the two surgical methods, we found that the recovery rate after segmental resection (62.5%) was greater than that after tumor curettage (12.5%). In the thoracic and sacral vertebrae, segmental resection surgery had a good prognosis. CONCLUSION: 68 Ga-DOTATATE PET/CT could serve as the first diagnostic tool in patients with vertebral TIO, and segmental resection could be used as the preferred surgery. This study would raise awareness of the clinical features and management of these rare vertebral TIO patients.

7.
J Cutan Med Surg ; : 12034754241265716, 2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39075672

RESUMO

Post inflammatory hyperpigmentation (PIH) affects all skin types with a heightened predilection for darker skin tones. Its course is chronic once developed and treatment is often difficult. This systematic review aims to summarize the treatment outcomes for PIH with a focus on skin of colour (SOC) individuals. A literature search was conducted using MEDLINE (from 1946), Embase (from 1974), PubMed, and Cochrane in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline. Results from 48 studies summarized 1356 SOC individuals. The mean age was 29 years (n = 1036) and 78% were female (n = 786). The ethnic prevalence was 70% Black, 27% Asian, and 3% Latin. Overall, 20% were Fitzpatrick skin type (FST) III, 40% FST IV, 34% FST V, and 6% FST VI. Most cases were precipitated by inflammatory conditions (89%) and localized to the face (83%). The most frequently reported interventions were topical retinoids (22%) and laser therapy (17%). Partial improvement was seen in 85% and 66% of participants, respectively. Laser was the only intervention that offered complete resolution in a subgroup of patients (26%); however, there were reported cases of PIH exacerbation following treatment. Chemical peels (9%) and hydroquinone (7%) were among other treatments with less effective outcomes. PIH and its persistence is a prevalent issue, significantly affecting many affected individuals with darker skin tones. Our results show a lack of robust efficacy across all treatment modalities. There is considerable room for improvement in interventions for at-risk populations.

8.
BMC Endocr Disord ; 24(1): 121, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39044175

RESUMO

BACKGROUND: Growth hormone (GH) positive pituitary neuroendocrine tumors do not always cause acromegaly. Approximately one-third of GH-positive pituitary tumors are classified as non-functioning pituitary tumors in clinical practice. They typically have GH and serum insulin-like growth factor 1 (IGF-1) levels in the reference range and no acromegaly-like symptoms. However, normal hormone levels might not exclude the underlying hypersecretion of GH. This is a rare and paradoxical case of pituitary tumor causing acromegaly-associated symptoms despite normal GH and IGF-1 levels. CASE PRESENTATION: We report a case of a 35-year-old woman with suspicious acromegaly-associated presentations, including facial changes, headache, oligomenorrhea, and new-onset diabetes mellitus and dyslipidemia. Imaging found a 19 × 12 × 8 mm pituitary tumor, but her serum IGF-1 was within the reference, and nadir GH was 0.7ng/ml after glucose load at diagnosis. A thickened skull base, increased uptake in cranial bones in bone scan, and elevated bone turnover markers indicated abnormal bone metabolism. We considered the pituitary tumor, possibly a rare subtype in subtle or clinically silent GH pituitary tumor, likely contributed to her discomforts. After the transsphenoidal surgery, the IGF-1 and nadir GH decreased immediately. A GH and prolactin-positive pituitary neuroendocrine tumor was confirmed in the histopathologic study. No tumor remnant was observed three months after the operation, and her discomforts, glucose, and bone metabolism were partially relieved. CONCLUSIONS: GH-positive pituitary neuroendocrine tumors with hormonal tests that do not meet the diagnostic criteria for acromegaly may also cause GH hypersecretion presentations. Patients with pituitary tumors and suspicious acromegaly symptoms may require more proactive treatment than non-functioning tumors of similar size and invasiveness.


Assuntos
Acromegalia , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Humanos , Feminino , Adulto , Acromegalia/diagnóstico , Acromegalia/complicações , Acromegalia/etiologia , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Doenças Ósseas/etiologia , Doenças Ósseas/diagnóstico , Doenças Ósseas/patologia
9.
ACS Sens ; 9(6): 3233-3243, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38832488

RESUMO

Amorphous metal oxide semiconductor (MOS) materials are endowed with great promise to modulate electronic structures for gas-sensing performance improvement. However, the elevated-temperature requirement of gas sensors severely impedes the application of amorphous materials due to their low thermal stability. Here, a cationic-assisted strategy to tailor the Ni-O microenvironment in an amorphous-dominated Zn/NiO heterogeneous structure with high thermal stability was developed. It was found that 6 mol % Zn incorporation into amorphous NiO can effectively preserve the amorphous-dominated NiO phase even at high temperature. After calcination, the amorphous oxide can only be converted to crystals partly thus leading to the formation of amorphous/crystalline compounds, and the content of the amorphous phase can be adjusted by changing the calcination temperature. This amorphous/crystalline configuration can induce more electron transfer from Ni to Zn species, leading to the formation of active Niδ+ (δ>2) centers. Ex situ XPS and in situ Raman spectroscopy studies proved that the generated Niδ+ species pronouncedly promote the electron transfer during the H2S adsorption process. The amorphous/crystalline-6 mol % Zn/NiO sensor exhibits exceptional hydrogen sulfide response (2 ppm, 3.23), outstanding repeatability (as long as 5 weeks), and low limit of detection (as low as 50 ppb), surpassing most reported nickel-based gas sensors such as the crystal nickel oxide prepared in this work. The response and detection limit of the latter is only (2 ppm, 1.89) and (0.05 ppm) respectively. Our work thus opens up more opportunities for fundamental understanding and modulating of highly active amorphous sensing materials.


Assuntos
Sulfeto de Hidrogênio , Níquel , Zinco , Níquel/química , Sulfeto de Hidrogênio/análise , Sulfeto de Hidrogênio/química , Zinco/química , Zinco/análise , Limite de Detecção , Semicondutores
10.
Nutrients ; 16(10)2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38794687

RESUMO

It has been strongly suggested that selenium deficiency and T-2 toxin contamination have a strong relationship with the occurrence and development of Kashin-Beck disease (KBD). In order to provide information for understanding the high prevalence of KBD in Tibet, this study collected the responses to a cubital venous blood and dietary questionnaire of 125 subjects including 75 KBD patients and 50 healthy controls in a KBD-prevalent county (Luolong County) in Tibet, China. A total of 10 household local families were randomly selected in this area, and local diet samples of brick tea, Zanba powder, milk residue, and hulless Barley were collected from these residents. Selenium content in blood was detected by inductively coupled plasma mass spectrometry (ICP-MS). The T-2 toxin contamination level in food sample was assayed using an ELISA kit. The selenium levels of patients and controls were 42.0 ± 19.8 and 56.06 ± 22.4 µg/L, respectively. The serum selenium level in controls was higher than that in patients, but there was no significant difference, and the serum selenium level both in patients and controls in Tibet was lower than the normal range. The results of the dietary survey showed that the number of respondents who consumed butter tea was large; 46.67% of patients indicated that they drank buttered tea every day, which was significantly higher than in controls. The contents of T-2 toxin in Zanba powder, milk residue, hulless barley and drinking water samples were below the detection limit (0.05 µg/kg); this result was labeled Tr. Unexpectedly, the contents of T-2 toxin in brick tea were higher, with average levels of 424 ± 56 µg/kg in Detong village and 396 ± 24 µg/kg in Langcuo village. For the first time, we report the presence of an extremely high concentration of T-2 toxin in brick tea of Tibet.


Assuntos
Contaminação de Alimentos , Doença de Kashin-Bek , Selênio , Toxina T-2 , Chá , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Dieta/estatística & dados numéricos , Inquéritos sobre Dietas , Contaminação de Alimentos/análise , Doença de Kashin-Bek/epidemiologia , Doença de Kashin-Bek/sangue , Prevalência , Selênio/sangue , Toxina T-2/análise , Chá/química , Tibet/epidemiologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-38722819

RESUMO

CONTEXT: X-linked hypophosphatemia (XLH) is a rare metabolic bone disease caused by inactivation mutations in the PHEX gene. Despite the extensive number of reported PHEX variants, only a few cases of chromosomal abnormalities have been documented. OBJECTIVE: We aimed to identify the pathogenic variants in six unrelated families with a clinical diagnosis of XLH and to propose a genetic workflow for hypophosphatemia patients suspected of XLH. METHODS: Multiple genetic testing assays were used to analyze the six families' genetic profiles, including whole exome sequencing, multiplex ligation-dependent probe amplification, whole genome sequencing, reverse transcript polymerase chain reaction, Sanger sequencing, and karyotyping. RESULTS: The study identified six novel pathogenic variants, including one mosaic variant (exon 16-22 deletion), three chromosomal abnormalities (46, XN, inv[X][pter→p22.11::q21.31→p22.11::q21.31 →qter], 46, XN, inv[X][p22.11p22.11], and XXY), a nonclassical intron variant (NM_000444.6, c.1701_31A > G), and a deletion variant (NM_000444.6, c.64_5464-186 del5215) of PHEX. Additionally, a genetic testing workflow was proposed to aid in diagnosing patients suspected of XLH. CONCLUSION: Our research expands the mutation spectrum of PHEX and highlights the significance of utilizing multiple genetic testing methods to diagnose XLH.

12.
G3 (Bethesda) ; 14(5)2024 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-38427916

RESUMO

Tanoak (Notholithocarpus densiflorus) is an evergreen tree in the Fagaceae family found in California and southern Oregon. Historically, tanoak acorns were an important food source for Native American tribes, and the bark was used extensively in the leather tanning process. Long considered a disjunct relictual element of the Asian stone oaks (Lithocarpus spp.), phylogenetic analysis has determined that the tanoak is an example of convergent evolution. Tanoaks are deeply divergent from oaks (Quercus) of the Pacific Northwest and comprise a new genus with a single species. These trees are highly susceptible to "sudden oak death" (SOD), a plant pathogen (Phytophthora ramorum) that has caused widespread deaths of tanoaks. In this study, we set out to assemble the genome and perform comparative studies among a number of individuals that demonstrated varying levels of susceptibility to SOD. First, we sequenced and de novo assembled a draft reference genome of N. densiflorus using cobarcoded library processing methods and an MGI DNBSEQ-G400 sequencer. To increase the contiguity of the final assembly, we also sequenced Oxford Nanopore long reads to 30× coverage. To our knowledge, the draft genome reported here is one of the more contiguous and complete genomes of a tree species published to date, with a contig N50 of ∼1.2 Mb, a scaffold N50 of ∼2.1 Mb, and a complete gene score of 95.5% through BUSCO analysis. In addition, we sequenced 11 genetically distinct individuals and mapped these onto the draft reference genome, enabling the discovery of almost 25 million single nucleotide polymorphisms and ∼4.4 million small insertions and deletions. Finally, using cobarcoded data, we were able to generate a complete haplotype coverage of all 11 genomes.


Assuntos
Fagaceae , Genoma de Planta , Fagaceae/genética , Filogenia , Anotação de Sequência Molecular , Genômica/métodos , Polimorfismo de Nucleotídeo Único
13.
Endocrine ; 85(1): 331-340, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38393510

RESUMO

BACKGROUND: 2q37 microdeletion syndrome is a rare clinical condition characterized by a series of physical abnormalities. Its Albright hereditary osteodystrophy (AHO)-like manifestations and possible complication of biochemical abnormalities indicating PTH resistance greatly increased the likelihood of misdiagnosis with classic pseudohypoparathyroidism (PHP) caused by GNAS mutation or methylation alteration, even though there have only been six reports of such clinical occasions. PURPOSE: to investigate the underlying genetic defect in a male patient presenting hypocalcemia, elevated PTH and with a history of kyphosis. METHOD: clinical information was collected, while the DNA was extracted from peripheral blood and subjected to methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and exome sequencing. RESULT: Physical characteristics featuring short stature, obesity, round face, short neck, and shortened 4th metacarpal and laboratory examination of the patient suggested the presence of PTH resistance, which is indicative of PHP. MS-MLPA did not reveal methylation alterations or deletions of GNAS, STX16 or other monogenetic alterations responsible for iPPSDs, but WES revealed a long-range deletion of approximately 4.18 Mb of the 2q37 region that spanned AGAP1 to NDUFA10, indicating that the patient had 2q37 microdeletion syndrome with PTH resistance. CONCLUSION: After undergoing MS-MLPA and exome sequencing, a novel deletion spanning 4.18 Mb on the 2q37 region was identified in one male patient, clarifying the diagnosis of 2q37 microdeletion syndrome with PTH resistance. The new genetic discovery added to our understanding of the molecular defects that cause inactivating PTH/PTH-related protein signaling disorders (iPPSDs).


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2 , Pseudo-Hipoparatireoidismo , Humanos , Masculino , Cromossomos Humanos Par 2/genética , Pseudo-Hipoparatireoidismo/genética , Transtornos Cromossômicos/genética , Hormônio Paratireóideo/sangue , China , População do Leste Asiático
15.
J Clin Endocrinol Metab ; 109(7): 1873-1882, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38181430

RESUMO

CONTEXT: The comparative effectiveness of denosumab and zoledronic acid for adult patients with osteogenesis imperfecta (OI) has not been established. OBJECTIVE: To evaluate the efficacy and safety of denosumab and zoledronic acid in adult patients with OI. METHODS: This was a prospective, open-label study. Patients were randomized to receive denosumab 60 mg every 6 months or zoledronic acid 5 mg once for 12 months. Pathogenic mutations of OI were identified by next-generation sequencing and confirmed by Sanger sequencing. Percentage changes in the areal bone mineral density (aBMD), trabecular bone score (TBS), and bone turnover biomarkers (BTMs) from baseline to 6 and 12 months of treatment, as well as safety, were evaluated. RESULTS: A total of 51 adults with OI (denosumab: 25, zoledronic acid: 26) were included, of whom 49 patients had identified pathogenic mutations. At 12 months, aBMD at the lumbar spine and total hip significantly increased by 4.34% (P = .005) and 1.45% (P = .023) in the denosumab group and by 4.92% (P = .006) and 2.02% (P = .016) in the zoledronic acid group, respectively. TBS showed an increasing trend by 1.39% and 2.70% in denosumab and zoledronic acid groups, respectively. Serum levels of ß-isomerized carboxy-telopeptide of type I collagen and alkaline phosphatase markedly decreased after denosumab treatment. Percentage changes in aBMD, TBS, and BTMs during the treatment were similar between the 2 groups. Patients with OI with milder phenotypes showed a significantly higher increase in the TBS after 12 months of denosumab treatment than those with more severe phenotypes (P = .030). During the study period, the denosumab group had fewer adverse events than the zoledronic acid group. CONCLUSION: Denosumab effectively increases aBMD in adults with OI, with similar efficacy to zoledronic acid. Long-term and large-sample studies are needed to confirm the antifracture efficacy and safety of denosumab in adult patients with OI.


Assuntos
Conservadores da Densidade Óssea , Densidade Óssea , Denosumab , Osteogênese Imperfeita , Ácido Zoledrônico , Humanos , Denosumab/uso terapêutico , Denosumab/efeitos adversos , Denosumab/administração & dosagem , Ácido Zoledrônico/uso terapêutico , Ácido Zoledrônico/administração & dosagem , Ácido Zoledrônico/efeitos adversos , Feminino , Masculino , Adulto , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Densidade Óssea/efeitos dos fármacos , Estudos Prospectivos , Resultado do Tratamento , Remodelação Óssea/efeitos dos fármacos , Adulto Jovem , Pessoa de Meia-Idade
16.
J Clin Endocrinol Metab ; 109(7): 1827-1836, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38198649

RESUMO

CONTEXT: Denosumab is a potential therapeutic agent for osteogenesis imperfecta (OI), but its efficacy and safety remain unclear in children with OI. OBJECTIVE: We aimed to investigate the effects of denosumab on bone mineral density (BMD), spinal morphometry, and safety in children with OI compared with zoledronic acid. METHODS: In this prospective study, 84 children or adolescents with OI were randomized to receive denosumab subcutaneous injection every 6 months or zoledronic acid intravenous infusion once. Changes of BMD and its Z-score, vertebral shape, serum levels of calcium and bone turnover biomarkers were assessed during the 1-year treatment. RESULTS: After 12 months of treatment, BMD at the lumbar spine, femoral neck, and total hip significantly increased by 29.3%, 27.8%, and 30.2% in the denosumab group, and by 32.2%, 47.1%, and 41.1% in the zoledronic acid group (all P < .001 vs baseline). Vertebral height and projection area significantly increased after denosumab and zoledronic acid treatment. Rebound hypercalcemia was found to be a common and serious side effect of denosumab, of which 14.3% reached hypercalcemic crisis. Rebound hypercalcemia could be alleviated by switching to zoledronic acid treatment. CONCLUSION: Treatment with denosumab or zoledronic acid is beneficial in increasing BMD and improving the spinal morphometry of children with OI. However, denosumab should be used with caution in pediatric patients with OI because of its common and dangerous side effect of rebound hypercalcemia. The appropriate dosage and dosing interval of denosumab need to be further explored in children with OI.


Assuntos
Conservadores da Densidade Óssea , Densidade Óssea , Denosumab , Osteogênese Imperfeita , Ácido Zoledrônico , Humanos , Denosumab/uso terapêutico , Denosumab/efeitos adversos , Denosumab/administração & dosagem , Osteogênese Imperfeita/tratamento farmacológico , Criança , Feminino , Masculino , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/administração & dosagem , Ácido Zoledrônico/uso terapêutico , Ácido Zoledrônico/efeitos adversos , Ácido Zoledrônico/administração & dosagem , Pré-Escolar , Adolescente , Estudos Prospectivos , Resultado do Tratamento , Remodelação Óssea/efeitos dos fármacos
17.
J Clin Endocrinol Metab ; 109(7): 1803-1813, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38214665

RESUMO

OBJECTIVE: Deficiency of cartilage-associated protein (CRTAP) can cause extremely rare autosomal recessive osteogenesis imperfecta (OI) type VII. We investigated the pathogenic mechanisms of CRTAP variants through functional studies on bones of patients with OI. METHODS: Two nonconsanguineous families with CRTAP mutations were included and their phenotypes and genotypes were evaluated. Bone specimens were obtained from 1 patient with OI and a normal control during orthopedic surgery. The impacts of the novel variant on the CRTAP transcript were confirmed. The expression levels of CRTAP mRNA and CRTAP protein were analyzed. The quantification of prolyl 3-hydroxylation in the α1 chain of type I collagen was evaluated. RESULTS: Patients with OI type VII had early-onset recurrent fractures, severe osteoporosis, and bone deformities. The c.621 + 1G > A and c.1153-3C > G mutations were identified in CRTAP in the patients with OI. The c.621 + 1G > A variant was a novel mutation that could impair mRNA transcription, leading to a truncated CRTAP protein. In a patient with c.621 + 1G > A and c.1153-3C > G mutations in CRTAP, the mRNA and protein levels of CRTAP in osteoblasts were significantly decreased and the osteoid volume and osteoblast numbers were markedly reduced compared with those in the normal control individual. This was simultaneously accompanied by significantly reduced prolyl 3-hydroxylation at Pro986 in the α1 chain of type I collagen and invisible active bone formation in bone. CONCLUSION: The novel c.621 + 1G > A mutation in CRTAP expands the genotypic spectrum of type VII OI. Biallelic mutations of c.621 + 1G > A and c.1153-3C > G in CRTAP can lead to reduced CRTAP mRNA and deficient CRTAP protein in osteoblasts, which reduces 3-hydroxylation in Pro986 of the α1 chain of type I collagen and impairs bone formation, thus contributing to severe OI type VII.


Assuntos
Proteínas da Matriz Extracelular , Chaperonas Moleculares , Osteogênese Imperfeita , Fenótipo , Humanos , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Masculino , Feminino , Chaperonas Moleculares/genética , Mutação , Criança , Linhagem , Pré-Escolar , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Genótipo , Osteoblastos/metabolismo , Osteoblastos/patologia , Cadeia alfa 1 do Colágeno Tipo I , Adulto , Adolescente
18.
Nutrients ; 16(1)2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38202004

RESUMO

This study aimed to screen out antibacterial peptides derived from sesame (Sesamum indicum L.) through in silico and in vitro methods. In silico proteolysis of sesame proteins with pepsin, trypsin, and chymotrypsin was performed with the online server BIOPEP-UWM. The CAMPR3 online server was used to predict the antimicrobial effect of peptides. The ToxinPred, PepCalc, and AllergenFP tools were utilized to forecast the physicochemical properties, toxicity, and allergen of the peptides. Molecular docking analysis showed that six cationic antimicrobial peptides could directly interact with the key sites of dihydropteroate synthase, whereas Ala-Gly-Gly-Val-Pro-Arg and Ser-Thr-Ile-Arg exhibited the strongest binding affinity. In vitro antibacterial experiment showed the minimum inhibitory concentration (MIC) of Ser-Thr-Ile-Arg against Escherichia coli and Staphylococcus aureus was 1024 and 512 µg/mL, respectively. Meanwhile, MIC of Ala-Gly-Gly-Val-Pro-Arg against both bacterial species was 512 µg/mL. Our results suggest that peptides from sesame possess the ability to potentially hinder bacterial activity.


Assuntos
Sesamum , Infecções Estafilocócicas , Staphylococcus aureus , Escherichia coli , Simulação de Acoplamento Molecular , Peptídeos Catiônicos Antimicrobianos , Antibacterianos/farmacologia
19.
Endocrine ; 84(1): 236-244, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38206435

RESUMO

BACKGROUND: Osteoporosis is a systemic skeletal disease with increasing bone fragility and prone to fracture. Osteocalcin (OC), as the most abundant non collagen in bone matrix, has been extensively used in clinic as a biochemical marker of osteogenesis. Two forms of OC were stated on circulation, including carboxylated osteocalcin (cOC) and undercarboxylated osteocalcin (ucOC). OC was not only involved in bone mineralization, but also in the regulation of muscle function. OBJECTIVE: This study explored the relationship between serum OC, cOC, ucOC levels and bone mineral density (BMD), bone microarchitecture, muscle mass and physical activity in Chinese postmenopausal women. METHOD: 216 community-dwelling postmenopausal women were randomized enrolled. All subjects completed biochemical measurements, including serum ß-isomer of C-terminal telopeptides of type I collagen (ß-CTX), N-terminal propeptide of type 1 procollagen (P1NP), alkaline phosphatase (ALP), OC, cOC and ucOC. They completed X-ray absorptiometry (DXA) scan to measure BMD, appendicular lean mass (ALM) and trabecular bone score (TBS). They completed high resolution peripheral quantitative CT (HR-pQCT) to assess peripheral bone microarchitectures. RESULTS: Serum OC, cOC and ucOC were elevated in osteoporosis postmenopausal women. In bone geometry, serum ucOC was positively related with total bone area (Tt.Ar) and trabecular area(Tb.Ar). In bone volumetric density, serum OC and ucOC were negatively associated with total volume bone mineral density (Tt.vBMD) and trabecular volume bone mineral density (Tb.vBMD). In bone microarchitecture, serum OC and ucOC were negatively correlative with Tb.N and Tb.BV/TV, and were positively correlated with Tb.Sp. Serum OC and ucOC were positively associated with Tb.1/N.SD. Serum OC was negatively related with Tb.Th. Serum ucOC was positively associated with ALM. The high level of serum OC was the risk factor of osteoporosis. ALM was the protective factor for osteoporosis. CONCLUSION: All forms of serum OC were negatively associated with BMD. Serum OC and ucOC mainly influenced microstructure of trabecular bone in peripheral skeletons. Serum ucOC participated in modulating both bone microstructure and muscle mass.


Assuntos
Osteoporose Pós-Menopausa , Osteoporose , Feminino , Humanos , Pequim/epidemiologia , Densidade Óssea/fisiologia , Músculos , Osteocalcina , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/epidemiologia , Pós-Menopausa
20.
J Endocrinol Invest ; 47(8): 1931-1939, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38161202

RESUMO

OBJECTIVE: Summarize and analyze the characteristics of patients with Multiple Endocrine Neoplasia type 1 (MEN-1) who were diagnosed with malignant tumors that do not belong to MEN-1 components. METHODS: Clinical data from patients with MEN-1 who visited Peking Union Medical College Hospital between April 2012 and April 2022 were collected. We compared the clinical characteristics of patients with malignant tumors outside of their MEN-1 components to those without additional tumors. MEN-1 gene testing was performed on most of these patients using Sanger sequencing, whole-exome sequencing, or MLPA. RESULTS: A total of 221 MEN-1 patients were diagnosed, of which 23 (10.40%) were found to have malignant tumors that did not belong to MEN-1 components, including papillary thyroid carcinoma (PTC) (4.52%), breast cancer (1.81%), urologic neoplasms (1.35%), primary hepatic carcinoma (PCC) (0.09%), meningeal sarcoma (0.05%), glioblastoma (0.05%), cervical cancer (0.05%), and lung carcinoma (0.05%). MEN-1 gene mutations were identified in 11 patients, including missense mutations, frameshift mutations, and splice mutations. The prevalence of each endocrine neoplasm, particularly gastroenteropancreatic neuroendocrine tumor, was higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignant tumors. CONCLUSION: Our retrospective study revealed a higher incidence of non-MEN-1 component malignant tumors in MEN-1 patients, especially breast cancer, PTC, and urologic neoplasms. These patients also exhibit more severe clinical phenotypes of MEN-1.


Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Humanos , Feminino , Masculino , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/epidemiologia , Neoplasia Endócrina Múltipla Tipo 1/complicações , Adulto , Pessoa de Meia-Idade , Mutação , Adulto Jovem , Idoso , Adolescente , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/epidemiologia , Fatores de Risco , Proteínas Proto-Oncogênicas
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