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Nature Communications Jun 2024Ligand-induced activation of G protein-coupled receptors (GPCRs) can initiate signaling through multiple distinct pathways with differing biological and physiological...
Ligand-induced activation of G protein-coupled receptors (GPCRs) can initiate signaling through multiple distinct pathways with differing biological and physiological outcomes. There is intense interest in understanding how variation in GPCR ligand structure can be used to promote pathway selective signaling ("biased agonism") with the goal of promoting desirable responses and avoiding deleterious side effects. Here we present an approach in which a conventional peptide ligand for the type 1 parathyroid hormone receptor (PTHR1) is converted from an agonist which induces signaling through all relevant pathways to a compound that is highly selective for a single pathway. This is achieved not through variation in the core structure of the agonist, but rather by linking it to a nanobody tethering agent that binds with high affinity to a separate site on the receptor not involved in signal transduction. The resulting conjugate represents the most biased agonist of PTHR1 reported to date. This approach holds promise for facile generation of pathway selective ligands for other GPCRs.
Topics: Ligands; Humans; Receptor, Parathyroid Hormone, Type 1; Single-Domain Antibodies; HEK293 Cells; Signal Transduction; Receptors, G-Protein-Coupled; Protein Binding; Animals; Peptides
PubMed: 38824166
DOI: 10.1038/s41467-024-49068-5 -
Frontiers in Endocrinology 2024Although active vitamin D (VD) has been used both preoperatively and postoperatively to prevent hypocalcemia risk in patients undergoing total thyroidectomy, the role of...
INTRODUCTION
Although active vitamin D (VD) has been used both preoperatively and postoperatively to prevent hypocalcemia risk in patients undergoing total thyroidectomy, the role of 1,25-dihydroxyvitamin D (1,25(OH)D) has not been examined. This study comprehensively investigated the effects of 1,25(OH)D on calcium (Ca) concentrations after total thyroidectomy.
METHODS
Serum Ca, parathyroid hormone (PTH), and 1,25(OH)D levels were measured in 82 patients with thyroid disease before and after surgery.
RESULTS
Serum Ca, PTH, and 1,25(OH)D levels decreased significantly on the morning of the first postoperative day. Notably, the decrease in 1,25(OH)D concentration was significantly lower than that of PTH concentration (10.5 ± 33.4% vs. 52.1 ± 30.1%, p<0.0001), with 28% of patients showing increases in 1,25(OH)D. The only factor predicting a postoperative 1,25(OH)D decrease was a high preoperative 1,25(OH)D concentration. Postoperative 1,25(OH)D concentrations, as well as the magnitude and rate of decrease from preoperative levels, showed strong positive correlations with preoperative 1,25(OH)D concentrations (p<0.0001 for all three variables) but not with PTH concentrations. These findings suggest that 1,25(OH)D concentrations after thyroidectomy were more strongly dependent on preoperative concentrations than on the effect of PTH decrease and were relatively preserved, possibly preventing sudden severe postoperative hypocalcemia. A high 1,25(OH)D level was the most important preoperative factor for hypocalcemia (<2 mmol/L; p<0.05) on the first postoperative day; however, only PTH decrease was statistically significant (p<0.001) when intraoperative factors were added. In the PTH >10 pg/mL group, the decrease in 1,25(OH)D levels was significantly associated with postoperative hypocalcemia (p<0.05). Similarly, in the PTH levels >15 pg/mL group, a decrease in 1,25(OH)D concentration was a significant factor, and the amount of PTH decrease was no longer significant.
CONCLUSION
1,25(OH)D plays an important role in preventing sudden, severe hypocalcemia due to decreased PTH levels after total thyroidectomy, whereas high preoperative 1,25(OH)D levels are a significant risk factor for postoperative hypocalcemia. Optimizing preoperative protocols to adjust Ca, PTH, and 1,25(OH)D levels to improve the management of patients undergoing total thyroidectomy and to prevent extreme intraoperative PTH decreases may reduce the risk of hypocalcemia.
Topics: Humans; Thyroidectomy; Female; Male; Middle Aged; Vitamin D; Prospective Studies; Calcium; Adult; Parathyroid Hormone; Hypocalcemia; Aged; Postoperative Complications; Postoperative Period; Thyroid Diseases
PubMed: 38803480
DOI: 10.3389/fendo.2024.1360464 -
Renal Failure Dec 2024Secondary hyperparathyroidism (SHPT) can progress to severe SHPT (sSHPT), which affects the survival rate and quality of life of patients. This retrospective cohort...
Secondary hyperparathyroidism (SHPT) can progress to severe SHPT (sSHPT), which affects the survival rate and quality of life of patients. This retrospective cohort study investigated risk factors for sSHPT and the association between SHPT and mortality (all-cause and infection-related) among 771 clinically stable patients (421 male patients; mean age, 51.2 years; median dialysis vintage, 28.3 months) who underwent >3 months of regular peritoneal dialysis (PD) between January 2013 and March 2021. The sSHPT and non-sSHPT groups comprised 75 (9.7%) (median progression, 35 months) and 696 patients, respectively. sSHPT was defined as a serum intact parathyroid hormone (PTH) level >800 pg/mL observed three times after active vitamin D pulse therapy. The influence of sSHPT on the prognosis of and risk factors for sSHPT progression were evaluated using logistic and Cox regression analyses. After adjusting for confounding factors, higher (each 100-pg/mL increase) baseline PTH levels (95% confidence interval (CI) 1.206-1.649, < .001), longer (each 1-year increase) dialysis vintages (95% CI 1.013-1.060, = .002), higher concomitant diabetes rates (95% CI 1.375-10.374, .010), and lower (each 1-absolute unit decrease) / values (95% CI 0.859-0.984, .015) were independent risk factors for progression to sSHPT in patients on PD. During follow-up, 211 deaths occurred (sSHPT group, = 35; non-sSHPT group, = 176). The sSHPT group had significantly higher infection-related mortality rates than the non-sSHPT group (12.0% vs. 4.3%; < .05), and sSHPT was associated with increased infection-related mortality. In conclusion, patients with sSHPT are at higher risk for death and infection-related mortality than patients without sSHPT.
Topics: Humans; Male; Hyperparathyroidism, Secondary; Middle Aged; Retrospective Studies; Female; Peritoneal Dialysis; Prognosis; Risk Factors; Parathyroid Hormone; Adult; Kidney Failure, Chronic; Disease Progression; Proportional Hazards Models
PubMed: 38803195
DOI: 10.1080/0886022X.2024.2356022 -
Endocrinology and Metabolism (Seoul,... Jun 2024
Topics: Hypoparathyroidism; Humans; Postoperative Complications
PubMed: 38798025
DOI: 10.3803/EnM.2024.2035 -
Medicina (Kaunas, Lithuania) May 2024Secondary hyperparathyroidism (SHPT) poses a common condition among patients with chronic kidney disease (CKD) due to the chronic stimulation of the parathyroid glands...
Secondary hyperparathyroidism (SHPT) poses a common condition among patients with chronic kidney disease (CKD) due to the chronic stimulation of the parathyroid glands as a result of persistently low calcium levels. As a first option for medical treatment, vitamin D receptor analogs (VDRAs) and calcimimetic agents are generally used. Apart from cinacalcet, which is orally taken, in recent years, another calcimimetic agent, etelcalcetide, is being administered intravenously during dialysis. In a 5-year retrospective study between 2018 and 2023, 52 patients undergoing dialysis were studied. The aim of this study is to highlight the possible effects and/or benefits that intravenously administered calcimimetic agents have on CKD patients. A total of 34 patients (65.4%) received cinacalcet and etelcalcetide while parathormone (PTH) and calcium serum levels were monitored on a monthly basis. A total of 29 out of 33 patients (87.9%) that received treatment with etelcalcetide showed a significant decrease in PTH levels, which rose up to 57% compared to the initial values. None of the included patients needed to undergo parathyroidectomy (PTx) due to either extremely high and persistent PTH levels or severe side effects of the medications. It is generally strongly advised that parathyroidectomies should be performed by an expert surgical team. In recent years, a significant decrease in parathyroidectomies has been recorded globally, a fact that is mainly linked to the constantly wider use of new calcimimetic agents. This decrease in parathyroidectomies has resulted in an important decrease in complications occurring in cervical surgeries (e.g., perioperative hemorrhage and nerve damage). Despite the fact that these surgical complications cannot be easily compared to the pharmaceutical side effects, the recorded decrease in parathyroidectomies is considered to be notable, especially in cases of relapse where a difficult reoperation would be considered based on previously published guidelines.
Topics: Humans; Hyperparathyroidism, Secondary; Retrospective Studies; Male; Female; Middle Aged; Cinacalcet; Aged; Calcimimetic Agents; Parathyroidectomy; Renal Dialysis; Peptides; Parathyroid Hormone; Renal Insufficiency, Chronic; Calcium; Adult
PubMed: 38792994
DOI: 10.3390/medicina60050812 -
Genes May 2024The 22q11.2 deletion syndrome (22q11.2DS) is associated with a heterogeneous neurocognitive phenotype, which includes psychiatric disorders. However, few studies have...
The 22q11.2 deletion syndrome (22q11.2DS) is associated with a heterogeneous neurocognitive phenotype, which includes psychiatric disorders. However, few studies have investigated the influence of socioeconomic variables on intellectual variability. The aim of this study was to investigate the cognitive profile of 25 patients, aged 7 to 32 years, with a typical ≈3 Mb 22q11.2 deletion, considering intellectual, adaptive, and neuropsychological functioning. Univariate linear regression analysis explored the influence of socioeconomic variables on intellectual quotient (IQ) and global adaptive behavior. Associations with relevant clinical conditions such as seizures, recurrent infections, and heart diseases were also considered. Results showed IQ scores ranging from 42 to 104. Communication, executive functions, attention, and visuoconstructive skills were the most impaired in the sample. The study found effects of access to quality education, family socioeconomic status (SES), and caregiver education level on IQ. Conversely, age at diagnosis and language delay were associated with outcomes in adaptive behavior. This characterization may be useful for better understanding the influence of social-environmental factors on the development of patients with 22q11.2 deletion syndrome, as well as for intervention processes aimed at improving their quality of life.
Topics: Humans; Male; Adolescent; Female; DiGeorge Syndrome; Child; Brazil; Adult; Young Adult; Neuropsychological Tests; Socioeconomic Factors; Intelligence; Quality of Life; Social Class
PubMed: 38790224
DOI: 10.3390/genes15050595 -
Veterinary Journal (London, England :... Jun 2024The pathogenesis of increased serum phosphate concentration and proteinuria in dogs with spontaneous hyperadrenocorticism (HAC) is unclear. A potential link between...
The pathogenesis of increased serum phosphate concentration and proteinuria in dogs with spontaneous hyperadrenocorticism (HAC) is unclear. A potential link between proteinuria and calcium/phosphate metabolism has never been studied in dogs with HAC. The aims of the study were: (1) To evaluate calcium/phosphate metabolism in dogs with spontaneous HAC and compare to healthy dogs as well as to dogs with non-HAC illness; (2) to look for associations between markers of calcium/phosphate metabolism and biomarkers of kidney disease in dogs with HAC. Fifty-four dogs were included in the study, classified as HAC (n=27), non-HAC disease (n=17), and healthy (n=10). Serum calcium, phosphate, 25(OH)Vitamin D, 1,25(OH)Vitamin D, plasma intact parathyroid hormone concentration (iPTH), FGF23, and urinary fractional excretion of calcium and phosphate were evaluated in all dogs at diagnosis and compared between each group. The correlation between these variables and urine protein-to-creatinine ratio (UPC) and urinary N-acetylglucosaminidase-to-creatinine ratio (uNAG/C) was evaluated in the HAC group. Medians [range] of serum phosphate concentration, urinary fractional excretion of calcium (FE(Ca)), and iPTH were significantly higher in dogs with HAC than in dogs with non-HAC illness (P<0.01) and healthy dogs (P<0.01). Increased 1,25(OH)Vitamin D/25(OH)Vitamin D was also observed (P<0.001). In HAC group, UPC was significantly negatively correlated with 25(OH)Vitamin D (r(s): -0.54; P<0.01). Urinary NAG/C was significantly positively correlated with serum phosphate (r(s): 0.46; P=0.019). Increased serum phosphate, urinary excretion of calcium, and hyperparathyroidism were observed in dogs with HAC. Vitamin D metabolism may be shifted towards increased 1-alpha hydroxylation.
Topics: Animals; Dogs; Dog Diseases; Biomarkers; Male; Phosphates; Female; Calcium; Adrenocortical Hyperfunction; Kidney Diseases; Parathyroid Hormone; Vitamin D; Proteinuria; Fibroblast Growth Factor-23
PubMed: 38788995
DOI: 10.1016/j.tvjl.2024.106146 -
Dentistry Journal May 2024Familial isolated hypoparathyroidism is a rare genetic disorder due to no or low production of the parathyroid hormone, disturbing calcium and phosphate regulation. The...
OBJECTIVE
Familial isolated hypoparathyroidism is a rare genetic disorder due to no or low production of the parathyroid hormone, disturbing calcium and phosphate regulation. The resulting hypocalcemia may lead to dental abnormalities, such as enamel hypoplasia. The aim of this paper was to describe the full-mouth rehabilitation of a 15-year-old girl with chronic hypocalcemia due to a rare congenital hypoparathyroidism.
CLINICAL CONSIDERATIONS
In this patient, in the young adult dentition, conservative care was preferred. Onlays or stainless-steel crowns were performed on the posterior teeth, and direct or indirect (overlays and veneerlays) were performed on the maxillary premolars, canines, and incisors, using a digital wax-up. The mandibular incisors were bleached. The treatment clearly improved the patient's oral quality of life, with fewer sensitivities, better chewing, and aesthetic satisfaction. The difficulties were the regular monitoring and the limited compliance of the patient.
CONCLUSION
Despite no clinical feedback in the literature, generalized hypomineralized/hypoplastic teeth due to hypoparathyroidism in a young patient can be treated as amelogenesis imperfecta (generalized enamel defects) with a conservative approach for medium-term satisfactory results.
HIGHLIGHTS
This study provides new insights into the management of enamel hypoplasia caused by familial isolated hypoparathyroidism, helping to improve patient outcomes in similar cases.
PubMed: 38786528
DOI: 10.3390/dj12050130 -
European Journal of Psychotraumatology 202422q11 Deletion Syndrome (22q11DS) is the most common microdeletion syndrome with broad phenotypic variability, leading to significant morbidity and some mortality. The...
22q11 Deletion Syndrome (22q11DS) is the most common microdeletion syndrome with broad phenotypic variability, leading to significant morbidity and some mortality. The varied health problems associated with 22q11DS and the evolving phenotype (both medical and developmental/behavioural) across the lifespan can strongly impact the mental health of patients as well as their caregivers. Like caregivers of children with other chronic diseases, caregivers of children with 22q11DS may experience an increased risk of traumatisation and mental health symptoms. The study's primary objective was to assess the frequency of traumatic experiences and mental health symptoms among mothers of children with 22q11DS. The secondary objective was to compare their traumatic experiences to those of mothers of children with other neurodevelopmental disorders (NDDs). A total of 71 mothers of children diagnosed with 22q11DS completed an online survey about their mental health symptoms and traumatic experiences. Descriptive statistics were used to summarise the prevalence of their mental health symptoms and traumatic experiences. Logistic regression models were run to compare the traumatic experiences of mothers of children with 22q11DS to those of 335 mothers of children with other neurodevelopmental disorders (NDDs). Many mothers of children with 22q11DS experienced clinically significant mental health symptoms, including depression (39%), anxiety (25%), and post-traumatic stress disorder (PTSD) symptoms (30%). The types of traumatic events experienced by mothers of children with 22q11DS differed from those of mothers of children with other NDDs as they were more likely to observe their child undergoing a medical procedure, a life-threatening surgery, or have been with their child in the intensive care unit. 22q11DS caregivers are likely to require mental health support and trauma-informed care, tailored to the specific needs of this population as they experience different kinds of traumatic events compared to caregivers of children with other NDDS.
Topics: Humans; Female; Mothers; Adult; Child; Male; Surveys and Questionnaires; Mental Health; Stress Disorders, Post-Traumatic; 22q11 Deletion Syndrome; Adolescent; Neurodevelopmental Disorders; Middle Aged; Caregivers
PubMed: 38780146
DOI: 10.1080/20008066.2024.2353532 -
Journal of Nippon Medical School =... 2024Detective flow imaging (DFI) is a new imaging technology that displays low-velocity blood flow, which is difficult to visualize on conventional color Doppler... (Comparative Study)
Comparative Study
BACKGROUND
Detective flow imaging (DFI) is a new imaging technology that displays low-velocity blood flow, which is difficult to visualize on conventional color Doppler ultrasonography (CDU). In this study, we compared the usefulness of DFI with that of CDU and methoxy-isobutyl-isonitrile (MIBI) scintigraphy for detecting parathyroid adenoma (PA) in patients with primary hyperparathyroidism (PHPT).
METHODS
From March 2021 to March 2023, 87 PHPT patients underwent surgery, and 66 had a single PA. We performed preoperative conventional ultrasonography with CDU, MIBI scintigraphy, and DFI for 42 patients (5 males and 37 females; mean age: 61.6 ± 15.4 years).
RESULTS
MIBI scintigraphy detected PA in 85.7% (36/42) patients, and both CDU and DFI detected PA in all patients. The rates of vascularity in PA detected by CDU and DFI were 71.4% (30/42) and 85.7% (36/42), respectively. Vascularity was detected by DFI in 6 patients who were negative for vascularity on MIBI scintigraphy. Furthermore, DFI detected blood supply in 6 of the 12 patients with undetectable blood supply on CDU. Fisher's exact test revealed that high or low blood flow, as determined by DFI, was significantly associated with detection of feeding vessels in PA by CDU (P < 0.001).
CONCLUSIONS
DFI was useful for preoperative detection of PA blood flow.
Topics: Humans; Female; Male; Middle Aged; Parathyroid Neoplasms; Hyperparathyroidism, Primary; Aged; Ultrasonography, Doppler, Color; Adenoma; Radionuclide Imaging; Technetium Tc 99m Sestamibi; Adult; Blood Flow Velocity
PubMed: 38777783
DOI: 10.1272/jnms.JNMS.2024_91-213