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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 -
Journal of Clinical Pathology May 2024This study aims to identify associations between parathyroid adenoma (PTA) characteristics (histology, weight and size) with the change in parathyroid hormone (PTH) and...
AIMS
This study aims to identify associations between parathyroid adenoma (PTA) characteristics (histology, weight and size) with the change in parathyroid hormone (PTH) and calcium levels.
METHODS
A historical cohort study was conducted on adult patients with solitary PTA removed in the Gold Coast Health Precinct, Australia, between 2017 and 2022.
RESULTS
PTA weight is correlated with the change in day 1 PTH level (r=0.26, p=0.036), the change in day 1 corrected calcium level (r=0.20, p=0.033), and the change in follow-up corrected calcium level (r=0.47, p<0.001). The largest dimension (size) of PTA is also correlated with the change in day 1 PTH (r=0.30, p=0.011) and the change in follow-up corrected calcium level (r=0.40, p<0.001). Adjusted for age and gender, a statistically significant negative correlation was found between day 1 PTH level and adenoma size, resulting in a 0.5% change in size for every percentage change in PTH level (equating to a 5.0% increase in variance explained, p=0.038). Similarly, a negative correlation was identified in day 1 corrected calcium levels and weight, with a 4.7% change in weight for every percentage of change in day 1 corrected calcium level (an increase of 5.6% variance explained, p=0.010). In addition, a negative correlation was identified, where every 3.1% change in size (an increase of 17.4% variance explained, p<0.001) and 7.6% change in weight (an increase of 22.7% variance explained, p<0.001) was seen with every percentage change in follow-up corrected calcium levels. Clear-cell PTA had the most significant percentage fall in day 1 corrected calcium levels compared with other PTA subtypes (p=0.007).
CONCLUSIONS
Preoperative calcium and PTH levels correlate with PTA weight and size. The degree of change in postoperative corrected calcium levels behaved differently in the clear-cell subtype.
PubMed: 38821854
DOI: 10.1136/jcp-2023-209340 -
Journal of the Pediatric Infectious... May 2024Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third trimester TDF exposure is associated with a 12% reduction in bone...
BACKGROUND
Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. Potential mechanisms underlying this observation are unknown.
METHODS
The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in third trimester versus none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4-30 days, to compare slopes by TDF exposure.
RESULTS
Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 versus -0.08/day (difference -0.50/day [95%CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] versus 26 [22,37] ng/mL). No differences were observed for other biomarkers.
CONCLUSIONS
Third trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.
PubMed: 38820092
DOI: 10.1093/jpids/piae054 -
The Journal of Surgical Research May 2024Total thyroidectomy (TTx) has been reported to be more challenging in patients with Graves' disease, especially in those who are hyperthyroid at the time of surgery. Our...
INTRODUCTION
Total thyroidectomy (TTx) has been reported to be more challenging in patients with Graves' disease, especially in those who are hyperthyroid at the time of surgery. Our aim was to compare outcomes in patients undergoing TTx for Graves' disease compared to other thyroid diseases at a large academic institution with high-volume fellowship-trained endocrine surgeons.
METHODS
In our retrospective analysis from December 2015 to May 2023, patients undergoing TTx for Graves' disease were compared to those undergoing TTx for all other indications excluding advanced malignancy (poorly differentiated thyroid cancer and concomitant neck dissections). Patient demographics, biochemical values, and postoperative outcomes were compared. A subgroup analysis was performed comparing hyperthyroid to euthyroid patients at the time of surgery.
RESULTS
There were 589 patients who underwent TTx, of which 227 (38.5%) had Graves' disease compared to 362 (61.5%) without. Intraoperatively in Graves' patients, nerve monitoring was used more frequently (65.6% versus 57.1%; P = 0.04) and there was a higher rate of parathyroid autotransplantation (32.0% versus 14.4%; P < 0.01). Postoperatively, transient voice hoarseness occurred less frequently (4.8% versus 13.6%; P < 0.01) and there was no difference in temporary hypocalcemia rates or hematoma rates. In our subgroup analysis, 83 (36%) of Graves' patients were hyperthyroid (thyroid-stimulating hormone < 0.45 and free T4 > 1.64) at the time of surgery and there were no differences in postoperative complications compared to those who were euthyroid.
CONCLUSIONS
At a high-volume endocrine surgery center, TTx for Graves' disease can be performed safely without significant differences in postoperative outcomes. Hyperthyroid patients demonstrated no differences in postoperative outcomes.
PubMed: 38805845
DOI: 10.1016/j.jss.2024.04.070 -
Current Opinion in Endocrinology,... Aug 2024Disturbances in mineral and bone metabolism occurring in osteoporosis and chronic kidney disease-associated osteoporosis place patients at high risk of fracture making... (Review)
Review
PURPOSE OF REVIEW
Disturbances in mineral and bone metabolism occurring in osteoporosis and chronic kidney disease-associated osteoporosis place patients at high risk of fracture making these conditions a major public health concern. Due to the limited use of bone histomorphometry in clinical practice, the gold standard for assessing bone turnover, extensive efforts have been made to identify bone turnover markers (BTMs) as noninvasive surrogates. Since the identification of certain commonly used markers several decades ago, considerable experience has been acquired regarding their clinical utility in such bone disorders.
RECENT FINDINGS
Mounting evidence suggested that BTMs represent a simple, low-risk, rapid and convenient way to obtain data on the skeletal health and that they may be useful in guiding therapeutic choices and monitoring the response to treatment.
SUMMARY
BTMs could provide clinicians with useful information, independent from, and often complementary to bone mineral density (BMD) measurements. They have proven valuable for monitoring the effectiveness of osteoporosis therapy, as well as promising for discriminating low and high turnover states. Improved performance is observed when BTMs are combined, which may be useful for selecting treatments for chronic kidney disease-bone mineral disorders (CKD-MBD).
Topics: Humans; Biomarkers; Osteoporosis; Bone Remodeling; Renal Insufficiency, Chronic; Bone Density; Chronic Kidney Disease-Mineral and Bone Disorder; Bone and Bones
PubMed: 38804196
DOI: 10.1097/MED.0000000000000869 -
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 -
Bone Aug 2024Excess parathyroid hormone (PTH) is associated with an increased risk of cardiovascular disease (CVD). (Meta-Analysis)
Meta-Analysis
BACKGROUND
Excess parathyroid hormone (PTH) is associated with an increased risk of cardiovascular disease (CVD).
PURPOSE
We aimed to evaluate the correlation between primary hyperparathyroidism (PHPT) and CVD or cardiovascular (CV) death.
DATA SOURCES
Comprehensive searches of PubMed, Embase and ClinicalTrials.gov until May 20, 2023 with the following keywords: "primary hyperparathyroidism," "cardiovascular disease," and "mortality."
STUDY SELECTIONS
Cohort studies and randomized controlled trials comparing PHPT patients to the general population and those who had received parathyroidectomy (PTX) to those who did not.
DATA EXTRACTION
Three investigators independently extracted data and assessed study quality.
DATA SYNTHESIS
Eleven cohort studies and one randomized controlled trial were identified, including 264,227 PHPT patients with or without PTX, and the average age reported in the studies was 62 years. PHPT was associated with a higher risk of total death (RR 1.39 [95 % confidence interval (CI) 1.23-1.57) and CV death (RR 1.61 [95 % CI 1.47-1.78]) than the general population. However, there was no significant difference in CVD risk between patients with PHPT and the general population (RR 1.73 [95 % CI 0.87-3.47]). When compared to patients without PTX, PTX had a lower risk of CV death (RR 0.75 [95 % CI 0.71-0.80]), total death (RR 0.64 [95 % CI 0.60-0.70]) and CVD (RR 0.92 [95 % CI 0.90-0.94]).
LIMITATION
High heterogeneity among the included articles, and most of them were retrospective and older studies.
CONCLUSIONS
PHPT was associated with higher risk of total death and CV death while PTX was associated with lower risk of total death, CV death, and CVD.
Topics: Humans; Cardiovascular Diseases; Hyperparathyroidism, Primary; Parathyroidectomy; Middle Aged; Risk Factors
PubMed: 38795811
DOI: 10.1016/j.bone.2024.117130 -
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