Generation and analysis of pseudohypoaldosteronism type II knock-in mice caused by a nonsense KLHL3 mutation in the Kelch domain.

Mutations in the Kelch-like 3 (KLHL3) gene are the most common cause of inherited pseudohypoaldosteronism type II (PHAII) featuring thiazide-sensitive hypertension and hyperkalemic metabolic acidosis. Although Klhl3R528H/+ knock-in (KI) mice carrying a missense mutation in the Kelch repeat domain have been reported, nonsense KLHL3 mutations in the same domain that cause PHAII have not been fully investigated in vivo. We generated and analyzed Klhl3 KI mice harboring a nonsense W523X mutation (corresponding to the human KLHL3 W470X mutation). Both heterozygous and homozygous Klhl3W523X/+ KI mice exhibited typical PHAII with low-renin hypertension, hyperkalemia with reduced renal potassium excretion, and hyperchloremic metabolic acidosis. Their kidney tissues showed the presence of Klhl3 mRNA and increased Klhl3 protein levels along with enhanced downstream Wnk1/4-Spak/Osr1-N(k)cc phosphorylation. Increased protein expression of total Spak, phosphor(p-)Spak, total Ncc, and p-Ncc from urinary extracellular vesicles (uEVs) also confirmed the activation of the Wnk-mediated Ncc pathway. In vitro studies showed that the human KLHL3 W470X mutation resulted in increased KLHL3 protein stability and disrupted its binding affinity for WNK1/4, leading to the attenuated degradation and increased abundance of total WNKs. In conclusion, nonsense Klhl3W523X/+ mice recapitulating PHAII phenotypes exhibit Klhl3 protein stability, abrogating its binding to Wnks, with enhanced Ncc expression in the kidney tissue and even in uEVs. Activation of the WNK-mediated Na+ -Cl- co-transporter reiterated the in vivo pathogenic role of nonsense KLHL3 mutations in PHAII.

An enigma of hypothyroidism and hyponatremia coexistence: a nationwide population-based retrospective study.

INTRODUCTION: Hypothyroidism is a rare and possible cause of hyponatremia. However, the clinical epidemiology and risk of mortality (ROM) when they coexist still remain elusive. OBJECTIVES: We assessed the epidemiology and ROM among index patients with coexisting hypothyroidism and hyponatremia via a national population database. PATIENTS AND METHODS: This retrospective cohort study utilized Taiwan's National Health Insurance program database. Distributions of definite sociodemographic factors were analyzed. The annual incidence among the overall group and sex-subgroups was investigated. In addition, potential factors influencing the ROM were also evaluated. RESULTS: Of 4,549,226 patients from 1998 to 2015, a total of 3,140 index patients with concurrent hypothyroidism and hyponatremia were analyzed. The incidence rate increased tenfold from 1998 to 2015; average annual incidence rate was 174. Among the total participants, 57.1% were women; mean age was 72.6 ± 14.7 years and 88.8% were aged > 55 years. Although average length of stay (LOS) was 13.1 ± 15.4 days, the mortality group had significantly longer LOS than that in the survival group (12.9 days vs 22.2 days). Old age, catastrophic illness, cardiac dysrhythmia, and low hospital hierarchy were independent predictors of hospital mortality. The optimal LOS cutoff value for ROM prediction was 16 days. Index patients with LOS > 16 days increased ROM by 2.3-fold. CONCLUSIONS: Coexistent hypothyroidism and hyponatremia is rare, although the incidence increased gradually. Factors influencing the ROM, such as old age, underlying catastrophic status, cardiac dysrhythmia, hospital hierarchy, and LOS should be considered in clinical care.

LncRNA HOTAIR impairs the prognosis of papillary thyroid cancer via regulating cellular malignancy and epigenetically suppressing DLX1.

PURPOSE: Papillary thyroid cancer (PTC) is the most common endocrine malignancy with a fast-growing incidence in recent decades. HOTAIR as a long non-coding RNA has been shown to be highly expressed in papillary thyroid cancer tissues with only a limited understanding of its functional roles and downstream regulatory mechanisms in papillary thyroid cancer cells. METHODS: We applied three thyroid cancer cell lines (MDA-T32, MDA-T41 and K1) to investigate the phenotypic influence after gain or loss of HOTAIR. The Cancer Genome Atlas (TCGA) database were utilised to select candidate genes possibly regulated by HOTAIR with validation in the cellular system and immunohistochemical (IHC) staining of PTC tissues. RESULTS: We observed HOTAIR was highly expressed in MDA-T32 cells but presents significantly decreased levels in MDA-T41 and K1 cells. HOTAIR knockdown in MDA-T32 cells significantly suppressed proliferation, colony formation, migration with cell cycle retardation at G1 phase. On the contrary, HOTAIR overexpression in MDA-T41 cells dramatically enhanced proliferation, colony formation, migration with cell cycle driven toward S and G2/M phases. Similar phenotypic effects were also observed as overexpressing HOTAIR in K1 cells. To explore novel HOTAIR downstream mechanisms, we analyzed TCGA transcriptome in PTC tissues and found DLX1 negatively correlated to HOTAIR, and its lower expression associated with reduced progression free survival. We further validated DLX1 gene was epigenetically suppressed by HOTAIR via performing chromatin immunoprecipitation. Moreover, IHC staining shows a significantly stepwise decrease of DLX1 protein from normal thyroid tissues to stage III PTC tissues. CONCLUSIONS: Our study pointed out that HOTAIR is a key regulator of cellular malignancy and its epigenetic suppression on DLX1 serves as a novel biomarker to evaluate the PTC disease progression.

Ovarian steroid cell tumor causing isosexual pseudoprecocious puberty in a young girl: an instructive case and literature review.

BACKGROUND: Steroid cell tumors (SCTs) are very rare sex cord-stromal tumors and account only for less than 0.1% of ovarian neoplasms. SCTs might comprise diverse steroid-secreting cells; hence, the characteristic clinical features were affected by their propensity to secrete a variety of hormones rather than mass effect resulting in compression symptoms and signs. To date, ovarian SCTs have seldom been reported in children, particularly very young children; and pseudoprecocious puberty (PPP) as its unique principal manifestation should be reiterated. CASE PRESENTATION: We reported a 1-year-8-month-old girl presenting with rapid bilateral breast and pubic hair development within a 2-month period. Undetectable levels of LH and FSH along with excessively high estradiol after stimulation with gonadotropin-releasing hormone (GnRH), as well as a heterogeneous mass inside left ovary shown in pelvic sonography indicate isosexual PPP. Her gonadal hormones returned remarkably to the prepubertal range the day after surgery, and histology of the ovary mass demonstrated SCTs containing abundant luteinized stromal cells. CONCLUSION: The case highlighted that SCTs causing isosexual PPP should be taken into consideration in any young children coexistent with rapidly progressive puberty given a remarkable secretion of sex hormones. This article also reviewed thoroughly relevant reported cases to enrich the clinical experience of SCTs in the pediatric group.

Stress hyperglycemia as first sign of asymptomatic type 1 diabetes: an instructive case.

BACKGROUND: Stress hyperglycemia (SH) is considered a transient manifestation and routine diagnostic evaluation was thought to be unnecessary due to the lack of definite correlation with diabetes mellitus (DM). Although SH was usually benign and long-term treatment was superfluous, it might be the first sign of insulinopenic status such as type 1 DM (T1DM). CASE PRESENTATION: We reported a boy with acute asthma attack presented incidentally with high blood glucose levels exceeding 300 mg/dL and obvious glycemic variability. A prolonged hyperglycemic duration of more than 48 h was also noticed. To elucidate his unique situation, glucagon test and insulin autoantibody survey were done which showed insulinopenia with positive anti-insulin antibody and glutamic acid decarboxylase antibody despite the absence of overt DM symptoms and signs. CONCLUSIONS: This case highlights that SH might be a prodromal presentation in T1DM children, especially when accompanied simultaneously with extreme hyperglycemia, apparent glucose variability, as well as prolonged hyperglycemic duration.

Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain.

The Kelch-like 3 ( KLHL3) mutations contributed to the most common causative genes in patients with pseudohypoaldosteronism type II (PHAII); however, the molecular mechanisms of PHAII-causing mutations in BTB domain of KLHL3 in vivo have not been investigated. We generated and analyzed Klhl3 knock-in (KI) mice carrying a missense M131V mutation in the BTB domain (corresponding to human KLHL3 M78V mutation). Klhl3M131V/+ KI mice exhibited typical PHAII phenotype with an exaggerated diuretic response to hydrochlorothiazide. Their kidney tissues showed an unchanged KLHL3, decreased cullin 3 (Cul3), and increased with-no-lysine kinases (WNKs) WNK1 and WNK4 along with an enhanced downstream ste20-related proline/alanine-rich kinase/oxidative stress response kinase 1-N(K)CC phosphorylation. Their Cul3 protein in the cytosol of distal convoluted tubule cells was also significantly attenuated on immunogold-labeling electron microscopy. In microdissected renal tubules, Klhl3M131V/+ KI mice expressed high levels of Wnk4 mRNA in the distal nephron. In vitro coimmunoprecipitation showed the KLHL3 BTB domain mutation retained intact interaction with WNKs but reduced binding to Cul3, thus leading to the increased abundance of total WNKs. In summary, Klhl3M131V/+ KI mice feature typical PHAII with a simultaneous increase of WNK1 and WNK4 through the impaired KLHL3 BTB domain binding to Cul3.-Lin, C.-M., Cheng, C.-J., Yang, S.-S., Tseng, M.-H., Yen, M.-T., Sung, C.-C., Lin, S.-H. Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain.

Cilostazol inhibits hyperglucose-induced vascular smooth muscle cell dysfunction by modulating the RAGE/ERK/NF-κB signaling pathways.

BACKGROUND: Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction. OBJECTIVES: In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. METHOD: We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected. RESULTS: Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture. CONCLUSIONS: Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.

Potential effects of valproate and oxcarbazepine on growth velocity and bone metabolism in epileptic children- a medical center experience.

BACKGROUND: Children with longstanding use of antiepileptic drugs (AEDs) are susceptible to developing low bone mineral density and an increased fracture risk. However, the literature regarding the effects of AEDs on growth in epileptic children is limited. The aim of this study was to investigate the potential effects of valproate (VPA) and/or oxcarbazepine (OXC) therapy on growth velocity and bone metabolism. METHODS: Seventy-three ambulatory children (40 boys and 33 girls) with epilepsy, aged between 1 and 18 years (mean age 9.8 ± 4.1 years), were evaluated for growth velocity before and for 1 year after VPA and/or OXC treatment. The bone resorption marker serum tartrate-resistant acid phosphatase 5b (TRAcP5b) and the bone formation marker serum bone-specific alkaline phosphatase (BAP) were measured post-AEDs therapy for 1 year. RESULTS: The difference in growth velocity (ΔHt) and body weight change (ΔWt) between pre- and post-AEDs treatment were -1.0 ± 2.8 cm/year (P < 0.05) and 0.1 ± 3.9 kg/year (P = 0.84), respectively. The study population had serum TRAcP5b-SDS of -1.6 ± 1.2 and BAP-SDS of 1.7 ± 3.7 compared with sex- and age-matched healthy children. Significant correlation between serum TRAcP 5b and BAP activities was noted (r = 0.60, p < 0.001). There was a positive correlation between growth velocity and serum TRAcP 5b activity after AED treatment (r = 0.42, p < 0.01). No correlation was found between ΔHt, ΔWt, serum TRAcP 5b, BAP activity and types of AEDs. CONCLUSION: Growth velocity was significantly decreased in epileptic children after 1 year of VPA and/or OXC treatment. The effect of VPA and/or OXC therapy on dysregulation of bone metabolism might play a crucial role in physical growth.

Endocrine dysfunction in Taiwanese children with human chorionic gonadotropin-secreting germ cell tumors.

BACKGROUND/PURPOSE: Human chorionic gonadotropin (HCG)-secreting germ cell tumors (GCTs) are rare childhood malignancies with unique clinical manifestations but delayed diagnosis is common. The purpose of this study is to investigate the clinical manifestations and endocrine dysfunction of Taiwanese children with HCG-secreting GCTs. METHODS: From 1991 to 2011, 24 children (19 boys and five girls) with HCG-secreting GCTs were evaluated for their clinical findings and endocrine functions. RESULTS: The mean age at diagnosis of the study patients was 10.8 ± 3.1 years. Of the 24 patients, 20 had central nervous system (CNS) GCTs and four had primary mediastinal GCTs (PMGCTs). The most common pathologic findings were germinomas and mixed type GCTs. The common initial symptoms and signs included polyuria, polydipsia, rapid growth, neurologic deficit,sexual precocity, and growth retardation. There was a delay in diagnosis in about 60% of patients. Diabetes insipidus and hypopituitarism were common endocrine dysfunctions in patients with CNSGCTs. Twelve boys had gonadotropin-independent puberty upon diagnosis, which were related to their high serum ß-hCG levels. None of the five girls had this disorder despite their high serum ß-hCG levels. Three of the four PMGCTs patients had the classic form of Klinefelter syndrome. CONCLUSION: Taiwanese children with HCG-secreting GCTs often have clinical manifestations related to endocrine dysfunction. High index of suspicion is important to avoid delayed diagnosis in these children.

Adrenal insufficiency following cerebellar intracranial hemorrhage: a case report.

This report presents a case of a previously healthy 58 years-old man who had suffered from persistent weakness and dizziness after a cerebellar intracranial hemorrhage (ICH). Endocrine function tests revealed low levels of plasma cortisol (3.05 µg/dL; normal range: 5-25 µg/dL) and adrenocorticotropic hormone (ACTH) (6.0 pg/mL; normal range: 10-60 pg/mL). The subsequent ACTH stimulation test suggested partial or recent hypopituitarism, resulting in adrenal gland atrophy and a subnormal cortisol response. Ultimately, the dizziness was found to be caused by undiagnosed adrenal insufficiency, which was detected when a hypotensive fainting incident occurred during rehabilitation. The symptoms improved significantly with oral prednisone supplementation. Notably, the duration of impaired hypothalamic-pituitary-adrenal axis may last as long as a year. This case highlights that adrenal insufficiency can easily be overlooked since its symptoms are similar to those commonly seen with cerebellar stroke alone. Physicians must be aware of the symptoms of adrenal insufficiency in patients with brain insults and conduct the appropriate endocrine tests to clarify the underlying comorbidity.

Impact of intravenous dexmedetomidine on postoperative gastrointestinal function recovery: an updated meta-analysis.

BACKGROUND: Postoperative ileus (POI) is a complication that may occur after abdominal or nonabdominal surgery. Intravenous dexmedetomidine (Dex) has been reported to accelerate postoperative gastrointestinal function recovery; however, updated evidence is required to confirm its robustness. METHODS: To identify randomized controlled trials examining the effects of perioperative intravenous Dex on gastrointestinal function recovery in patients undergoing noncardiac surgery, databases including MEDLINE, EMBASE, Google Scholar, and Cochrane Library were searched on August 2023. The primary outcome was time to first flatus. Secondary outcomes included time to oral intake and defecation as well as postoperative pain scores, postoperative nausea/vomiting (PONV), risk of hemodynamic instability, and length of hospital stay (LOS). To confirm its robustness, subgroup analyses and trial sequential analysis were performed. RESULTS: The meta-analysis of 22 randomized controlled trials with 2566 patients showed that Dex significantly reduced the time to flatus [mean difference (MD):-7.19 h, P <0.00001), time to oral intake (MD: -6.44 h, P =0.001), time to defecation (MD:-13.84 h, P =0.008), LOS (MD:-1.08 days, P <0.0001), and PONV risk (risk ratio: 0.61, P <0.00001) without differences in hemodynamic stability and pain severity compared with the control group. Trial sequential analysis supported sufficient evidence favoring Dex for accelerating bowel function. Subgroup analyses confirmed the positive impact of Dex on the time to flatus across different surgical categories and sexes. However, this benefit has not been observed in studies conducted in regions outside China. CONCLUSIONS: Perioperative intravenous Dex may enhance postoperative gastrointestinal function recovery and reduce LOS, thereby validating its use in patients for whom postoperative ileus is a significant concern.

Efficacy of electroacupuncture in improving postoperative ileus in patients receiving colorectal surgery: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis aimed to evaluate the efficacy and safety of electroacupuncture (EA) in improving postoperative ileus after colorectal surgery. METHODS: Electronic databases (e.g. Medline) were screened to identify randomized controlled trials that focused on the association between EA and postoperative ileus. Time to first flatus served as the primary outcome, while the secondary outcomes included time required for the recovery of other gastrointestinal functions (e.g. bowel sound recovery), time to tolerability of liquid/solid food, postoperative pain scores, risk of overall complications, and hospital length of stay. RESULTS: Our meta-analysis focusing on 16 studies with a total of 1562 patients demonstrated positive associations of EA with shorter times to the first flatus [mean difference (MD): -10.1 h, P <0.00001, n =1562], first defecation (MD: -11.77 h, P <0.00001, n =1231), bowel sound recovery (MD: -10.76 h, P <0.00001, n =670), tolerability of liquid (MD: -16.44 h, P =0.0002, n =243), and solid food (MD: -17.21 h, P =0.005, n =582) than those who received standard care. The use of EA was also correlated with a lower risk of overall complications (risk ratio:0.71, P =0.04, n =1011), shorter hospital length of stay (MD: -1.22 days, P =0.0001, n =988), and a lower pain score on postoperative days two (standardized MD: -0.87, P =0.009, n =665) and three (standardized MD: -0.45, P <0.00001, n =795), without a difference in time to first ambulation. CONCLUSION: Our findings showed an association between EA and enhanced gastrointestinal functional recovery and reduced pain severity following colorectal surgery, highlighting the potential benefits of incorporating EA into perioperative care to enhance recovery outcomes in this setting.

Recalcitrant intussusception: exploring potential associations with Helicobacter pylori infection - a case report and literature review.

BACKGROUND: Intussusception, a common cause of abdominal pain in children, often lacks clear underlying causes and is mostly idiopathic. Recurrence, though rare, raises clinical concerns, with rates escalating after each episode. Factors like pathological lead points and Henoch-Schönlein purpura (HSP) are associated with recurrent cases. On the other hand, the prevalence of Helicobacter pylori (H. pylori), often asymptomatic, in children has been declining. Although its infection is reported to be linked with HSP, its role in recurrent intussusception remains unexplored. Further research is needed to understand the interplay among H. pylori (culprit pathogen), HSP (trigger), and intractable intussusception so as to develop effective management strategies. CASE PRESENTATION: A two-year-old girl experienced four atypical episodes of intussusception at distinct locations, which later coincided with HSP. Despite treatment with steroids, recurrent intussusception persisted, suggesting that HSP itself was not a major cause for intractable presentations. Subsequent identification of H. pylori infection and treatment with triple therapy resulted in complete resolution of her recalcitrant intussusception. CONCLUSION: This instructive case underscored a sequence wherein H. pylori infection triggered HSP, subsequently resulting in recurrent intussusception. While H. pylori infection is not common in young children, the coexistence of intractable intussusception and steroid-resistant recurrent HSP necessitates consideration of H. pylori infection as a potential underlying pathogen.

Association between systemic sclerosis and risk of cerebrovascular and cardiovascular disease: a meta-analysis.

We aimed to evaluate the association between systemic sclerosis (SSc) and major cerebrovascular/cardiovascular risks through a systematic approach. Databases were systematically searched from their inception to October 10, 2023 for studies comparing cerebrovascular/cardiovascular event rates between patients with SSc and controls. The primary outcome was the stroke risk in patients with SSc. Secondary outcomes included risk of myocardial infarction (MI), cardiovascular disease (CVD), peripheral vascular disease (PVD), and venous thromboembolism (VTE). Seventeen studies with 6,642,297 participants were included. SSc was associated with a significantly increased risk of stroke (HR, 1.64; 95% confidence interval [CI], 1.35-2.01), CVD (HR, 2.12; 95% CI, 1.36-3.3), MI (HR, 2.15; 95% CI, 1.23-3.77), VTE (HR, 2.75; 95% CI, 1.77-4.28), and PVD (HR, 5.23; 95% CI, 4.25-6.45). Subgroup analysis revealed a significantly increased stroke risk in the non-Asian group (HR, 1.55; 95% CI, 1.26-1.9), while the Asian group displayed a higher but not statistically significant risk (HR, 1.86; 95% CI, 0.97-3.55). The study found that SSc is associated with a significantly increased risk of cerebrovascular/cardiovascular events. These findings highlight the importance of vasculopathy in SSc and suggest the need for enhanced clinical monitoring and preventive measures in this high-risk population.

Efficacy and safety of herbal medicine combined with acupuncture in pediatric epilepsy treatment: A meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of herbal medicine and acupuncture combination for pediatric epilepsy treatment. METHODS: Databases were searched from their interception until October 2023 to identify randomized controlled trials focusing on the therapeutic efficacy of herbal medicine-acupuncture combination (intervention group) for pediatric epilepsy. The primary outcome was the risk of treatment failure, whereas the secondary outcomes included the risk of post-treatment electroencephalogram (EEG) abnormalities and adverse events. Subgroup analyses were conducted based on the type of herbal compound formulas. Meta-regression analysis was conducted to examine the influence of patient demographics and clinical history on the therapeutic efficacy of herbal medicine-acupuncture combination for pediatric epilepsy. To assess the cumulative evidence, trial sequential analysis (TSA) was performed. RESULTS: The analysis included 10 trials involving a total of 882 pediatric patients. Meta-analysis revealed that the intervention group had a lower risk of treatment failure than the control group (risk ratio [RR] = 0.3, 95% confidence interval [CI]: 0.19-0.47, P<0.00001, I2 = 0%, 10 trials). Subgroup analyses showed that therapeutic efficacy was consistent among the different herbal compound formulas. Meta-regression analysis revealed that the efficacy of the treatments did not significantly vary with patient age, male sex, and duration of seizure history. TSA suggested that herbal medicine-acupuncture combination exerted a robust and conclusive effect on seizure treatment. Although the combined used of herbal medicine and acupuncture was not associated with a lower risk of post-treatment EEG abnormalities (RR = 0.82, 95%CI:0.6-1.11, P = 0.2, 3 trials), the risk of adverse events was reduced (RR = 0.27, 95%CI:0.18-0.41, P<0.00001, 4 trials). CONCLUSION: The meta-analysis suggested that combined use of herbal medicine and acupuncture is a promising and safe clinical approach for pediatric epilepsy treatment. Further large-scale studies are necessary to conclusively determine the efficacy and safety of herbal medicine and acupuncture in pediatric epilepsy treatment.

Identification and characterization of a novel CASR mutation causing familial hypocalciuric hypercalcemia.

Context: Although a monoallelic mutation in the calcium-sensing receptor (CASR) gene causes familial hypocalciuric hypercalcemia (FHH), the functional characterization of the identified CASR mutation linked to the clinical response to calcimimetics therapy is still limited. Objective: A 45-year-old male presenting with moderate hypercalcemia, hypocalciuria, and inappropriately high parathyroid hormone (PTH) had a good response to cinacalcet (total serum calcium (Ca2+) from 12.5 to 10.1 mg/dl). We identified the genetic mutation and characterized the functional and pathophysiological mechanisms, and then linked the mutation to calcimimetics treatment in vitro. Design: Sanger sequencing of the CASR, GNA11, and AP2S1 genes was performed in his family. The simulation model was used to predict the function of the identified mutant. In vitro studies, including immunoblotting, immunofluorescence, a cycloheximide chase study, Calbryte™ 520 Ca2+ detection, and half-maximal effective concentration (EC50), were examined. Results: This proband was found to carry a de novo heterozygous missense I554N in the cysteine-rich domain of CASR, which was pathogenic based on the different software prediction models and ACGME criteria. The simulation model showed that CASR I554N mutation decreased its binding energy with Ca2+. Human CASR I554N mutation attenuated the stability of CASR protein, reduced the expression of p-ERK 1/2, and blunted the intracellular Ca2+ response to gradient extracellular Ca2+ (eCa2+) concentration. The EC50 study also demonstrated the correctable effect of calcimimetics on the function of the CASR I554N mutation. Conclusion: This novel CASR I554N mutation causing FHH attenuates CASR stability, its binding affinity with Ca2+, and the response to eCa2+ corrected by therapeutic calcimimetics.

Impact of the geriatric nutritional risk index on long-term outcomes in patients undergoing hemodialysis: a meta-analysis of observational studies.

Background: This meta-analysis aimed to synthesize current evidence on the association between the Geriatric Nutritional Risk Index (GNRI) and long-term outcomes in patients undergoing hemodialysis. Methods: Electronic databases were systematically searched for relevant studies that investigated the association between GNRI and long-term outcomes in hemodialysis patients until November 2023. The primary outcome was the association between the GNRI (i.e., low versus high) and overall mortality risk, while the secondary outcome was the relationship between the GNRI and cardiovascular mortality risk. Results: Thirty cohort studies involving 55,864 patients were included. A low GNRI was found to be significantly associated with increased overall mortality (hazard ratio [HR]: 2.42, 95% confidence interval [CIs]: 2.10-2.79, p < 0.00001, I2 = 65%). Each unit increase in GNRI corresponded to a 5% reduction in mortality risk (HR: 0.95, 95% CI: 0.93-0.96, p < 0.00001, I2 = 79%). The association remained consistent across Asian (HR = 2.45, 95% CI: 2.08-2.88, p < 0.00001, I2 = 70%) and non-Asian subgroups (HR = 2.3, 95% CI: 1.72-3.06, p < 0.00001, I2 = 23%). Meta-regression analysis of patient age (coefficient: -0.002; p = 0.896), male proportion (coefficient: 0.002; p = 0.875), percentage of diabetes mellitus (coefficient: -0.003; p = 0.605), and follow-up duration (coefficient: -0.003; p = 0.431) revealed that these moderator variables did not significantly influence the association between GNRI and overall mortality risk. Cardiovascular mortality risk also increased with low GNRI (HR, 1.93; 95%CI: 1.51-2.45, p < 0.00001; I2 = 2%). Similarly, an inverse association was observed between the GNRI values and cardiovascular mortality risk (HR, 0.94; 95% CI: 0.91-0.97; p < 0.0001; I2 = 65%) (per unit increase). Conclusion: The GNRI is a simple nutritional screening tool that can be used to effectively stratify patients undergoing hemodialysis globally. Further studies are warranted to determine whether nutrition optimization based on the GNRI improves long-term outcomes. Systematic review registration: https://www.crd.york.ac.uk/prospero/, CRD42023483729.

New dimension on potential factors of successful pediatric peripheral intravenous catheterization.

BACKGROUND: Peripheral intravenous catheterization (PIVC) is pivotal to pediatric medical care; however, it is a challenging technique for pediatricians, and the parameters affecting successful pediatric PIVC establishment have not been fully investigated. METHODS: This prospective observational study collected data from pediatric patients aged less than 18 years who required PIVC. The participants were categorized into five groups for subgroup analysis: newborn, infant, toddler, pre-school, and student (children and adolescent). Data on demography, biochemistry, and PIVC executors were examined to elucidate the most powerful factors affecting the success of PIVC. RESULTS: A total of 935 peripheral venous cannulations conducted within 1 year were studied. Age-subgroup analysis showed the highest failure rate (FR) of PIVC in the infant group (18.4%). No significant difference in BMI standard deviation score was noted among the groups (p-value = 0.430). Compared with those for the success group, more attempts, longer completion time, and more medical staff were needed for the failure group (all p-values < 0.05). A high serum procalcitonin level was correlated with an increased FR (p-value = 0.016). In addition, the success rate was positively associated with the seniority of the operators, except for the 3-year experienced R3 group (93.5%) showing a higher success rate than the 4-year experienced CR group (84.2%). CONCLUSIONS: Difficulty in setting up PIVC was the greatest in infants and even greater than that in newborns. Even though seniority was a cardinal factor in successful PIVC, a high FR was still noted despite the lack of continuous and steady practice.

The use of remimazolam versus propofol for induction and maintenance of general anesthesia: A systematic review and meta-analysis.

Background: The primary objective of this study was to compare the risk of hypotension, as well as the induction and recovery characteristics between remimazolam and propofol in patients receiving surgery under general anesthesia. Methods: The Embase, Medline, Google scholar, and the Cochrane Library databases were searched from inception to March 2022 for randomized controlled trials The primary outcome was the risk of post-induction hypotension between the two agents, while the secondary outcomes included anesthetic depth, induction efficacy, time to loss of consciousness (LOC), hemodynamic profiles, time to eye opening, extubation time as well as the incidence of injection pain and postoperative nausea/vomiting (PONV). Results: Meta-analysis of eight studies published from 2020 to 2022 involving 738 patients revealed a significantly lower risk of post-induction hypotension with the use of remimazolam compared to that with propofol [risk ratio (RR) = 0.57, 95% confidence interval (CI): 0.43 to 0.75, p < 0.0001, I2 = 12%, five studies, 564 patients]. After anesthetic induction, the anesthetic depth measured by bispectral index (BIS) was lighter in the remimazolam group than that in the propofol group (MD = 9.26, 95% confidence interval: 3.06 to 15.47, p = 0.003, I2 = 94%, five studies, 490 patients). The time to loss of consciousness was also longer in the former compared to the latter (MD = 15.49 s, 95%CI: 6.53 to 24.46, p = 0.0007, I2 = 61%, three studies, 331 patients). However, the use of remimazolam correlated with a lower risk of injection pain (RR = 0.03, 95%CI: 0.01 to 0.16, p < 0.0001, I2 = 0%, three studies, 407 patients) despite comparable efficacy of anesthetic induction (RR = 0.98, 95%CI: 0.9 to 1.06, p = 0.57, I2 = 76%, two studies, 319 patients). Our results demonstrated no difference in time to eye opening, extubation time, and risk of PONV between the two groups. Conclusion: Remimazolam was associated with a lower risk of post-induction hypotension after anesthetic induction compared with propofol with similar recovery characteristics. Further studies are required to support our findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/; Identifier: CRD42022320658.