Prevalence, diagnostic utility, and clinical characteristics of ZnT8 antibody in children with type 1 diabetes in Northern Taiwan.

BACKGROUND: The ZnT8 autoantibody is used to independently diagnose type 1 diabetes (T1D) and as a prediction factor in high-risk populations. This is the first report in Taiwan on the prevalence, diagnostic utility, and clinical characteristics of zinc transporter 8 autoantibody (ZnT8A) in children with T1D. METHODS: We performed a retrospective analysis of 268 children (130 boys, 138 girls) newly diagnosed with T1D at three hospitals in North Taiwan from February 1994 to August 2021. RESULTS: ZnT8A was detected in 117 patients (43.7 %). The combined diagnostic rate of the four antibodies, including glutamic acid decarboxylase autoantibody (GADA), islet antigen 2 autoantibody (IA2A), insulin autoantibody (IAA), and ZnT8A, can reach 86.19 % while that of the original three antibodies is 84.3 %. IA2A (64.9 %) showed the highest positive rate, followed by GADA (64.2 %), ZnT8A (43.7 %), and IAA (22.0 %). Of the 268 patients, five (1.9 %) were only ZnT8A+. All antibodies were positive in 19 (7.1 %) people, whereas 37 others (13.8 %) had all antibodies negative. ZnT8A has the strongest relationship with IA2A. 5 patients had ZnT8A positive only. 5/(37 + 5) (about 12 %) T1D patients were diagnosed by ZnT8A testing. CONCLUSIONS: ZnT8A testing can diagnose up to 12 % more patients with T1D along with three other antibodies. Furthermore, since the ZnT8A titer decreased over time, it should be tested within six months of onset in Taiwanese patients with T1D.

Influencing factors for treatment escalation from metformin monotherapy in youth-onset type 2 diabetes in Northern Taiwan.

With the increasing prevalence of obesity, childhood type 2 diabetes (T2D) is a growing concern in Taiwan. Unlike its adult counterpart, T2D in children exhibits a more aggressive nature and earlier onset of complications. Metformin represents the first line of drug, but if blood sugar levels do not improve, other drugs are used. This retrospective cohort study endeavors to scrutinize and assess the pattern of treatment modification and associate factors among 79 young people with T2D in Taiwan. The study categorized participants into three distinct groups based on their treatment trajectory and outcomes: (1) those maintaining metformin (n = 34); (2) cases achieving remission (n = 7); and (3) individuals experiencing escalation through oral drugs or insulin (n = 38). The average follow-up period spanned 3.48 years. Findings from univariate analysis using a Cox proportional hazards model and propensity score weighting revealed that HbA1c and weight gain correlated with elevated risk of treatment escalation. Conversely, factors such as hypertension, high weight or body mass index (BMI) SDS, leptin levels, c-peptide concentrations, peak c-peptide values during glucagon stimulation test and LDL-cholesterol levels were associated with reduced risk of escalation. However, in multivariate analyses employing stepwise selection, the sole predictive factor for treatment escalation emerged as weight gain one year post-therapy (HR: 1.06, p < 0.001). This study underscores the interconnectedness between weight management and the trajectory toward either treatment escalation or disease remission. Furthermore, it highlights the cost-effective potential of intervening in younger populations. Ultimately, these insights accentuate the considerable opportunity for enhancing health care management strategies concerning pediatric T2D in Taiwan.

Spectrum of PHEX Mutations and FGF23 Profiles in a Taiwanese Cohort With X-Linked Hypophosphatemia Including 102 Patients.

BACKGROUND/AIM: X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, results from loss-of-function mutations in the phosphate-regulating PHEX gene. Elevated fibroblast growth factor 23 (FGF23) contributes to hypophosphatemia in XLH. This study aimed to characterize PHEX variants and serum FGF23 profiles in Taiwanese patients with XLH. PATIENTS AND METHODS: We retrospectively reviewed the records of 102 patients clinically suspected of having hypophosphatemic rickets from 2006 to 2022. Serum intact Fibroblast growth factor-23 (iFGF23) levels were measured on clinic visit days. PHEX mutations were identified using Sanger sequencing, and negative cases were analyzed using whole-exome sequencing. RESULTS: The majority (92.1%) of patients exhibited elevated FGF23 compared with normal individuals. Among 102 patients, 44 distinct PHEX mutations were identified. Several mutations recurred in multiple unrelated Taiwanese families. We discovered a high frequency of novel PHEX mutations and identified variants associated with extreme FGF23 elevation and tumorigenesis. CONCLUSION: Our findings revealed the PHEX genotypic variants and FGF23 levels in Taiwanese patients with XLH. These results are crucial given the recent approval of burosumab, a monoclonal FGF23 antibody, for XLH therapy. This study provides key insights into the clinical management of XLH in Taiwan.

Recoverable Palladium-Catalyzed Carbon-Carbon Bond Forming Reactions under Thermomorphic Mode: Stille and Suzuki-Miyaura Reactions.

The reaction of [PdCl2(CH3CN)2] and bis-4,4'-(RfCH2OCH2)-2,2'-bpy (1a-d), where Rf = n-C11F23 (a), n-C10F21 (b), n-C9F19 (c) and n-C8F17 (d), respectively, in the presence of dichloromethane (CH2Cl2) resulted in the synthesis of Pd complex, [PdCl2[4,4'-bis-(RfCH2OCH2)-2,2'-bpy] (2a-d). The Pd-catalyzed Stille arylations of vinyl tributyltin with aryl halides were selected to demonstrate the feasibility of recycling usage with 2a as the catalyst using NMP (N-methyl-2-pyrrolidone) as the solvent at 120-150 °C. Additionally, recycling and electronic effect studies of 2a-c were also carried out for Suzuki-Miyaura reaction of phenylboronic acid derivatives, 4-X-C6H4-B(OH)2, (X = H or Ph) with aryl halide, 4-Y-C6H4-Z, (Y = CN, H or OCH3; Z = I or Br) in dimethylformamide (DMF) at 135-150 °C. At the end of each cycle, the product mixtures were cooled to lower temperature (e.g., -10 °C), and then catalysts were recovered by decantation with Pd leaching less than 1%. The products were quantified by gas chromatography/mass spectrometry (GC/MS) analysis or by the isolated yield. The complex 2a-catalyzed Stille reaction of aryl iodides with vinyl tributyltin have good recycling results for a total of 8 times, with a high yield within short period of time (1-3 h). Similarly, 2a-c-catalyzed Suzuki-Miyaura reactions also have good recycling results. The electronic effect studies from substituents in both Stille and Suzuki-Miyaura coupling reactions showed that electron withdrawing groups speed up the reaction rate. To our knowledge, this is the first example of recoverable fluorous long-chained Pd-catalyzed Stille reactions under the thermomorphic mode.

Recoverable Phospha-Michael Additions Catalyzed by a 4-N,N-Dimethylaminopyridinium Saccharinate Salt or a Fluorous Long-Chained Pyridine: Two Types of Reusable Base Catalysts.

Phospha-Michael addition, which is the addition reaction of a phosphorus-based nucleophile to an acceptor-substituted unsaturated bond, certainly represents one of the most versatile and powerful tools for the formation of P-C bonds, since many different electrophiles and P nucleophiles can be combined with each other. This offers the possibility to access many diversely functionalized products. In this work, two kinds of basic pyridine-based organo-catalysts were used to efficiently catalyze phospha-Michael addition reactions, the 4-N,N-dimethylaminopyridinium saccharinate (DMAP·Hsac) salt and a fluorous long-chained pyridine (4-Rf-CH2OCH2-py, where Rf = C11F23). These catalysts have been synthesized and characterized by Lu's group. The phospha-Michael addition of diisopropyl, dimethyl or triethyl phosphites to α, ß-unsaturated malonates in the presence of those catalysts showed very good reactivity with high yield at 80-100 °C in 1-4.5 h with high catalytic recovery and reusability. With regard to significant catalytic recovery, sometimes more than eight cycles were observed for DMAP·Hsac adduct by using non-polar solvents (e.g., ether) to precipitate out the catalyst. In the case of the fluorous long-chained pyridine, the thermomorphic method was used to efficiently recover the catalyst for eight cycles in all the reactions. Thus, the easy separation of the catalysts from the products revealed the outstanding efficacy of our systems. To our knowledge, these are good examples of the application of recoverable organo-catalysts to the DMAP·Hsac adduct by using non-polar solvent and a fluorous long-chained pyridine under the thermomorphic mode in phospha-Michael addition reactions.

Short-Chained Platinum Complex Catalyzed Hydrosilylation under Thermomorphic Conditions: Heterogeneous Phase Separation at Ice Temperature.

Homogeneous catalysts PtCl2[5,5'-bis-(n-ClCF2(CF2)3CH2OCH2)-2,2'-bpy] (2A) and PtCl2[5,5'-bis-(n-HCF2(CF2)3CH2OCH2)-2,2'-bpy] (2B), which contained short fluorous chains, were synthesized and used in catalysis of hydrosilylation of alkynes. In these reactions the thermomorphic mode was effectively used to recover these catalysts from the reaction mixture up to eight cycles by taking advantage of heterogeneous phase separation at ice temperature. This kind of catalysis had previously been observed in fluorous catalysts of platinum containing about 50% F-content, but in this work the percentage of F-content is decreased to only about 30%, by which we termed them as "very light fluorous". Our new type of catalyst with limited number of F-content is considered as the important discovery in the fluorous technology field as the reduced number of fluorine atoms will help to be able to comply the EPA 8-carbon rule. The metal leaching after the reaction has been examined by ICP-MS, and the testing results show the leaching of residual metal to be minimal. Additionally, comparing these results to our previous work, fluorous chain assisted selectivity has been observed when different fluorous chain lengths of the catalysts are used. It has been found that there exists fluorous chain assisted better selectivity towards ß-(E) form in the Pt-catalyzed hydrosilylation of non-symmetric terminal alkyne when the Pt catalyst contains short fluorous chain (i.e., 4 Cs). Phenyl acetylenes showed the opposite regioselectivity due to pi-pi interaction while using the same catalyst via Markovnikov's addition to form terminal vinyl silane, which is then a major product for Pt-catalyzed hydrosilylation of terminal aryl acetylene with triethylsilane. Finally, the kinetic studies indicate that the insertion of alkyne into the Pt-H bond is the rate-determining step.

Neurological and endocrinological manifestations of 49 children with intracranial pure germinoma at initial diagnosis in Taiwan.

BACKGROUND: Intracranial pure germinoma is a rare extragonadal neoplasm. Affected patients may have motor impairment, visual disturbance, neurological signs, and endocrine disorder, depending on the size and location of the tumor. This study investigated and analyzed patients' demographic data and neuroimaging, clinical, laboratory, and endocrinological findings. METHODS: We performed a retrospective chart review of 49 children diagnosed with pure germinoma in Taiwan from 1990 to 2018. The initial clinical presentation, tumor markers (beta-hCG, alpha fetoprotein, and carcinoembryonic antigen), pituitary function, and brain images were reviewed and analyzed. RESULTS: This study included 49 patients (37 boys and 12 girls). Their ages ranged from 7.5 to 17.9 years, and the mean age at diagnosis was 13.6 years. Initial symptoms included visual disturbance (n = 23, 47.9%), motor impairment (n = 20, 40.8%), polyuria (n = 20, 40.8%), headache (n = 17, 34.7%), dizziness or vertigo (n = 14, 28.6%), nausea/vomiting (n = 13, 26.5%), and short stature (n = 8, 18.2%). Laboratory data indicated growth hormone deficiency or low IGF-1 levels (n = 18, 85.7%), adrenal insufficiency (n = 21, 77.8%), central diabetes insipidus (n = 27, 55.1%), central hypothyroidism (n = 15, 48.4%), and hypogonadotropic hypogonadism (n = 4, 44.4%). CONCLUSION: Intracranial pure germinomas may initially manifest as neurological symptoms or endocrinological findings at diagnosis. As endocrinologic presentation is related to delayed diagnosis, clinicians should be aware of patients with such complaints. Laboratory data should be surveyed carefully, and neuroimaging must be considered if the result is abnormal.

Pathological and Incidental Findings in 403 Taiwanese Girls With Central Precocious Puberty at Initial Diagnosis.

Background: Whether girls with central precocious puberty (CPP) should undergo routine brain magnetic resonance imaging (MRI) to identify potential intracranial pathologies is controversial. Aims: To evaluate the brain MRI results of girls with CPP and identify the clinical and endocrine predictors of brain abnormalities. Methods: This retrospective study obtained data from pediatric endocrine clinics at Chang Gung Children's Hospital. From 1997 and 2017, 403 girls were consecutively diagnosed with CPP. After the exclusion of patients with a history of central nervous system (CNS) insults or associated neuropsychiatric symptom or signs, we studied the prevalence of brain abnormalities in 251 girls with CPP who received detailed MRI examinations of the hypothalamus and pituitary area. We also recorded the demographic data of the participants, including the onset of puberty; initial pubertal status; height; weight; uterus and ovary sizes; and basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol levels, and the response to GnRH stimulation test. Results: Among the 251 girls with CPP, we observed no brain alterations in 190 (75.70%), abnormalities in the hypothalamic-pituitary (H-P) area in 54 (21.51%), and abnormalities in the non-H-P area in 7 (2.79%). Among the 54 patients that had H-P lesions, we noted pathological findings related to CPP (hypothalamic hamartoma) in only one (0.4%) girl aged below 6 years old. We also identified incidental findings in the other girls with H-P lesions, including non-functioning pituitary microadenomas (12.35%), pituitary pars intermedia cysts (4.38%), Rathke's pouch cysts (1.99%), pituitary hypoplasia (1.59%), and pineal gland cysts (0.8%). The patients that had non-H-P lesions were found to have arachnoid cysts (1.59%), Chiari I malformation (0.4%), prepontine nodule (0.4%), and choroidal fissure cyst (0.4%). Of all the patients with brain lesions, 45 (73.77%) underwent regular MRI follow-up. While none of the H-P and non-H-P lesions showed progression, 19.67% of these regressed during the follow-up. None of the participants exhibited other hormonal abnormalities or underwent surgery. Conclusion: The prevalence of true pathological brain lesions related to CPP in girls without prior symptoms or signs of CNS lesions was low (0.4%). None of the girls with intracranial lesions required further intervention besides the GnRH agonist treatment. These data question the routine use of brain MRI in all girls with CPP, especially in those who are healthy without neurologic symptoms.

Nonketotic Hyperglycinemia of Infants in Taiwan.

BACKGROUND: Nonketotic hyperglycinemia (NKH) is a rare, inherited disease, with very poor outcome. It is difficult to confirm the diagnosis due to nonspecific presentations and rapid progression. The incidence was reported in a few countries. We report the clinical and genetic features of typical neonatal NKH with novel splicing mutation, c.1058+3A>C, in the intron 7 of the glycine decarboxylase (GLDC) gene. Furthermore, this study aimed to delineate the estimated incidence and clinical characteristics of NKH in the Taiwanese population. METHODS: Reports of Health Promotion Administration, Ministry of Health and Welfare of Taiwan, during the period from 2000 to 2013; the Human Gene Mutation Database; and literature regarding NKH in Taiwan were reviewed. Demographic information, age of onset, clinical characteristics, genetic analysis, electroencephalography examinations, and outcome of the patients were analyzed. RESULTS: The estimated incidence of NKH in the Taiwanese population was 7.2 cases per 1,000,000 live births. Among the 12 cases reported in Taiwan, more than 90% were of neonatal type. Fifty-five percent of affected patients died within 5 years, and all survivors had severe neurologic outcomes. Only three infants underwent genetic analysis during the study period. Two neonatal NKH infants had mutation in the GLDC gene, and the other one, who had late-onset NKH, had mutation in the glutaredoxin 5 gene. CONCLUSION: Compared with other countries, the estimated incidence of NKH was relatively rare in the Taiwanese population. It is important to characterize all index cases at the genetic level. With more awareness of NKH, increased knowledge of gene mutation, and improvement of diagnostic tools, NKH can be diagnosed more accurately.