Integrated transcriptomics and metabolomics analyses to investigate the anticancer mechanisms of cinobufagin against liver cancer through interfering with lipid, amino acid, carbohydrate, and nucleotide metabolism.

Liver cancer has characteristics of high morbidity, high mortality, and poor prognosis. Metabolic reprogramming is a prominent characteristic of tumors and plays a key role in promoting tumorigenesis. The metabolic process of liver cancer cells has undergone many significant changes including abnormal active glycolysis, enhanced de novo synthesis of fatty acids, and hyperactive metabolism of amino acids and nucleotides. Targeting metabolic reprogramming through regulation of anomalously expressed key metabolic enzymes and signaling molecules is considered to be an important strategy for liver cancer treatment. Multi-omics association analyses currently facilitate precise diagnosis, personalized clinical therapy, and revelation of mechanisms of drug action. Cinobufagin, as the major anti-tumor active ingredient of Chansu, the famous chinese medicine used in clinic for cancer treatment, has been reported to exert anticancer effects through many different kinds of mechanisms, but the effects of cinobufagin on metabolic reprogramming of cancer cells still remain unclear. In our study, we identify that cinobufagin exhibits anti-hepatoma effects through interfering with metabolic reprogramming (lipid, amino acid, carbohydrate, and nucleotide metabolism) based on integrated transcriptomics and metabolomics analyses. Furthermore, the results of integrated multi-omics analyses enrich various core regulatory mechanisms of anti-tumor effects of cinobufagin which are associated with metabolic pathway. In addition, some verifications of the enriched mechanisms related to intervention of lipid and carbohydrate metabolism in response to cinobufagin are also performed. This work will promote the innovation of the research model of TCM, and lay a solid theoretical foundation for the clinical application of cinobufagin and Chansu.

Effects of Fufang Banmao Capsule Associated with Sorafenib on Liver Function, Immune Status, Quality of Life Improvement, and Survival in Patients with Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study.

Objective: A case-control study was carried out to explore the influences of Fufang Banmao capsule (FBC) associated with sorafenib on liver function, immune status, life quality, and survival in patients with advanced hepatocellular carcinoma (HCC). Methods: During January 2019 to October 2021, in our hospital, the clinical data of 144 patients with advanced HCC treated were collected and measured retrospectively. The patients were cured with transcatheter arterial chemoembolization (TACE) in the control group, and the patients were cured with FBC associated with sorafenib in the observation group. The clinical effect, liver function index, humoral immunity index (IgG, IgM, and IgA), cellular immunity index (CD3, CD4, CD4/CD8, and CD8), tumor marker alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and life quality were compared before and after treatment. Results: Regarding the therapeutic effects, the observation group had CR4, PR 48, SD 18, and PD2; the total remission rate was 97.22%. There were 2 individuals with CR, 32 with PR, 22 with SD, and 16 with PD in the observation group. 77.79% of the total remissions occurred. The total remission rate in the observation group was higher, and the difference was statistically significant (P < 0.05). A comparison of liver function index levels before and after treatment was done. As a result of treatment, the levels of AST, ALT, and TBIL lessened. In addition, the levels of AST, ALT, and TBIL in the observation group were lower as well, and the difference was statistically significant (P < 0.05). In the control group, the levels of serum IgG, IgM, and IgA were lower after treatment than before treatment, but in the observation group, the levels were higher. Additionally, the levels of IgG, IgM, and IgA were higher, and the difference was statistically significant (P < 0.05). With regard to the cellular immune indexes, compared to those before treatment, the CD3, CD4 and CD4/CD8 of the patients in the control group were lower, CD8 was higher, while CD3, CD4, and CD4/CD8 in the observation group were higher, CD8 was lower, and the difference was statistically significant (P < 0.05). AFP and CA199 levels lessened after treatment in the control group, indicating that the markers were reducing tumor growth, and the difference was statistically significant (P < 0.05). The value of CEA lessened, and the difference was statistically significant (P < 0.05). There was a marked decrease in AFP, CEA, and CA199 serum levels in the observation group compared to those before treatment, and the difference was statistically significant (P < 0.05). After treatment, the contents of AFP, CEA, and CA199 in the observation group were lower, and the difference was statistically significant (P < 0.05). In terms of the life quality after treatment, 36 patients (50.00%) had augmented KPS score and 38 patients (52.78%) had augmented ZPS score in the observation group, which was noticeably higher compared to the control group, and the difference was statistically significant (P < 0.05). The progression-free survival (PFS) of the observation group was 31.67 months (95% confidence interval was 0.09657∼0.3019), and the PFS of the control group was 26.73 months (95% confidence interval was 3.313∼10.36). The PFS time of the observation group was noticeably longer, and the difference was statistically significant (P < 0.05). Conclusion: FBC associated with sorafenib can noticeably strengthen the clinical effect of patients with advanced HCC, enhance the liver function and immune function of patients with advanced HCC, accelerate the speed of rehabilitation and ease clinical symptoms, reduce the level of tumor markers, strengthen the quality of life, and prolong the survival time of patients.

Clinical Study on Prevention of Irinotecan-Induced Delayed-Onset Diarrhea by Hot Ironing with Moxa Salt Packet on Tianshu and Shangjuxu.

Objective: To study the clinical efficacy of hot ironing of the Tianshu and Shangjuxu with moxa salt packet to prevent irinotecan (CPT-11)-induced delayed-onset diarrhea (IIDD). Methods: A randomized controlled study was conducted on a sample of 120 patients with advanced colorectal cancer who were hospitalized in our oncology department and treated with FOLFIRI chemotherapy regimen from February 2018 to July 2021. They were equally divided into study group (n = 60) and control group (n = 60) according to whether they were treated with hot ironing with moxa salt packs or not. The general conditions, occurrence of IIDD, occurrence of delayed chemotherapy due to IIDD, time of occurrence and duration of IIDD, Karnofsky performance score (KPS) score, occurrence of leukopenia, and myelosuppression were compared between the two groups. Result: The incidence of grade 1, 2, 3, and 4 diarrhea in the study group was 11.67% (7/60), 5.00% (3/60), 3.33% (2/60), and 0.00% (0/60), respectively, while the incidence of grade 1, 2, 3, and 4 diarrhea in the control group was 21.67% (13/60), 8.33% (5/60), 10.00% (6/60), and 3.33% (2/60). The incidence of severe diarrhea and total diarrhea in the study group was (3.33% and 20.00%) lower than that in the control group (13.33% and 43.33%) (P < 0.05). The incidence of delayed chemotherapy was lower in the study group (8.33%) (1/12) than in the control group (23.08%) (6/26) but the difference between the groups was not statistically significant (P > 0.05). The time to onset of IIDD in the study group (6.45 ± 1.53) days was comparable to that in the control group (6.40 ± 1.77 days) (P > 0.05), but the duration of IIDD in the study group (3.25 ± 1.05 days) was shorter than that in the control group (5.70 ± 1.72 days) (P < 0.05). After treatment, the incidence of KPS improvement, stabilization, and reduction in the study group was 38.33% (23/60), 51.67% (31/60), and 10.00% (6/60), respectively, the incidence of KPS improvement, stabilization, and reduction in the control group was 23.33% (14/60), 50.00% (30/60), and 26.67% (16/60), respectively, and the percentage of KPS reduction in the study group was less than that in the control group (P < 0.05). During the observation period after treatment, the total incidence of leucopenia in the study group was 11.67% (7/60) which is lower than 31.67% (19/60) in the control group (P < 0.05). During the observation period after treatment, the incidence of III°+°IV myelosuppression in the study group was 5.00% (3/60) which is lower than 25.00% (15/60) in the control group (P < 0.05). Conclusion: The hot ironing with moxa salt packet on Tianshu and Shangjuxu was more effective in preventing IIDD, which could reduce the incidence and severity of IIDD, shorten the duration of diarrhea and significantly increase the quality of life of patients with no significant adverse effects.

Cinobufagin restrains the growth and triggers DNA damage of human hepatocellular carcinoma cells via proteasome-dependent degradation of thymidylate synthase.

Anti-tumor candidate drugs from natural products have gained increasing attention. Cinobufagin is a natural product isolated from the traditional chinese medicine Chansu. Herein, we find that cinobufagin inhibits the proliferation and colony-forming ability of human hepatoma HepG2 and SK-HEP-1 cells. Furthermore, cinobufagin induces G2-phase cell cycle arrest and DNA damage in cancer cells. Thymidylate synthase (TYMS), the major target of chemotherapeutic drugs 5-FU or other fluoropyrimidines, which catalyzes the conversion of dUMP to dTMP and provides the sole de novo source of thymidylate for DNA synthesis. We demonstrate that cinobufagin suppresses TYMS expression via proteasome-dependent degradation in human hepatoma cells, moreover, depletion of TYMS restrains the proliferation and colony formation of tumor cells, and the results of western blotting and immunofluorescence assay indicate DNA damage is induced in tumor cells transfected with TYMS-targeting siRNA (siTYMS), additionally, knockdown of TYMS enhances the inhibitory effect of cinobufagin on the proliferative potential of HepG2 and SK-HEP-1 cells. It is worth noting that cinobufagin in combination with 5-FU exhibits antagonism or synergism combined effects on the proliferation of human hepatoma cells, indicating that Chansu-related preparations such as cinobufacini injection and Huachansu capsules applied to clinical practice should be used with caution in combination with 5-FU for the treatment of liver cancer. Collectively, cinobufagin exerts good anti-hepatoma activity through inhibition of growth and induction of DNA damage by promoting the degradation of TYMS. Our results provide evidence that cinobufagin might be a potential agent for the treatment of cancers such as hepatocellular carcinoma. It can also promote the scientific development of Chansu, and has great significance for enriching the application of TCM in the development of new anti-tumor drugs.

A network pharmacology approach to investigate the anticancer mechanism of cinobufagin against hepatocellular carcinoma via downregulation of EGFR-CDK2 signaling.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers with high mortality and poor prognosis, and the investigation on new approaches and effective drugs for HCC therapy is of great significance. In our study, we demonstrate that treatment with cinobufagin, a natural compound isolated from traditional chinese medicine Chansu, reduces proliferation and the colony formation capacity of the human hepatoma cells in vitro, in addition, cinobufagin induces mitotic arrest in human hepatoma cells. The results of a network pharmacology-based analysis show that EGFR, MAPK1, PTK2, CDK2, MAPK3, ESR1, CDK1, PRKCA, AR, and CSNK2A1 are the key targets involved in the anti-tumor activities of cinobufagin, additionally, several signaling pathways such as proteoglycans in cancer, pathways in cancer, HIF-1 signaling pathway, VEGF signaling pathway, ErbB signaling pathway, and PI3K-AKT signaling pathway are identified as the potential pathways involved in the inhibitory effects of cinobufagin against HCC. Furthermore, at the molecular level, we find that cinobufagin decreases EGFR expression and CDK2 activity in human hepatoma cells. Inhibition of EGFR or CDK2 expression could not only suppress the growth of tumor cells but also enhance the inhibitory effects of cinobufagin on the proliferative potential of human hepatoma cells. We also demonstrate that EGFR positively regulates CDK2 expression. Furthermore, EGFR inhibitor gefitinib or CDK2 inhibitor CVT-313 synergistically enhances anticancer effects of cinobufagin in human hepatoma cells. Taken together, these findings indicate that cinobufagin may exert antitumor effects by suppressing EGFR-CDK2 signaling, and our study suggests that cinobufagin may be a novel, promising anticancer agent for the treatment of HCC.

Identification of an 11-lncRNA signature with high performance for predicting the prognosis of hepatocellular carcinoma using bioinformatics analysis.

ABSTRACT: Hepatocellular carcinoma (HCC) is a common primary liver cancer with a high incidence and mortality. This study was conducted to identify a long non-coding RNA (lncRNA) signature that may serve as a predictor for HCC prognosis.RNA-seq data were extracted from The Cancer Genome Atlas database. Differentially expressed genes, lncRNAs, and miRNAs were identified in HCC (n = 374) and control samples (n = 50) and used to screen prognosis-associated lncRNA signatures. The association of the lncRNA signature with HCC prognosis was analyzed and a competitive endogenous RNA regulatory network involving the lncRNA signature was constructed.A total of 199 mRNAs, 1092 lncRNAs, and 251 miRNAs were differentially expressed between HCC and control samples. Among these lncRNAs, 11 prognosis-associated lncRNAs were used to construct a lncRNA signature. Cox regression analysis showed that patients with higher risk scores of the lncRNA signature were at risk of poor prognosis. Four lncRNAs (including LINC01517, DDX11-AS1, LINC01136, and RP11-20J15.2) and 7 miRNAs (including miR-195, miR-199b, miR-326, miR-424, and let-7c) in the ceRNA network interacted with the upregulated gene E2F2, which was associated with the overall prognosis of patients with HCC.The 11-lncRNA signature might be useful for predicting the prognosis of patients with HCC.

Autoantibodies against islet cell antigens in children with type 1 diabetes mellitus.

We investigated the prevalence of glutamic acid decarboxylase 65 autoantibody (GADA), insulinoma-associated protein 2 autoantibody (IA2A), and insulin autoantibody (IAA) in 750 children with type 1 diabetes (T1D) living in Taiwan. GADA, IA2A, and IAA were measured by radioimmunoassay. The data were assessed by χ2 test, binary logistic regression, and Spearman rank correlation. Of the 750 T1D patients, 66.3% had GADA, 65.3% IA2A, 35.7% IAA, and 17.2% no autoantibodies. The prevalence of GADA and IA2A significantly decreased along T1D duration. The positivity of either GADA or IA2A was 89.4% within the first year of disease and decreased to 36.7% after 9 years (P = 1.22 × 10-20). Female patients had significantly higher prevalence of GADA compared with male patients (72.3% vs. 59.7%, P = 0.00027). The patients diagnosed before 12 years of age had a positive rate of 92.2% for either GADA or IA2A. Patients diagnosed at age 12 or above had a significantly lower positive rate of 81.6% (P = 0.011). GADA and IA2A significantly correlated with each other (rs = 0.245, P = 1.09 × 10-11). We concluded that autoantibodies were detectable in 89.4% of T1D patients within one year after diagnosis. Their prevalence declined with disease duration. GADA was more prevalent in female patients. GADA and IA2A weakly correlated with each other.

Changes of Atrial Natriuretic Peptides after Defibrillation Threshold Testing Predicted Future Ventricular Arrhythmia Event.

BACKGROUND: We investigated the change of natriuretic peptides during defibrillation threshold (DFT) testing and its relationship with future ventricular arrhythmia (VA) events in patients implanted with an implantable cardioverter defibrillator (ICD). METHODS: Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP) were measured in 21 patients (mean age 61 ± 13 years; 67% male) undergoing ICD implantation. Blood samples of the patients were drawn at pre-implantation, 30 minutes, 60 minutes, and 24 hours after DFT testing. The patients were followed and divided into two groups according to the occurrence of VA in 18 months. The biomarker levels and their changes were compared in patients with and without further VA. RESULTS: The pre-implantation ANP levels were higher at pre-implantation and increased significantly at 30 minutes after DFT testing (Δ30minANP) among patients with VA events. The BNP and CNP levels did not change significantly after DFT testing in both groups. The area under curve was 0.82 for the change in Δ30minANP determining further ventricular events. The optimal Δ30minANP cutoff value was 0.51 pg/ml, with sensitivity of 0.83 and specificity of 0.68. Multivariable analysis confirmed that patients with Δ30minANP more than 0.51 pg/ml have a higher risk of further ventricular events (hazard ratio 39.8, 95% confidence interval: 2.87-553.01, p = 0.006). The pre-implantation ANP level could not predict future VA events (hazard ratio 1.06, 95% CI: 1.00-1.14, p = 0.06). CONCLUSIONS: The increase of ANP concentration after DFT testing predicted future VA events after ICD implantation while the BNP and CNP levels did not predict future VA events.

Responses of cardiac natriuretic peptides after paroxysmal supraventricular tachycardia: ANP surges faster than BNP and CNP.

Atrial natriuretic peptide (ANP) secretion increases after 30 min of paroxysmal supraventricular tachycardia (PSVT). Whether this phenomenon also applies to brain or C-type natriuretic peptides (BNP or CNP) remains unknown. Blood samples of 18 patients (41 ± 11 yr old; 4 men) with symptomatic PSVT and normal left ventricular systolic function (ejection fraction 65 ± 6%) were collected from the coronary sinus (CS) and the femoral artery (FA) before and 30 min after the induction, and 30 min after the termination of PSVT. The results showed that the ANP levels rose steeply after the PSVT and then reduced at 30 min after the termination (baseline vs. post-PSVT vs. posttermination: CS: 34.0 ± 29.6 vs. 74.1 ± 42.3 vs. 46.1 ± 32.9; FA: 5.9 ± 3.24 vs. 28.2 ± 20.7 vs. 10.0 ± 4.6 pg/ml; all P < 0.05). In contrast, compared with ANP, the increases of BNP and CNP in CS after the PSVT were less sharp, but continued to rise after the termination of tachycardia (BNP, 10.2 ± 6.4 vs. 11.3 ± 7.1 vs. 11.8 ± 7.9; CNP, 4.5 ± 1.2 vs. 4.9 ± 1.4 vs. 5.0 ± 1.4 pg/ml; all P < 0.05). The rise of BNP and CNP in FA was similarly less sharp after the PSVT and remained stationary after the termination. PSVT exerted differential effects on cardiac natriuretic peptide levels. ANP increased greater after a 30-min induced PSVT, but dropped faster after termination of PSVT, compared with BNP and CNP.

Effects of carbenoxolone on flow-mediated vasodilatation in healthy adults.

Gap junctions play a key role in maintaining the functional integrity of the vascular wall. Using carbenoxolone (CBX) as a gap junction blocker, we aimed to assess the contribution of gap junctions in the vascular wall to flow-mediated vasodilatation (FMD) in healthy adults. Percentage FMD (%FMD) and circulating vasoactive molecules/activity, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), aldosterone, cortisol, plasma renin activity (PRA), and endothelin (ET-1), were measured in 25 healthy volunteers (mean age: 30.1 ± 5.4 yr; 14 males) before and after oral administration of CBX (100 mg). %FMD decreased after ingestion of CBX (9.71 ± 3.1 vs. 3.40 ± 2.0%; P < 0.0001). The levels of ANP, BNP, cortisol, and ET-1 remained stationary, while both PRA and aldosterone decreased (P < 0.005) after CBX ingestion. Blood pressure and heart rate were minimally changed by CBX. Inhibition of gap junctional communication by CBX impairs FMD in healthy persons, suggesting that physiologically, vascular gap junctions participate in the maintenance of FMD. CBX does not induce the release of vasoconstricting molecules or enhance vasoconstriction, suggesting that inhibition of gap junctional communication by CBX underlies the impairment of FMD. Therefore, administering CBX in FMD examination can be a way to follow the effect of gap junctions on endothelial function, but further work remains to verify the specificity of CBX effect.

C-type natriuretic peptide in individuals with normal left ventricular systolic function.

OBJECTIVE: The objective of this study was to evaluate production or release of CNP in individuals without CHF. METHODS: Nineteen patients with symptomatic paroxysmal supraventricular tachycardia (PSVT) and normal left ventricular systolic function were enrolled into the study. Blood samples were collected from the coronary sinus (CS), the femoral artery (FA), and the peripheral vein (PV) before pacing, after rapid RA pacing, and post electrophysiological study (EPS) and/or radiofrequency (RF) ablation. RESULTS: The CNP level in the CS, compared to FA and PV, was significantly higher before pacing (CS, 3.2+/-0.8; FA, 2.6+/-0.7; PV, 2.5+/-0.5 pg/ml; CS vs. either FA or PV, both p<0.001), after the pacing (CS, 3.2+/-1.3; FA, 2.4+/-0.6 pg/ml; p=0.004), and post the EPS and/or RF ablation (CS, 3.1+/-0.7; FA, 2.6+/-0.9; PV, 2.5+/-0.8 pg/ml; CS vs. either FA or PV, both p<0.01). CONCLUSION: The myocardium regularly produces or releases CNP in patients with normal LV systolic function. Brief periods of rapid RA pacing, PSVT, or EPS does not change the production and/or release.

Metabolic disorders in children and adolescents with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) in children and adolescents is increasing in incidence worldwide. It is the leading type of newly diagnosed diabetes in Taiwan among school children. T2DM is associated with metabolic syndrome in adults, so we tried to find out if these metabolic disorders are present in children. METHODS: From 1989 to 2003, 22 children and adolescents were diagnosed with T2DM in our hospital. Their ages ranged from 8.8 to 17.0 (11.7+/-2.3) years; 6 of them were boys. We compared their clinical characteristics with those of 42 healthy and 237 obese children and adolescents. Physical examination was performed and plasma glucose and serum cholesterol, triglycerides, uric acid, creatinine, HDL-cholesterol, and insulin levels were measured and LDL-cholesterol was calculated. Demographic and laboratory data were compared among the T2DM, obese and control groups. RESULTS: The female: male ratio among the patients was 2.7: 1; 18% were overweight and 68% obese, and 64% had acanthosis nigricans. There were no significant differences between the T2DM and obese groups in terms of biochemistry profiles except for the higher plasma glucose in the T2DM group. Children with T2DM had higher levels of cholesterol and triglycerides but lower levels of HDL-cholesterol compared with healthy children. Among obese children without T2DM, the levels of glucose, triglycerides, uric acid, insulin, HOMA-IR were higher than in the healthy group, and HDL-cholesterol levels were lower. CONCLUSIONS: Children with T2DM or obesity should be evaluated for metabolic disorders.

Brain natriuretic peptide and C-type natriuretic peptide are differently regulated by age but similarly elevated in coronary artery disease.

OBJECTIVE: We investigated the effect of age and coronary angioplasty on brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). METHODS AND RESULTS: Serum levels of both peptides immediately before catheterization and at the end of angioplasty in 15 patients (age 68 +/- 8 years, 8 men) with coronary artery disease (CAD) were compared to 12 elderly (65 +/- 7 years, 8 men) and 16 non-elderly (34 +/- 7 years, 10 men) healthy individuals. The results showed that in healthy individuals the levels of both peptides are age-dependent dissimilarly. Compared to the non-elderly, while BNP increases in the elderly (7.81 +/- 1.60 vs. 10.01 +/- 2.06 pg/ml, p = 0.002), CNP decreases (5.39 +/- 1.30 vs. 2.22 +/- 0.80 pg/ml, p < 0.001). On the other hand, compared to the elderly healthy persons, patients with CAD have a marked increase in the baseline levels of BNP (20.02 +/- 17.43 pg/ml, p = 0.03) and CNP (4.41 +/- 1.20 pg/ml, p < 0.001). However, both peptides remain stationary immediately after angioplasty (BNP, 21.02 +/- 16.95; CNP, 4.51 +/- 1.06 pg/ml; both p = 0.4). CONCLUSIONS: BNP and CNP are differentially regulated by age in a healthy state, suggesting that each peptide has a distinct role during the aging process. The elevation of both peptides in CAD but little change shortly after angioplasty may indicate that both peptides respond to a chronic state rather than an acute episode of vascular damage.

Insulin resistance in obese adolescents.

The prevalence of obesity in adolescents is increasing rapidly. Obesity is associated with insulin resistance, which increases the risk for type 2 diabetes. We investigated insulin resistance in obese adolescents and its relationship to acanthosis nigricans. Height, weight and body mass index (BMI) were measured and each was expressed as a standard deviation score (SDS) based on national growth standards. Insulin resistance was estimated by using the homeostasis model assessment (HOMA-IR) score, calculated as fasting insulin (microU/mL) x fasting glucose (mmol/L)/22.5. Obese adolescents had significantly greater weight-SDS, BMI-SDS, fasting insulin levels, and HOMA-IR than did controls with normal weight. Acanthosis nigricans was present in 58.4% of obese adolescents. Fasting insulin levels and BMI-SDS were positively correlated with the degree of acanthosis nigricans (r = 0.383, P<0.0001 and r = 0.164, P < 0.05, respectively). On multiple regression analysis, HOMA-IR and BMI-SDS explained 16.8% of the degree of acanthosis nigricans (P<0.0001). Acanthosis nigricans thus may be a marker of insulin resistance and should be carefully looked for in obese adolescents.

Wolfram (DIDMOAD) syndrome: report of two patients.

We report a girl with Wolfram syndrome who presented with juvenile-onset diabetes mellitus when she was 4 3/12 years old. Optic atrophy and high frequency sensorineural hearing loss were found at 7 and 9 5/12 years of age, respectively. Her younger brother also developed Wolfram syndrome when he was 3 2/12 years old. Wolfram syndrome is also called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness). This syndrome is transmitted as an autosomal recessive trait and is a progressive neurodegenerative disorder. It should be considered in a diabetic patient with unexplained optic atrophy, hearing loss, or polyuria and polydipsia in the presence of adequate blood glucose control. Visual acuity should be checked annually in patients with juvenile-onset diabetes mellitus. Optic atrophy should be considered if visual acuity is impaired.

Thyroid function in children with newly diagnosed type 1 diabetes mellitus.

Evaluation of thyroid hormone indices was performed in 138 children with newly diagnosed type 1 diabetes, with their siblings serving as controls. The DKA group consisted of 76 children who had diabetic ketoacidosis (DKA) at initial diagnosis. The non-DKA group consisted of 62 children and the control group of 35. The thyroid function tests of the patients were measured within 3 days of the initial diagnosis of diabetes and at least one follow-up test one month to two years after adequate treatment of diabetes. The DKA group had significantly lower levels of T3, T4, free T4 and FTI than did the other two groups (p < 0.0001, p < 0.0001, p < 0.0001, and p < 0.0001, respectively). T3 concentration was lower in non-DKA subjects than in controls (p = 0.0003), but the two groups did not significantly differ in terms of T4, free T4, and FTI. The TSH level did not differ among the three groups. We conclude that DKA changes thyroid function measurements. In the absence of true thyroid disease, abnormal thyroid function tests are reversible after institution of good diabetic control. We suggest that thyroid function tests should be restricted to those patients suspected of having thyroid disorders at the initial diagnosis of type 1 diabetes.