[Topography-guided transepithelial corneal collagen cross-linking by sequential ultraviolet A irradiation in different diameters for progressive keratoconus in adults].

Objective: To compare the efficacy and safety of a novel customized topography-guided transepithelial corneal collagen cross-linking (TG-CXL) procedure by sequential ultraviolet A irradiation in different diameters and conventional transepithelial corneal collagen cross-linking (TE-CXL) in adult patients with progressive keratoconus. Methods: A prospective cohort study was conducted. Adult patients diagnosed with progressive keratoconus in the Affiliated Xiamen Eye Center of Xiamen University were continuously recruited and randomly assigned to receive the TG-CXL or TE-CXL procedure from March 2020 to March 2021. Patients in the TE-CXL group were irradiated in the central 9-mm zone of the cornea (total energy, 7.2 J/cm2; irradiance, 45 mW/cm2), while patients in the TG-CXL group were first irradiated with the protocol used in the TE-CXL group, and further irradiated in the central 6-mm zone (total energy, 3.6 J/cm2; irradiance, 9 mW/cm2). The subjective symptom of pain and corneal fluorescein sodium staining were scored within postoperative 3 days. Slit lamp examination, measurements of uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA), corneal topography, anterior segment optical coherence tomography, in vivo corneal confocal microscopy, corneal endothelial cell count, and non-contact tonometry were performed before surgery and at 3, 6, and 12 months after surgery. Results: A total of 66 patients were enrolled (mean age, 23.0±3.3 years old), with 33 patients (33 eyes) in each group. No statistically significant differences were found in age, gender, and maximum keratometry (Kmax) between the two groups (P>0.05). On day 1 after surgery, the average pain score of the TG-CXL group (2.21±0.45) was significantly higher than that of the TE-CXL group (1.32±0.33) (P<0.05). The pain was rapidly alleviated in both groups on days 2 and 3. On days 1 and 2, the corneal fluorescein sodium staining scores in the TG-CXL group (4.15±0.83 and 2.21±0.60, respectively) were significantly higher than those in the TE-CXL group (1.76±0.56 and 0.85±0.51, respectively, P<0.001), while there was no significant difference between the two groups at day3 (P=0.184). The UCVA and BCVA of the TG-CXL group at 3, 6, and 12 months after surgery were significantly improved when compared with the baseline. At 3, 6, and 12 months, the BCVA (LogMAR) of the TG-CXL group (0.21±0.15, 0.22±0.16, and 0.22±0.16, respectively) were significantly improved when compared with those of the TE-CXL group(0.32±0.15, 0.34±0.15, and 0.36±0.16, respectively, P<0.01). However, there was no significant difference in UCVA between groups at any time point after surgery (P>0.05). The spherical and cylindrical power values of the TG-CXL group were improved when compared with the baseline (P<0.05). However, no significant difference in spherical power values was found between the two groups at any time point after surgery (P>0.05). Meanwhile, there were significant differences in cylindrical power values between the two groups at 6 and 12 months after surgery (P<0.05). The Kmax in the TG-CXL group was improved at all of the time points after surgery when compared with the baseline (P<0.001), while no significant difference in Kmax was found at any time point after surgery in the TE-CXL group when compared with the baseline (P>0.05). At 6 and 12 months after surgery, the Kmax values in the TG-CXL group were significantly lower than the TE-CXL group (P<0.05). No significant differences were found in flat keratomety, steep keratometry, the minimal thickness of the cornea, endothelial cell density, and intraocular pressure between the two groups at any time point after surgery (P>0.05). Within one month after surgery, optical coherence tomography revealed the increased density in the anterior stroma in both groups. In most patients in the TG-CXL group, a demarcation line was visible in the central and para-central corneal stroma, representing a clear and continuous, high-signal arc-shaped linear structure, which was deeper in the central cornea than the para-central cornea. In contrast, a demarcation line, fuzzy and focally discontinuous, was visible only in a few patients in the TE-CXL group, with an almost uniform depth in the central and the para-central cornea. Confocal microscopy demonstrated an apparent mesh-like cross-linked collagen structure in the superficial and intermediate corneal stroma at all time points after surgery in the TG-CXL group, with thickening stromal collagen fibers and an increased number of interconnections. In contrast, the mesh-like structure and number of interconnections in the superficial corneal stroma were significantly reduced at 12 months after surgery in the TE-CXL group, with no cross-linking structure in the intermediate corneal stroma at any time point after surgery. No serious complications such as corneal infection, sterile corneal ulcer, and persistent epithelial defect were observed in both groups during the follow-up of 12 months. Conclusions: The TG-CXL procedure by sequential irradiation in two different diameters with ultraviolet A light was effective and safe in the management of progressive keratoconus in adults, achieving significant refractive improvement. This might be a good technical alternative for refractive corneal cross-linking surgery.

[Efficacy of deproteinized calf blood extract eye drops on early recovery after pterygium surgery].

Objective: To investigate the effect of deproteinized calf blood extract eye drops on early postoperative recovery in primary pterygium patients. Methods: This is a prospective randomized controlled study. Patients diagnosed with primary pterygium in single eye at affiliated Xiamen Eye Center of Xiamen University during March 2016 to May 2016 were enrolled. After Pterygium excision with autologous conjunctival transplantation, patients were randomly assigned into four groups by a random number table, treated with anti-inflammaroty drugs only (control group) or combined with the following agents: deproteinized calf blood extract eye drops (DCBE group), carboxymethylcellulose sodium eye drops (CMC group), and recombinant human epidermal growth factor eye drops (rEGF group). Short-form McGill pain questionnaire, slit lamp and corneal fluorescein sodium staining, non-contact intraocular pressure, uncorrected visual acuity (UCVA) and best corrected visual acquity (BCVA) as well as redness score of bulbar conjunctiva were performed before surgery (d0) and on day 1 (d1), day 2 (d2), day 3 (d3), day 7 (d7) and day 14 (d14) after surgery. Results: One hundred and fourteen patients including 43 males and 71 females, aged (48.9±12.5) years, were eventually included in this study. The McGill scores gradually decreased after surgery in all groups. On d2, the McGill score in DCBE group, control group, CMC group and rEGF group was (1.42±0.67), (2.21±0.88), (1.93±1.08) and (1.77±1.18), respectively; On d3, the score was (1.32±0.54), (1.93±0.72), (1.79±0.87) and (1.52±0.77), respectively. On d2 and d3, statistical difference was recorded among groups (d2, F=3.43, P=0.019; d3, F=4.047, P=0.009), and the McGill score of DCBE group was significantly lower than that of CMC group (d2, P=0.047, d3, P=0.017). On d2, the percentage of corneal epithelium defect in DCBE group, control group, CMC group and rEGF group was 8.6%±1.9%, 11.7%±1.7%, 11.5%±1.9% and 10.4%±1.8%, respectively; On d3, the percentage was 4.5%±2.2%, 9.2%±2.4%, 7.4%±2.5% and 5.9%±2.3%, respectively. On d2 and d3, statistical difference of corneal epithelium defect percentage was recorded among groups (d2, F=17.17, P<0.001; d3, F=21.4, P<0.001). On d2, the percentage of corneal epithelium defect in DCBE group was significantly lower than the other three groups (P<0.01); On d3, the percentage of corneal epithelium defect in DCBE group was significantly lower than control group and CMC group (P<0.001), while no difference was found between DCBE group and rEGF group (P>0.05). However, no statistical differences were recorded in the number of patients with vision improvement among the groups (P>0.05). The intraocular pressure remained stable. No differences in the conjunctival redness score were found among the groups after surgery (P>0.05). Conclusion: Our data demonstrated the efficacy of deproteinized calf blood extract eye drops on the postoperative management in patients with primary patients, with faster pain relief and promoted epithelium recovery. (Chin J Ophthalmol, 2019, 55:134-140).

[Accelerated transepithelial corneal collagen cross-linking for progressive keratoconus with a thin cornea: one-year results].

Objective: To evaluate the clinical results of keratoconic eyes with a thin cornea treated with accelerated transepithelial corneal collagen cross-linking (A-TE-CXL) within 1 year. Methods: Nineteen eyes of 19 patients with progressive keratoconus with a minimum corneal thickness from 380 µm to 420 µm (including the epithelium) were included in this prospective, nonrandomized clinical study and treated with A-TE-CXL. Scoring of pain and foreign body sensation, slit lamp examination, uncorrected visual acuity, best corrected distance visual acuity, corneal topography, anterior segment optical coherence tomography, in vivo corneal confocal microscopy and endothelial cell count were assessed before surgery and at 1, 3, 6 and 12 months postoperatively. Paired t test was applied for statistical analysis. Results: Mild pain and moderate foreign body sensation were reported by most patients within postoperative 24 hours, but rapidly disappeared on day 2. Extremely mild epithelial damage was observed within postoperative 24 hours, and the epithelium fully recovered on day 2. Improvement of visual acuity was recorded at 3 and 12 months. Pentacam corneal topography revealed a significant reduction of the thickness of the thinnest location from(395.2±13.8)µm preoperatively to (378.9±17.1)µm at 1 month postoperatively (t=2.982, P<0.01). Front curvature values were reduced postoperatively. K(MAX) was significantly decreased at 12 months (55.67±4.91) compared with (57.35±5.54) preoperatively, while K2 was also significantly decreased at 12 months (52.18±3.70) compared with (52.70±3.56) preoperatively (K(MAX), t=3.044, P<0.01. K2, t=2.384, P<0.05) . Within 1 month postoperatively, optical coherence tomography exhibited an increase of reflectance with a demarcation line in the anterior stroma. In vivo confocal microscopy also showed significant thickening and increased connections of collagen fibers with a maximal depth at about 90 to 120 µm. The corneal endothelial cell density remained stable (t=0.692, P>0.05). None of the patients showed postoperative complications such as corneal infection, scarring and ulceration. Conclusions: Within 1 year postoperatively, A-TE-CXL was effective and safe for the management of progressive keratoconus with a thin cornea. A-TE-CXL showed the advantages of very short time consuming in surgery, rapid recovery and very few complications, and had the potential to become a valid alternative for the treatment of keratoconus. (Chin J Ophthalmol, 2017, 53: 694-700).

Diagnostic value of apoptosis biomarkers in severe sepsis-A pilot study.

Severe sepsis is associated with significant mortality and massive immune cell lose, or apoptosis. It is unclear whether plasma apoptosis biomarkers could be used as a diagnostic test for severe sepsis. Forty patients with severe sepsis and 35 healthy controls were enrolled. The percentage and apoptosis of monocytes and lymphocytes were detected by flow cytometric analysis. Plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR), soluble Fas (sFas), Fas ligand (FasL), caspase-1, and procalcitonin (PCT) were measured. Plasma caspase-1 level was positively correlated with CD4 lymphocyte apoptosis in controls and patients, and with CD8 lymphocyte apoptosis in all subjects. Plasma FasL level was negatively correlated with CD4 and CD8 lymphocyte apoptosis in all subjects. The sFas/FasL ratio was positively correlated with CD4 and CD8 lymphocyte apoptosis and negatively with monocyte apoptosis in all subjects. Compared with PCT, caspase-1, FasL, and sFas/FasL ratio had better negative predictive value and likelihood ratio for a negative test. PCT had better positive predictive value and likelihood ratio for a positive test. This work demonstrated caspase-1, FasL, and sFas/FasL ratio could be candidates for diagnosis of severe sepsis and their diagnostic value was not inferior to that of PCT.

Effect of adenovirus-mediated RNA interference of IL-1ß expression on spinal cord injury in rats.

STUDY DESIGN: We introduced an adenoviral vector expressing interleukin-1ß (IL-1ß) small-hairpin RNA (shRNA) into the injured spinal cords to evaluate the therapeutic potential of IL-1ß downregulation in a rat model of spinal cord injury (SCI). OBJECTIVES: The purpose of this study was to investigate the possible protective effects of the IL-1ß downregulation on traumatic SCI in rats. SETTING: Department of Orthopedic Surgery, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, People's Republic of China. METHODS: An adenoviral shRNA targeting IL-1ß was constructed and injected at the T12 section 7 days before SCI. The rats' motor functions were evaluated by the Basso-Beattie-Bresnahan (BBB) rating scale. Immunofluorescence, enzyme-linked immunosorbent assay, flow-cytometric analysis and western blots were also performed. RESULTS: Animals downregulating IL-1ß had significantly better recovery of locomotor function and less neuronal loss after SCI. In addition, IL-1ß downregulation significantly decreased tumor necrosis factor-alpha (TNF-α) level and Bax expression, reduced the activity of caspase-3 and increased Bcl-2 expression after SCI. CONCLUSION: This study demonstrated that the IL-1ß downregulation may have potential therapeutic benefits for both reducing secondary damages and improving the outcomes after traumatic SCI.

Concurrent hypopituitarism and leukemic retinopathy in a child with B-precursor acute lymphoblastic leukemia and isolated central nervous system relapse.

Hypopituitarism in leukemia is very rare. In addition, central nervous system (cns) relapse and leukemic retinopathy in childhood acute lymphoblastic leukemia (all) have declined with the use of modern systemic chemotherapy that includes cns prophylaxis. Here, we report the case of a 4-year-old girl who received chemotherapy and intrathecal therapy without cns radiation after a diagnosis of B-precursor all without cns involvement. Three months after chemotherapy completion, she presented with lower-extremity weakness and was diagnosed with an isolated cns relapse. Concurrent hypopituitarism and leukemic retinopathy were also found. After receiving craniospinal radiotherapy and systemic chemotherapy, her retinopathy and vision improved. She is now in complete remission, and she is still on chemotherapy according to the guideline from the Pediatric Oncology Group. Although rare, hypopituitarism and leukemic retinopathy should be taken into consideration in patients with cns involvement by leukemia.

Polymorphisms in genes in the RANKL/RANK/OPG pathway are associated with bone mineral density at different skeletal sites in post-menopausal women.

UNLABELLED: Association between 22 single nucleotide polymorphisms (SNPs) in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in 881 post-menopausal women. Our results suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women. INTRODUCTION: The aim of this study was to assess the relationship of polymorphisms in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in a cohort of Chinese post-menopausal women. METHODS: A cross-sectional study was conducted in 881 post-menopausal women aged 50-89 years. All participants underwent lumbar spinal (LS) and femoral neck (FN) BMD evaluation by dual-energy X-ray absorptiometry. Twenty-two TNFSF11, TNFRSF11A, and TNFRSF11B SNPs were genotyped. We tested whether a single SNP or a haplotype was associated with BMD variations. RESULTS: Two SNPs in the TNFSF11 gene (rs2277439 and rs2324851) and one in the TNFRSF11A gene (rs7239261) were found to be significantly associated with FN BMD (p = 0.014, 0.013, and 0.047, respectively). Haplotype TGACGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was a genetic risk factor toward a lower FN BMD (beta = -0.1473; p = 0.01126). In contrary, haplotype TAGCGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was genetic protective factor for LS BMD (beta = 0.3923; p = 0.04917). CONCLUSIONS: Our findings suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women. This contributes to the understanding of the role of genetic variation in this pathway in determining bone health.

Multi-modulus algorithm based on global artificial fish swarm intelligent optimization of DNA encoding sequences.

Aimed to address the defects of the large mean square error (MSE), and the slow convergence speed in equalizing the multi-modulus signals of the constant modulus algorithm (CMA), a multi-modulus algorithm (MMA) based on global artificial fish swarm (GAFS) intelligent optimization of DNA encoding sequences (GAFS-DNA-MMA) was proposed. To improve the convergence rate and reduce the MSE, this proposed algorithm adopted an encoding method based on DNA nucleotide chains to provide a possible solution to the problem. Furthermore, the GAFS algorithm, with its fast convergence and global search ability, was used to find the best sequence. The real and imaginary parts of the initial optimal weight vector of MMA were obtained through DNA coding of the best sequence. The simulation results show that the proposed algorithm has a faster convergence speed and smaller MSE in comparison with the CMA, the MMA, and the AFS-DNA-MMA.

Dasatinib for a child with Philadelphia chromosome-positive acute lymphoblastic leukemia and persistently elevated minimal residual disease during imatinib therapy.

Imatinib has improved outcomes in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (all). Minimal residual disease (mrd) is a useful tool for predicting leukemia relapse. However, there is no consensus on how to treat children with elevation of BCR-ABL transcripts but no evidence of hematologic relapse during chemotherapy combined with imatinib. Here, we report the case of a child with Ph+ all who had persistent elevation of mrd, but no evidence of hematologic relapse while receiving imatinib plus intensive chemotherapy. Dasatinib was substituted for imatinib because no suitable donor for allogeneic hematopoietic stem-cell transplantation (hsct) was available. Less-intensive chemotherapy with methotrexate and 6-mercaptopurine was administered concomitantly. No serious adverse events were encountered. With continuous dasatinib combined with chemotherapy, but no allogeneic hsct, our patient reached complete molecular remission and has been in complete molecular remission for more than 13 months. This report is the first about the long-term use of dasatinib in patients with Ph+ all and mrd elevation but hematologic remission during imatinib chemotherapy. In a similar situation, chemotherapy combined with dasatinib instead of allogeneic hsct could be considered to avoid hsct-related mortality and morbidity. Clinical trials are needed.

Epidemiology of pediatric critically-ill patients presenting to the pediatric emergency department.

This study aimed to analyze the epidemiologic patterns of pediatric critically-ill patients presenting to the emergency department (ED) and the etiologies of intensive care unit (ICU) admission of different age groups.This retrospective study of all children aged less than 18 years presenting with critical illnesses to the ED was conducted in a tertiary medical center in Taiwan from 2003 to 2007. All patients transferred to the ICU from the ED were included without distinction. Demographic data of critically-ill children admitted to the ED and ICU were analyzed. Etiologies of the ICU admissions were analyzed by various age groups.There were 2978 critically-ill children admitted to the ICU from the ED. In 120 pediatric patients with out-of-hospital cardiac arrest, cases with pulseless electrical activity or ventricular fibrillation had higher successful CPR rates than patients with asystole (both p<0.05). In patients admitted to ICUs, complications from the perinatal period, respiratory system diseases, accidental injuries and poisoning were the predominant etiologies respectively in young children (42.5%), school-aged children (38.5%), and adolescents (47.9%). Moreover, the most common of which was respiratory distress syndrome in neonates followed by bacterial pneumonia and status epilepticus.Epidemiologic analysis may provide primary clinicians to identify significant differences in admission rates based on different etiologies of various age groups.

Signaling by Synaptic Zinc is Required for Whisker-Mediated, Fine Texture Discrimination.

Zinc-containing terminals are found throughout the neocortex, concentrated predominantly in layers II/III, V, and VI. Synaptic zinc is a potent neurotransmitter/modulator and, therefore, may mediate inter- or intra-cortical integration of sensory information. We have previously shown that levels of synaptic zinc are rapidly modulated in somatosensory (barrel) cortex, in an experience- and activity-dependent manner. Zinc transporter 3 (ZnT3) knockout (KO) mice lack synaptic zinc and provide us with a good model to examine the contribution of synaptic zinc to barrel cortex-dependent behavior. In the present study, we show that ZnT3 KO mice display a marked decrease in acuity for whisker-dependent texture discrimination. ZnT3 KO mice were not able to discriminate between textures having an average particle diameter less than 300 µm while control mice were able to discriminate between textures having particle diameters separated by as little as 25 µm. This loss of texture discrimination acuity in ZnT3 KO mice was whisker-dependent and was observed in young (2 months-of-age) and older mice (12 months-of-age). These results show that zincergic signaling is necessary for the normal integration of somatosensory information.

Ba3B10O17Br2: a new barium borate halide with B-O layered structure.

A new barium borate halide, Ba3B10O17Br2, has been obtained. A detailed structural comparison with other barium borate halides suggested that Ba3B10O17Br2 is the first barium borate halide with a B-O layered structure. First-principles theoretical studies were conducted to aid understanding of the electronic structure and optical properties.

Wurtzite-to-rocksalt structural transformation in nanocrystalline CoO.

Hexagonal CoO nanocrystals are coarsened under hydrothermal conditions to investigate the effect of particle size on phase transformation and stability property. Structural stability and phase transformation of the hexagonal CoO phase have been investigated by X-ray powder diffraction with Rietveld refinement, transmission electron microscopy, X-ray absorption fine structure, and differential scanning calorimeter. It is found that the hexagonal CoO phase is a metastable phase, which increases its grain size from 50 to 250 nm for refluxing times from 1 to 6 h at 200 degrees C. After 12 h, cubic-structured CoO grains with an average grain size of 20 nm are observed, which spread around big hexagonal CoO grains. After about 24 h, only the cubic CoO phase with an average grain size of 25 nm is detected. The onset temperature of hexagonal-to-cubic phase transformation in CoO is estimated to be 378 degrees C by DSC, using a heating rate of 20 deg/min. The results obtained indicate that the hexagonal-to-cubic phase transformation in nanocrystalline CoO is by nucleation and growth mechanism, starting from the surface to the center of the hexagonal grains.

Indium-111-diethylenetriaminepentaacetic acid-octreotide is delivered in vivo to pancreatic, tumor cell, renal, and hepatocyte lysosomes.

To better understand the factors that govern the target-to-background ratios of 111In-diethylenetriaminepentaacetic acid (DTPA) polypeptides, we studied 111In-DTPA-octreotide and a model nontargeted compound, 111In-DTPA-poly(D)lysine-biotin. We evaluated the fate of 111In-DTPA-octreotide after it localizes in somatostatin receptor-positive tissues and sought to determine why such a large fraction of these and other 111In-DTPA-polypeptides accumulate in the liver and kidneys. Biodistribution studies in rats with an implanted pancreatic adenocarcinoma demonstrated rapid accumulation of 111In-DTPA-octreotide in the pancreas and tumor. Indium-111 also accumulated in the liver and kidneys. Subcellular fractionation of the liver, kidneys, tumor, and pancreas showed that the majority of the radioactivity copurified with lysosomal enzymes. Even at 1 h, little radioactivity was found in the fractions containing a cell surface enzyme. This suggests that in each tissue, the 111In-DTPA-octreotide was rapidly shuttled from the cell surface to lysosomes. In the liver, hepatocyte lysosomes were separated from sinusoidal and Kupffer cell lysosomes by administering chloroquine prior to sacrifice. This density shift experiment indicated that 111In-DTPA-octreotide accumulated predominantly in hepatocyte lysosomes. A low molecular weight 111In-DTPA-poly(D)lysine-biotin compound was synthesized, and biodistribution studies showed substantial renal accumulation. The poly(D)lysine backbone conferred resistance to degradation, and this fact allowed determination of the distribution of this compound at the cellular level using an antibiotin antibody and immunohistochemical techniques. These experiments, as well as subcellular fractionation studies, demonstrated that the 111In-DTPA-poly(D)lysine-biotin compound accumulated in the lysosomes of proximal renal tubular cells. These results indicate that lysosomes play a critical role in the cellular physiology of radiolabeled polypeptides. Using these data, we propose a comprehensive model that summarizes the factors that govern the target to background ratios of radiolabeled polypeptides.

Transcomplementation of HLA DQA1-DQB1 in DR3/DR4 and DR3/DR9 heterozygotes and IDDM in Taiwanese families.

OBJECTIVE: To study the human leukocyte antigen (HLA)-DQ heterodimers in the susceptible DR haplotypes for patients with insulin-dependent diabetes mellitus (IDDM) in Taiwan. RESEARCH DESIGN AND METHODS: Extended class II HLA haplotypes were studied in 57 unrelated IDDM patients, 31 simplex IDDM families, and 105 unrelated control subjects recruited from the same area in Taiwan. Class II HLA genotyping was based on PCR-SSO DNA typing techniques. Extended class II HLA haplotypes were deduced unequivocally by the Taiwanese pedigree studies. RESULTS: DR3/DR3, DR3/DR4, and DR3/DR9 genotypes were strongly associated with IDDM susceptibility in this population. In addition to the reported DR3/DR4 in Caucasians, the heterozygotic effect of DR3/DR9 for IDDM was remarkable in the Taiwanese population. Extended HLA haplotypes studies revealed that DRB1*0301/DQA1*0501/DQB1*0201, DRB1*0405/DQA1*0301/DQB1*0302, and DRB1*0405/DQA1*0301/DQB1*0401 were the susceptible haplotypes in this population. There were several hypothetical ways to produce susceptible HLA-DQ heterodimers to explain the susceptibility carried by DR3/DR4 and DR3/DR9 genotypes. Among all DR4 subtypes, only DRB1*0405 was associated with the increased risk of IDDM. CONCLUSIONS: These data strongly suggest that the HLA-DR-associated IDDM susceptibility is most likely explained by the formation of the susceptible DQ heterodimers encoded by the DQA1/DQB1 either in cis or in trans.

No association between the Gly971Arg variant of the insulin receptor substrate 1 gene and NIDDM in the Taiwanese population.

OBJECTIVE: To study the role of the Gly971Arg variant of the insulin receptor substrate 1 (IRS-1) gene in the development of NIDDM in the Chinese population living in Taiwan. RESEARCH DESIGN AND METHODS: A total of 82 unrelated normal control subjects, 89 subjects with NIDDM, and 23 multiplex families were recruited in Taiwan. All of them were Han Chinese. Pedigree members without a history of diabetes were studies by the standard 75-g oral glucose tolerance test. Detection of the Gly971Arg variant of the IRS-1 gene was performed by polymerase chain reaction and restriction fragment-length polymorphism analysis. RESULTS: The frequency of Gly971Arg variant of the IRS-1 gene in the normal population was 1.2% which was lower than frequencies reported in white populations. The prevalence of the Gly971Arg variant was not significantly increased in both the nonselected NIDDM population (1.1%) and the probands of the multiplex families (4.3%). More importantly, the Gly971Arg variant of the IRS-1 gene did not cosegregate with BMI and NIDDM in these families, CONCLUSIONS: The Gly971Arg variant of the IRS-1 gene is an infrequent normal allele among Taiwanese. This variant is neither associated nor cosegregated with NIDDM in the Taiwanese population and families. Gly971Arg of IRS-1 gene does not play an important role in the development of NIDDM in this population.

Development of macrovascular diseases in NIDDM patients in northern Taiwan. A 4-yr follow-up study.

OBJECTIVE: To assess the development of macrovascular diseases and explore major associative factors in NIDDM. RESEARCH DESIGN AND METHODS: A total of 479 NIDDM patients > or = 40 yr of age were recruited from four community primary care health centers of northern Taiwan in July 1986 for a cohort study with a 4-yr follow-up. No patient required insulin therapy within 1 yr of diagnosis nor had a history of diabetic ketoacidosis. All were able to participate independently in the activities of daily living. BP and ECG were measured, and a structured questionnaire was asked of each patient. Venous blood after overnight fasting was collected every year to measure cholesterol, HDL cholesterol, plasma glucose, and HbA1c. RESULTS: The duration of diabetes was associated with the development of stroke with a relative risk of 1.063 for every 1-yr increment (P = 0.07). As for HVDs, the significant risk factors were serum cholesterol and HbA1c. For every 1-mg/dl increase in mean total cholesterol level, the relative risk of developing HVD increased 1.016-fold (P = 0.04). For every 1% increase in HbA1c, the relative risk of developing HVD increased 1.170-fold (P = 0.01). With regard to leg VDs, sex and cigarette smoking were significant risk factors. Women diabetic subjects had a higher relative risk than men. Cigarette smoking was significantly associated with leg VD with a relative risk of 6.9 for smokers compared with nonsmokers. The most significant risk factor for LVD was the total cholesterol level. For every 1-mg/dl increase in mean serum cholesterol level, the relative risk of LVD increased 1.013-fold. CONCLUSIONS: In the prevention of macrovascular diseases, effective intervention of the nondiabetic cardiovascular risk factors may be as important as or even more important than the good control of diabetes.

HLA-DQB1 codon 57 and IDDM in Chinese living in Taiwan.

OBJECTIVE: To study the human leukocyte antigen (HLA)-DQB1 genetic background in the Chinese population in Taiwan and its association with the low incidence of insulin-dependent diabetes mellitus (IDDM) in this population. RESEARCH DESIGN AND METHODS: Forty-eight IDDM patients and 59 nondiabetic unrelated control subjects were recruited from the population in Taiwan. HLA-DQB1 exon 2 was enzymatically amplified by polymerase chain reaction. HLA-DQB1 alleles were diagnosed by dot blotting and hybridization with 16 sequence-specific oligonucleotide probes. RESULTS: DQB1*0201 and DQB1*0302 alleles were more frequent and DQB1*0301 and DQB1*0601 were less frequent in Chinese with IDDM than in control subjects. Genotypes for homozygous non-aspartic acid residue (NA/NA) at position 57 were positively associated with IDDM at a relative risk of 4.34 (P < 0.001), and those for homozygous aspartic acid (A/A) were negatively associated with IDDM at a relative risk of 0.14 (P < 0.001). Among the NA/A heterozygotes, only DQB1*0201/DQB1*0303 was significantly increased in IDDM subjects. CONCLUSIONS: The amino acid residue at position 57 of HLA-DQ beta-chain is significantly associated with the development or prevention of IDDM in Chinese subjects living in Taiwan. Other genetic and environmental factors may also play important roles in pathogenesis of IDDM.

Polyether mimics of naturally occurring cytotoxic annonaceous acetogenins.

On the basis of the ionophore model, polyether analogues 4 and 6 were designed and synthesized to mimic the naturally occurring annonaceous acetogenins corossolin (2) and bullatin (5), which were discovered as members of a large family of novel polyketides with cytotoxicity, antitumoral, and other biological activities since 1982. The preliminary screening shows that they have compatible cytotoxicity with the corresponding natural annonaceous acetogenins. These results open a potential way to find more active antitumor agents with simplified structures based on natural annonaceous acetogenins.

The clinicopathological correlation of epithelial subtyping in thymoma: a study of 112 consecutive cases.

The clinicopathological features of 112 thymomas collected from the surgical pathological files of Taipei Veterans General Hospital from 1961 to 1991 were investigated to determinate the clinical efficacy of epithelial subtyping. All thymomas were categorized based on the Müller-Hermelink system into three subtypes: cortical thymoma, mixed thymoma, and medullary thymoma. The former was further subclassified into organoid thymoma, conventional cortical thymoma, and well differentiated thymic carcinoma (WDTC) according to the systems of Pescarmona and Kirchner. The association of each subtype with sex, age at diagnosis, clinical stage, presence of myasthenia gravis, and length of survival was studied. As classified by the Müller-Hermelink system, the cortical thymomas as a whole tended to occur in younger patients and were more frequently associated with myasthenia gravis than the medullary thymomas. The cortical thymomas also showed a propensity to be invasive in nature, whereas the medullary thymomas generally behaved as benign tumors. Further subclassification of cortical thymomas into organoid thymoma, conventional thymoma, and WDTC did not provide more information about clinical behavior. By Kaplan-Meier's actuarial survival analyses none of the epithelial subtypes displayed a statistically significant influence on prognosis. It is concluded that staging remains the most important factor affecting the patient's outcome. Because of the existence of many intermediate forms and the deficiency of clinical relevance, the subclassification of cortical thymomas should be interpreted as a morphological continuum rather than as distinct histological variants.