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Background: Using maximum length sequence brainstem auditory evoked response (MLS BAER) to study brainstem neural conduction and maturation in fetal growth restriction (FGR) babies born very prematurely and assess the effect of FGR on brainstem neural maturation., Methods: MLS BAER was recorded and analyzed at a mean 40 week postmenstrual age in babies born at 27-32 week gestation without other major perinatal conditions or problems. The data were compared between babies with FGR (n = 30) and age-matched babies without FGR (n = 34) to define any differences., Results: A notable difference in MLS BAER was found in interpeak intervals between the babies with FGR and those without FGR. The FGR babies manifested significantly shortened I-III interval, moderately prolonged III-V interval, and significantly decreased III-V/I-III interval ratio. The slope of the I-III interval-rate function in FGR babies was moderately decreased, relative to that in the babies without FGR., Conclusion: FGR babies born very prematurely are associated with accelerated or precocial neural maturation at caudal brainstem regions, but moderately delayed maturation at rostral brainstem regions. The altered brainstem neural maturation is different from previously reported mildly delayed maturation in FGR babies born less prematurely, and may have important implication for neurodevelopmental outcome., Impact: This first MLS BAER study in FGR found that brainstem neural maturation in very premature FGR babies differed from age-matched non-FGR babies. Neural maturation in very premature FGR babies is accelerated or precocial at caudal brainstem regions but moderately delayed at rostral brainstem regions. The altered maturation is different from previously reported mild delay in brainstem neural maturation in FGR babies born less prematurely. FGR exerts a major and differential effect on brainstem neural maturation in babies born very prematurely. This alteration in very premature FGR babies may have important implication for their neurodevelopment., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Ion cyclotron resonance heating (ICRH), one of the main auxiliary methods, for high-power and long-pulse plasma heating had been developed in Experimental Advanced Superconducting Tokamak (EAST). An impedance matching system, one important part of ICRH, had been developed for high-power injection and transmitter protection by reducing the reflected power from the antenna. The input impedance in the outlet of the stub tuner can be measured by voltage-current probes installed on the coaxial transmission line between the antenna and triple liquid stub tuners, and the optimum liquid levels in the stub tuners can be calculated based on the input impedance. The calculation and adjustment process of the optimum liquid levels are described comprehensively in this article. Finally, impedance matching had been achieved between two shots during EAST experiments. In the near future, a real-time impedance matching system will be developed to prevent large variations of the ICRH antenna impedance and achieve steady-state and long-pulse operation with the ICRH system.

Curdlan (CN)-doped montmorillonite/poly(N-isopropylacrylamide-co-N,N'-methylene-bis-acrylamide) [CN/MT/P(NIPA-co-MBA)] smart nanocomposites (NCs) were developed for efficient erlotinib HCl (ERL) delivery to lung cancer cells. The placebo NCs demonstrated excellent biodegradability, pH/thermo-responsive swelling profiles and declined molar mass (M¯c) between the crosslinks with increasing temperature. The XRD, FTIR, DSC, TGA, and SEM analyses revealed the architectural chemistry of these NC scaffolds. The NCs loaded with ERL (F-1-F-3) displayed acceptable diameter (734-1120 nm) and zeta potential (+1.16 to -11.17 mV), outstanding drug entrapping capability (DEE, 78-99%) and sustained biphasic ERL elution patterns (Q 8h , 53-91%). The ERL release kinetics of the optimal matrices (F-3) obeyed Higuchi model and their transport occurred through anomalous diffusion. The mucin adsorption behaviour of these matrices followed Freudlich isotherms. As compared to pure ERL, the formulation (F-3) displayed an improved anti-proliferative potential and induced apoptosis more effectively on A549 cells. Thus, the CN-doped smart NCs could be utilized as promising drug-cargoes for lung cancer therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Functional status of the brainstem auditory pathway was examined at four months of corrected postnatal age in infants born below 30 week gestation to assess the effect of very or extremely preterm birth on postnatal development of the pathway., Methods: Thirty-four preterm infants born at 24-29 week gestation (GA24-29w) were studied at four months of corrected postnatal age. Normal controls were 38 postnatal age-matched term infants. Maximum length sequence brainstem auditory evoked response (MLS BAER) were recorded and analysed with 60 dB nHL clicks., Results: Compared with term control group, GA24-29w group manifested higher BAER threshold (p < 0.05), longer MLS BAER wave latencies at all click rates 91-910/s (p < 0.01-0.001), and lower wave amplitudes at most click rates (p < 0.05-0.01). No significant differences were found between the two groups in I-V interval at any click rates. I-III interval was shorter while III-V interval was longer in GA24-29w group than in term group at higher rates (all p < 0.05). III-V/I-III interval ratio in GA24-29w group was greater at 455 and 910/s clicks (p < 0.05 and 0.01). These interval variables showed similar changes when 4 GA24-29w infants with threshold elevation were excluded., Conclusions: At four months of corrected postnatal age, infants born below 30 week gestation manifested elevated BAER threshold, increased wave latencies, and reduced amplitude. They also manifested a small decrease in I-III interval but a small increase in III-V interval at high rates. Very or extremely preterm birth exerts a mild or moderate effect on postnatal development of the brainstem auditory pathway., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We theoretically investigate the quantum phase transition in the collective systems of qubits in a high quality cavity, where the cavity field is squeezed via the optical parametric amplification process. We show that the squeezed light induced symmetry breaking can result in quantum phase transition without the ultrastrong coupling requirement. Using the standard mean field theory, we derive the condition of the quantum phase transition. Surprisingly, we show that there exists a tricritical point where the first- and second-order phase transitions meet. With specific atom-cavity coupling strengths, both the first- and second-order phase transition can be controlled by the nonlinear gain coefficient, which is sensitive to the pump field. These features also lead to an optical switching from the normal phase to the superradiant phase by just increasing the pump field intensity. The signature of these phase transitions can be observed by detecting the phase space Wigner function distribution with different profiles controlled by the squeezed light intensity. Such superradiant phase transition can be implemented in various quantum systems, including atoms, quantum dots, and ions in optical cavities as well as the circuit quantum electrodynamics system.

A passive and noninvasive diagnostic system based on high-frequency B-dot probes (HFBs) has been designed and developed for the measurement and identification of ion cyclotron emission (ICE) in the Experimental Advanced Superconducting Tokamak (EAST). Details of the hardware components of this system including HFBs, direct current blockers, radio frequency splitters, filters, and power detectors as well as data acquisition systems are presented. A spectrum analyzer is used in addition to the ordinary speed acquisition card for data registration and analysis. The reliability of a HFB based diagnostic system has been well validated during the 2018 spring experiments on the EAST. ICE signals corresponding to fundamental cyclotron frequency of hydrogen ions and harmonics of deuterium ions were observed in experiments where deuterium plasmas were heated with deuterium neutral beams. The field dependence of ICE has been verified by recent experiments with three different background magnetic fields. The observed ratio of the ICE frequency is consistent with the ratio of the magnetic field intensity within measurement errors of a few percent.

Objective: To identify the effect of pregnancy induced hypertension on neonatal outcomes in early and moderate preterm infants of gestational age less than 34 weeks., Study Design: Prospectively collected data in 773 premature deliveries less than 34 weeks from 10 centers in China between July 2014 and July 2016 were analyzed in this cohort study. Univariate and Multivariate regression analyses were conducted to exam the effect of pregnancy induced hypertension on neonatal outcomes, including mortality to discharge, intrauterine growth restriction, severe brain injury, neonatal respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, early onset of sepsis and retinopathy of prematurity., Results: The incidence of PIH in this cohort was 18.4%. Women with PIH tended to have a higher cesarean delivery rate (78.2% vs 40.9%, P < 0.001). More tocolytics and magnesium sulfate were used in PIH women (72.5% vs 48.7%, P < 0.001; 59.2% vs 34.7%, P < 0.001). Mean birth weight was lower in infants of PIH mothers than infants of non-PIH mothers (1522.1 ± 348.8 g vs 1683.4 ± 345.3, P < 0.001). In multivariate regression models, PIH was associated with increased risk of IUGR (OR 8.402; 95% CI 4.350-16.227) and lower odds of NRDS (OR 0.526; 95% CI 0.332-0.853)., Conclusion: Preterm infants less than 34 weeks born to PIH women had a higher risk of intrauterine growth restriction and lower birth weight. PIH warrants more intensive interventions to prevent relevant infant morbidities., (Copyright © 2018. Published by Elsevier B.V.)

Chronic lymphocytic leukaemia (CLL) is uncommon in Chinese population and its biology, genetics and treatment outcome in Chinese patients have not been comprehensively investigated. In this study, we studied the clinicopathological features and outcome of 212 Chinese patients with newly diagnosed CLL in Hong Kong and Singapore. The median age at diagnosis was 64 years. The majority of patients presented with early-stage disease (Binet stage A, 56.1%). Del(13)(q14) was the most frequent abnormality (41.7%) detected by fluorescence in situ hybridization (FISH) analysis. Del(17p) and TP53 gene mutations were detected in 7.8% and 8.2% of patients, respectively. MYD88 mutations were found at a higher frequency (11.5%) than expected. CLL with unmutated variable region of the immunoglobulin heavy chain genes (IGHV) occurred in only 31.2% of cases, and was associated with advanced-stage disease (p <0.01) and adverse FISH abnormalities (p<0.01). With a median follow-up of 39 months, the median overall survival (OS) was 108 months. The presence of del(17p) or TP53 mutations was associated with a significantly shorter time to first treatment and an inferior OS (p <0.01). Unmutated IGHV was also associated with a significantly shorter time to treatment (p <0.01). Among patients who required treatment, the median OS and progression-free survival (PFS) were 107 and 23 months, respectively. The presence of del(17p) was associated with a significantly inferior OS and PFS (p <0.01). In summary, Chinese CLL patients had similar genetic aberrations at diagnosis compared with those of Western populations. FISH abnormalities are major factors affecting outcome.

Objective: To examine brainstem auditory electrophysiology in high-risk babies born at 28-32week gestation by analysing the amplitudes of wave components in maximum length sequence brainstem auditory evoked response (MLS BAER)., Methods: 94 preterm babies, ranging in gestation 28-32weeks, with perinatal problems (high-risk) were recruited. The amplitudes of MLS BAER wave components were studied at term age (37-42weeks postconceptional age)., Results: Compared with normal term controls, the amplitude in the high-risk preterm babies was significantly smaller at the highest click rate 910/s for wave I (p<0.01), at all 91-910/s for wave III (all p<0.01) and at 455 and 910/s (p<0.05 and 0.01) for wave V. Compared with age-matched low-risk preterm controls, the amplitude was significantly smaller at 455 and 910/s for wave I (p<0.05 and 0.05), 91-910/s for wave III (p<0.05-0.001), and 227-910/s (p<0.05 and 0.01) for wave V. No differences in the V/I and V/III amplitude ratios were found between the high-risk preterm babies and the controls., Conclusions: The amplitudes of MLS BAER wave components, mainly more central components, were reduced in the high-risk preterm babies born at 28-32week gestation. Electrophysiological activity of the brainstem auditory neuron in such babies is depressed, mainly attributed to or related to the associated perinatal problems., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: Babies born extremely preterm are predisposed to brain damage. We test the hypothesis that functional integrity of the auditory brainstem, particularly the rostral regions, is impaired in extremely preterm babies., Methods: We recruited 68 babies who were born at 23-27 weeks of gestation. At term date, these babies were studied by recording and analysing maximum length sequence brainstem auditory evoked response (MLS BAER) with click rates 91-910/s. Detailed data analysis was performed in 65 babies from whom reliable MLS BAER measurements were obtained., Results: Compared with normal term controls, the extremely preterm babies showed a significant increase in wave V latency, and I-V interval at all rates 91-910/s (p<0.01-0.001). Of two small intervals, I-III interval showed no apparent abnormality, but III-V interval was significantly increased at all rates, which was supported by a significant increase in III-V/I-III interval ratio (all p<0.001). These abnormalities were more significant at higher than at lower rates. The slopes of wave V latency-, I-V interval- and particularly III-V interval-rate functions were all increased. The same was true for the slope of III-V/I-III interval ratio-rate function., Conclusions: MLS BAER variables that mainly reflect central neural conduction in the extremely preterm babies were abnormally increased. The most important abnormality was a significant increase in III-V interval and its click rate-dependent change. The abnormalities tended to be more significant than those previously reported in late and very preterm babies., Significance: Babies born extremely preterm have a major impairment or maturational delay in functional integrity of the rostral regions of the immature brainstem, which is more significant than in less preterm babies., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: Infants with slight/mild or late-onset hearing impairment might be missed in universal newborn hearing screening (UNHS). We identified the mutation hot spot of common deaf gene in the newborns in Jinan area population by screening the mutation spot with neonate cord blood, in order to make clear whether the neonate cord blood for screening is feasible., Methods: Six hundred and forty-six newborns were subjected to both UNHS and genetic screening for deafness by using neonate cord blood. The newborn genetic screening targeted four deafness-associated genes, which were commonly found in the Chinese population including gap junction beta-2 protein (GJB2), gap junction beta-3 protein (GJB3), solute carrier family 26 member 4 (SLC26A4), and mtDNA 12S rRNA. The most common 20 spot mutations in 4 deaf genes were detected by MassARRAY iPLEX platform and mitochondrial 12S rRNA A1555G and C1494T mutations were sequenced using Sanger sequencing., Results: Among the 646 newborns, 635 cases passed the UNHS and the other 11 cases (1.7%) did not. Of the 11 failures, two cases were found to carry homozygous GJB2 p.R143W pathogenic mutation, one case was found to have heterozygous GJB2 235delC mutation, and another one case carried heterozygous GJB3 p.R180X pathogenic mutation. Six hundred and thirty-five babies passed the newborn hearing screening, in which 25 babies were identified to carry pathogenic mutations, including 12 heterozygotes (1.9%) for GJB2 235delC, eight heterozygotes (1.3%) for SLC26A4 IVS7-2A>G, one heterozygote (0.2%) for p.R409H, two homozygotes (0.3%) for m.1494C>T, and two homozygotes (0.3%) for m.1555A>G., Conclusion: Newborn genetic screening through the umbilical cord blood for common deafness-associated mutations may identify carriers sensitive to aminoglycoside antibiotic, and can effectively prevent or delay hearing loss occurs.

Background: Neonatal necrotizing enterocolitis (NEC) is associated with an increased incidence of poor neurodevelopment. The knowledge of underlying neurophysiology is very limited, and the influence of NEC on the preterm brainstem is very poorly understood., Objective: To assess the effect of NEC on the immature auditory brainstem by excluding any possible confounding effect of preterm birth., Methods: We recorded and analyzed brainstem auditory evoked response (BAER) at different click rates in preterm babies (30-34 weeks gestation) after NEC. The results were compared with those in age-matched healthy preterm babies who had no NEC., Results: At click rate 21/s, the latencies of BAER waves I and III in the preterm NEC babies were similar to those babies without NEC. However, wave V latency was longer in the NEC babies than in those without NEC. The I-V interpeak interval was also longer in the NEC babies than in those without NEC. These abnormalities were persistent at higher click rates 51 and 91/s. Wave I amplitude in the preterm NEC babies did not differ significantly from that in those without NEC, but wave III and V amplitudes were smaller than in those without NEC at all 21-91/s clicks., Conclusions: Compared with healthy preterm babies, preterm babies after NEC showed a major increase in wave V latency and I-V interval at all 21-91/s clicks. Brainstem auditory function is impaired in preterm NEC babies after excluding the possible confounding effect of preterm birth. Neonatal NEC and associated perinatal conditions adversely affect the premature brainstem.

Conclusion: The hearing threshold in preterm infants was 23 dB above adult hearing level at 30 weeks gestation, and decreased to around 13 dB at term date. There was no major difference in the threshold for infants born at different gestations. At term, 9% had hearing threshold elevation., Objective: To examine changes in hearing threshold from preterm to term in infants born at 30-36 weeks gestation and to detect the prevalence of threshold elevation., Methods: The threshold in brainstem auditory evoked response (BAER) was obtained 656 times from postconceptional age (PCA) 30 to 42 weeks in 268 infants born at 30-36 weeks gestation., Results: The BAER threshold was 23 dB nHL at the youngest age (PCA 30 weeks), and then decreased to around 13 dB nHL at later preterm and term dates (PCA 35-42 weeks). The threshold was decreased with increasing age at a rate of 1.24 dB per week from PCA 30 to 36 weeks and 0.65 dB per week from PCA 30 to 42 weeks. At PCA 33-42 weeks, there were no significant differences in BAER threshold between the infants born at gestational age (GA) 30-32 weeks and those at GA 33-36 weeks. At term, 9% had threshold elevation (>20 dB nHL).

Objective: To investigate the effect of pulmonary surfactant (PS) on the Th1/Th2 balance and serum levels of interleukin-4 (IL-4), interferon-γ (IFN-γ) and IgE in neonates with respiratory distress syndrome (RDS)., Methods: A total of 58 neonates with RDS were divided into control (n=20) and PS treatment groups (n=38). The control group underwent mechanical ventilation and other conventional treatment, while the PS treatment group received with bovine PS treatment within 1 hour of being admitted to the hospital together with mechanical ventilation and other conventional treatment. Enzyme-linked immunosorbent assay was used to measure serum levels of IL-4, IFN-γ and IgE before treatment and 24, 48 and 72 hours after treatment. Simultaneously, arterial blood gas, respiratory system compliance, and other ventilator parameters were recorded., Results: Compared with the control group, the PS treatment group showed significantly shorter duration of mechanical ventilation and oxygen exposure time (P<0.05), significantly better respiratory system compliance and significantly lower oxygenation index 24, 48 and 72 hours after treatment (P<0.05). At 48 and 72 hours after treatment, serum levels of IFN-γ were significantly lower in the PS treatment group than in the control group (120±46 ng/L vs 229±59 ng/L, P<0.05; 141±40 ng/L vs 282±44 ng/L, P<0.05), and serum levels of IL-4 were significantly higher in the PS treatment group than in the control group (263±48 pg/mL vs 152±45 pg/mL, P<0.05; 417±49 pg/mL vs 201±46 pg/mL, P<0.05). At 72 hours after treatment, serum level of IgE was significantly lower in the PS treatment group than in the control group (115±44 pg/mL vs 199±43 ng/mL; P<0.05)., Conclusions: PS treatment can shorten the duration of mechanical ventilation and oxygen exposure time, regulate serum levels of IFN-γ, IL-4 and IgE, and influence Th1/Th2 balance in neonates with RDS, thus inhibiting lung inflammatory response and reducing lung injury.

Aim: To examine brainstem auditory function and detect any abnormality at term in preterm infants after neonatal necrotizing enterocolitis (NEC)., Methods: Brainstem auditory evoked response (BAER) was recorded at 21/sec and 60 dB nHL in 37 preterm infants who had NEC. The data obtained at term equivalent age were analyzed and compared with those in normal term infants., Results: The threshold of BAER in infants after NEC, though slightly elevated, did not differ significantly from that in the controls. The latencies of waves I and III were slightly longer than in the controls, without any statistical significance. However, wave V latency was prolonged and differed significantly from the controls (p < 0.01). I-V interpeak interval was also prolonged (p < 0.05). The data point distribution of wave V latency and I-V interval was higher in the infants after NEC than in the controls. The amplitudes of BAER wave components in the infants after NEC did not differ significantly from those in the controls., Conclusion: Preterm infants after NEC have no major abnormality in peripheral auditory function. However, neural conduction in the brainstem auditory pathway is abnormal, suggesting that NEC adversely affects brainstem auditory conduction., (© 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.)

Objective: To examine whether late preterm infants with perinatal problems are at risk of brainstem auditory impairment., Methods: 68 high-risk late preterm infants (gestation 33-36 weeks) with perinatal problems or conditions were studied at term using maximum length sequence brainstem auditory evoked response. The controls were 41 normal term infants and 37 low-risk late preterm infants., Results: Compared with normal term infants, the high-risk late preterm infants demonstrated a significant abnormal increase in MLS BAER variables that mainly reflect more central function of the brainstem auditory pathway, including wave V latency, III-V and I-V interpeak intervals, and III-V/I-III interval ratio. The abnormalities were more significant at higher than at lower click rates. The slopes of MLS BAER-rate function for these variables were increased. Compared with low-risk late preterm infants, the high-risk infants showed similar, though slightly less significant, abnormalities, mainly a significant increase in III-V and I-V intervals., Conclusions: Maximum length sequence brainstem auditory evoked response components that mainly reflect central function of the auditory brainstem were abnormal at term in high-risk late preterm infants., Significance: More central regions of the auditory brainstem are impaired in high-risk late preterm infants, which is mainly caused by associated perinatal problems or conditions., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Aim: To examine brainstem auditory function at term in late preterm infants admitted to neonatal intensive care unit (NICU)., Methods: Fifty-two preterm infants, born at 33-36 week gestation, were recruited in an NICU and were studied at term using brainstem auditory evoked response (BAER)., Results: Compared with normal term infants, BAER wave V latency in the NICU preterm infants was increased at 51 and 91/sec (p<0.05, 0.05). Intervals of III-V and I-V were increased at all 21, 51 and 91/sec clicks (p<0.05-0.01), which was more significant at higher than lower rates. Interval ratio of III-V/I-III was increased significantly at 51 and 91/sec (p<0.05 and 0.01). Wave I and III latencies and I-III interval did not differ significantly from normal controls at any click rates. All amplitudes of waves I, III and V amplitude tended to be reduced at higher rates, while wave I amplitude was reduced significantly at 91/sec clicks., Conclusion: There were BAER abnormalities in the NICU late preterm infants, suggesting compromised brainstem auditory function. Compared with a basically normal BAER in low-risk late preterm infants previously reported, the abnormalities suggest that perinatal problems or complications adversely affect the late preterm auditory brainstem., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Aim of the Study: Postmenopausal osteoporosis is mainly treated with estrogen replacement therapy (ERT). However, ERT causes side effects, mainly breast cancer, uterine cancer and thromboembolic problems. Labisia pumila var. arata (LPva), a herb with phytoestrogenic effects has the potential to be used as an alternative agent to ERT. This study was conducted to determine the effects of LPva on bone biochemical markers and bone calcium content in ovariectomised rats., Materials and Methods: Thirty two Wistar rats were divided into 4 groups, with 8 rats in each group. The first group was sham operated (Sham), the second group was ovariectomised (OVX), the third (LPva) and fourth group (ERT) were also ovariectomised and given LPva 17.5 mg/kg and Premarin(®) 64.5 μg/kg, respectively. Blood samples were taken before and after treatment to measure osteocalcin and C-terminal telopeptide of type 1 collagen levels using ELISA while the fifth lumbar bone samples were taken to measure bone calcium content using the Atomic Absorption Spectrophotometer (AAS)., Results: The osteocalcin levels were significantly higher in both the LPva and ERT groups compared to the OVX group. The CTX levels were significantly lower in both the LPva and ERT groups compared to the OVX group. However, only the ERT group had significantly higher bone calcium level compared to the OVX group., Conclusion: The supplementation of 17.5 mg/kg of LPva to ovariectomised rats for 8 weeks was able to prevent the changes in bone biochemical markers but failed to prevent the bone calcium loss induced by ovariectomy., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: X-linked adrenoleukodystrophy (X-ALD) is the most common inherited disorder of peroxisomal metabolism which is characterized by demyelination of central nervous system, impaired adrenal cortex and abnormal accumulation of very long chain fatty acids in body fluid and tissues. In this study, the clinical features and the genotype-phenotype relationship were investigated so as to help early diagnosis., Methods: Clinical data of 89 Chinese patients with X-ALD were analyzed and mutation spectrums in 53 of the patients were investigated by polymerase chain reaction and DNA sequencing., Results: Of the 89 cases, 60 (67.4%) had childhood cerebral ALD (CCALD, mean age of onset was 6.5 years, range 2 - 10 years), 18 (20.2%) had adolescent cerebral ALD (ACALD, mean age of onset 12.1 years, range 11 - 19 years), 7 (7.9%) had adrenomyeloneuropathy (AMN, mean age of onset 23 years, range 6 - 39.5 years), and two cases were asymptomatic and another 2 had simple Addison's disease only. CCALD was the most common and severe phenotype, visual impairment was the most common initial symptom in CCALD and ACALD patients. Twenty four cases (63%) in whom hydrocortisone and ACTH were measured showed adrenal insufficiency. Forty five different mutations were identified in 53 patients. Missense mutations were the most common. No hotspot mutation was found in these patients and 1415delAG, the most frequent mutation found worldwide seemed not to be the real "hotspot" in these Chinese patients. The same phenotype may be due to diverse genomic mutations. A single mutation may result in different phenotypes even within a family., Conclusion: The phenotype distribution, initial symptom and gene mutation spectrum of Chinese patients may not be completely consistent with those in other countries. The clinical phenotype of the disease had no definite relationship with the nature of gene mutations.

Objective: To make prenatal dignosis of X-linked adrenoleukodystrophy (ALD) for the prevention of the disease., Methods: Eighteen amniocenteses were performed on 17 suspected carriers of X-ALD during 18-30 gestation weeks. The very long chain fatty acids (VLCFAs) levels of cultured amniocytes were tested by gas chromatography-mass spectrometry (GC/MS). The plasma VLCFAs levels were measured in 8 of the 18 prenatal diagnosed children when they were born or after abortion. ABCD1 gene mutation analysis was carried out in 8 cases by PCR and sequencing. ALDP of amniocytes was tested by Western blotting in 2 cases from a family, one female, another male, and the VLCFAs of cultured amniocytes were increased in both of them., Results: Among the 18 fetuses, 10 were males and 8 were females. The VLCFAs levels of the cultured amniocytes were increased in 3 males and 4 females. The postnatal plasma VLCFAs were normal in 5 cases with normal VLCFAs levels of amniocytes, and increased in 3 cases with high VLCFAs levels of amniocytes. ABCD1 gene mutations were found in 4 cases with high VLCFAs levels of amniocytes, no mutation was found in other 4 cases with normal VLCFAs levels of amniocytes. ALDP of amniocytes could be detected in the female with high VLCFAs levels of amniocytes, and it could not be detected in the male with high VLCFAs levels of amniocytes. Three male fetuses with high VLCFAs levels of amniocytes were aborted. The others who were born were normal clinically so far., Conclusion: The prenatal diagnosis is very important for the prevention of ALD. Amniocyte VLCFAs level analysis combined with ABCD1 gene mutation analysis and ALDP test could make a proper prenatal diagnosis.

Objective: To elucidate the phenotype and the genotype-phenotype correlations in Chinese patients with X-linked adrenoleukodystrophy (X-ALD)., Methods: Clinical features of 40 Chinese patients with X-ALD were studied and mutation spectrums were investigated by polymerase chain reaction (PCR) and sequencing., Results: Among these patients, four were siblings from two unrelated families, the others were unrelated. There were 31 cases with childhood cerebral (CCALD), 8 cases with adolescent cerebral (ACALD) and 1 case with adrenomyeloneuropathy (AMN). Visual impairment, which presented in 12 cases (30%), was the most common initial symptom. Nine (69%) of 13 cases who had hydrocortisone and ACTH measured showed adrenal insufficiency. By follow-up date, 19 cases (47.5%) were dead. The interval from onset to death varied from 1 to 6 years and the average were 3.3 years. The mean age at death was 10.5 years. Eleven cases (27.5%) were in vegetable state. The mean interval from onset to apparently vegetable state was 2.8 years (range from 1 to 6 years). Four cases had progressive neurological disability. Four cases were lost follow-up. One case with CCALD and one case with ACALD progressed slowly. The courses of the disease of these two patients were 5 years and 15 years respectively. Thirty five mutations were identified in 40 cases. Most were located within exon 1-3 (40%, 16/40) and exon 6-8 (42%, 17/40). There is a distinct clustering of missense mutations in exon 6 (17%, 7/40). Five types of mutations were associated with CCALD, three with ACALD and a missense mutation was identified in the patients with AMN. The two patients with long disease courses had a missense mutation c.1559 T>A and a nonsense mutation c.1785 G>A respectively. The siblings with similar manifestations and onset age were observed in two families, whose mutations were c.887 A>G and c.1028 G>T., Conclusion: The phenotypes, disease severity and rate of neurodegeneration could not be predicted by the nature of mutations.

Aberrant methylation of promoter CpG regions is a putative mechanism whereby tumor suppressor genes are inactivated. We used a candidate gene approach to investigate the patterns and significance of this epigenetic change in natural killer (NK) cell malignancies. Thirty-three patients were studied for promoter methylation in five putative tumor suppressor genes by methylation-specific polymerase chain reaction (MSP), which has a sensitivity of 10(-3). The p73 gene was methylated in 94% of cases, a frequency that is the highest known for any human malignancy. In the NK cell lymphoma line NK92, p73 was also completely methylated, and the p73 transcript was correspondingly not detectable by quantitative polymerase chain reaction. Treatment of the cell line with 5-azacytidine, a demethylation reagent, led to demethylation of the p73 promoter and reinduction of p73 gene expression. These results suggested that promoter CpG methylation might be an important mechanism in suppressing p73 gene expression in NK cells. Other methylated genes included hMLH1 (63%), p16 (63%), p15 (48%), and RAR beta (47%). Methylation of two or more genes occurred in 88% of cases. With promoter methylation as a molecular marker, MSP identified two cases of occult marrow metastasis. Interestingly, the primary tumor and metastasis showed different methylation patterns, implying that separate clonal evolutions might have occurred at these sites. Furthermore, MSP also identified tumor infiltration in random oropharyngeal biopsies in a case where histological examination could not show evidence of tumor involvement. We conclude that NK cell malignancies show a specific pattern of promoter methylation, with p73 being consistently involved. These results suggest that p73 may be an important target in the neoplastic transformation of NK cells, and the demonstration of its methylation may serve as a potential molecular tool for NK cell lymphoma detection.