BACKGROUND & AIMS: BACKGROUND:This study explored the combined impact of depression and inflammation on memory functioning among Mexican-American adults and elders. METHODS:Data were analyzed from 381 participants of the Health and Aging Brain study among Latino Elders (HABLE). Fasting serum samples were collected and assayed in duplicate using electrochemiluminesce on the SECTOR Imager 2400A from Meso Scale Discovery. Positive DepE (depression endophenotype) was codified as any score >1 on a five-point scale based on the GDS-30. Inflammation was determined by TNFα levels and categorized by tertiles (1st, 2nd, 3rd). WMS-III LMI and LMII as well as CERAD were utilized as measures of memory. ANOVAs examined group differences between positive DepE and inflammation tertiles with neuropsychological scale scores as outcome variables. Logistic regressions were used to examine level of inflammation and DepE positive status on the risk for MCI. RESULTS:Positive DepE as well as higher inflammation were both independently found to be associated with lower memory scores. Among DepE positive, those who were high in inflammation (3rd tertile) were found to perform significantly worse on WMS-III LM I (F = 4.75, p = 0.003), WMS-III LM II (F = 8.18, p < 0.001), and CERAD List Learning (F = 17.37, p < 0.001) when compared to those low on inflammation (1st tertile). The combination of DepE positive and highest tertile of inflammation was associated with increased risk for MCI diagnosis (OR = 6.06; 95% CI = 3.9-11.2, p < 0.001). CONCLUSION:Presence of elevated inflammation and positive DepE scores increased risk for worse memory among Mexican-American older adults. Additionally, the combination of DepE and high inflammation was associated with increased risk for MCI diagnosis. This work suggests that depression and inflammation are independently associated with worse memory among Mexican-American adults and elders; however, the combination of both increases risk for poorer memory beyond either alone.

背景与目标：

BACKGROUND & AIMS: OBJECTIVES:Monochorionic (MC) twins are at increased risk of early fetal loss secondary to vascular complications such as twin-twin transfusion syndrome (TTTS). This study compared the early perinatal loss rates between MC and dichorionic (DC) twins in an era of invasive treatment for TTTS. METHODS:This was a retrospective study of all twin pregnancies of known chorionicity from a large regional cohort of nine hospitals over a 10-year period. Ultrasound data were matched to hospital delivery records and to a mandatory national register of pregnancy losses. Prospective risk of pregnancy loss from 14 to 24 weeks' gestation was calculated and the survival trend of MC and DC twins was analyzed using Kaplan-Meier survival analysis. RESULTS:The analysis included 3117 twin pregnancies (605 MC and 2512 DC). The total risk of early pregnancy loss (miscarriage and neonatal death) before 24 weeks was significantly higher in MC twins (60.3 per 1000 fetuses) than in DC twins (6.6 per 1000 fetuses), with a relative risk of 9.18 (95% CI, 6.0-13.9). Survival analysis showed a significant difference in overall and early mortality between MC and DC twins (log-rank test, P < 0.0001), while no difference was noted after 24 weeks' gestation (log-rank test, P = 0.08). CONCLUSIONS:Early pregnancy loss is significantly more common in MC than in DC twins, but no difference in the prospective risk of mortality between MC and DC twins is evident after 24 weeks' gestation. The observed early mortality rate has almost halved in comparison with previous studies in the published literature. Early detection and prompt treatment of complications in MC twins are likely to have contributed to this improvement in outcome.

背景与目标：

BACKGROUND & AIMS: :Triple-negative breast cancer is characterized by aggressive tumours whose cells lack oestrogen and progesterone receptors and do not over-express HER2. It accounts for approximately 10-15% of breast cancer cases. We sought to generate a cellular model of chemotherapy drug resistance for this type of disease to provide the tools for the development of new therapies. Doxorubicin is a component of some chemotherapy regimes used to treat this form of cancer but resistance preventing disease eradication frequently occurs, mainly due to over-expression of drug transporters such as P-glycoprotein. CALDOX cells were generated by exposure of CAL51 to doxorubicin. Resistance to doxorubicin did not involve drug transporters, as the both parental and resistant cells accumulated doxorubicin to comparable levels. CALDOX cells had slower proliferation rate and an extended G1 cell cycle stage than the parental line, mainly due to an intrinsic activation of CDNK1 (p21), but this cell cycle block was not involved in the mechanism of resistance. CALDOX cells had reduced levels of TOP2A (topoisomerase IIα) and were cross resistant to the topoisomerase II inhibitors etoposide and mitoxantrone. CALDOX cells showed collateral sensitivity to carmustine due to the lack of O⁶-methylguanine-DNA-methyltransferase (MGMT) expression, related to the hypermethylation of its promoter. The collateral sensitivity of CALDOX cells to carmustine provides the rationale to evaluate MGMT promoter methylation status to design better therapeutic strategies for triple negative breast cancer.

背景与目标： : 三阴性乳腺癌的特征是侵袭性肿瘤，其细胞缺乏雌激素和孕激素受体，并且不会过度表达her2。它约占乳腺癌病例的10-15%。我们试图为这种类型的疾病生成化学疗法耐药性的细胞模型，以为开发新疗法提供工具。阿霉素是用于治疗这种癌症的某些化学疗法方案的组成部分，但经常发生抗药性预防疾病根除，这主要是由于药物转运蛋白 (例如P-糖蛋白) 的过表达。CALDOX细胞是通过将CAL51暴露于阿霉素而产生的。对阿霉素的耐药性不涉及药物转运蛋白，因为亲本和耐药细胞都积累了阿霉素的水平相当。与亲本系相比，钙氧化细胞的增殖速度较慢，G1细胞周期阶段延长，这主要是由于CDNK1 (p21) 的内在激活，但这种细胞周期阻滞不参与抗性机制。钙氧化细胞的TOP2A (拓扑异构酶II α) 水平降低，并且对拓扑异构酶II抑制剂依托泊苷和米托蒽醌具有交叉抗性。由于缺乏o-甲基鸟嘌呤-DNA-甲基转移酶 (MGMT) 表达，CALDOX细胞对卡莫司汀表现出附带敏感性，这与其启动子的高甲基化有关。CALDOX细胞对卡莫司汀的附带敏感性为评估MGMT启动子甲基化状态以设计更好的三阴性乳腺癌治疗策略提供了依据。

BACKGROUND & AIMS: :Polybrominated diphenyl ethers (PBDEs), chemicals commonly used as flame-retardants in consumer products, are emerging persistent organic pollutants that are ubiquitous in the environment. In this study, we report a PBDE-respiring isolate - Dehalococcoides mccartyi strain GY50, which debrominates the most toxic tetra- and penta-BDE congeners (∼1.4 µM) to diphenyl ether within 12 days with hydrogen as the electron donor. The complete genome sequence revealed 26 reductive dehalogenase homologous genes (rdhAs), among which three genes (pbrA1, pbrA2 and pbrA3) were highly expressed during PBDE debromination. After 10 transfers of GY50 with trichloroethene or 2,4,6-trichlorophenol as the electron acceptor instead of PBDEs, the ssrA-specific genome island (ssrA-GI) containing pbrA1 and pbrA2 was deleted from the genome of strain GY50, leading to two variants (strain GY52 with trichloroethene, strain GY55 with 2,4,6-trichlorophenol) with identically impaired debromination capabilities (debromination of penta-/tetra-BDEs ceased at di-BDE 15). Through analysis of Illumina paired-end sequencing data, we identified read pairs that probably came from variants that contain ssrA-GI deletions, indicating their possible presence in the original strain GY50 culture. The two variant strains provide real-time examples on rapid evolution of organohalide-respiring organisms. As PBDE-respiring organisms, GY50-like strains may serve as key players in detoxifying PBDEs in contaminated environments.

背景与目标： : 多溴联苯醚 (PBDEs) 是消费品中常用作阻燃剂的化学品，是环境中普遍存在的新兴持久性有机污染物。在这项研究中，我们报告了一个PBDE呼吸分离物-Dehalococcoides mccartyi菌株GY50，该菌株在12天内以氢为电子供体将毒性最大的四溴化和五溴化同系物 (〜1.4 µ m) 脱溴为二苯醚。完整的基因组序列揭示了26个还原脱卤酶同源基因 (rdha)，其中三个基因 (pbrA1，pbrA2和pbrA3) 在PBDE脱溴过程中高度表达。用三氯乙烯或2,4，6-三氯苯酚作为电子受体而不是多溴二苯醚对GY50进行10次转移后，从菌株GY50的基因组中删除了含有pbrA1和pbrA2的ssrA特异性基因组岛 (ssrA-GI)，导致两个变体 (具有三氯乙烯的菌株GY52，具有2,4的菌株GY55，6-三氯苯酚) 的脱溴能力同样受损 (五溴/四溴二苯醚的脱溴在二溴二苯醚15时停止)。通过对Illumina配对末端测序数据的分析，我们确定了可能来自包含ssrA-GI缺失的变体的读取对，表明它们可能存在于原始菌株GY50培养物中。这两个变体菌株提供了有关有机卤化物呼吸生物快速进化的实时示例。作为多溴二苯醚呼吸的生物，GY50-like菌株可能是污染环境中多溴二苯醚解毒的关键角色。

BACKGROUND & AIMS: OBJECTIVE:Unidentified hearing loss at birth can adversely affect speech and language development as well as academic achievement and social-emotional development. Historically, moderate-to-severe hearing loss in young children was not detected until well beyond the newborn period. Around 0.5 to 5 in every 1000 neonates and infants have congenital or early childhood onset sensorineural hearing impairment. When identification and intervention occur at no later than 6 months of age, the infants perform much higher on school-related measures. Therefore, early detection is vitally important. Toward the end of 2009, the Israeli ministry of health issued a directive establishing a universal newborn hearing screening program in all hospitals in the country from 01.01.10. The objectives of this study are to evaluate a newly established universal newborn hearing screening program, to assess performance and to compare measurements of performance to performance benchmarks representing a consensus of expert opinion. The benchmarks are the minimal requirements that should be attained by high-quality early hearing detection programs. METHODS:As specified by the ministry of health, a two-stage screening protocol was implemented using otoacoustic emissions and automated auditory brainstem response. Screening results of all neonates born from the initiation of the program on 15th March 2010 until the end of 2011 were reviewed. RESULTS:The total number of live births during the study period was 5496. Of these, 5334 (97%) started screening for hearing loss but only 5212 completed the screening process, giving a screening coverage of 94.8%. Of the 5212 neonates completing the screening process, 270 (5.18%) were referred for full diagnostic testing. CONCLUSIONS:The newly established universal newborn hearing screening program at the Ziv Medical Center in Zefat closely approaches, but does not yet meet the minimal requirements that should be attained by high-quality early hearing detection programs. Every effort should be made to complete the screening tests before discharge from hospital. Screening staff should actively encourage parents to participate in all stages of early detection.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Reductions in admissions for myocardial infarction (MI) have been reported in locales where smoke-free workplace laws have been implemented, but no study has assessed sudden cardiac death in that setting. In 2002, a smoke-free restaurant ordinance was implemented in Olmsted County, Minnesota, and in 2007, all workplaces, including bars, became smoke free. METHODS:To evaluate the population impact of smoke-free laws, we measured, through the Rochester Epidemiology Project, the incidence of MI and sudden cardiac death in Olmsted County during the 18-month period before and after implementation of each smoke-free ordinance. All MIs were continuously abstracted and validated, using rigorous standardized criteria relying on biomarkers, cardiac pain, and Minnesota coding of the electrocardiogram. Sudden cardiac death was defined as out-of-hospital deaths associated with coronary disease. RESULTS:Comparing the 18 months before implementation of the smoke-free restaurant ordinance with the 18 months after implementation of the smoke-free workplace law, the incidence of MI declined by 33% (P < .001), from 150.8 to 100.7 per 100,000 population, and the incidence of sudden cardiac death declined by 17% (P = .13), from 109.1 to 92.0 per 100,000 population. During the same period, the prevalence of smoking declined and that of hypertension, diabetes mellitus, hypercholesterolemia, and obesity either remained constant or increased. CONCLUSIONS:A substantial decline in the incidence of MI was observed after smoke-free laws were implemented, the magnitude of which is not explained by community cointerventions or changes in cardiovascular risk factors with the exception of smoking prevalence. As trends in other risk factors do not appear explanatory, smoke-free workplace laws seem to be ecologically related to these favorable trends. Secondhand smoke exposure should be considered a modifiable risk factor for MI. All people should avoid secondhand smoke to the extent possible, and people with coronary heart disease should have no exposure to secondhand smoke.

背景与目标：

BACKGROUND & AIMS: JUSTIFICATION:Hearing impairment is one of the most critical sensory impairments with significant social and psychological consequences. Evidence-based, standardized national guidelines are needed for professionals to screen for hearing impairment during the neonatal period. PROCESS:The meeting on formulation of national consensus guidelines on developmental disorders was organized by Indian Academy of Pediatrics in Mumbai, on 18th and 19th December, 2015. The invited experts included Pediatricians, Developmental Pediatricians, Pediatric Neurologists and Clinical Psychologists. The participants framed guidelines after extensive discussions. OBJECTIVE:To provide guidelines on newborn hearing screening in India. RECOMMENDATIONS:The first screening should be conducted before the neonate's discharge from the hospital - if it 'fails', then it should be repeated after four weeks, or at first immunization visit. If it 'fails' again, then Auditory Brainstem Response (ABR) audiometry should be conducted. All babies admitted to intensive care unit should be screened via ABR. All babies with abnormal ABR should undergo detailed evaluation, hearing aid fitting and auditory rehabilitation, before six months of age. The goal is to screen newborn babies before one month of age, diagnose hearing loss before three months of age and start intervention before six months of age.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:Although there is evidence for a beneficial effect of increased quadriceps strength on knee symptoms, the effect on knee structure is unclear. We undertook this study to examine the relationship between change in vastus medialis cross-sectional area (CSA) and knee pain, tibial cartilage volume, and risk of knee replacement in subjects with symptomatic knee osteoarthritis (OA). METHODS:One hundred seventeen subjects with symptomatic knee OA underwent magnetic resonance imaging of the knee at baseline and at 2 and 4.5 years. Vastus medialis CSA was measured at baseline and at 2 years. Tibial cartilage volume was measured at baseline and at 2 and 4.5 years. Knee pain was assessed by the Western Ontario and McMaster Universities Osteoarthritis Index at baseline and at 2 years. The frequency of knee joint replacement over 4 years was determined. Regression coefficients (B) and odds ratios were determined along with 95% confidence intervals (95% CIs). RESULTS:After adjusting for confounders, baseline vastus medialis CSA was inversely associated with current knee pain (r = -0.16, P = 0.04) and with medial tibial cartilage volume loss from baseline to 2 years (B coefficient -10.9 [95% CI -19.5, -2.3]), but not with baseline tibial cartilage volume. In addition, an increase in vastus medialis CSA from baseline to 2 years was associated with reduced knee pain over the same time period (r = 0.24, P = 0.007), reduced medial tibial cartilage loss from 2 to 4.5 years (B coefficient -16.8 [95% CI -28.9, -4.6]), and reduced risk of knee replacement over 4 years (odds ratio 0.61 [95% CI 0.40, 0.94]). CONCLUSION:In a population of patients with symptomatic knee OA, increased vastus medialis size was associated with reduced knee pain and beneficial structural changes at the knee, suggesting that management of knee pain and optimizing vastus medialis size are important in reducing OA progression and subsequent knee replacement.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:In Xenopus the bone morphogenetic protein growth and differentiation factor 6 (GDF6) is expressed at the edge of the neural plate, and within the anterior neural plate including the eye fields. Here we address the role of GDF6 in neural and eye development by morpholino knockdown experiments. RESULTS:We show that depletion of GDF6 (BMP13) resulted in a reduction in eye size, loss of laminar structure and a reduction in differentiated neural cell types within the retina. This correlated with a reduction in staining for Smad1/5/8 phosphorylation indicating a decrease in GDF6 signalling through loss of phosphorylation of these intracellular mediators of bone morphogenetic protein (BMP) signalling. In addition, the Pax6 expression domain is reduced in size at early optic vesicle stages. Neural cell adhesion molecule (NCAM) is generally reduced in intensity along the neural tube, while in the retina and brain discreet patches of NCAM expression are also lost. GDF6 knock down resulted in an increase in cell death along the neural tube and within the retina as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. CONCLUSION:Our data demonstrate that GDF6 has an important role in neural differentiation in the eye as well as within the central nervous system, and that GDF6 may act in some way to maintain cell survival within the ectoderm, during the normal waves of programmed cell death.

背景与目标：

BACKGROUND & AIMS: The effects of medium composition, nutrient limitation and dilution rate on the loss of the recombinant plasmid pLG669-z and plasmid-borne beta-galactosidase expression were studied in batch and chemostat cultures of Saccharomyces cerevisiae strain CGpLG. The difference in growth rates between plasmid-free and plasmid-containing cells (delta mu) and the rate of segregation (R) were determined and some common factors resulting from the effect of medium composition on plasmid loss were identified. Glucose-limited chemostat cultures of CGpLG grown on defined medium were more stable at higher dilution rates and exhibited delta mu-dominated plasmid loss kinetics. Similar cultures grown on complex medium were more stable at lower dilution rates and exhibited R-dominated plasmid loss kinetics. Overall plasmid stability was greatest in phosphate-limited chemostat cultures grown on defined medium and was least stable in magnesium-limited cultures grown on defined medium. delta mu decreased and R increased with increased dilution rate, irrespective of medium composition. Increased plasmid loss rates at high or low dilution rates would appear to be characteristic of loss kinetics dominated by R or delta mu, respectively. Growth of glucose-limited chemostat cultures on complex medium decreased delta mu values but increased R values, in comparison to those cultures grown on defined medium. Any increased stability that a complex medium-induced reduction of delta mu may have conferred was counteracted by an increased R value. Increased beta-galactosidase productivity was correlated with increased plasmid stability only in glucose-limited chemostat cultures grown on defined medium and not in those grown on complex medium. Previous studies have yielded contrasting responses with regard to the effect of dilution rate on recombinant plasmid loss from S. cerevisiae. Our findings can account for these differences and may be generally valid for the stability of similar yeast plasmid constructs. This information would facilitate the design of bioprocesses, where recombinant plasmid instability results in reduced culture productivity.

背景与目标： 在酿酒酵母菌株CGpLG的分批和恒化器培养中，研究了培养基组成，营养限制和稀释率对重组质粒pLG669-z丢失和质粒传播的 β-半乳糖苷酶表达的影响。确定了无质粒和含质粒细胞之间的生长速率差异 (delta mu) 和分离速率 (R)，并确定了由培养基组成对质粒丢失的影响引起的一些常见因素。在确定的培养基上生长的CGpLG的葡萄糖限制的恒化器培养物在较高的稀释率下更稳定，并表现出delta mu主导的质粒丢失动力学。在复杂培养基上生长的类似培养物在较低的稀释率下更稳定，并表现出R主导的质粒丢失动力学。在限定培养基上生长的磷酸盐限制的恒化器培养物中，总体质粒稳定性最高，而在限定培养基上生长的镁限制的培养物中，质粒稳定性最低。与培养基组成无关，delta mu降低，R随着稀释率的增加而增加。在高或低稀释率下增加的质粒丢失率似乎分别是R或delta mu主导的损失动力学的特征。与在确定的培养基上生长的那些培养物相比，在复杂培养基上生长的葡萄糖限制的恒化器培养物的生长降低了delta mu值，但增加了r值。复杂的培养基诱导的 δ mu减少可能带来的任何增加的稳定性都被r值的增加所抵消。仅在在确定的培养基上生长的葡萄糖限制的恒化器培养物中，而不是在复杂培养基上生长的那些中，β-半乳糖苷酶生产率的提高与质粒稳定性的提高相关。先前的研究在稀释率对酿酒酵母重组质粒丢失的影响方面产生了相反的反应。我们的发现可以解释这些差异，并且通常对于类似酵母质粒构建体的稳定性有效。此信息将有助于生物过程的设计，其中重组质粒的不稳定性导致培养生产率降低。

BACKGROUND & AIMS: The genes responsible for the development of neuroblastoma following in vivo deletion or mutation are largely unknown. We have performed loss of heterozygosity studies on a series of 24 Portuguese primary neuroblastomas using 6 polymorphic markers located at chromosome 9p21 spanning the p16/MTS1/CDKN2, p15/MTS2/CDKN2B, and the interferon alpha and beta genes. Loss of heterozygosity was observed in 4 of the 24 tumors (17%), a somewhat lower percentage than a previous study that identified patients by a mass screening program. A correlation was also observed between 9p21 LOH and 1p36 LOH in our group of tumors. Two distinct regions of 9p21 deletion were observedone located in the region adjacent to the markers D9S162 and D9S1747 and a second located centromerically of the p16 gene near the D9S171 marker. The latter region is exclusive of the p16 gene. This result suggests the presence of at least one other tumor suppressor gene at 9p21, apart from the p16 and p15 genes, which may be of importance to the development of neuroblastoma.

背景与目标： 在体内缺失或突变后负责神经母细胞瘤发展的基因在很大程度上是未知的。我们使用位于9p21染色体上的6个多态性标记，跨越p16/MTS1/CDKN2，p15/MTS2/CDKN2B以及干扰素 α 和 β 基因，对一系列24个葡萄牙原发性神经母细胞瘤进行了杂合性缺失研究。在24个肿瘤中的4个 (17%) 中观察到杂合性丧失，这比以前通过大规模筛查程序识别患者的研究略低。在我们的肿瘤组中，还观察到9p21 LOH和1p36 LOH之间的相关性。观察到两个不同的9p21缺失区域位于与标记D9S162和D9S1747相邻的区域，第二个位于D9S171标记附近的p16基因的着丝粒。后一个区域不包含p16基因。该结果表明，除了p16和p15基因外，在9p21上还存在至少一个其他抑癌基因，这可能对神经母细胞瘤的发展很重要。

BACKGROUND & AIMS: :The majority of randomized, controlled trials (RCTs) show only modest weight loss with exercise intervention alone, and slight increases in weight loss when exercise intervention is added to dietary restriction. In most RCTs, the energy deficit produced by the prescribed exercise is far smaller than that usually produced by dietary restriction. In prospective studies that prescribed high levels of exercise, enrolled individuals achieved substantially greater weight loss-comparable to that obtained after similar energy deficits were produced by caloric restriction. High levels of exercise might, however, be difficult for overweight or obese adults to achieve and sustain. RCTs examining exercise and its effect on weight-loss maintenance demonstrated mixed results; however, weight maintenance interventions were usually of limited duration and long-term adherence to exercise was problematic. Epidemiologic, cross-sectional, and prospective correlation studies suggest an essential role for physical activity in weight-loss maintenance, and post hoc analysis of prospective trials shows a clear dose-response relationship between physical activity and weight maintenance. This article reviews the role of physical activity in producing and maintaining weight loss. We focus on prospective, RCTs lasting at least 4 months; however, other prospective trials, meta-analyses and large systematic reviews are included. Limitations in the current body of literature are discussed.

背景与目标： : 大多数随机对照试验 (RCTs) 仅通过运动干预仅能适度减轻体重，而在饮食限制中加入运动干预后，体重减轻略有增加。在大多数随机对照试验中，规定运动产生的能量不足远远小于饮食限制通常产生的能量不足。在规定高水平运动的前瞻性研究中，参与者的体重减轻明显更大-与热量限制产生类似能量不足后获得的体重减轻相当。然而，对于超重或肥胖的成年人来说，高水平的运动可能很难实现和维持。RCTs检查运动及其对减肥维持的影响显示出不同的结果; 然而，体重维持干预通常持续时间有限，长期坚持运动是有问题的。流行病学，横断面和前瞻性相关研究表明，体力活动在减肥维持中的重要作用，前瞻性试验的事后分析表明，体力活动与体重维持之间存在明显的剂量反应关系。本文回顾了体育活动在产生和维持体重减轻中的作用。我们专注于持续至少4个月的前瞻性rct; 但是，还包括其他前瞻性试验，荟萃分析和大型系统评价。讨论了当前文献中的局限性。

BACKGROUND & AIMS: :Haploinsufficiency of the zinc finger transcription factor GATA3 causes the triad of hypoparathyroidism, deafness and renal dysplasia, known by its acronym HDR syndrome. The purpose of the current study was to describe in detail the auditory phenotype in human HDR patients and compare these to audiometrical and histological data previously described in a mouse model of this disease. Pure tone audiometry, speech audiometry, speech in noise, auditory brainstem responses and transiently evoked otoacoustic emissions were measured in 2 patients affected by HDR syndrome. Both patients were affected by a moderate-to-severe sensorineural hearing loss. Speech reception thresholds were shifted and speech recognition in noise was disturbed. No otoacoustic emissions could be generated in either patient. Auditory brainstem response interpeak intervals were normal. The human and murine audiological phenotypes seem to correspond well. Hearing loss in HDR syndrome is moderate to severe, seems to be slightly worse at the higher end of the frequency spectrum and may be progressive with age. The absence of otoacoustic emissions and the loss of frequency selectivity suggest an important role for outer hair cells in causing the hearing loss.

背景与目标： : 锌指转录因子GATA3的单倍不足导致甲状旁腺功能减退，耳聋和肾发育不良的三联征，其首字母缩写为HDR综合征。本研究的目的是详细描述人类HDR患者的听觉表型，并将其与先前在该疾病的小鼠模型中描述的听觉和组织学数据进行比较。在2例受HDR综合征影响的患者中测量了纯音测听，言语测听，噪声语音，听觉脑干反应和瞬时诱发的耳声发射。两名患者均受到中度至重度感音神经性听力损失的影响。语音接收阈值偏移，噪声中的语音识别受到干扰。任何一名患者都不会产生耳声发射。听觉脑干反应峰间间隔正常。人类和鼠的听力学表型似乎很吻合。HDR综合征的听力损失为中度至重度，在频谱的高端似乎稍差，并且可能随着年龄的增长而逐渐恶化。耳声发射的缺乏和频率选择性的丧失表明外毛细胞在引起听力损失中起着重要作用。

BACKGROUND & AIMS: :Relationships between eating and affective disorders remain complex and unclear. Brain glucose metabolism of anorectic patients has been demonstrated to be reduced both globally and regionally, with a particular relative hypometabolism in the parietal cortex. To explore the possible influence of weight loss or depressive symptomatology on brain metabolism, we studied age- and sex-matched low-weight anorectic and depressed patients, normal-weight depressed patients, and healthy volunteers. Absolute global and regional glucose activity levels were reduced in low-weight patients, with the lowest values being found for anorectic patients. In relative values, anorectic patients showed a significant parietal hypometabolism in comparison to control subjects while they had higher metabolism in the caudate nuclei when compared with the other groups. Absolute hypometabolism of glucose seems to be a consequence of low weight as it was found in both low-weight anorectic and low-weight depressive patients. In addition, absolute glucose values were significantly correlated with body mass index in all subjects. Future positron emission tomographic studies in psychiatric patients should control for alimentary parameters.

背景与目标： : 饮食和情感障碍之间的关系仍然复杂且不清楚。厌食症患者的脑葡萄糖代谢已被证明在全球和区域范围内均降低，顶叶皮层中存在特定的相对代谢不足。为了探讨体重减轻或抑郁症状对大脑代谢的可能影响，我们研究了年龄和性别相匹配的低体重厌食和抑郁症患者，正常体重的抑郁症患者以及健康志愿者。低体重患者的绝对全球和区域葡萄糖活性水平降低，厌食症患者的最低值。在相对值中，与对照组相比，厌食患者表现出明显的顶叶代谢低下，而与其他组相比，他们在尾状核中的代谢更高。葡萄糖的绝对低代谢似乎是低体重的结果，因为在低体重的厌食症和低体重的抑郁症患者中都发现了它。此外，在所有受试者中，绝对葡萄糖值与体重指数显着相关。未来精神病患者的正电子发射断层扫描研究应控制饮食参数。

BACKGROUND & AIMS: :The standard strategy for analysis by tandem mass spectrometry of protein phosphorylation at serine or threonine utilizes the neutral loss of H3PO4 (= 97.977/z) from proteolytic peptide molecular ions as marker fragmentation. Manual control of automatically performed neutral loss-based phosphopeptide identifications is strongly recommended, since these data may contain false-positive results. These are connected to the experimental neutral loss m/z error, to competing peptide fragmentation pathways, to limitations in data interpretation software, and to the general growth of protein sequence databases. The fragmentation-related limitations of the neutral loss approach cover (i) the occurrence of abundant 'close-to-98/z' neutral loss fragmentations, (ii) the erroneous assignment of a neutral loss other than loss of H3PO4 due to charge state mix-up, and (iii) the accidental occurrence of any fragment ion in the m/z windows of interest in combination with a charge-state mix-up. The 'close-to-98/z' losses comprise loss of proline (97.053/z), valine (99.068/z), threonine (101.048/z), or cysteine (103.009/z) preferably from peptides with N-terminal sequences PP, VP, TP, or CP, and loss of 105.025/z from alkylated methionine. Confusion with other neutral losses may occur, when their m/z window coincides with a 98/z window as result of a charge state mix-up. Neutral loss of sulfenic acid from oxidized methionine originating from a doubly charged precursor (63.998/2 = 31.999) may thus mimic the loss of phosphoric acid from a triply charged phosphopeptide (97.977/3 = 32.659). As a consequence of the large complexity of proteomes, peptide sequence ions may occur in one of the mass windows of H3PO4 loss around 97.977/z. Practical examples for false-positive annotations of phosphopeptides are given for the first two groups of error. The majority of these can be readily recognized using the guidelines presented in this study.

背景与目标： : 通过串联质谱分析丝氨酸或苏氨酸蛋白磷酸化的标准策略利用蛋白水解肽分子离子中H3PO4 (= 97.977/z) 的中性损失作为标记片段。强烈建议手动控制自动执行的基于中性损失的磷酸肽鉴定，因为这些数据可能包含假阳性结果。这些与实验中性损失m/z误差，竞争性肽片段化途径，数据解释软件的局限性以及蛋白质序列数据库的总体增长有关。中性损失方法与碎片相关的限制涵盖 (i) 大量 “接近98/z” 中性损失碎片的发生，(ii) 由于电荷状态混淆而导致的除了H3PO4损失之外的中性损失的错误分配，(iii) 在感兴趣的m/z窗口中意外发生任何碎片离子，并结合电荷状态混合。“接近-98/z” 损失包括脯氨酸 (97.053/z) 、缬氨酸 (99.068/z) 、苏氨酸 (101.048/z) 或半胱氨酸 (103.009/z) 的损失，优选地来自具有N端序列PP、VP、TP或CP的肽，以及烷基化甲硫氨酸的105.025/z的损失。当电荷状态混合导致其m/z窗口与98/z窗口重合时，可能会发生与其他中性损耗的混淆。源自双重电荷前体 (63.998/2 = 31.999) 的氧化蛋氨酸的亚砜酸的中性损失因此可以模拟来自三重电荷磷酸肽 (97.977/3 = 32.659) 的磷酸的损失。由于蛋白质组的大量复杂性，肽序列离子可能出现在H3PO4丢失的质量窗口之一中，约97.977/z。针对前两组错误，给出了磷酸肽假阳性注释的实际示例。使用本研究中提出的指南可以很容易地识别出其中的大多数。