Neural dynamics in a model of the thalamocortical system. II. The role of neural synchrony tested through perturbations of spike timing

Activity in the mammalian thalamocortical system is often accompanied by a synchronous discharge of cortical and thalamic neurons. Although many functions have been attributed to such synchronous firing, it is not known whether or how synchrony of firing per se affects thalamocortical operations. Direct experimental tests of the consequences of neuronal synchronization in vivo are hard to carry out, whereas theoretical studies based on single-neuron models cannot reveal the effects of synchrony at the system level. To overcome these limitations, we have used a perturbational approach to test the causal efficacy of synchrony per se in large-scale simulations of the thalamocortical system. The test consists of selectively disrupting firing synchrony by 'jittering' the timing of action potentials in the simulations and determining whether firing rates are modified by this perturbation. The simulations are based in detail on the known anatomy and physiology of the thalamocortical-visual system of the cat, and have been shown in a companion paper to produce episodes of fast synchronous activity at multiple levels. By carrying out the perturbation analysis, we established that neurons can have long membrane time constants (8-16 ms) and balanced synaptic activations, and yet function collectively in such a way that synchrony within a time window of 4 ms significantly affects the rates and selectivity of the responses to visual stimuli. The simulations also revealed a complex interplay, at the network level, between synchrony of firing and rate of firing. The dynamic consequences of firing synchrony were most evident when spike jittering was applied to specific polysynaptic loops involving corticocortical and corticothalamic connections. These results support the view that firing synchrony within thalamocortical and corticocortical loops plays a causal role in the cooperative and competitive neural interactions that produce pattern-selective responses in the cortex.      

Polymorphism of the promoter of the HLA-A locus

Of the first 350 bases upstream of the ATG signal sequences were obtained representing the following HLA-A locus alleles: A^*01, A^*0102, A^*02, A^*0202, A^*0206, A^*0207, A^*03, A^*0302, A11.2, A11.1, A^*68, A^*68011, A^*30, A^*3002, A^*23, A^*24, A^*26, A^*2602, A^*25, A^*29, A^*2902, A^*31, A^*31011, A^*32, A^*3201, A^*33, A^*3301, A^*3303, A^*34, A^*6601, A^*6602 A^*74, A^*80. We found 21 polymorphic positions of which a surprisingly large number (altogether 9) represent allele specific exchanges. For all 35 alleles tested of the HLA-A locus we found 16 different types of promoter. While all tested A2 subtypes, A^*0201, A^*0202, A^*0206, A^*0207 share the same promoter, there were in contrast several situations in which different subtypes of the same group have different promoters. This is true for HLA A^*01, A^*0102; A^*03, A^*0302; A^*30, A^*3002; A^*6601, A^*6602; A^*32, A^*3201; A^*29, A^*2902. Looking at the binding sites for nuclear factors, we observe that TATA-box, CAT-box, Enhancer B, the interferon response sequence and the Enhancer A (except HLA-A30 has one base exchange) are conserved within the HLA-A locus. The interferon response sequence shows for all A-locus alleles a double base pair exchange (TT for AC). In comparison with the promoter polymorphism of the HLA-B locus (Yao et al., 1995) we find a surprising diversity of the promoters in the HLA-A locus. While for the B-locus promoters large groups of sometimes strongly different alleles share the same promoter, in the HLA-A locus there is a private promoter for almost each allele and sometimes even each subtype. This lead to the conclusion that the promoter polymorphisms of the HLA-A and the HLA-B locus have been subjected to different selection pressure in evolution.     

Accuracy of specific IgE in the prediction of asthma: development of a scoring formula for general practice

BACKGROUND: For the diagnosis of asthma in young children, GPs have to rely on history taking and physical examination, as spirometry is not possible. The additional diagnostic value of specific immunoglobulin E (IgE) to inhalent allergens remains unclear. AIM: To assess the predictive accuracy of specific IgE to cat, dog, and/or house dust mites in young children for the subsequent development of asthma at the age of 6 years. DESIGN OF STUDY: Prospective follow-up study. SETTING: Seventy-two general practices. METHOD: A total of 654 children, aged 1-4 years, visiting their GPs for persistent coughing (>/= 5 days), were tested for IgE antibodies by radio allergosorbent testing (RAST). Parents completed a questionnaire on potential risk indicators. Those children who showed an IgE-positive status (12.7%) and a random sample of those with an IgE-negative status (<0.5 U/ml) were followed up to the age of 6 years when the asthma status was established. The main outcome measure was asthma at the age of 6 years (combination of both symptoms and/or use of asthma medication, and impaired lung function). RESULTS: Addition of RAST results to a prediction model based on age, wheeze, and family history of pollen allergy increased the area under the receiver operating characteristic (ROC) curve from 0.76 to 0.87. Furthermore, RAST improved patient differentiation as indicated by a change in the range of asthma probabilities from 6-75% before the IgE test, to 1-95% after the IgE-test. CONCLUSION: Sensitisation to inhalant allergens in 1-4-year-olds, as shown by RAST, is a useful diagnostic indicator for the presence of asthma at the age of 6 years, even after a clinical history has been obtained. This model should preferably be validated in a new population before it can be applied in practice.     

Characteristics associated with the transition to partial breastfeeding prior to 6 months of age: Data from seven sites in a birth cohort study

The WHO recommends exclusive breastfeeding for the first 6 months of life. However, the transition of the infants'' diet to partial breastfeeding with the addition of animal milks and/or solids typically occurs earlier than this. Here, we explored factors associated with the timing of an early transition to partial breastfeeding across seven sites of a birth cohort study in which twice weekly information on infant feeding practices was collected. Infant (size, sex, illness and temperament), maternal (age, education, parity and depressive symptoms), breastfeeding initiation practices (time of initiation, colostrum and pre‐lacteal feeding) and household factors (food security, crowding, assets, income and resources) were considered. Three consecutive caregiver reports of feeding animal milks and/or solids (over a 10‐day period) were characterized as a transition to partial breastfeeding, and Cox proportional hazard models with time (in days) to partial breastfeeding were used to evaluate associations with both fixed and time‐varying characteristics. Overall, 1470 infants were included in this analysis. Median age of transition to partial breastfeeding ranged from 59 days (South Africa and Tanzania) to 178 days (Bangladesh). Overall, higher weight‐for‐length z‐scores were associated with later transitions to partial breastfeeding, as were food insecurity, and infant cough in the past 30 days. Maternal depressive symptoms (evaluated amongst 1227 infants from six sites) were associated with an earlier transition to partial breastfeeding. Relative thinness or heaviness within each site was related to breastfeeding transitions, as opposed to absolute z‐scores. Further research is needed to understand relationships between local perceptions of infant body size and decisions about breastfeeding.     

Fibroblast growth factor-7 regulates stratification of the bladder urothelium.

PURPOSE: The cellular and molecular mechanisms that regulate the organization of bladder urothelium into basal, intermediate and superficial cell layers remain poorly understood. We tested the hypothesis that fibroblast growth factor (FGF)-7 is essential for generating a multilayered stratified bladder epithelium. MATERIALS AND METHODS: The morphological and molecular characteristics of bladder urothelium in age and sex matched FGF-7 +/+ wild-type and -/- null mice were evaluated. In addition, the effect of exogenous FGF-7 on the growth and differentiation of primary murine urothelial cells was assessed. RESULTS: Morphometric analyses demonstrate that FGF-7 null urothelium is markedly thinned compared with wild-type urothelium. Electron microscopy revealed that null urothelium lacks the intermediate cell layers and molecular marker analyses confirmed this observation. In vitro cell culture experiments indicated that FGF-7 regulates urothelial cell growth, differentiation and stratification. Primary urothelial cultures maintained without FGF-7 ceased to divide and expressed proteins characteristic of terminally differentiated umbrella cells. In contrast, cultures maintained with exogenous FGF-7 contained proliferating epithelial cells with protein expression patterns consistent with those of intermediate cells in addition to terminally differentiated, post-mitotic umbrella cells. Importantly, isolated urothelial cells maintained with exogenous FGF-7 formed a multilayered epithelium in vitro. CONCLUSIONS: Collectively these data indicate that FGF-7 is essential for normal bladder urothelial stratification, specifically the formation of the intermediate cell layers. Fibroblast growth factor-7 stimulates urothelial proliferation and delays the differentiation of these cells into post-mitotic umbrella cells.     

Brain photodiagnosis (PD), fluorescence guided resection (FGR) and photodynamic therapy (PDT): Past, present and future

Intracranial tumours are an excellent target for photodiagnosis (PD), fluorescence guided resection (FGR) and photodynamic therapy (PDT), because the tumour to brain ratio of photosensitizers’ concentration is very high. However, several attempts of proving the value of PDT in the most malignant type of brain tumours, gliobastoma multeforme (GBM) failed to demonstrate any significant worthwhile survival advantage in the past because of the very nature of this cancer and several compounding factors that led to this apparent disappointing outcome; variations in the photosensitizer and light dosages, variations in the photosensitizer administration to treatment time-intervals, and variations in photosensitizers used are just few to mention in this article. However, after a very long gestation period of brain PD, FGR and PDT, three randomized controlled trials (RCT) in brain PD, FGR and PDT were concluded by 2007. The first trial demonstrated that time to tumour progression (TTP) was significantly longer in patients who had PD and FGR compared to standard surgical resection but this difference did not translate into survival advantage in GBM due to the variability in the management of recurrent tumours and significant residual tumour cells left after FGR in about a third of patients leading to GBM relapse. The second trial compared single shot PDT in GBM and standard therapy. Neither the treatment nor the control group received PD or FGR. Again this RCT did not provide any survival advantage in patients who had had PDT due to the fact that standard surgical resection had left significant residual tumour in a large number of patients canceling any potential benefit from PDT. The last trial compared combined PD, FGR and repetitive PDT and standard therapy and confirmed that TTP was significantly longer in the treatment group and demonstrated that the treatment group had significant survival advantage in GBM. In conclusion, PD, FGR and PDT need to be combined to be effective in brain tumours and in the future, we will see more and more scientific evidence accumulating in support of brain PD, FGR and PDT. The next decade will see further refinement and evolution of the techniques and technology employed and expansion of the indications of brain PD, FGR and PDT.     

垂体催乳素瘤的诊断和治疗指南

治疗的目的是PRL水平正常.然而,许多学者认为,最好是降低PRL水平到可能的最低值,因为这一策略能最大可能地缩小肿瘤体积甚至于肿瘤消失.为了避免不能耐受药物和药物不良反应,从低剂量开始治疗,并逐步加量.肿瘤缩小后假使PRL水平保持在正常范围,则可以慢慢减少DA剂量.