ERK2 and CREB activation in the amygdala when an event is remembered as “Fearful” and not when it is remembered as “Instructive”

A training protocol was developed based on durable exposure to the two‐way shuttle avoidance task, in which the conditioned stimulus (CS), which was fear evoking for both training conditions on the first day of training, becomes instructive at the end of training under controllable conditions but remains fear evoking under the uncontrollable conditions. The protocol was utilized to examine whether, depending on the training regime, the memory formed will result in a different level of involvement of the amygdala. Three groups of rats were tested: controllable, subjected to durable avoidance learning; uncontrollable, subjected to the same training schedule but with no control over the stressor; and naïve. Two weeks later, after the introduction of a reminder cue, freezing response, defecation, and blood corticosterone (CORT) of the uncontrollable group were higher than in the controllable and naïve groups, indicating that indeed, for this group, the CS remained fear evoking. Significantly higher than chance shuttling responses of the controllable group indicated that, for them, the CS became ”instructive.” Activation of ERK2 and CREB in the basolateral amygdala (BLA) was highest in the uncontrollable group compared with the controllable and naïve groups. Overall, the results indicate that the training procedure succeeded in dissociating between the physical (electric shock) and the psychological (control) attributes of the experience. Also, our findings support the view that an emotionally charged reminder cue activates the amygdala but that, as a previously fear‐evoking memory cue becomes instructive, the involvement of the amygdale lessens. © 2009 Wiley‐Liss, Inc.     

Identification of new risk factors for pneumonia: population-based case-control study

Background

Certain conditions are established as risk factors for community-acquired pneumonia. There are a number of other conditions that may also be risk factors, but information on these is limited.

Aim

To determine new independent risk factors for community-acquired pneumonia using a very large primary care database.

Design of study

Nested case-control study.

Setting

Four hundred and forty-three general practices in the UK contributing to the QRESEARCH database.

Method

A total of 17 172 incident cases of all ages diagnosed with pneumonia between 1996 and 2005 were matched with up to five controls by age, sex, general practice, and calendar year. Associations between pneumonia and each established condition and potential risk factors were determined with odds ratios (ORs), using multiple conditional logistic regression analysis adjusted for smoking, socioeconomic status, and use of influenza and pneumococcal vaccines.

Results

The analysis confirmed the higher risk of pneumonia among patients with at least one of the established risk factors; the adjusted OR was 2.29 (95% confidence interval [CI] = 2.20 to 2.39). In addition, patients with the following conditions had a higher risk of pneumonia despite adjustment for known risk factors and confounders: stroke or transient ischaemic attack, rheumatoid arthritis, Parkinson''s disease, cancers, multiple sclerosis, dementia, and osteoporosis. The adjusted OR for pneumonia among patients without an established risk factor but with at least one of the new conditions was 2.44 (95% CI = 2.24 to 2.65).

Conclusion

As well as confirming some established risk factors, this study has determined seven new independent risk factors for community-acquired pneumonia.     

The neutralizing human recombinant antibodies to pathogenic Orthopoxviruses derived from a phage display immune library

A panel of recombinant human antibodies to orthopoxviruses was isolated from a combinatorial phage display library of human scFv antibodies constructed from the Vh and Vl genes cloned from the peripheral blood lymphocytes of Vaccinia virus (VACV) immune donors. Plaque-reduction neutralization tests showed that seven selected phage-displaying scFv antibodies (pdAbs) neutralized both CPXV and VACV, and five of them neutralized Monkeypox virus (MPXV). Western blot analysis of VACV and CPXV proteins demonstrated that seven neutralizing antibodies recognized a 35 kDa protein. To identify this target protein, we produced a recombinant J3L protein of CPXV and showed that all the selected neutralizing antibodies recognized this protein. Neutralizing pdAb b9 was converted into fully human mAb b9 (fh b9), and scFv b9 displayed high binding affinities (K_d of 0.7 and 3.2 nM). The fh b9 reduced VACV plaque formation in a dose-dependent manner.     

Aberrant functional connectivity of cortico-basal ganglia circuits in major depression

There is considerable evidence of functional abnormalities of the cortico-basal ganglia circuitry in affective disorders. However, it has been unknown whether this represented primary pathology within these circuits or altered activation as a result of aberrant input from other brain regions. The aim of this study was to test the hypothesis that cortico-basal ganglia circuit dysfunction represents primary pathology in unipolar depression. Eighteen male subjects with recurrent unipolar depression and eighteen controls without psychiatric illness were studied using functional MRI and functional connectivity analyses. All unipolar subjects were unmedicated and without current psychiatric comorbidity. Compared to controls, unipolar subjects exhibited altered connectivity between bilateral subcortical components of the circuitry (putamen-thalamus) and left hemisphere input and output components. Results provided evidence that functional abnormalities of these circuits represent primary pathology. Further, we found that age of onset but not duration of illness impacts circuit function. These findings suggest that the cortico-basal ganglia circuitry is likely one of several loci of primary pathology in major depression. Additionally, early age of onset is associated with greater circuit abnormality and as such may impact clinical characteristics and/or treatment response through a mechanism of decreasing functional connectivity of some circuit segments. Finally, altered cortico-basal ganglia circuit connectivity with cortical regions (anterior cingulate, inferior frontal gyrus and sensorimotor) may contribute to the emotional dysregulation, impaired emotional recognition and psychomotor symptoms associated with unipolar illness.     

Combined extraction of acyl carnitines and 26:0 lysophosphatidylcholine from dried blood spots: prospective newborn screening for X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic disorder that affects the nervous system, and the adrenal cortex. Newborn screening for X-ALD has been proposed to allow improved diagnosis along with prospective monitoring and treatment for this severe disorder. Newborn dried whole blood spot (DBS) 26:0 lysophosphatidyl choline was validated as a diagnostic marker for X-ALD and other peroxisomal disorders of peroxisomal β-oxidation. In this study, we developed a new one step extraction procedure that simultaneously extracts acyl carnitines and the lysophosphatidyl cholines from DBS. Further analysis of these metabolites has been performed by two different high throughput LC-MS/MS methods. The 26:0 lysophosphatidyl choline levels in this study were consistent with previously published values and discriminate between healthy and abnormal profiles. There is a very minor modification to the original acyl carnitine extraction procedure and our data indicates that there is no significant effect on acyl carnitine levels in DBS. Our new method potentially can be complementary to the current newborn screening panel. It successfully combines the existing method for acyl carnitine analysis and 26:0 lysophosphatidyl choline that can be applied for prospective X-ALD newborn screening.     

<Emphasis Type="Italic">Fasciola hepatica</Emphasis> miracidia: Lectin binding and stimulation of <Emphasis Type="Italic">in vitro</Emphasis> miracidium-to-sporocyst transformation

The lectin binding properties of Fasciola hepatica miracidia were studied by a panel of fluorescein- and gold-conjugated lectins (ConA, LCA, WGA, LEA, SBA, HPA and UEA-I). The presence of mannose and/or glucose residues was demonstrated with ConA and LCA as weak diffuse fluorescence of the miracidial surface, which was more intense at the anterior part of the larva. The N-acetylglucosamine-binding lectins WGA and LEA reacted intensely with the whole miracidial surface. No labelling with N-acetylgalactosamine and/or galactose-specific (SBA and HPA) and fucose-specific UEA-I lectins was observed. The possibility that the specific recognition of the miracidial surface carbohydrates by lectins may initiate the process of transformation of the miracidia into sporocysts was examined in vitro in physiological saline for Galba truncatula. Incubation in the presence of ConA and WGA resulted in facilitation of the transformation process. Facilitation was absent in the presence of inhibitor sugars. Incubation in the presence of SBA or UEA-I had no effect. The results suggested a possible impact of carbohydrate-lectin interactions in transformation of miracidia of F. hepatica to sporocysts in vivo.     

发作间期/发作期SPECT rCBF显像在癫痫灶定位诊断中的价值

目的探讨发作间期/发作期SPECT局部脑血流灌注显像(regional cerebral blood flow,rCBF)在癫痫术前定位诊断中的价值。方法回顾性分析第三军医大学新桥医院神经外科行外科手术治疗的115例癫痫患者,术前分别行发作间期/发作期SPECT显像、常规脑电图(electroencephalogram,EEG)、视频脑电图(vedio-EEG,VEEG)、CT或MRI检查,术中行皮层脑电图(electrocorticogram,ECoG)监测,与发作间期/发作期SPECT、EEG、VEEG、CT和MRI检查结果进行比较分析。结果发作间期/发作期SPECT检出癫痫的阳性率为90.4%,高于EEG的37.4%(P<0.05)、VEEG的82.6%(P>0.05)、CT的48.8%(P<0.05)和MRI的54.2%(P<0.05)。与术中ECoG结果比较,发作间期/发作期SPECT对癫痫灶定侧率为91.3%,定位率为71.2%。结论术前发作间期/发作期SPECT显像与ECoG在癫痫灶定位诊断上具有较高的一致性,在术前综合定位诊断中具有重要意义。     

99Tcm-MIBI融合显像辅助肺癌放疗靶区定位及对化疗疗效的预测

目的探讨99Tcm-MIBI SPECT/CT同机融合显像辅助肺癌放疗靶区定位的价值,分析肿瘤组织摄取99Tcm-MIBI与化疗疗效之间的关系。方法回顾性分析经病理确诊的19例非小细胞肺癌患者,放、化疗前均行99Tcm-MIBISPECT/CT显像,通过感兴趣区技术勾画肿瘤靶区并确定计划靶区;获取感兴趣区放射性计数,计算肿瘤早期摄取比(T/NTe)、延迟摄取比(T/NTd)及肿瘤组织滞留率(RI%),分析T/NTe、T/NTd、RI%与患者临床分期及病理类型的关系。结果 19例患者中99Tcm-MIBI显像阳性18例,修改CT计划靶区15例,占78.9%;明确区分肺不张与肿瘤病灶11例,占57.9%。化疗有效患者T/NTe、T/NTd比值分别为(2.47±0.23)、(2.35±0.19),无效患者分别为(1.72±0.10)、(1.63±0.12),两者差异统计学有意义(P<0.01),两者RI%比较差异无统计学有意义(P>0.05),T/NTe、T/NTd、RI%在不同临床分期、病理类型中差异均无统计学有意义(P>0.05)。结论99Tcm-MIBI SPECT/CT融合显像有助于优化肺癌立体放疗靶区,选取T/NTe=2.0作为预测化疗有效的阈值有较高的准确性,且不受患者临床分期及病理类型的影响。