高血压患者不同左室构型的肺静脉血流比较

用脉冲多普勒超声评价不同左室构型高血压患者的肺静脉血流频谱.材料和方法:对110例单纯高血压患者(男81例,女29例),进行二维和脉冲多普勒超声检查,根据左室重量及相对室壁厚度分成四种不同构型,比较四组间肺静脉血流频谱特点.结果:110例高血压患者中构型正常者占55.45%(61例),向心性重构者占21.82%(24例),向心性肥厚者占10%(11例),偏心性肥厚者占12.73%(14例).肺静脉血流频谱示向心性肥厚组及偏心性肥厚组的VTIs、VTIs/(VTIs+VTId)较正常组及向心性重构组低(P<0.05),ARD增大,ARD/AD延长(P<0.005).结论:左室不同构型的高血压患者肺静脉血流频谱不同,提示向心性肥厚组及偏心性肥厚组左室舒张功能的损害较向心性重构组更明显.     

Influence of Melatonin on the Sleep-Independent Component of Prolactin Secretion

Sleep has a stimulatory effect on prolactin secretion. Recent studies in the human suggest the hypothesis that prolactin has also an endogenous sleep-independent rhythm, which can be influenced by endogenous melatonin. To investigate this hypothesis, the prolactin response to nighttime exposure to bright light was studied in eight women in detail. Light exposure induces a decrease in nocturnal melatonin secretion. It was demonstrated that exposure to bright light for 2 h at night caused a decrease in prolactin secretion, which surpassed significantly the decline one would expect by sleep deprivation only (P less than 0.01). This was associated with a similar decline in melatonin secretion. Fall and rise of prolactin secretion under these conditions were always preceded by decrease and rise in melatonin levels in all eight women studied. Based on these observations, it is concluded that melatonin is associated with an endogenous circadian component of prolactin secretion. As specific melatonin receptors have been identified in the human nucleus suprachiasmaticus, which is the "master" circadian pacemaker, the observed phenomenon might be mediated through this structure. An alternative explanation of our findings could be based on the fact that melatonin influences dopamine metabolism, which in turn alters prolactin secretion. It can also not be ruled out that melatonin might act via the opioid system, which then could affect prolactin secretion. The total secretory activity for both hormones (area under the curve) did not change under experimental conditions, when compared to a control group. This suggests that acute light exposure and sleep deprivation influence the secretory process rather than the synthesis of these two hormones. This is in agreement with the observation that changes in natural light exposure throughout the year do alter the amplitude, but not the total amount of melatonin secreted. Further studies are needed to answer the question of melatonin storage definitively, as it is commonly believed that melatonin is immediately released after synthesis. It is concluded that melatonin through its external modulator light might entrain the circadian sleep-independent component of prolactin secretion and via its action on prolactin could modulate reproductive processes.     

CA3 size predicts the precision of memory recall

There is enduring interest in why some of us have clearer memories than others, given the substantial individual variation that exists in retrieval ability and the precision with which we can differentiate past experiences. Here we report novel evidence showing that variation in the size of human hippocampal subfield CA3 predicted the amount of neural interference between episodic memories within CA3, which in turn predicted how much retrieval confusion occurred between past memories. This effect was not apparent in other hippocampal subfields. This shows that subtle individual differences in subjective mnemonic experience can be accurately gauged from measurable variations in the anatomy and neural coding of hippocampal region CA3. Moreover, this mechanism may be relevant for understanding memory muddles in aging and pathological states.Our memories often contain overlapping elements, because they tend to feature the same people and places that form the cornerstones of our lives. Nevertheless, we are generally able to recall many of these past experiences as distinct episodes, although we are not all equally adept at doing so. There is substantial individual variation in retrieval ability and the precision with which we can differentiate past events (1, 2). This is most acute as we age and in conditions such as dementia, where confusion about the past is often evident (2). There is keen interest, therefore, in elucidating the neural mechanisms that allow us to recollect numerous life experiences despite a high degree of intermemory similarity.We know little about how this is achieved in humans, but theoretical models propose that computations within hippocampal subfields facilitate the efficient storage and retrieval of similar memories (3–7). When we experience an event, pattern separation leads to the formation of a distinct neural representation within region CA3 (8–11). At retrieval, a previously stored memory representation within CA3 can be reactivated through the process of pattern completion (12, 13). However, when episodes are highly similar, the CA3 neuronal representations may not be completely distinct, leading to partial overlap (14). It is therefore not clear precisely what the limits of CA3 pattern separation might be. Here we directly tested the capacity of human CA3 to maintain distinct episodic representations in the presence of overlapping elements. We further investigated whether variation in this ability provides an explanatory account of individual differences in the precision of episodic memory retrieval.     

DIAGNOSTIC ACCURACY OF PIT PATTERN AND VASCULAR PATTERN ANALYSES IN COLORECTAL LESIONS

Background: The aim of this prospective study is to compare the usefulness of magnifying narrow band imaging (NBI) and magnifying chromoendoscopy in the diagnosis of colorectal lesions. Methods: The subjects were 1185 patients who underwent a complete colonoscopic examination and endoscopic or surgical treatment, from January 2006 to February 2008. A total of 1473 lesions were evaluated (53 hyperplastic polyps, 1317 adenomas, 103 submucosally invasive cancers). The digital images with NBI or chromoendoscopy were recorded and diagnosed independently from each other by two endoscopists who were blinded to the final pathological diagnosis. Results: We could differentiate between neoplastic and non‐neoplastic lesions with sensitivity of 88.9%, specificity of 98.5% and accuracy of 98.2% according to the vascular pattern. By recognizing an irregular or sparse pattern with NBI, massively invasive submucosal cancer could be diagnosed with the sensitivity and specificity of 94.9% and 76.0%. Using chromoendoscopy, we could differentiate between neoplastic and non‐neoplastic lesions with sensitivity of 86.8% and specificity of 99.2%. We were able to differentiate between massively invasive cancers and slightly invasive cancers using the pit patterns with sensitivity of 89.7% and specificity of 88.0%. The specificity was superior to that of NBI colonoscopy. Conclusion: Both NBI and chromoendoscopy can be useful for distinguishing between neoplastic and non‐neoplastic lesions. In the diagnosis of submucosal cancer, pit pattern diagnosis was slightly superior to vascular pattern diagnosis. It is desirable to perform chromoendoscopy in addition to NBI for distinguishing between slightly and massively invasive submucosal cancer lesions and determining the treatment.     

Fidelity of neural reactivation reveals competition between memories

Remembering an event from the past is often complicated by the fact that our memories are cluttered with similar events. Though competition is a fundamental part of remembering, there is little evidence of how mnemonic competition is neurally represented. Here, we assessed whether competition between visual memories is captured in the relative degree to which target vs. competing memories are reactivated within the ventral occipitotemporal cortex (VOTC). To assess reactivation, we used multivoxel pattern analysis of fMRI data, quantifying the degree to which retrieval events elicited patterns of neural activity that matched those elicited during encoding. Consistent with recent evidence, we found that retrieval of visual memories was associated with robust VOTC reactivation and that the degree of reactivation scaled with behavioral expressions of target memory retrieval. Critically, competitive remembering was associated with more ambiguous patterns of VOTC reactivation, putatively reflecting simultaneous reactivation of target and competing memories. Indeed, the more weakly that target memories were reactivated, the more likely that competing memories were later remembered. Moreover, when VOTC reactivation indicated that conflict between target and competing memories was high, frontoparietal mechanisms were markedly engaged, revealing specific neural mechanisms that tracked competing mnemonic evidence. Together, these findings provide unique evidence that neural reactivation captures competition between individual memories, providing insight into how well target memories are retrieved in the present and how likely competing memories will be remembered in the future.     

Local auxin biosynthesis regulation by PLETHORA transcription factors controls phyllotaxis in Arabidopsis

Lateral organ distribution at the shoot apical meristem defines specific and robust phyllotaxis patterns that have intrigued biologists and mathematicians for centuries. In silico studies have revealed that this self-organizing process can be recapitulated by modeling the polar transport of the phytohormone auxin. Phyllotactic patterns change between species and developmental stages, but the processes behind these variations have remained unknown. Here we use regional complementation experiments to reveal that phyllotactic switches in Arabidopsis shoots can be mediated by PLETHORA-dependent control of local auxin biosynthesis.     

Formation and structure of ramified charge transportation networks in an electromechanical system

We present findings in an experiment where we obtain stationary ramified transportation networks in a macroscopic nonbiological system. Our purpose here is to introduce the phenomenology of the experiment. We describe the dynamical formation of the network which consists of three growth stages: (I) strand formation, (II) boundary formation, and (III) geometric expansion. We find that the system forms statistically robust network features, like the number of termini and the number of branch points. We also find that the networks are usually trees, meaning that they lack closed loops; indeed, we find that loops are unstable in the network. Finally, we find that the final topology of the network is sensitive to the initial conditions of the particles, in particular to its geometry.     

Statistical image analysis reveals features affecting fates of Myxococcus xanthus developmental aggregates

Starving Myxococcus xanthus bacteria use their motility systems to self-organize into multicellular fruiting bodies, large mounds in which cells differentiate into metabolically inert spores. Despite the identification of the genetic pathways required for aggregation and the use of microcinematography to observe aggregation dynamics in WT and mutant strains, a mechanistic understanding of aggregation is still incomplete. For example, it is not clear why some of the initial aggregates mature into fruiting bodies, whereas others disperse, merge, or split into two. Here, we develop high-throughput image quantification and statistical analysis methods to gain insight into M. xanthus developmental aggregation dynamics. A quantitative metric of features characterizing each aggregate is used to deduce the properties of the aggregates that are correlated with each fate. The analysis shows that small aggregate size but not neighbor-related parameters correlate with aggregate dispersal. Furthermore, close proximity is necessary but not sufficient for aggregate merging. Finally, splitting occurs for those aggregates that are unusually large and elongated. These observations place severe constraints on the underlying aggregation mechanisms and present strong evidence against the role of long-range morphogenic gradients or biased cell exchange in the dispersal, merging, or splitting of transient aggregates. This approach can be expanded and adapted to study self-organization in other cellular systems.     

Identification of innate immunity elicitors using molecular signatures of natural selection

The innate immune system is an ancient and broad-spectrum defense system found in all eukaryotes. The detection of microbial elicitors results in the up-regulation of defense-related genes and the elicitation of inflammatory and apoptotic responses. These innate immune responses are the front-line barrier against disease because they collectively suppress the growth of the vast majority of invading microbes. Despite their critical role, we know remarkably little about the diversity of immune elicitors. To address this paucity, we reasoned that hosts are more likely to evolve recognition to "core" pathogen proteins under strong negative selection for the maintenance of essential cellular functions, whereas repeated exposure to host-defense responses will impose strong positive selective pressure for elicitor diversification to avoid host recognition. Therefore, we hypothesized that novel bacterial elicitors can be identified through these opposing forces of natural selection. We tested this hypothesis by examining the genomes of six bacterial phytopathogens and identifying 56 candidate elicitors that have an excess of positively selected residues in a background of strong negative selection. We show that these positively selected residues are atypically clustered, similar to patterns seen in the few well-characterized elicitors. We then validated selected candidate elicitors by showing that they induce Arabidopsis thaliana innate immunity in functional (virulence suppression) and cellular (callose deposition) assays. These finding provide targets for the study of host-pathogen interactions and applied research into alternative antimicrobial treatments.     

一种新的ICA亚型及其与胰岛细胞类型关系的免疫组化研究

目的 在用免疫组化方法大量检测ＩＣＡ基础上发现有弥漫型ＩＣＡ和边缘型ＩＣＡ两种迥然不同的形态学表现。为探明这两种ＩＣＡ所着染的细胞类型及其临床意义，进行了以下实验。方法 选取２０例弥漫型ＩＣＡ和２０例边缘型ＩＣＡ，用免疫组化双标技术鉴定。结果 弥漫型ＩＣＡ着染β、α两种细胞，边缘型ＩＣＡ仅着染α细胞。结论 经初步统计，弥漫型ＩＣＡ多见于１型糖尿病，２型糖尿病边缘型ＩＣＡ比例高于弥漫型ＩＣＡ；弥漫型     

From the Cover: JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation

Extracellular high-mobility group box (HMGB)1 mediates inflammation during sterile and infectious injury and contributes importantly to disease pathogenesis. The first critical step in the release of HMGB1 from activated immune cells is mobilization from the nucleus to the cytoplasm, a process dependent upon hyperacetylation within two HMGB1 nuclear localization sequence (NLS) sites. The inflammasomes mediate the release of cytoplasmic HMGB1 in activated immune cells, but the mechanism of HMGB1 translocation from nucleus to cytoplasm was previously unknown. Here, we show that pharmacological inhibition of JAK/STAT1 inhibits LPS-induced HMGB1 nuclear translocation. Conversely, activation of JAK/STAT1 by type 1 interferon (IFN) stimulation induces HMGB1 translocation from nucleus to cytoplasm. Mass spectrometric analysis unequivocally revealed that pharmacological inhibition of the JAK/STAT1 pathway or genetic deletion of STAT1 abrogated LPS- or type 1 IFN-induced HMGB1 acetylation within the NLS sites. Together, these results identify a critical role of the JAK/STAT1 pathway in mediating HMGB1 cytoplasmic accumulation for subsequent release, suggesting that the JAK/STAT1 pathway is a potential drug target for inhibiting HMGB1 release.High-mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein, is a promiscuous sensor driving nucleic acid-mediated immune responses and a pathogenic inflammatory mediator in sepsis, arthritis, colitis, and other disease syndromes (1–5). Immune cells actively release HMGB1 after activation by exposure to pathogen-associated molecular patterns or damage-associated molecular patterns, including lipopolysaccharide (LPS) and inflammasome agonists (1, 6, 7). High levels of extracellular HMGB1 accumulate in patients with infectious and sterile inflammatory diseases. Extracellular disulfide HMGB1 stimulates macrophages to release TNF and other inflammatory mediators by binding and signaling through Toll-like receptor (TLR)4. Reduced HMGB1 facilitates immune cell migration by interacting with the receptor for advanced glycation end products (RAGE) and CXCL12 (8–12), a process regulated by posttranslational redox-dependent mechanisms. Administration of neutralizing anti-HMGB1 mAbs or other HMGB1 antagonists significantly reduces the severity of inflammatory disease, promotes bacterial clearance during Pseudomonas aeruginosa or Salmonella typhimurium infection and attenuates memory impairment in sepsis survivors (1, 13–15). Together, these and other findings indicate the importance of a mechanistic understanding of HMGB1 release from activated immune cells and the regulatory signaling pathways controlling these processes.Most cytokines harbor a leader peptide that facilitates secretion through the endoplasmic reticulum–Golgi exocytotic route. HMGB1, which lacks a leader peptide, is released via unconventional protein secretion pathways (1, 6, 7). In quiescent cells, most HMGB1 is localized in the nucleus. Upon activation of immune cells, efficient HMGB1 release requires acetylation of HMGB1 within the two nuclear localization sequence (NLS) sites and subsequent HMGB1 accumulation in the cytoplasm (1, 6, 16–20). HMGB1 release is mediated by inflammasome activation during pyroptosis, a form of proinflammatory programmed cell death (6, 7, 22–24). Protein kinase (PK)R is a critical regulator of inflammasome-dependent HMGB1 release (6, 25). Pharmacological inhibition of PKR abrogates LPS-induced HMGB1 release by macrophages but does not prevent nuclear translocation of HMGB1 to cytoplasm. This suggests that some other, as yet unknown, inflammasome-independent pathway regulates HMGB1 translocation from nucleus to cytoplasm.We and others have previously established an important role of type 1 and type 2 interferons (IFNs) and downstream JAK/STAT1 signaling activation in mediating HMGB1 release (26–28). Pharmacological inhibition of JAK/STAT, genetic deletion of STAT1, or inhibition of extracellular IFN-β with neutralizing antibodies significantly abrogates LPS-induced HMGB1 release from macrophages (26–28). Importantly, pharmacological inhibition of the JAK/STAT1 pathway, genetic deletion of STAT1, or inhibition of IFN-β expression by genetic deletion of IRF3 significantly promotes survival in both lethal endotoxemia and experimental sepsis (28–30). Accordingly, we reasoned here that JAK/STAT1 may represent a critical signaling mechanism controlling HMGB1 translocation from nucleus to cytoplasm.     

Differential Diagnosis of rSr’ Pattern in Leads V1‐V2. Comprehensive Review and Proposed Algorithm

One of the more frequent dilemmas in ECG interpretation is the differential diagnosis of an rSr’ pattern in leads V₁‐V₂. We often face this finding in asymptomatic and otherwise healthy individuals and the causes may vary from benign nonpathological variants to severe or life‐threatening heart diseases, such as Brugada syndrome or arrhythmogenic right ventricular dysplasia. In other cases, a normal variant of rSr’ pattern can be misinterpreted as pathological after the occurrence of certain clinical events such as cardiac arrest or syncope of unknown cause. In this review we analyze in detail all the possible conditions, both benign and pathological that may explain the presence of this electrocardiographic pattern. We also propose a simple electrocardiographic algorithm for differential diagnosis.     

Prototypical model for tensional wrinkling in thin sheets

The buckling and wrinkling of thin films has recently seen a surge of interest among physicists, biologists, mathematicians, and engineers. This activity has been triggered by the growing interest in developing technologies at ever-decreasing scales and the resulting necessity to control the mechanics of tiny structures, as well as by the realization that morphogenetic processes, such as the tissue-shaping instabilities occurring in animal epithelia or plant leaves, often emerge from mechanical instabilities of cell sheets. Although the most basic buckling instability of uniaxially compressed plates was understood by Euler more than two centuries ago, recent experiments on nanometrically thin (ultrathin) films have shown significant deviations from predictions of standard buckling theory. Motivated by this puzzle, we introduce here a theoretical model that allows for a systematic analysis of wrinkling in sheets far from their instability threshold. We focus on the simplest extension of Euler buckling that exhibits wrinkles of finite length--a sheet under axisymmetric tensile loads. The first study of this geometry, which is attributed to Lamé, allows us to construct a phase diagram that demonstrates the dramatic variation of wrinkling patterns from near-threshold to far-from-threshold conditions. Theoretical arguments and comparison to experiments show that the thinner the sheet is, the smaller is the compressive load above which the far-from-threshold regime emerges. This observation emphasizes the relevance of our analysis for nanomechanics applications.     

Clinical implications and mechanism of histopathological growth pattern in colorectal cancer liver metastases

Liver is the most common site of metastases of colorectal cancer, and liver metastases present with distinct histopathological growth patterns (HGPs), including desmoplastic, pushing and replacement HGPs and two rare HGPs. HGP is a miniature of tumor-host reaction and reflects tumor biology and pathological features as well as host immune dynamics. Many studies have revealed the association of HGPs with carcinogenesis, angiogenesis, and clinical outcomes and indicates HGP functions as bond between microscopic characteristics and clinical implications. These findings make HGP a candidate marker in risk stratification and guiding treatment decision-making, and a target of imaging observation for patient screening. Of note, it is crucial to determine the underlying mechanism shaping HGP, for instance, immune infiltration and extracellular matrix remodeling in desmoplastic HGP, and aggressive characteristics and special vascularization in replacement HGP (rHGP). We highlight the importance of aggressive features, vascularization, host immune and organ structure in formation of HGP, hence propose a novel "advance under camouflage" hypothesis to explain the formation of rHGP.     

Detection of urinary glycoprotein GP 41 in leukemic patients and in healthy donors

Summary Urinary glycoprotein patterns from leukemic patients and from healthy donors were found to be identical, when the detection was carried out with the same quantities of protein. Two dimensional polyacrylamide gel electrophoresis revealed seven independent glycoproteins in the molecular weight region of 41,000 dalton, regardless of the origin of the urine, indicating, that these glycoproteins do not reflect any specificity of cytoreduction in the course of chemotherapy.     

Increasing incidence of diabetes mellitus in Norwegian children 0–14 years of age 1973–1982

Summary A retrospective technique was used to register all newly diagnosed cases of diabetes mellitus in Norwegian children 0–14 years of age during the ten-year period 1973–1982. A total of 1,914 newly diagnosed cases were detected, from an average population of 932,037 children. The degree of ascertainment was near to 99%. The male incidence exceeded the female incidence by 12% (p<0.02). The mean yearly incidence for the ten-year period was 20.5 per 100,000. Comparing the two five-year periods 1973–1977 and 1978–1982, the mean yearly incidence increased from 18.5 to 22.7 per 100,000 (p<0.0001). There was a marked geographic variation with the highest incidence in the south-east and lower incidence in the northern part of the country. However, in the northern part of the country, there was a remarkable increase of the annual incidence from the first to the second five-year period (12.9 vs 19.3 per 100,000). The highest numbers of new cases were detected in the months of January and October, and the lowest numbers in May and July. The seasonal pattern was significantly different from a uniform distribution of new cases throughout the year (p<0.001). The age-specific incidence increased towards a peak at 12 years for both sexes. In conclusion, Norway has a high and apparently increasing incidence of childhood diabetes. The geographic variation and secular trend present challenging clues for a search of etio-pathogenic factors.     

我国功能性消化不良临床类型概况及治疗回顾的研究

目的：了解我国功能性消化不良临床症状出现频率、类型及治疗的情况，将有助于此类患者的合理治疗。方法：对符合国际诊断标准805例患者（来自全国各大区的18所大型医院）的材料进行上述方面的分析。结果：临床症状出现频率依次为腹胀（90．9％），嗳气（75．7％），早饱（71．2％），上腹痛（59．9％），反酸（410％），烧心（4．9％），恶心（3．4％），厌食（3．4％），胸骨后痛（23．0％）及呕吐（14.2％）。临床类型：运动障碍样型（61．7％），溃疡样型（17．5％），复合型及未定型（13．0％），反流样型（7．8％）。患者既往治疗时间达1～14个月，半数以上无明显疗效，三分之一还有症状加重乃至出现不良反应。结论：和西方报道不同，我国的功能性消化不良以运动障碍样型最为常见，说明此症和生活方式与习惯密切相关，而其治疗仍应深入研究。