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71.
    
Other than exposure to gluten and genetic compatibility, the gut microbiome has been suggested to be involved in celiac disease (CD) pathogenesis by mediating interactions between gluten/environmental factors and the host immune system. However, to establish disease progression markers, it is essential to assess alterations in the gut microbiota before disease onset. Here, a prospective metagenomic analysis of the gut microbiota of infants at risk of CD was done to track shifts in the microbiota before CD development. We performed cross-sectional and longitudinal analyses of gut microbiota, functional pathways, and metabolites, starting from 18 mo before CD onset, in 10 infants who developed CD and 10 matched nonaffected infants. Cross-sectional analysis at CD onset identified altered abundance of six microbial strains and several metabolites between cases and controls but no change in microbial species or pathway abundance. Conversely, results of longitudinal analysis revealed several microbial species/strains/pathways/metabolites occurring in increased abundance and detected before CD onset. These had previously been linked to autoimmune and inflammatory conditions (e.g., Dialister invisus, Parabacteroides sp., Lachnospiraceae, tryptophan metabolism, and metabolites serine and threonine). Others occurred in decreased abundance before CD onset and are known to have anti-inflammatory effects (e.g., Streptococcus thermophilus, Faecalibacterium prausnitzii, and Clostridium clostridioforme). Additionally, we uncovered previously unreported microbes/pathways/metabolites (e.g., Porphyromonas sp., high mannose–type N-glycan biosynthesis, and serine) that point to CD-specific biomarkers. Our study establishes a road map for prospective longitudinal study designs to better understand the role of gut microbiota in disease pathogenesis and therapeutic targets to reestablish tolerance and/or prevent autoimmunity.

Celiac disease (CD) is a chronic systemic autoimmune disorder that occurs in genetically predisposed individuals and is characterized by loss of tolerance to dietary gluten protein. CD affects ∼1% of the global population, with regional variations depending on human leukocyte antigen (HLA) presence and dietary gluten consumption (1). The incidence of CD most likely will continue to increase, along with other autoimmune conditions, despite the fact that its associated genes, HLA, and the trigger, gluten, have not changed (1). Nevertheless, more than 30% of the population carries the predisposing gene and is exposed to gluten, yet only 2 to 3% develop CD in their lifetime (2). This suggests that other factors such as the intestinal microbiota may also contribute to CD pathogenesis.The inflammatory process underlying CD involves both innate and adaptive immune systems (3). While the adaptive immune response in CD has been described, less is known about the innate immune response following gluten exposure, which drives early steps in CD pathogenesis and eventually leads to loss of gluten tolerance (4). Previous work has linked the trigger of CD, gluten, the intestinal microbiota, and the innate immune response (58).Given the cross-talk between the gut microbiota and immune system, alterations in the gut microbiota have been linked to several autoimmune conditions (9) such as inflammatory bowel disease (10), type 1 diabetes (T1D) (11), multiple sclerosis (12), and CD (1318). We, and others, have looked for changes in the gut microbiota of infants at risk for CD (15, 1719). For example, using 16S ribsosomal ribonucelic acid (rRNA) amplicon sequencing, we previously reported higher abundance of Lactobacillus up to 12 mo of age in one infant who later developed CD compared with 15 at-risk infants who did not (15). Other studies of gut microbiota and CD assessed changes in gut microbiota composition of individuals during the first year after birth who later developed CD compared with controls (17, 18). For example, Olivares et al. (17) used a prospective cohort of 200 infants at risk for CD to compare, with 16S rRNA sequencing, the intestinal microbiota of 10 cases who developed CD during the 5-y study period and 10 matched controls at 4 and 6 mo of age. They reported increases in abundance of Firmicutes, Enterococcaceae, and Peptostreptococcaceae in controls from 4 to 6 mo (17). Rintala et al. (18) also examined intestinal microbiota of infants at risk for CD, using 16S rRNA sequencing, at 9 and 12 mo of age in nine subjects who developed CD by ages 4 and 18 and matched controls, but did not identify any significant differences in microbiota composition. Huang et al. (20) examined intestinal microbiota, using 16S rRNA sequencing, at ages 1, 2.5, and 5 y in 16 subjects with CD (11 of whom developed CD after age 5) and 16 controls and found significant differences in taxonomic composition of the microbiota in cases compared with controls at all of the time points. Finally, a recent study using 16S rRNA sequencing to examine differences in the gut microbiota of children with untreated CD compared with children with treated CD and healthy control subjects did not identify changes in alpha diversity at CD diagnosis (21) but did identify differences in taxonomic composition, such as a lower abundance in Alistipes in subjects with CD compared with healthy controls (21). A separate study utilizing 16S rRNA sequencing also identified significant differences in taxonomic composition between patients with newly diagnosed CD and healthy control subjects, with subjects with recently diagnosed CD having a lower abundance of Bacteroides–Prevotella, Akkermansia, and Staphylococcaceae (22).While these studies provide an important foundation concerning alterations in gut microbiota of subjects at risk for CD early in life, they analyzed only up to three time points in the first year after birth (17, 18, 20) or were restricted to only one subject with CD (15). In addition, the studies used 16S rRNA sequencing to analyze intestinal microbiota, which cannot provide information about functional characteristics of the microbiota nor provide taxonomic data at the strain level, both of which are necessary to design effective treatment for CD. Furthermore, metabolomic analysis (if any) in these studies was generally limited to serum (as opposed to fecal) metabolites, which do not provide direct information about metabolic activity of the gut microbiota. More importantly, here we argue that, to gain mechanistic insight into the pathogenesis of CD and other autoimmune diseases, we need to transition from case–control microbiome studies to prospective longitudinal studies, which prospectively examine subjects at multiple time points before disease development (23). Studies aimed at identifying changes in the microbiome (11, 24) and intestinal permeability (25) have been performed and identified taxonomic changes prior to T1D (11) and necrotizing enterocolitis (24) as well as increased intestinal permeability up to 3 y prior to the development of Crohn’s disease (25). However, longitudinal birth cohort studies focused on multiomic data collection and analysis are limited and have not been developed for CD.The first step toward achieving this goal was to establish a prospective cohort study for CD, the Celiac Disease Genomic, Environmental, Microbiome, and Metabolomic (CDGEMM) study (26), where we have been following approximately 500 infants in the United States, Italy, and Spain who have a first-degree relative with CD and therefore, are at a high risk of developing CD. We have previously utilized other study subjects from this cohort and multiomics analysis to investigate the impact of genetic and environmental risk factors on the development of the gut microbiota in infants at risk for CD (19). In the current study, we present proof of concept intersubject and intrasubject analyses using fecal metagenomic and metabolomic data collected at multiple time points before onset of CD in 10 cases and 10 matched controls in order to identify alterations in the intestinal microbiota and metabolome, which may serve as markers of progression toward CD onset.  相似文献   
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The classical concept of the autonomic innervation of the nasal mucosa states that the postganglionic sympathetic neurones lie in the superior cervical ganglion and those of the postganglionic parasympathetic neurones are in the pterygopalatine ganglion. We have carried out a study of the fine structure of the respiratory nasal mucosa in man and in the cat using the techniques described by Jabonero, Champy Maillet and Koelle-Friedenwald. The most striking finding was the presence of microganglia deep within the mucosa of the inferior turbinate close to the glands. These microganglia were cholinergic in nature since they demonstrated a positive reaction to anticholinesterase. From this we deduce that the nasal parasympathetic pathway has its postganglionic neurones not only in the pterygopalatine ganglion but also in these microganglia of the inferior turbinate. Each of four groups of cats were submitted to different techniques, including administration of neostigmine, inferior turbinectomy and Vidian neurectomy. Resection of the microganglia by means of turbinectomy reduced the hypersecretion caused by neostigmine and this was most noticeable when a Vidian neurectomy was carried out in addition.  相似文献   
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Avulsions and intrusions are the most complicated and controversial displacement injuries of permanent teeth. Clinical guidelines published by authorities such as the American Association of Endodontists, the Royal College of Surgeons of England and the International Association of Dental Traumatology are inconsistent. While a certain amount of inconsistency might be expected, some of these guidelines recommend treatments that are experimental or have not incorporated research information from the past 5 years, and in one case the guidelines incorrectly describe the nature of Hank's balanced salt solution. Recent laboratory studies support previous clinical outcome studies in emphasizing that only for teeth replanted within 5 minutes of avulsion is there a chance of regeneration of the periodontal ligament and normal function. Teeth replanted beyond 5 minutes will take another path, that of repair followed by root resorption, ankylosis and eventual extraction. Dentists should explain these outcomes at the time of the replantation decision. Severe intrusions also have predictable outcomes. Teeth intruded beyond 6 mm cannot regenerate a functional periodontal ligament and so are prone to root resorption and eventual extraction as well. In this situation the decision is one of immediate extraction or repositioning, with the understanding that it is inevitable that the tooth will eventually be extracted. Authoritative clinical guidelines available on the Internet provide the clinician with useful outlines for treatment. However, individual inconsistencies stimulate academic controversies and, in some cases, clinical misdirection.  相似文献   
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A new method of automated sleep-wake staging in the rat is described. Hippocampal electroencephalographic (HPC) and nuchal electromyographic signals were recorded by a digital polygraph. The HPC channel was filtered off-line to obtain the original plus theta and delta waves. Statistics of each of these four channels were obtained every 5 s and exported to a standard spreadsheet. The automated staging consisted of five steps: (1) automatic detection of waking, nonrapid eye movement sleep and rapid eye movement sleep patterns (5-s periods); (2) calculation of statistics for each vigilance state; (3) final classification of 5-s periods; (4) construction of a primary 20-s epoch hypnogram; and (5) automatic refinement of the previous hypnogram. The system includes indices about the accuracy of the staging and was validated with five recordings of 23 h each. The global agreement between human and automatic scoring in the validation recordings was 94.32%.  相似文献   
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Introduction Prostate volume involves a defined toxicity predictor in the radiation therapy of localized prostate cancer. Neoadjuvant hormone therapy (nHT) can reduce prostate volume and, therefore, the planned volume. The objective of this study was to establish if the value of nHT reduces the planned volume and if this reduction correlates with a reduction of the dose received in the target organs. Material and methods 28 patients diagnosed of localized prostate cancer and referred to our departments for radiation therapy with radical intention, in the period ranging between April 2002 and October 2003, were included prospectively. The patients received nHT (triptorelin+flutamide) for 2 months and adjuvant HT until completing 2 years in the high-risk cases. A transrectal ultrasound study was performed in all patients, simulation CT and planning before the start of HT and after 2 months of treatment. The radiation therapy was carried out with 6 or 18 MV LINAC photons, with a dose fractioning scheme of 5×180–200 cGy, a total dosage of 66–72 Gy to prostate, 56 Gy to seminal vesicles and, in the high-risk cases, 46 Gy to pelvic lymph nodes. Results The distribution according to risk group was: low risk 3.6%, intermediate risk 28.6% and high risk 67.9%. By transrectal ultrasound, prostate volume on diagnosis was 50.65 cc pre HT and 38.97 cc post HT (p<0.001), which means a volume reduction of 24%. The comparative analysis of the dose-volume histograms of the first versus the second CT shows a reduction in the planned volume GTV1 (prostate) (81.33 cc vs 63.96 cc, p<0.05), PTV1 (prostate and margin) (197.51 cc vs 168.38 cc, p<0.001) and PTV2 (prostate, vesicles and margin) (340.5 cc vs 307.26 cc, p<0.05), a reduction of the maximum dose in the seminal vesicles (70.2 versus 68.75 Gy, p<0.05), a reduction of the mean dose in the seminal vesicles (65.07 Gy versus 63.07 Gy, p<0.05), PTV2 (67.72 Gy versus 66.9 Gy, p<0.01) and PTV3 (prostate, vesicles, pelvic lymph nodes and margin) (58.86 Gy versus 57.21 Gy, p<0.01), a reduction of the D90 in the seminal vesicles (61.83 Gy versus 60.06 Gy, p<0.05) and PTV2 (61.04 Gy versus 59.45 Gy, p<0.05) and a reduction of V60 of the rectum (32.45% versus 28.22%, p<0.05) and V60 of the bladder (41.78% versus 31.67%, p<0.005). Conclusions Neoadjuvant hormone therapy reduces significantly prostate volume and as a result the planned volume and consequently the rectal and bladder V60 can be significantly reduced.  相似文献   
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