Succinate is an inflammatory signal that induces IL-1ß through HIF-1α.

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1ß but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1ß as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1ß production during inflammation.

Decline in Dental Fluorosis Severity during Adolescence: A Cohort Study.

Dental fluorosis occurs from overingestion of fluoride during tooth formation. However, there is little evidence in the literature on whether or how fluorosis prevalence and severity change over time after tooth eruption. Permanent dentition dental examinations were conducted at ages 9, 13, 17, and 23 as part of the Iowa Fluoride Study, which has followed a cohort from birth. Fluorosis was assessed using the Fluorosis Risk Index (FRI) and Russell's criteria for differential diagnosis. Measures of fluorosis severity at the person and tooth level were calculated: second highest FRI score at the person level (the maximum FRI score for each tooth was determined and the tooth with the second highest maximum FRI score was used) and highest FRI score at the tooth level. At both the person and tooth levels, a decline in mild to moderate fluorosis severity was observed across adolescence and young adulthood. Across each pair of adjacent examinations at the person level, for participants with a baseline second highest FRI of 0, most participants stayed at 0 (82% to 91%). Many participants with a baseline second highest FRI of 1 had a follow-up score of 0 (47% to 54%), while about a third had a follow-up score of 1 (34% to 38%), and a lower percentage had an increase to a score of 2 (9% to 15%). For participants with baseline second highest FRI score of 2, between 25% and 44% of participants had follow-up FRI scores each of 0, 1, and 2. Similar patterns were observed at the tooth level. These results were consistent with most of the existing, limited literature. Overall, fluorosis severity, which was initially mild to moderate, tended to decline during adolescence and young adulthood. Additional study of how this trend affects esthetic perceptions of fluorosis is warranted.

Examining caries aetiology in adolescence with structural equation modelling.

OBJECTIVES: This analysis examines the aetiology of caries development in adolescents using structural equation modelling to identify behavioural mediators of the relationship between socioeconomic status (SES) and caries incidence, and to investigate the role of sex on caries-preventive behaviour and caries. METHODS: This analysis was based on data from the Iowa Fluoride Study, a longitudinal study of a birth cohort. We hypothesized that socioeconomic status earlier in life has a direct effect on caries development and an indirect effect from improved behavioural variables-dental visit attendance, toothbrushing frequency and percentage of beverage intake consisting of sugar-sweetened beverages-and that sex also plays a role in behavioural variables, as well as caries. A structural equation model was developed based on these hypotheses, and direct and indirect standardized path coefficients were calculated, as well as their standard errors. RESULTS: Based on our proposed model, SES at birth significantly influences SES during adolescence, but not adolescent behaviours. The effect of SES during adolescence on caries in the permanent dentition is mediated by adolescent behaviours. Female participants have worse caries than male participants, despite lower self-reported percentages of sugar-sweetened beverage intake and more frequent brushing and dental attendance. CONCLUSIONS: This analysis models the relationships among known causal factors for caries and suggests that the role of SES in caries may not be as important as previously thought and different behaviours that affect oral health between males and females as well as differences in caries between the sexes could begin during adolescence. These findings could help improve caries prevention programmes for adolescents.

Circadian rhythms of melatonin and behaviour in juvenile sheep in field conditions: Effects of photoperiod, environment and weaning.

Entrainment of circadian rhythms (CR) to the light dark cycle has been well described under controlled, experimental conditions. However, studies in rodents have reported that rhythms in the laboratory are not always reproduced under field conditions. The aim of this study was to characterise the CR of sheep maintained under conditions of standard UK farm animal husbandry and to investigate the effects of environmental challenges presented by season, weaning and changes in housing on CR. Male sheep (n = 9) were kept at pasture, or group housed in barns, under natural photoperiod for one year. CR in locomotor activity were monitored using accelerometry, and 24 h patterns in plasma cortisol and melatonin were measured every 4 h by ELISA. CR was measured before and after weaning, in summer and winter, and at pasture and by barn housing. Cosinor analysis revealed high amplitude, diurnal rhythms in locomotor activity that were disrupted by weaning and by barn housing. Rhythms in winter showed an interrupted night time activity pattern, but only when the sheep were kept at pasture. Cortisol and melatonin secretion followed typical circadian patterns in winter and summer. The CR of the sheep under the field conditions of this study were strikingly robust under basal conditions, but easily disrupted by environmental challenges. Interrupted patterns of activity during the long nights of wintertime, not previously reported for sheep kept in experimental conditions were recorded. Based on these findings, we propose that animals require exposure to more complex environments than the laboratory in order to exhibit their true circadian phenotype.

Role of computed tomography in the staging of primary melanoma.

PURPOSE: To evaluate the role of body computed tomography (CT) for the staging of patients with early melanoma. PATIENTS AND METHODS: A total of 151 new patients with American Joint Committee (AJC) clinical stage I, II, and III melanoma who received a CT scan of at least the chest and abdomen are the subject of this study. CT scans considered suspicious for metastases were reviewed again by one of the investigators (A.McB.C.). RESULTS: Of 151 patients, 63 had AJC clinical stage I, 61 stage II, and 23 stage III disease. In addition, one patient each had primary melanoma of the anal canal, esophagus, or vulva. Twenty-nine (19%) of 151 patients had a CT scan that was considered suspicious for metastases. The most common radiologic findings were single hepatic, and single or multiple pulmonary nodules. Of these 29 patients with suspicious scans, 24 subsequently proved to have benign processes by biopsy or follow-up studies, three had second primary tumors (well-differentiated lymphocytic lymphoma, Hodgkin's disease, and renal cell carcinoma), and only two were found to have metastatic melanoma. Of these two patients, one had regional nodal disease (unsuspected on physical examination) and one had distant nodal metastases. CONCLUSION: Body CT is not a useful imaging study in the detection of occult metastases in patients with primary melanoma. Although body CT commonly shows suspicious radiologic abnormalities in patients with early melanoma, these abnormalities most likely represent benign processes or a second primary tumor, rather than metastatic melanoma. The value of body CT in patients who present with nodal metastases needs further study.

Gray scale ultrasonography, computerized tomography, and nephrotomography in evaluation of polycystic kidney and liver disease.

A comparison of gray scale ultrasonography and computerized axial tomography in adults with known adult-type polycystic disease and of ultrasonography and high-dose nephrotomography in their progeny is being conducted. Although all three modalities have proved capable of demonstrating cysts of the kidney and liver, ultrasound has been the most consistent in identifying these lesions. Ultrasound is valuable in diagnosing polycystic disease in adult with large, poorly functioning kidneys; in addition, since cysts could be identified by ultrasound in children who had normal nephrotograms, it provides a safe and useful method of obtaining information for genetic counseling.

Primary oesophageal melanocarcinoma.

Three patients with melanocarcinoma of the oesophagus are described. Reasons are given for believing that these were primary tumours. The clinical features and pathology of the condition are discussed.

Metastatic disease to the chest in patients with extrathoracic malignancy.

The search for metastases to the lung parenchyma and other intrathoracic structures is a commonly encountered problem. The radiographic appearance of intrathoracic metastases is varied, and multiple imaging modalities may aid in their detection. Knowledge of relative frequency, growth rates, and mechanisms of spread may guide the sequence of radiographic studies.

p38 mitogen-activated protein kinase targets the production of proinflammatory endothelial microparticles.

BACKGROUND: Endothelial microparticles (EMPs) are irregularly shaped membrane fragments shed into the circulation in patients with vascular diseases, and may themselves act to enhance the endothelial response to inflammation. On the basis of the importance of p38 mitogen-activated protein kinase (MAPK) in endothelial responses to inflammatory stimuli, we sought to define the role of p38 in EMP generation and function. METHODS: Microparticle generation from cultures of human aortic endothelial cells (hAECs) treated with tumor necrosis factor-alpha (TNF-alpha) and p38 inhibition was quantified via multiple modalities. The response of target endothelial cells was assessed by treatment of cells with EMPs generated under various conditions. RESULTS: Inhibition of p38 in hAECs, using pharmacologic agents, resulted in a 50% reduction of TNF-alpha-induced EMPs. Importantly, suppression of microparticles was specific to p38 MAPK pathways. EMPs triggered by TNF-alpha activation induced an approximately four-fold increase in soluble intercellular adhesion molecule-1 (sICAM-1) release from targeted cells. However, inhibition of p38 MAPK in the targeted cell prior to EMP treatment did not alter the sICAM1 response. CONCLUSIONS: Our findings implicate p38 MAPK signaling as significant and selective in the formation and maturation of EMPs. EMPs elicited a proinflammatory response from targeted hAECs that was dependent on the conditions under which EMPs were generated. However, our results imply a unidirectional model in which p38 MAPK is critical at the source of microparticle formation, but not the target cell response to EMPs. These findings indicate a novel mechanism by which p38 inhibition may offer therapeutic benefit in vivo via direct inhibition of EMP formation.

Sequelae of stomach surgery.

Gastric surgery has undergone continuous evolution since the 19th century. At present it is a highly sophisticated technique which provides symptomatic relief for the vast majority of patients operated upon for peptic ulcer disease. Although the overall incidence of complications has decreased, a variety of complications continues to occur and radiological examination plays a critical role in their detection, evaluation, and management. Knowledge of the variations in surgical terminology and commonly used eponyms provides the basic framework for discussion. Familiarity with the radiological appearance of the normal postoperative stomach together with an understanding of its physiology are essential prerequisites to the recognition of possible complications. Operative techniques may result in a radiographic appearance which simulates disease. Conditions as diverse as bezoars, afferent and efferent loop problems, marginal ulceration, anastomotic leakage, prolapse, and intussuception may all be characterized by distinct and highly specific radiographic changes. Physiologic problems such as dumping and malabsorption may also reflect their presence by X-ray changes. The radiographic features in a large number of surgical complications are discussed and illustrated. The importance of the radiographic examination in the postsurgical stomach is emphasized.

Air crescent sign of invasive aspergillosis.

Pulmonary infection in immunocompromised patients is frequently difficult to diagnose. Therapy for the more common pathogens differs greatly from that for infection with unusual opportunistic organisms. However, neither of these infectious agents offers specific radiographic signs. The authors report on 4 patients with acute leukemia and invasive aspergillosis whose radiographs demonstrated a distinctive feature of one or more air crescents within an area of pulmonary infiltrate. Autopsy studies correlated the radiographic changes with an infection due to Aspergillus species fungi. While the sign is not pathognomonic for Aspergillus infection, seen in a suitable host, it would suggest the possibility of invasive aspergillosis.

Roentgen manifestations of carcinoma in the gastric remnant.

Awareness of the increased incidence of carcinoma in the gastric remnant has not been accompanied by improved diagnosis or prolonged survival. The long latent period prior to development of tumor, the insidious nature of symptoms, and the anatomical distortion produced by surgery contribute to the difficulty in detection of these lesions. The radiological spectrum of carcinoma of the gastric remnant is discussed and both characteristic and unique radiographic features are illustrated.

Thickening of the posterior tracheal stripe: a sign of squamous cell carcinoma of the esophagus.

A thickened posterior tracheal stripe (wider than 4.5 mm) was identified on the lateral check radiographs of 20 patients with squamous cell carcinoma of the esophagus. Autopsy studies confirmed that peri-esophageal lymphatic involvement was responsible for the thickening of the stripe in the nonobstructed esophagus. This sign appeared on the lateral chest radiograph as early as 6 months prior to the development of symptoms in 50% of the cases studied.

Intraaortic counterpulsation balloon: radiographic considerations.

The intraaortic counterpulsation balloon is being used with increasing frequency in the setting of cardiogenic shock and/or high risk cardiac surgery. The radiologist should be aware of the normal function of this cardiac assist device, as well as its potential complications. The principal complications apparent on the plain chest radiograph are related to improper positioning of the balloon catheter.

Thoracic alterations after cardiac surgery.

A series of 92 adult patients undergoing elective cardiac surgery was reviewed to distinguish routine postoperative radiographic alterations from signs of clinically significant complications. Two postoperative complications required decisive clinical intervention: mediastinal hemorrhage (7% of cases) and sternal wound infections (3% of cases). Mediastinal hemorrhage was most often diagnosed by excessive bloody mediastinal tube drainage alone, although progressive mediastinal widening and pleural or apical extrapleural hematomas provided corroborating or, rarely, the sole evidence of mediastinal hemorrhage. Sternal wound infections were most often diagnosed clinically, but increasing pre- and retrosternal gas collections provided radiographic confirmation. Atelectasis was the most common postoperative finding. There were many abnormal gas and soft-tissue collections posteroperatively that were notable for their lack of clinical importance. Serial postoperative films were necessary to demonstrate the progression of radiographic findings which indicate the two important postoperative complications.

The three syndromes of fat embolism: pulmonary manifestations.

The clinical course and radiographs of 30 patients with fat embolism syndrome were reviewed. In all cases the classic triad of neurologic dysfunction, respiratory insufficiency, and petechiae were present. Three responses to embolized fat were noted. The hyperacute response was seen in two patients with paradoxical embolization of fat to the systemic circulation. A "classic response" was noted in 18 patients with transient respiratory compromise and variable radiographic findings. The two deaths in the group responding in the classical manner were attributed to massive pulmonary emboli. The third response, noted in ten patients, consisted of a chest radiograph compatible with pulmonary edema in the clinical setting of the adult respiratory distress syndrome. In this group the degree of respiratory dysfunction and pulmonary damage correlated with the development of disseminated intravascular coagulation. Pathologic correlations are presented and the mechanisms by which embolic fat produces tissue damage are discussed.

The efficacy of full-lung tomography in the detection of early metastatic disease from melanoma.

In a prospective study, 62 patients with proved melanoma and negative chest radiographs underwent full-lung tomography. Of 109 examinations performed, 12 patients had positive findings on tomography; nine were false-positive and three were true-positive. Of the true-positive examinations, two patients already had widespread metastatic disease and one had an advanced local lesion. Clinical staging and therapy were changed in only one patient as a result of information provided by full-lung tomography. It appears from these results that full-lung tomography is of limited use in detection of metastases from melanoma in the presence of a negative chest radiograph.