Identification of circulating biomarkers for differentiating patients with papillary thyroid cancers from benign thyroid tumors.

BACKGROUND: This study aimed to identify the potential circulating biomarkers of protein, mRNAs, and long non-coding RNAs (lncRNAs) to differentiate the papillary thyroid cancers from benign thyroid tumors. METHODS: The study population of 100 patients was classified into identification (10 patients with papillary thyroid cancers and 10 patients with benign thyroid tumors) and validation groups (45 patients with papillary thyroid cancers and 35 patients with benign thyroid tumors). The Sengenics Immunome Protein Array-combined data mining approach using the Open Targets Platform was used to identify the putative protein biomarkers, and their expression validated using the enzyme-linked immunosorbent assay. Next-generation sequencing by Illumina HiSeq was used for the detection of dysregulated mRNAs and lncRNAs. The website Timer v2.0 helped identify the putative mRNA biomarkers, which were significantly over-expressed in papillary thyroid cancers than in adjacent normal thyroid tissue. The mRNA and lncRNA biomarker expression was validated by a real-time polymerase chain reaction. RESULTS: Although putative protein and mRNA biomarkers have been identified, their serum expression could not be confirmed in the validation cohorts. In addition, seven lncRNAs (TCONS_00516490, TCONS_00336559, TCONS_00311568, TCONS_00321917, TCONS_00336522, TCONS_00282483, and TCONS_00494326) were identified and validated as significantly downregulated in patients with papillary thyroid cancers compared to those with benign thyroid tumors. These seven lncRNAs showed moderate accuracy based on the area under the curve (AUC = 0.736) of receiver operating characteristic in predicting the occurrence of papillary thyroid cancers. CONCLUSIONS: We identified seven downregulated circulating lncRNAs with the potential for predicting the occurrence of papillary thyroid cancers.

B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway.

This corrects the article DOI: 10.1038/onc.2014.43.

B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway.

B-cell lymphoma/leukemia 10 (BCL10) is an apoptotic regulatory protein related to advanced TNM stage and disease recurrence in oral squamous cell carcinoma (OSCC). However, the regulatory mechanism of BCL10 in OSCC progression is still unknown. Here, we showed that knockdown of endogenous BCL10 could significantly reduce cell migration and invasion abilities, retard cell proliferation by G0/G1 phase accumulation and inhibit tumorigenicity in vivo. In molecular level, we identified S100P as a crucial downstream effector of BCL10-inhibited OSCC progression by high-throughput microarray analysis. S100P messenger RNA and protein expression levels were significantly diminished in silenced-BCL10 clones, and transfected S100P expression plasmids restored migration, invasion, proliferation abilities and tumorigenicity in shBCL10 transfectants. Furthermore, we provided evidence that BCL10 regulated S100P expression through signal transducers and activators of transcription 1 (STAT1) and activating transcription factor 4 (ATF4). Knockdown of BCL10 decreased S100P promoter activity, but showed no effect in truncated STAT1/ATF4 S100P promoter.  In addition, we also found that the P50/P65 signaling pathway was involved in BCL10-enhanced OSCC progression. Restored S100P in silenced-BCL10 clones could markedly reverse P65 activation via outside-in signaling. Taken together, we discovered a novel axis of BCL10-regulated OSCC progression via STAT1/ATF4/S100P/P65 signaling, which could predict the prognosis of OSCC and will be beneficial for developing therapeutic strategy against advanced OSCC.

Laparoscopic omega-loop gastric bypass for the conversion of failed sleeve gastrectomy: early experience.

OBJECTIVES: Despite the initial effectiveness of sleeve gastrectomy (SG), some patients who undergo this purely restrictive technique have inadequate weight loss or renewed weight gain and persistent obesity-related co-morbidities with their potentially lethal complications. In such patients, the conversion of SG by the addition of a malabsorptive technique may then be necessary. PATIENTS AND METHODS: Conversion of SG to a mini gastric bypass (MGBP) was evaluated for failure of weight loss. An ante-colic end-to-side stapled gastro-jejunal anastomosis was performed laparoscopically, connecting the long narrow gastric tube to the jejunum at a point 200cm downstream from the ligament of Treitz. RESULTS: Between October 2006 and February 2012, 651 laparoscopic MGBP were performed for morbid obesity. Twenty-three of these patients (3.5%) had previously undergone SG. The conversion from SG to MGPB was performed laparoscopically in 19 of the 23 patients (81%) at a mean interval of 26.3months (8.2-63.7). The 30-day postoperative mortality rate was zero and the morbidity rate was 9.5%. The mean BMI before MGBP was 44±7.7kg (35.8-55.4). Conversion of SG to MGBP resulted in additional weight loss, achieving a mean BMI of 39.9 with a 26.8% loss of excess BMI (EBL) at 3months, mean BMI of 36.5 with 37.2% EBL at 12months, mean BMI of 36.2 with 48.6% EBL at 18months, and mean BMI of 35.7 with EBL of 51.6% at 24months. The overall mean EBL was 57.3±19.5% (range: 25-82%) at 42.3months (range 16.7-60.8months). CONCLUSION: Conversion of SG to MGBP is feasible, safe and effective, and results in significant additional weight loss. Definitive results at 2 and 5years are awaited for the long-term procedure validation.

X-ray phase-contrast imaging with nanoradian angular resolution.

We present a new quantitative x-ray phase-contrast imaging method based on the edge illumination principle, which allows achieving unprecedented nanoradian sensitivity. The extremely high angular resolution is demonstrated theoretically and through experimental images obtained at two different synchrotron radiation facilities. The results, achieved at both very high and very low x-ray energies, show that this highly sensitive technique can be efficiently exploited over a very broad range of experimental conditions. This method can open the way to new, previously inaccessible scientific applications in various fields including biology, medicine and materials science.

[Total knee arthroplasty - GPs' views in Germany: a questionnaire-based study]. / Beurteilung des Verfahrens der Knieendoprothetik durch deutsche Hausärzte: Eine Fragebogenstudie.

To assess general knowledge and individual views of general practitioners (GPs) on total knee arthroplasty (TKA), we conducted a questionnaire-based survey involving 170 GPs in Germany. Eighty-one GPs returned the questionnaire. They treat a mean of 10.6+/-8.3 patients with TKA. General knowledge can be estimated as good. Compared with the data in the literature, GPs assessed the rate of satisfied patients as lower and the risk for revision surgery as higher. The mean risk of potential complications (infection, instability, persistent pain) in association with TKA was estimated correctly. Seventy-eight percent of GPs consider an allergic reaction to the implant or bone cement as problematic. The number of cases per year, personal experience with the surgeon, and - less important - local accessibility are important factors for GPs when recommending an operating centre to a patient.A broad spectrum of individual responses indicates the need to improve the information transfer between orthopaedic surgeons and referring GPs.

[Metal sensitivity in patients with joint replacement arthroplasties before and after surgery]. / Metallallergie bei Patienten vor bzw. nach endoprothetischem Gelenkersatz.

The object of the present study was to determine the incidence of metal sensitivity in patients with joint replacement arthroplasties before and after surgery and whether this is of significance as regards the final outcome of the operative procedure. A questionnaire-based survey involved 1,335 patients with an average age of 61 years and joint replacement arthroplasties before and after surgery. A history of dermal sensitivity to metal was given in 99 (7%) patients with almost equal frequency in the pre- and postoperative groups (7.6 vs 7.2%). In only 27 of 99 cases was the metal sensitivity recorded in the patient chart. In 46 cases investigation was done after knee or hip replacement arthroplasty with an average implant time in situ of 68 months. In 32 of 46 patients a sensitivity to the implanted material was known and they did not show any complications related to the metal sensitivity.It is currently unclear whether metal sensitivity could be induced by joint replacement arthroplasties and it remains uncertain whether loosening or infection causes the sensitization as a consequence of increased release of metal ions or vice versa. To draw further conclusions considerably more detailed studies involving more patients are clearly indicated.

[Gallbladder cancer revealed by a jaundice caused by an endobiliary tumor thrombus]. / Cancer de la vésicule biliaire révélé par un ictère dû a un thrombus tumoral endobiliaire.

Main bile duct neoplasic thrombosis is a rare cause of jaundice in case of gallbladder cancer. We report the case of 27-year-old woman in whom the endoluminal biopsy of biliary thrombus confirmed the suspected diagnosis of gallbladder cancer. An initial laparoscopic exploration found a localized peritoneal carcinomatosis. However, in this exceptional situation with an unknown prognostic, a surgical procedure has been performed including hepatectomy IV-V with biliary principal bile duct removal, hepatico-jejunal anastomosis (Roux-en-Y), with complete resection of localized peritoneal carcinomatosis. Post-operative course were uneventful and this patient was asymptomatic under chemotherapy with a six month follow-up.

Noninvasive bone replacement with a new injectable calcium phosphate biomaterial.

The use of injectable calcium phosphate (CaP) biomaterials in noninvasive surgery should provide efficient bone colonization and implantation. Two different kinds of injectable biomaterials are presently under development: ionic hydraulic bone cements that harden in vivo after injection, and an association of biphasic calcium phosphate (BCP) ceramic granules and a water-soluble polymer vehicle (a technique particularly investigated by our group), providing an injectable CaP bone substitute (IBS). In our study, we compared these two approaches, using physicochemical characterizations and in vivo evaluations in light microscopy, scanning electron microscopy, and three-dimensional microtomography with synchrotron technology. Three weeks after implantation in rabbit bone, both biomaterials showed perfect biocompatibility and bioactivity, but new bone formation and degradation of the biomaterial were significantly greater for BCP granules than for ionic cement. Newly formed bone developed, binding the BCP granules together, whereas new bone grew only on the surface of the cement, which remained dense, with no obvious degradation 3 weeks after implantation. This study confirms that BCP granules carried by a cellulosic polymer conserve bioactivity and are conducive to earlier and more extensive bone substitution than a carbonated-hydroxyapatite bone cement. The presence of intergranular spaces in the BCP preparation, as shown on microtomography imaging, seems particularly favorable, allowing body fluids to reach each BCP granule immediately after implantation. Thus, the IBS functions as a completely interconnected ceramic with total open macroporosity. This new bone replacement approach should facilitate microinvasive bone surgery and local delivery of bone therapy agents.

[Technique of pancreatic anastomosis]. / Technik der Pankreasanastomose.

Postoperative morbidity after pancreatic resection is primarily due to leakage of the pancreatic anastomosis. The duct-to-mucosa pancreatico-jejunostomy either as an end-to-end or end-to-side anastomosis is the preferred technique in our hands. The use of a temporarily catheter to drain the main pancreatic duct is optimal. The pancreatic leakage rate depends in many series on the consistence of the pancreatic parenchyma, the diameter of the major pancreatic duct and the local perfusion. A meticulous, standardized technique, the possibility to adapt the technique in case of unexpected findings and the operative routine of the surgeon are of paramount importance for achieving a low leakage rate. In so called "high volume" centers the pancreatic fistula rate today is in the range of 3 to 13% and the mortality of pancreatic head resection varies between 0.5 and 3%.

Bacterial brain abscess: microbiological features, epidemiological trends and therapeutic outcomes.

BACKGROUND: Despite the advent of modern neurosurgical techniques, new antibiotics, and powerful imaging technologies, brain abscess remains a potentially fatal central nervous system infection. AIM: To determine the epidemiological trends, prognostic factors, and outcomes of bacterial brain abscess, to improve the therapeutic strategy for this disease. DESIGN: Retrospective hospital-based epidemiology study. METHODS: Over a period of 15 years (1986-2000), 123 patients were retrospectively identified as having brain abscesses at Kaohsiung Chang Gung Memorial Hospital. To compare changes over time, the appearance of disease among our patients was divided into two time periods: 1986-1993 and 1994-2000. RESULTS: The prevalence rate of brain abscesses caused by Gram-negative organisms significantly increased in the second study period. Viridans streptococci and Klebsiella pneumoniae were the two prevalent pathogens associated with haematogenous spread. Metastatic septic abscess, a devastating complication of K. pneumoniae septicaemia, frequently occurs in diabetic patients, with a high mortality rate. Viridans streptococci were the most prevalent pathogens from infection in paranasal sinusitis, but no fatality occurred. In recent years, head trauma and/or post-neurosurgical states have become important predisposing factors, and nosocomial infections also play an important role. DISCUSSION: Despite the availability of new antibiotics and the development of better neurosurgical techniques, therapeutic outcomes of brain abscess showed no significant change when comparing the two study periods, and only the presence of septic shock influenced outcome.

Klebsiella brain abscess in adults.

BACKGROUND: We analyzed the clinical manifestations and therapeutic outcomes of Klebsiella brain abscesses. PATIENTS AND METHODS: The clinical data of 15 patients with Klebsiella brain abscesses, retrospectively collected over a 14-year period, were studied. RESULTS: The 15 patients included 13 cases of Klebsiella pneumoniae infection and two cases of Klebsiella oxytoca. All but one case were community-acquired infections. Locations of all of these abscesses were supratentorial. 12 cases involved a single abscess, and three involved multiple abscesses. Gas formation was also found in two cases (13%). Common predisposing factors included metastatic spread, chronic otitis media and neurosurgical procedures. Among these 15 patients, 11 were treated surgically and four received antibiotics alone. In total, 11 patients survived and four died, with an overall mortality rate of 26.7%. CONCLUSION: The clinical presentations and therapeutic outcomes varied according to the different Klebsiella species. While debilitating diseases were common in K. pneumoniae infections, they were not common in K. oxytoca infection. And while metastatic septic abscess is a well-known, devastating complication of K. pneumoniae septicemia, usually seen as a brain abscess with a gas-forming appearance, all of these K. oxytoca infections had both otogenic infections and more favorable outcomes.

Is fibromyalgia a distinct clinical syndrome?

The validity of the fibromyalgia syndrome (FMS) as a distinct clinical entity has been challenged for several reasons. Many skeptics express concern about the subjective nature of chronic pain, the subjectivity of the tender point (TeP) examination, the lack of a gold standard laboratory test, and the absence of a clear pathogenic mechanism by which to define FMS. Another expressed concern has been the relative nature of the pain-distress relationship in the rheumatology clinic. The apparently continuous relationship between TePs and somatic distress across a variety of clinical disorders is said to argue against FMS as a separate clinical disorder. The most aggressive challenges of the FMS concept have been from legal defenses of insurance carriers motivated by economic concerns. Other forms of critique have presented as psychiatric dogma, uninformed posturing, suspicion of malingering, ignorance of nociceptive physiology, and occasionally have resulted from honest misunderstanding. It is not likely that a few paragraphs of data and logic will cause an unbeliever to change an ingrained opinion. Therefore, this review describes the clinical manifestations of FMS, responds to some of the theoretic arguments against it, and discusses some possible pathophysiologic mechanisms by which FMS may develop and persist as a unique syndrome.

Elevation of vascular endothelial growth factor-A serum levels following acute myocardial infarction. Evidence for its origin and functional significance.

Following the onset of acute myocardial infarction (AMI), a number of serum parameters show well-defined changes reflecting myocardial injury. During the consecutive repair phase, compensatory processes are initiated including the formation of a collateral circulation on the basis of angiogenesis and arteriogenesis. An important angiogenic factor is vascular endothelial growth factor-A (VEGF-A), shown to be upregulated in the ischemic myocardium. It is unclear, however, whether acute myocardial ischemia leads to a detectable elevation of VEGF-A serum concentrations. With the use of an immunoradiometric assay, we measured the levels of VEGF-A in the serum of patients after AMI at defined time intervals, of patients with unstable angina pectoris (UAP) and of healthy individuals. In addition, in a small group of patients with subacute myocardial infarction VEGF-A concentrations were measured in coronary sinus blood. The data are given as median followed by the 25th and 75th percentiles. In the group with AMI serum VEGF-A measured 105 [78; 176] pg/ml on day 1 and 114 pg/ml [72; 163] pg/ml on day 3 after onset of AMI. Serum levels of VEGF-A significantly increased on day 7 after AMI to 189 [119; 373] pg/ml (P=0.0103) and on day 10 to 255 [162; 371] pg/ml (P=0.0007). The VEGF-A serum level in healthy controls and in patients with UAP measured 98 [75; 137] pg/ml and 116 [57; 140] pg/ml, respectively. Serum at day 10 after AMI contained VEGF-A at a biologically relevant concentration capable of stimulating proliferation of endothelial cells. Surprisingly, VEGF-A serum levels were similar in samples taken from the coronary sinus with 61 [43; 83] pg/ml. Therefore the main source for VEGF-A in the blood stream is not the infarcted myocardium. However, the number of platelets, a rich source of VEGF-A, is significantly increased after myocardial infarction, i.e. 284 [252; 363] x 10(9)/litre v 220 [177; 250] x 10(9)/litre. In conclusion, the time course of VEGF-A elevation following AMI strongly suggests that VEGF-A plays a role as an endogenous activator of coronary collateral formation in the human heart. The most likely source of the elevated VEGF-A are platelets, rather than the infarcted myocardium.

Patterns of palmar skin temperature alterations during transthoracic endoscopic T2 sympathectomy for palmar hyperhidrosis.

Transthoracic endoscopic T2 sympathectomy has been widely applied to the treatment of a variety of sympathetically mediated disorders. Palmar hyperhidrosis is probably the most common indication for thoracic sympathectomy, especially in certain subtropical areas. Which sympathetic ganglion is to be ablated and how extensive such ablation is enough to eliminate palm sweating are two important issues. Intraoperative monitoring of palmar skin temperature (PST) is the most frequently used method for assessing the accuracy as well as adequacy of ablation of the target sympathetic ganglia. With continuous monitoring of bilateral PST during the operative course of T2 sympathectomy, it was possible to depict the alterations of bilateral PST in response to specific surgical procedures in a real-time manner. For each case, a PST graph was obtained, which represented the graphical expression of intraoperatively recorded bilateral PST data plotted against time. The PST graphs of 93 consecutive cases were analysed. Three types of PST graphs existed, reflecting different responses of bilateral PST to different surgical procedures during the operation. In Type I PST graph pattern, found in 58 cases, skin incision and intercostal muscle dissection caused dramatic bilateral PST drop; and unilateral T2 sympathectomy induced synchronous bilateral PST elevation. Twenty-four cases demonstrated Type II PST graph pattern, in which unilateral T2 sympathectomy caused only ipsilateral PST elevation, although the PST-depressing effect of skin incision and muscle dissection was as significant as in Type I graph pattern. In the 11 cases who showed Type III PST graph pattern, neither skin incision nor T2 sympathectomy induced any apparent changes of PST on either side, giving rise to two rather flat PST curves on the PST graphs. These findings implicate that reciprocal interactions between bilateral sympathetic activities exist in the majority of cases, and that crossover sympathetic modulation may play a role in the neural control of the sudomotor and vasomotor activities of the palms. This study also provides information regarding how PST would possibly change following specific surgical procedures during transthoracic endoscopic T2 sympathectomy, which may be of importance to those who use intraoperative PST monitoring as a guide in determining whether or not the correct sympathetic ganglia are ablated for adequate sympathetic denervation of the palms.

A logistic regression model for the decision to perform access surgery.

Access surgery may be recommended to about 80% of patients who present with advanced forms of periodontal disease. In this report, a multivariate logistic regression analysis which incorporated several clinical parameters for each tooth examined, i.e., tooth type, furcation involvement, bleeding on probing, attachment level, probing depth, mobility and BANA test score, was conducted using generalized estimating equations (GEE). This approach identified parameters that were significantly associated at p < 0.05 level with the need for access surgery or extraction for periodontal purposes. The estimated probabilities derived from the GEE model were plotted over the complete spectrum of operating conditions to obtain a receiver-operator characteristic (ROC) curve. At a probability cutpoint of 0.8, the decision threshold for surgery/extraction at the pretreatment examination would have a sensitivity of 76.1% and a specificity of 75.3%. We have taken this 0.8 cut point to look at specific clinical decisions made by our examiners after the patients had received scaling and root planing plus 2 weeks unsupervised usage of systemic antimicrobials. The clinicians' decision was taken as the primary reference standard. The model's estimated decision agreed with the clinicians' decision in 226 of the 284 teeth, for an accuracy of 80%. The specificity was 90% and the sensitivity was 43%.

Nonsurgical treatment of patients with periodontal disease.

OBJECTIVE: To determine whether the short-term use of systemic antimicrobials (metronidazole or doxycycline) and locally delivered antimicrobials (metronidazole, chlorhexidine) in patients with advanced forms of periodontal disease could prevent the normally necessary access surgery. STUDY DESIGN: Ninety-four patients were randomly assigned with the use of a double-blind protocol. RESULTS: There was a 93% reduction in the need for periodontal surgery about individual teeth and an 81% reduction in the need for tooth extractions. Only 93 teeth of an initial total of 783 teeth actually needed surgery or extractions. Eighty-one percent of the patients entered into the maintenance phase of treatment without needing surgical treatments. CONCLUSION: These findings indicate that a treatment paradigm based on the diagnosis and treatment of anaerobic infections is likely to be successful in those patients for whom access surgery is recommended.

Scanning tunneling microscopy study of poly-L-proline.

Differences in its peptide bonds allow the imino acid poly-L-proline to exist in two significantly different geometric structures. Form I with cis peptide bonds is supposed to be a right-handed helix and form II with trans peptide bonds a left-handed helix. Cis/trans isomerization about the proline imide is believed to cause the denaturation of a number of proteins and may be a key step in protein folding. Using scanning tunneling microscopy (STM), we present high-resolution images of air-dried poly-L-proline. It is found that the electric conductivity of one monolayer of poly-L-proline is sufficient to allow for STM imaging without significant tip-sample interaction. Only at locations where stacking of poly-L-proline chains occurs, a direct contact of the probing tip to the molecules becomes apparent and prevents us, at present, from resolving the atomic structure of the topmost layer. Our STM images of poly-L-proline show that form II is relatively rigid and forms aggregates in most cases. Form I, which is occasionally observed, is very flexible and exhibits sharp bends as well as 180 degrees backfolding. These observations confirm theoretical predictions on the existence of two peptide bond conformations of poly-L-proline.

High-resolution, real-space imaging of conformational structures of poly-L-proline helixes.

In 1954, Edsall postulated that the imino-acid proline, which is a frequently found constituent of protein molecules, is a key determinant to the three-dimensional architecture of proteins. It not only should play a fundamental role in stabilizing helical structures of polypeptides, it should allow for sharp bends and even for a complete reversal of the direction of a helix looping back on itself. No direct evidence has yet been published to prove this prediction. Using scanning tunneling microscopy, we have presented high-resolution, real-space images of two conformations of poly-L-proline, where one structure clearly exhibits the predicted 180 degrees back-folding behavior. The measured length, 1.89 nm, of the repeating unit cells agrees with available X-ray data for poly-L-proline I with cis-peptide bonds. We further observe aggregated poly-L-proline II, consisting of highly-ordered, periodically and parallel-linked trans-peptide chains which are 2.4 nm apart from each other. Stacking of these aggregates with their orientation rotated by 90 degrees is also observed.

Disposition and tissue distribution of angiopeptin in the rat.

The disposition and tissue distribution of angiopeptin, a long-acting octapeptide analogue of somatostatin, were studied in rats following single iv and sc administration of the drug. Similar plasma levels and excretion values of angiopeptin were observed by using radioimmunoassay and radiolabeling techniques. Angiopeptin was absorbed fairly rapidly, with a mean peak plasma level of 25 +/- 4.1 ng/ml at 10-15 min after administration. The kinetics of angiopeptin following sc administration closely resembled those following iv administration due to rapid absorption. The pharmacokinetics of angiopeptin can be described by a two-compartment model. The plasma half-life of the drug ranged from 2.6-2.9 hr when administered sc and 1.98-2.5 hr when given iv. Distribution of angiopeptin was rapid, with the highest concentration appearing in the liver. Half-lives in the liver and bile were short. Most of the drug was excreted in the feces via the bile, while approximately 10% was excreted in the urine. Angiopeptin was also found to be secreted in the saliva. TLC and HPLC of blood, urine, feces, and bile samples did not reveal the presence of any metabolites. In conclusion, the in vivo fate of angiopeptin is characterized by little or no hepatic metabolism and rapid biliary excretion.