White noise speech illusions in the general population: The association with psychosis expression and risk factors for psychosis.

INTRODUCTION: Positive psychotic experiences are associated with increased rate of white noise speech illusions in patients and their relatives. However, findings have been conflicting to what degree speech illusions are associated with subclinical expression of psychosis in the general population. The aim of this study was to investigate the link between speech illusions and positive psychotic experiences in a general population sample. In addition, the hypothesis that speech illusions are on the pathway from known risk factors for psychosis (childhood adversity and recent life events) to subthreshold expression of psychosis, was examined. METHODS: In a follow-up design (baseline and 6 months) the association between the number of white noise speech illusions and self-reported psychotic experiences, assessed with the Community Assessment of Psychic Experiences (CAPE), was investigated in a general population sample (n = 112). In addition, associations between speech illusions and childhood adversity and life events, using the Childhood Experiences of Care and Abuse questionnaire and the Social Readjustment Rating Scale, were investigated. RESULTS: No association was found between the CAPE positive scale and the number of white noise speech illusions. The CAPE positive scale was significantly associated with childhood adversity between 12 and 16 years (B = 0.980 p = 0.001) and life events (B = 0.488 p = 0.044). The number of speech illusions showed no association with either life events or childhood adversity. CONCLUSION: In the nonclinical population, the pathway from risk factors to expression of subclinical psychotic experiences does not involve white noise speech illusions as an intermediate outcome.

Understanding external cervical resorption patterns in endodontically treated teeth.

AIM: To understand the patterns of external cervical resorption (ECR) in endodontically treated teeth. To compare characteristics and mechanisms of ECR in root filled teeth with those established in teeth with vital pulps. METHODOLOGY: Seven cases of endodontically treated permanent teeth displaying ECR were investigated. ECR diagnosis was based on clinical findings and radiographic examination with cone-beam computed tomography. The extracted teeth were further analysed by a nano-focus computed tomographic (nano-CT) system, hard-tissue histology and scanning electron microscopy (SEM). To make a comparison with teeth with vital pulps, representative cases with ECR were also included. RESULTS: All endodontically treated teeth had a similar ECR pattern. This pattern reflected many similarities to that seen in teeth with vital pulps; that is, three stages were observed namely initiation, resorption and repair. In particular, during the initiation stage (1st stage), the resorption started below the gingival epithelial attachment, at the level of cementum. In the resorption stage (2nd stage), ECR spreads towards the treated pulp space and in a coronal-apical direction, creating multiple resorption channels. The pulp and the pericanalar resorption resistant sheet (PRRS) had been removed during root canal treatment and thus offered no retarding or defence mechanism towards ECR. In the reparative stage (3rd stage), reparative hard-tissue formation occurred at a localized scale. CONCLUSIONS: Similar ECR patterns were observed in all examined teeth. These patterns consisted of an initiation, a resorption and a reparative stage. Some differences were noticed between endodontically treated and teeth with vital pulps, mainly in the resorption and reparative stages. The resorption stage in root filled teeth was more intense than the repair stage, as many clastic cells and abundant granulation tissue were observed in all samples. This is possibly due to the absence of the pulp and protective PRRS layer and/or to the altered chemical composition of the root dentine after root canal treatment. Furthermore, at the repair stage, formation of reparative bonelike tissue took place to a lesser extent in root filled teeth.

Cortical processes of speech illusions in the general population.

BACKGROUND: There is evidence that experimentally elicited auditory illusions in the general population index risk for psychotic symptoms. As little is known about underlying cortical mechanisms of auditory illusions, an experiment was conducted to analyze processing of auditory illusions in a general population sample. In a follow-up design with two measurement moments (baseline and 6 months), participants (n = 83) underwent the White Noise task under simultaneous recording with a 14-lead EEG. An auditory illusion was defined as hearing any speech in a sound fragment containing white noise. RESULTS: A total number of 256 speech illusions (SI) were observed over the two measurements, with a high degree of stability of SI over time. There were 7 main effects of speech illusion on the EEG alpha band-the most significant indicating a decrease in activity at T3 (t = -4.05). Other EEG frequency bands (slow beta, fast beta, gamma, delta, theta) showed no significant associations with SI. CONCLUSION: SIs are characterized by reduced alpha activity in non-clinical populations. Given the association of SIs with psychosis, follow-up research is required to examine the possibility of reduced alpha activity mediating SIs in high risk and symptomatic populations.

A novel multimodular methodology to investigate external cervical tooth resorption.

AIM: To introduce a multimodular combination of techniques as a novel minimal invasive approach to investigate efficiently and accurately external cervical resorption (ECR). METHODOLOGY: One case of a central incisor with extensive external cervical resorption was selected to demonstrate the potential of a comparative novel study methodology. ECR diagnosis was based on clinical inspection, digital radiography and cone-beam computed tomography (CBCT). After extraction, the tooth was investigated using microfocus computed tomography (micro-CT), nano-CT and hard tissue histology. These techniques were compared for their accuracy and applicability to highlight their advantages and disadvantages. RESULTS: Nano-CT was more effective than micro-CT and CBCT for detailed ex vivo exploration of ECR. The reparative tissue, pericanalar resorption resistant sheet (PRRS), pulp tissue reactions, resorption channels and their interconnection with the periodontal ligament space were accurately visualized by detailed processing and analysis of the nano-CT data set with Dataviewer and CTAn software. Nano-CT analysis provided better insight in the true extent of the resorption, based on quantitative measurements and 3D visualization of the tooth structure. Nano-CT imaging results were similar to hard tissue histology at the mineralized tissue level. To clarify the dynamic phenomenon of reparative tissue formation and substitution of the resorbed tissues, nano-CT needed to be associated with hard tissue histology. CONCLUSION: Nano-CT is a fast and minimal invasive technique for the ex vivo analysis and understanding of ECR and is complementary with hard tissue histology. A combined approach of clinical and CBCT examination, with nano-CT and histological mapping measurements, can provide an ideal platform for future ECR imaging and exploration studies.

Development and validation of an ultra-high performance liquid chromatography-tandem mass spectrometry method to measure creatinine in human urine.

Despite decades of creatinine measurement in biological fluids using a large variety of analytical methods, an accurate determination of this compound remains challenging. Especially with the novel trend to assess biomarkers on large sample sets preserved in biobanks, a simple and fast method that could cope with both a high sample throughput and a low volume of sample is still of interest. In answer to these challenges, a fast and accurate ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to measure creatinine in small volumes of human urine. In this method, urine samples are simply diluted with a basic mobile phase and injected directly under positive electrospray ionization (ESI) conditions, without further purification steps. The combination of an important diluting factor (10(4) times) due to the use of a very sensitive triple quadrupole mass spectrometer (XEVO TQ) and the addition of creatinine-d3 as internal standard completely eliminates matrix effects coming from the urine. The method was validated in-house in 2012 according to the EMA guideline on bioanalytical method validation using Certified Reference samples from the German External Quality Assessment Scheme (G-Equas) proficiency test. All obtained results for accuracy and recovery are within the authorized tolerance ranges defined by G-Equas. The method is linear between 0 and 5 g/L, with LOD and LOQ of 5 × 10(-3) g/L and 10(-2) g/L, respectively. The repeatability (CV(r) = 1.03-2.07%) and intra-laboratory reproducibility (CV(RW) = 1.97-2.40%) satisfy the EMA 2012 guideline. The validated method was firstly applied to perform the German G-Equas proficiency test rounds 51 and 53, in 2013 and 2014, respectively. The obtained results were again all within the accepted tolerance ranges and very close to the reference values defined by the organizers of the proficiency test scheme, demonstrating an excellent accuracy of the developed method. The method was finally applied to measure the creatinine concentration in 210 urine samples, coming from 190 patients with a chronic kidney disease (CKD) and 20 healthy subjects. The obtained creatinine concentrations (ranging from 0.12 g/L up to 3.84 g/L) were compared, by means of a Passing Bablok regression, with the creatinine contents obtained for the same samples measured using a traditional compensated Jaffé method. The UHPLC-MS/MS method described in this paper can be used to normalize the concentration of biomarkers in urine for the extent of dilution.

Review of protein-bound toxins, possibility for blood purification therapy.

Protein-bound uremic retention solutes, i.e. phenolic compounds, such as p-cresylsulfate, and indolic compounds, such as indoxyl sulfate, have been intensively studied in recent years and have been shown to be associated especially with cardiovascular toxicity and adverse outcomes in chronic kidney disease. In this review, we will focus on their toxicity and their removal by dialysis strategies, which is hampered due to their protein binding. Hemodiafiltration slightly improves the removal of protein-bound solutes as compared to hemodialysis, although the clinical benefit on outcomes still needs to be demonstrated. Removal by means of absorption and interference with intestinal generation or renal tubular excretion are interesting alternative strategies under investigation.

An update on uremic toxins.

In the last decade, uremic toxicity as a potential cause for the excess of cardiovascular disease and mortality observed in chronic kidney disease gained more and more interest. This review focuses on uremic toxins with known cardiovascular effects and their removal. For protein-bound solutes, for example, indoxylsulfate and the conjugates of p-cresol, and for small water-soluble solutes, for example, guanidines, such as ADMA and SDMA, there is a growing evidence for a role in cardiovascular toxicity in vitro (e.g., affecting leukocyte, endothelial, vascular smooth muscle cell function) and/or in vivo. Several middle molecules (e.g., beta-2-microglobulin, interleukin-6, TNF-alpha and FGF-23) were shown to be predictors for cardiovascular disease and/or mortality. Most of these solutes, however, are difficult to remove during dialysis, which is traditionally assessed by studying the removal of urea, which can be considered as a relatively inert uremic retention solute. However, even the effective removal of other small water-soluble toxins than urea can be hampered by their larger distribution volumes. Middle molecules (beta-2-microglobulin as prototype, but not necessarily representative for others) are cleared more efficiently when the pore size of the dialyzer membrane increases, convection is applied and dialysis time is prolonged. Only adding convection to diffusion improves the removal of protein-bound toxins. Therefore, alternative removal strategies, such as intestinal adsorption, drugs interfering with toxic biochemical pathways or decreasing toxin concentration, and extracorporeal plasma adsorption, as well as kinetic behavior during dialysis need further investigation. Even more importantly, randomized clinical studies are required to demonstrate a survival advantage through these strategies.

Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration.

During chronic kidney disease (CKD), drug metabolism is affected leading to changes in drug disposition. Furthermore, there is a progressive accumulation of uremic retention solutes due to impaired renal clearance. Here, we investigated whether uremic toxins can influence the metabolic functionality of human conditionally immortalized renal proximal tubule epithelial cells (ciPTEC) with the focus on UDP-glucuronosyltransferases (UGTs) and mitochondrial activity. Our results showed that ciPTEC express a wide variety of metabolic enzymes, including UGTs. These enzymes were functionally active as demonstrated by the glucuronidation of 7-hydroxycoumarin (7-OHC; K(m) of 12±2µM and a V(max) of 76±3pmol/min/mg) and p-cresol (K(m) of 33±13µM and a V(max) of 266±25pmol/min/mg). Furthermore, a wide variety of uremic toxins, including indole-3-acetic acid, indoxyl sulfate, phenylacetic acid and kynurenic acid, reduced 7-OHC glucuronidation with more than 30% as compared with controls (p<0.05), whereas UGT1A and UGT2B protein expressions remained unaltered. In addition, our results showed that several uremic toxins inhibited mitochondrial succinate dehydrogenase (i.e. complex II) activity with more than 20% as compared with controls (p<0.05). Moreover, indole-3-acetic acid decreased the reserve capacity of the electron transport system with 18% (p<0.03). In conclusion, this study shows that multiple uremic toxins inhibit UGT activity and mitochondrial activity in ciPTEC, thereby affecting the metabolic capacity of the kidney during CKD. This may have a significant impact on drug and uremic retention solute disposition in CKD patients.

From uremic toxin retention to removal by convection: do we know enough?

The uremic syndrome is defined by a complex clinical picture, characterized by the dysfunction of most organs which are affected by the retention of multiple solutes. Recent research has helped to unravel the pathophysiology and to identify several as yet unknown responsible compounds. In this publication, we summarize which compounds play the most important pathophysiologic role, and which dialysis strategies can be considered to decrease their concentration and improve outcomes. The main pathophysiologic role is played by molecules which are so-called 'difficult to remove by dialysis'. Essentially observational studies have suggested that enhancement of removal of these molecules, by improving convection (hemodiafiltration), creates an improvement of survival. The knowledge of uremic toxicity is still far from complete however, and we need extra information about responsible compounds and mechanisms, eventually leading to a classification of the most important culprits, to allow the development of even more efficient or specific removal strategies.

Uremic toxins: do we know enough to explain uremia?

BACKGROUND: The uremic syndrome is characterized by a complex clinical picture, whereby the function of multiple organ systems is affected by the retention of a host of solutes. Recent research of the last decade has helped to unravel multiple pathophysiologic mechanisms and to identify as yet unknown responsible compounds. METHODS: The literature was screened to appreciate which compounds play the most important pathophysiologic role. RESULTS: The picture that ensues is that the main role is played by molecules which are so-called 'difficult to remove by dialysis'. The knowledge of uremic toxicity is still far from complete and we need extra information about responsible compounds and mechanisms, eventually leading to a classification of the most important culprits, to allow the development of efficient removal strategies and of pharmacologic methods to counteract pathophysiologic mechanisms. CONCLUSIONS: Uremic retention is a complex phenomenon and the most toxic compounds are difficult to remove by dialysis. Furthermore, our knowledge of the responsible pathways is still incomplete, and needs to be extended to develop new and more efficient treatment strategies.

Intra-oral microbial profiles of beagle dogs assessed by checkerboard DNA-DNA hybridization using human probes.

Some investigators suggest a similarity between the oral microbiota of dogs and humans. The in vivo assessment of ecologic relationships among bacterial species and between bacterial species and their habitat is difficult to carry out. Consequently, this aspect is often neglected in animal oral microbiological studies. This study aimed to examine the proportions of 40 bacterial species in samples from five intra-oral habitats in beagle dogs using checkerboard DNA-DNA hybridization. Microbial samples were taken from subgingival and supra-gingival plaque, the tongue, tonsils and cheek mucosa in seven beagle dogs. Samples were individually evaluated for their content of 40 bacterial species and the percentage of total DNA probe count was determined for each species, at each habitat. All tested species could be detected in all sampled habitats but each habitat had a distinct community structure. The microbiotas colonizing the hard surfaces in the oral cavity were quite different from the microbiotas colonizing the soft tissues. Bacterial species that are in humans considered to be periodontopathogens are present in high proportions. This study underlines the importance of the habitat and the host on the local microbial profile.

Uremic toxins in chronic renal failure.

The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal conditions are excreted by healthy kidneys. During recent years major steps have been taken in the area of identification and characterization of uremic retention solutes and in the knowledge of their pathophysiological importance; however, our knowledge remains far from complete. In the present paper the general classification based on their molecular weight and on their protein-binding characteristics, with reflections on their removal, will be discussed. In addition, current knowledge about the main uremic retention products and their clinical and biological effects will be reviewed in detail.

Guiding periodontal pocket recolonization: a proof of concept.

The complexity of the periodontal microbiota resembles that of the gastro-intestinal tract, where infectious diseases are treatable via probiotics. In the oropharyngeal region, probiotic or replacement therapies have shown some benefit in the prevention of dental caries, otitis media, and pharyngitis, but their effectiveness in the treatment of periodontitis is unknown. Therefore, this study addressed the hypothesis that the application of selected beneficial bacteria, as an adjunct to scaling and root planing, would inhibit the periodontopathogen recolonization of periodontal pockets. Analysis of the data showed, in a beagle dog model, that when beneficial bacteria were applied in periodontal pockets adjunctively after root planing, subgingival recolonization of periodontopathogens was delayed and reduced, as was the degree of inflammation, at a clinically significant level. The study confirmed the hypothesis and provides a proof of concept for a guided pocket recolonization (GPR) approach in the treatment of periodontitis.

What is uremia? Retention versus oxidation.

The uremic syndrome is characterized by the retention of a host of compounds which in healthy subjects are secreted into the urine by the healthy kidneys. These compounds disturb many physiologic functions, resulting in toxicity. However, many of the retained compounds as well as many of the pathophysiologic actions of the known retention solutes remain unknown. In this publication, we review recent information on uremic toxicity. Especially the difficulty to remove compounds, such as protein-bound compounds and larger molecules, seems to play a crucial role. New strategies enhancing their removal might be highly useful. Part of the retained compounds are the result of oxidative processes due to the inflammatory status of uremic patients; however, other compounds are not, and even the concentration of oxidative compounds will be further increased by disturbances of urinary clearance.

Microanatomical and histological assessment of the content of superior genial spinal foramen and its bony canal.

OBJECTIVES: To assess histologically the true content of the superior genial spinal foramen and to match these findings to the microanatomical canal content observed using high-resolution magnetic resonance images of the same region. METHODS: Ten human mandibular specimens were imaged using a 9.4 Tesla MRI unit. Afterwards, eight specimens were decalcified, embedded in paraffin and serially sectioned (7 microm) for histological examination; the remaining two were embedded in methylmethacrylate and sectioned (50-60 microm). All sections were examined using routine light microscopy to inspect the superior genial spinal foramen region and its content. RESULTS: Histological observations of the superior genial spinal foramen confirmed the presence of a well-defined neurovascular bundle, with branches of the lingual nerve and lingual artery. The canal had an average diameter exceeding 1 mm and could thus be considered significant. CONCLUSIONS: The present study confirms the existence of a true superior genial spinal foramen's bony canal with neural and blood vessel content. These findings imply that surgical procedures should consider a proper preoperative assessment of the neurovascular trajectory of the superior genial spinal foramen.

Conserved regions in the sequence of the F4 (K88) fimbrial adhesin FaeG suggest a donor strand mechanism in F4 assembly.

Oral immunization of newly weaned piglets with recombinant F4 (K88) fimbrial adhesin FaeG induces a F4-specific immune response, significantly reducing F4+ Escherichia coli excretion following challenge. In order to use FaeG subunits in an oral vaccine against F4+ enterotoxigenic E. coli, it is necessary to determine the conservation of the adhesin subunit. Hereto, the faeG sequence was determined of 21 F4ac+ E. coli field isolates from piglets with diarrhoea and subsequently compared with these of the reference strain GIS26 and previously reported FaeG sequences from F4ab, F4ac and F4ad antigenic variant strains. The FaeG amino acid sequence was 96-100% homologous within each F4 serotype, but only 92 and 88% when the F4ab and F4ad antigenic variants were compared with the F4ac antigenic variant. Furthermore, the conserved regions of the adhesin suggest a donor strand mechanism in F4 fimbriae assembly as reported for type 1 and P pili. In conclusion, the results of the reported experiments support the usefulness FaeG in an oral subunit vaccine against F4+ E. coli infections or as a mucosal carrier since the adhesin is conserved among F4+ E. coli field isolates.

A teratocyte gene from a parasitic wasp that is associated with inhibition of insect growth and development inhibits host protein synthesis.

After parasitization, some wasps induce hosts prematurely to initiate metamorphic development that is then suspended in a postwandering, prepupal state. Following egression of the parasite larva, the host remains in this developmentally arrested state until death. Teratocytes, cells released at egg hatch from extra-embryonic serosal membranes of some wasp parasites, inhibit growth and development when injected into host larvae independent of other parasite factors (e.g. venom, polydnavirus). Synthesis of some developmentally regulated, abundantly expressed Heliothis virescens host proteins is inhibited in hosts parasitized by Microplitis croceipes and by teratocyte injection. A cDNA encoding a 13.9 kDa protein (TSP14) that inhibited protein synthesis, growth and development was isolated from a protein fraction secreted by teratocytes. TSP14 appears to be responsible, in part, for the teratocyte-mediated inhibition of host growth and development. Interestingly, this cDNA encoded a cysteine-rich amino acid motif similar to that described from Campoletis sonorensis polydnavirus, a mutualistic virus that enables wasp parasitization of lepidopteran larvae. Moreover, TSP14 inhibited protein synthesis in a dose-dependent manner in rabbit reticulocyte lysate and wheat germ extract translation systems. We hypothesize that some wasp parasites inhibit translation as a general means to regulate and redirect lepidopteran host physiology to support endoparasite development.

Cephalometric evaluation of maxillary advancement with an internal distractor in an adult boxer dog.

OBJECTIVE: The aim of the study was to evaluate cephalometrically the effects of distraction of the maxilla over a 1-year period by means of an internal distractor applied in a boxer dog. DESIGN: Internal distractors were placed bilaterally in the internal cavity of the maxillary sinus of a 2-year-old boxer dog after a Le Fort I osteotomy. Distraction was started 5 days after surgery and activations were continued for 14 days at a rate of 1 mm/day. Standardized lateral cephalograms were taken with an extemal source of 90 kV, 60 mS immediately pre-surgery, at day 1 after the start of the distraction (dp) and at day 5 dp, day 7 dp, day 10 dp, day 14 dp (end of distraction), at 14 days of consolidation period (cp), at 28 days cp and at 56 days cp (removal of the distractors). One year after the removal of the distractor, a final lateral cephalogram was taken. Cephalometric analysis was performed and superimpositions were used for the evaluation of the sagittal position of the maxilla. RESULTS: The linear measurements, as well as the superimposition showed evidence for a significantly advanced position of the maxilla, which was stable 1 year after removal of the distractor. CONCLUSION: The application of the internal maxillary distractor in a boxer dog resulted in a sagittal advancement of the midface that was still present after 1 year.

Maxillary distraction using a trans-sinusal distractor: technical note.

In this pilot study, the principle of distraction osteogenesis was used to advance the midface of a boxer dog. A modified high Le Fort I-type osteotomy was performed. Following a latency period of 5 days the maxilla was distracted 14 mm in 14 consecutive days at a rate of 1 mm per day. Ten weeks after the completion of the distraction, multiple biopsies were taken across the distraction gap. Histological observation showed bone deposition in the osteotomy sites. Soft and hard tissue formation resulted in complete healing across the distraction gap. The maxillary sinus was used to accommodate the distraction device. Superimposition of the standardized lateral cephalograms taken at the end of distraction and 14 months after the removal of the distractors showed no sign of relapse in the achieved sagittal advancement of the maxilla. This small, intraoral trans-sinusal placed distractor has a completely new conceptual design, and may be helpful in distraction of maxilla in children and adults with midfacial hypoplasia.

A newly designed vertebral replacement implant to reconstruct the thoracolumbar spine anteriorly.

Calcium phosphate compounds are becoming of increasingly great importance in the field of biomaterials and, in particular, as bone substitutes. In this way donor-side morbidity can be avoided. A type A lesion of the vertebral body can be the reason of a neurological deficit, requiring a corpectomy by means of an anterior approach, tricortical bone grafting and internal stabilization to get a fusion over time. It is our aim to introduce in this study a newly designed vertebral replacement device, tested in an animal model, using domestic pigs. Two biomaterials, Cementek and Biobon were primarily macroscopically and microscopically evaluated, using a critically sized bone defect of a vertebral body and compared with autologous bone grafts. The final tests consisted of two groups of four animals. A corpectomy at the level of L4 was created and stabilized by means of the newly designed vertebral replacement implant. Autologous bone grafts were applied in one group of animals and Cementek in the other to fill the remaining space. Fusion was studied using anteroposterior and lateral radiographs, followed by a computer tomography. The biocompatibility of the biomaterials and autologous bone grafts were in order of: Cementek > autologous bone grafts > Biobon. In the final tests after a six months period, a fusion was diagnosed in four cases, two delayed unions, and two obvious non-unions. An analysis of the failures in this animal study can possibly clarify the shortcomings of this concept. Perhaps, subtle changes of the design combined with other synthetic bone substitutes can possibly improve the fusion rate in the near future.