Background

Motivational and cognitive abnormalities are frequently reported in pathological gambling. However, studies simultaneously investigating motivational and cognitive processing in problematic gamblers are lacking, limiting our understanding of the interplay between these systems in problematic gambling. Studies in non-clinical samples indicate that interactions between dorsal “executive” and ventral “affective” processing systems are necessary for adequate responses in various emotive situations.

Methods

We conducted a generalized Psycho-Physiological Interaction (gPPI) analysis to assess the influence of affective stimuli on changes in functional connectivity associated with response inhibition in 16 treatment seeking problematic gamblers (PRGs) and 15 healthy controls (HCs) using an affective Go-NoGo fMRI paradigm including neutral, gambling-related, positive and negative pictures as neutral and affective conditions.

Results

Across groups, task performance accuracy during neutral inhibition trials was positively correlated with functional connectivity between the left caudate and the right middle frontal cortex. During inhibition in the gambling condition, only in PRGs accuracy of task performance was positively correlated with functional connectivity within sub-regions of the dorsal executive system. Group interactions showed that during neutral inhibition, HCs exhibited greater functional connectivity between the left caudate and occipital cortex than PRGs. In contrast, during inhibition in the positive condition, PRGs compared to HCs showed greater functional connectivity between the left caudate and occipital cortex. During inhibition trials in the negative condition, a stronger functional connectivity between the left caudate and the right anterior cingulate cortex in PRGs compared to HCs was present. There were no group interactions during inhibition in the gambling condition.

Conclusions

During gamble inhibition PRGs seem to benefit more from functional connectivity within the dorsal executive system than HCs, because task accuracy in this condition in PRGs is positively correlated with functional connectivity, although the groups show similar connectivity patterns during gamble inhibition. Greater functional connectivity between the ventral affective system and the dorsal executive system in PRGs in the affective conditions compared to HCs, suggests facilitation of the dorsal executive system when affective stimuli are present specifically in PRGs.

A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.

Humans vary in their ability to delay gratification and impulsive decision making is a common feature in various psychiatric disorders. The level of delay discounting is a relatively stable psychological trait, and therefore neural processes implicated in delay discounting are likely to be based on the overall functional organization of the brain (under task-free conditions) in which state-dependent shifts from baseline levels occur. The current study investigated whether delay discounting can be predicted by intrinsic properties of brain functioning. Fourteen healthy male subjects performed a delay discounting task. In addition, resting state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (¹H MRS) were used to investigate the relationship between individual differences in delay discounting and molecular and regional measures of resting state (baseline) activity of dorsal anterior cingulate cortex (dACC). Results showed that delay discounting was associated with both dACC glutamate concentrations and resting state functional connectivity of the dACC with a midbrain region including ventral tegmental area and substantia nigra. In addition, a neural pathway was established, showing that the effect of glutamate concentrations in the dACC on delay discounting is mediated by functional connectivity of the dACC with the midbrain. The current findings are important to acknowledge because spontaneous intrinsic brain processes have been proposed to be a potential promising biomarker of disease and impulsive decision making is associated with several psychiatric disorders.

The odorous steroid compound 4,16-androstadien-3-one (androstadienone), found in axillary sweat, was previously reported to evoke hypothalamic activation in heterosexual women, but not in heterosexual men. However, subjects were exposed to the pure crystalline form of androstadienone, which raised the question whether the observed hypothalamic response is physiologically relevant. Therefore, in the present study, we asked whether sexually dimorphic hypothalamic responses could be measured when subjects were exposed to lower, more physiologically relevant concentrations of androstadienone. A total of 21 women and 16 men, all heterosexual, participated in our functional magnetic resonance imaging study (fMRI). Three different concentrations of androstadienone diluted in propylene glycol (10 mM “high,” 0.1 mM “medium” and 0.001 mM “low”) were delivered to the subjects’ nostrils using a computer-controlled stimulator. When exposed to the “high” androstadienone concentration, women showed stronger hypothalamic activation than men. By contrast, men showed more hypothalamic activation when exposed to the “medium” androstadienone concentrations in comparison to women. Thus, we replicated that smelling the chemo-signal androstadienone elicits a hypothalamic activation. However, this effect does not seem to be gender-specific, because androstadienone activated the hypothalamus in both men and women, suggesting that androstadienone exerts specific effects in heterosexual individuals of both sexes.

Stimulant dependence is associated with neuropsychological impairments. Here, we summarize and integrate the existing neuroimaging literature on the neural substrates of neuropsychological (dys)function in stimulant dependence, including cocaine, (meth-)amphetamine, ecstasy and nicotine dependence, and excessive caffeine use, comparing stimulant abusers (SAs) to nondrug using healthy controls (HCs). Despite some inconsistencies, most studies indicated altered brain activation in prefrontal cortex (PFC) and insula in response to reward and punishment, and higher limbic and anterior cingulate cortex (ACC)/PFC activation during craving and attentional bias paradigms in SAs compared with HCs. Impulsivity in SAs was associated with lower ACC and presupplementary motor area activity compared with HCs, and related to both ventral (amygdala, ventrolateral PFC, insula) and dorsal (dorsolateral PFC, dorsal ACC, posterior parietal cortex) systems. Decision making in SAs was associated with low dorsolateral PFC activity and high orbitofrontal activity. Finally, executive function in SAs was associated with lower activation in frontotemporal regions and higher activation in premotor cortex compared with HCs. It is concluded that the lower activations compared with HCs are likely to reflect the neural substrate of impaired neurocognitive functions, whereas higher activations in SAs compared with HCs are likely to reflect compensatory cognitive control mechanisms to keep behavioral task performance to a similar level as in HCs. However, before final conclusions can be drawn, additional research is needed using neuroimaging in SAs and HCs using larger and more homogeneous samples as well as more comparable task paradigms, study designs, and statistical analyses.

Sleep complaints increase profoundly with age; prevalence estimates of insomnia in the elderly reach up to 37%. The three major types of nocturnal complaints are difficulties initiating (DIS) and maintaining (DMS) sleep and early morning awakening (EMA), of which the latter appears most characteristic for aging. The neural correlates associated with these complaints have hardly been investigated, hampering the development of rational treatment and prevention. A recent study on structural brain correlates of insomnia showed that overall severity, but not duration, of insomnia complaints is associated with lower gray matter (GM) density in part of the left orbitofrontal cortex (OFC). Following up on this, we investigated, in an independent sample of people not diagnosed with insomnia, whether individual differences in GM density are associated with differences in DIS, DMS, and EMA. Sixty five healthy participants (mean age = 41 years, range 18–56) filled out questionnaires and underwent structural magnetic resonance imaging. Three compound Z-scores were computed for questionnaire items relating to DIS, DMS, and EMA. Whole-brain voxel-based morphometry was used to investigate their association with GM density. Results show that participants with lower GM density in a region where the left inferior OFC borders the insula report more EMA, but not DIS or DMS. This is the first study to investigate structural brain correlates of specific sleep characteristics that can translate into complaints in insomniacs. The selective association of EMA with orbitofrontal GM density makes our findings particularly relevant to elderly people, where EMA represents the most characteristic complaint. It is hypothesized that low GM density in aforementioned orbitofrontal area affects its role in sensing comfort. An intact ability to evaluate comfort may be crucial to maintain sleep, especially at the end of the night when sleep is vulnerable because homeostatic sleep propensity has dissipated.

This study aimed to determine variations in the dental status of a dentate adult population in terms of “decayed,” “missing,” and “filled” teeth in relation to several sociodemographic and behavioral factors. Quota sampling was used to draw 2531 subjects aged 20 years and over. Data were collected by means of a questionnaire and an oral examination. Multiple logistic regression analyses were performed to observe associations between “decayed,” “missing,” and “filled” teeth and the factors of interest. The mean numbers of “decayed,” “missing,” and “filled” teeth were 2.2, 6.7, and 4.9, respectively. Molar teeth were significantly more often “missing” than premolar and anterior teeth. Age, gender, education, and tooth brushing revealed most noticeable associations. Increasing age was associated with a lower chance of having “decayed” and “filled” teeth, but with a higher chance of having “missing” teeth. Females were more likely to have “missing” and “filled” teeth. Higher education was associated with a lower chance of having “missing” teeth. More frequent tooth brushing was associated with a lower chance of having “decayed” and “missing” teeth, but with a higher chance of having “filled” teeth. These risk indicators should be considered in prevention program planning if reduction of tooth loss is to be achieved.

Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.

Disinhibition over drug use, enhanced salience of drug use and decreased salience of natural reinforcers are thought to play an important role substance dependence. Whether this is also true for pathological gambling is unclear. To understand the effects of affective stimuli on response inhibition in problem gamblers (PRGs), we designed an affective Go/Nogo to examine the interaction between response inhibition and salience attribution in 16 PRGs and 15 healthy controls (HCs).

Four affective blocks were presented with Go trials containing neutral, gamble, positive or negative affective pictures. The No-Go trials in these blocks contained neutral pictures. Outcomes of interest included percentage of impulsive errors and mean reaction times in the different blocks. Brain activity related to No-Go trials was assessed to measure response inhibition in the various affective conditions and brain activity related to Go trials was assessed to measure salience attribution.

PRGs made fewer errors during gamble and positive trials than HCs, but were slower during all trials types. Compared to HCs, PRGs activated the dorsolateral prefrontal cortex, anterior cingulate and ventral striatum to a greater extent while viewing gamble pictures. The dorsal lateral and inferior frontal cortex were more activated in PRGs than in HCs while viewing positive and negative pictures. During neutral inhibition, PRGs were slower but similar in accuracy to HCs, and showed more dorsolateral prefrontal and anterior cingulate cortex activity. In contrast, during gamble and positive pictures PRGs performed better than HCs, and showed lower activation of the dorsolateral and anterior cingulate cortex.

This study shows that gambling-related stimuli are more salient for PRGs than for HCs. PRGs seem to rely on compensatory brain activity to achieve similar performance during neutral response inhibition. A gambling-related or positive context appears to facilitate response inhibition as indicated by lower brain activity and fewer behavioural errors in PRGs.

Summary

Background Improvements in knowledge of molecular mechanisms in cancer are the basis for new studies combining chemotherapy with targeted drugs. Inhibition of the epidermal growth factor receptor (EGFR) by erlotinib or cetuximab has limited or no activity, respectively, in pancreatic cancer. The crosstalk between EGFR and mammalian target of rapamycin (mTOR) pathways is a potential mechanism of resistance; therefore we conducted a study to explore safety and efficacy of multiple pathway inhibition by cetuximab and everolimus in combination with capecitabine. Methods Safety and efficacy of fixed standard dose cetuximab in combination with various dose levels of everolimus (5–10 mg/day) and capecitabine (600–800 mg/m2 bid, 2 weeks every 3 weeks) were investigated in a phase I/II study in patients with advanced pancreatic cancer. The primary endpoint was objective response. Results Sixteen patients were treated in the phase I part at two dose levels. Mucositis, rash and hand-foot syndrome were dose-limiting toxicities. Dose level 1 (everolimus 5 mg/day, capecitabine 600 mg/m2 bid for 2 weeks every 3 weeks and cetuximab 250 mg/m2 weekly) was considered the maximum tolerated dose (MTD). Of 31 patients in the phase II part, partial response was documented in two patients (6.5%) and five (16.1%) had stable disease. Median overall survival was 5.0 months (CI 3.1–6.8). Conclusion The schedule of capecitabine, everolimus and cetuximab resulted in considerable epidermal and mucosal toxicities and prevented escalation to optimal dose levels. Because of toxicity and low efficacy this treatment combination cannot be recommended for treatment in pancreatic cancer patients.

The epithelial lining of the intestine is characterized by an immense cellular turn-over ascertaining an extensive regenerative capacity. Multiple reports suggest that besides the local intestinal stem cell pool, circulating cells of bone marrow origin (BMDCs) contribute to this process by fusing with the epithelial lineage. However, the functional relevance of these observations is unknown. In the present study we employ a model system in which we cannot only detect cell fusion but also examine the functional importance of this process in vivo. Our results indicate that fusion between BMDCs and intestinal epithelial cells is an extremely rare event under physiological conditions. More importantly, by employing a system in which fusion-derived cells can be specifically deleted after extensive tissue damage, we present evidence that cell fusion is not relevant for tissue regeneration. Our data decisively demonstrates that intestinal epithelial homeostasis and regeneration is not dependent on cell fusion involving BMDCs.

Neuroticism and extraversion are personality factors associated with the vulnerability for developing depression and anxiety disorders, and are possibly differentially related to brain structures implicated in the processing of emotional information and the generation of mood states. To date, studies on brain morphology mainly focused on neuroticism, a dimension primarily related to negative affect, yielding conflicting findings concerning the association with personality, partially due to methodological issues and variable population samples under study. Recently, extraversion, a dimension primarily related to positive affect, has been repeatedly inversely related to with symptoms of depression and anxiety disorders. In the present study, high resolution structural T1-weighted MR images of 65 healthy adults were processed using an optimized Voxel Based Morphometry (VBM) approach. Multiple regression analyses were performed to test for associations of neuroticism and extraversion with prefrontal and subcortical volumes. Orbitofrontal and right amygdala volume were both positively related to extraversion. Extraversion was differentially related to volume of the anterior cingulate cortex in males (positive) and females (negative). Neuroticism scores did not significantly correlate with these brain regions. As extraversion is regarded a protective factor for developing anxiety disorders and depression and has been related to the generation of positive affect, the present results indicate that the reduced likelihood of developing affective disorders in individuals high on extraversion is related to modulation of emotion processing through the orbitofrontal cortex and the amygdala.

The objective of this study is to investigate the prevalence of missing teeth and prosthodontic replacements in a Chinese adult population using a hierarchical dental functional classification system. A total of 1,462 dentate subjects over 40 years from Shandong Province, China were included and categorized in the functional classification system with and without tooth replacements. Depending on replacements, subjects could be reclassified (promoted) to categories reflecting higher functionality. “Promotions” were considered indicators for prosthodontic effectiveness. Homogeneities after dichotomization into functional categories appeared to be moderate to good. In the “≥10 teeth in each jaw” branch, mean number of teeth and posterior occluding pairs were 27.93 ± 2.74 and 7.10 ± 1.94, respectively. In the branch “<10 teeth in each jaw,” these figures were 16.17 ± 5.54 and 1.49 ± 1.45. Fixed dental prostheses (FDPs) added on average 3.5 artificial teeth; 46% of subjects with FDP promoted to a higher functional level. For removable dental prostheses (RDPs), these numbers were 8.5% and 79%, respectively. Promotion value per tooth added was significantly higher for FDPs. The classification system was able to quantify the effectiveness of teeth replacements. It was shown that RDPs were more effective when higher numbers of teeth were replaced, while FDPs were more effective per artificial tooth added.

In children who are born small for gestational age (SGA), an adverse intrauterine environment has led to underdevelopment of both the body and the brain. The delay in body growth is (partially) restored during the first two years in a majority of these children. In addition to a negative influence on these physical parameters, decreased levels of intelligence and cognitive impairments have been described in children born SGA. In this study, we used magnetic resonance imaging to examine brain anatomy in 4- to 7-year-old SGA children with and without complete bodily catch-up growth and compared them to healthy children born appropriate for gestational age. Our findings demonstrate that these children strongly differ on brain organisation when compared with healthy controls relating to both global and regional anatomical differences. Children born SGA displayed reduced cerebral and cerebellar grey and white matter volumes, smaller volumes of subcortical structures and reduced cortical surface area. Regional differences in prefrontal cortical thickness suggest a different development of the cerebral cortex. SGA children with bodily catch-up growth constitute an intermediate between those children without catch-up growth and healthy controls. Therefore, bodily catch-up growth in children born SGA does not implicate full catch-up growth of the brain.

Summary

Background Everolimus is an oral mTOR-inhibitor. Preclinical data show synergistic effects of mTOR inhibition in combination with 5-fluorouracil-based anticancer therapy. The combination of everolimus with capecitabine seems therefore an attractive new, orally available, treatment regimen. Patients and methods Safety, preliminary efficacy and pharmacokinetics of everolimus in combination with capecitabine were investigated in patients with advanced solid malignancies. Patients were treated with fixed dose everolimus 10 mg/day continuously, plus capecitabine bid for 14 days in three-weekly cycles. Dose escalation of capecitabine proceeded according to the standard 3 × 3 phase I design in four predefined dose levels (500–1,000 mg/m2 bid). Results In total, 18 patients were enrolled. Median (range) treatment duration with everolimus was 70 days (21–414). Capecitabine 1,000 mg/m2 bid combined with 10 mg/day everolimus was declared the maximum tolerated dose, at which level one patient developed dose-limiting toxicity (stomatitis grade 3). Drug-related adverse events were mostly grade ≤2 and included mainly fatigue (56%), stomatitis (50%), and hand-foot syndrome (33%). Partial response was documented in three patients, and four had stable disease. There was no pharmacokinetic interaction between everolimus and capecitabine. Conclusion Everolimus 10 mg/day continuously combined with capecitabine 1,000 mg/m2 bid for 14 days every 3 weeks is a patient-convenient, safe and tolerable oral treatment regimen. This is the first study to demonstrate feasibility of this combination at doses with proven single agent efficacy in a number of tumors. Prolonged clinical benefit was observed in an encouraging 39% of patients with advanced solid malignancies.

Background

This study aims to (1) describe the dental status using DMFT for the whole dentition and the anterior, premolar and molar regions; (2) determine associations of demographic variables and socio-economic status (SES) with DMFT and tooth replacement; (3) analyze to what extent the goal as proposed by the WHO -'the retention of not less than 20 teeth throughout life' is achieved.

Methods

DMFT and tooth replacement data of 1588 subjects over 40 years from urban and rural sites in Qingdao (Shandong Province, China) were collected. Relative D, M, and F scores per dental region were calculated and compared by paired T-tests. Multivariable logistic regression was used to determine relationships with age, gender, place of residence, and SES.

Results

Mean numbers of D and F were low (1.36 respectively 0.27) at all ages. Molars had highest chance for D and M. For the molar region every additional year of age gave significantly lower chance for D and higher chance for M (OR: 0.98 and 1.02 respectively; both p ≤ 0.01). Mean number of M was associated with age (approximately 1.5 in each jaw at 40 years and 6 at 80 years). Females had higher chance for D (OR: 1.34; p ≤ 0.05) and F (OR: 1.69; p ≤ 0.01), and lower chance for M (OR: 0.60; p ≤ 0.01). Urban and rural subjects had similar chance for D; urban subjects had approximately 5 times more chance for F (p ≤ 0.01). SES had no relationship with D and M, however SES low was associated with F (OR: 0.45; p ≤ 0.01). Replacements were significantly associated with age (all dental regions except anterior region), gender (all dental regions), place of residence (whole dentition and molar region), and SES (whole dentition and premolar and molar regions).

Conclusions

The majority of subjects presented a reduced dentition. Molars were most frequently affected by D and M. D, M, F and replaced teeth were associated with the background variables, however differently for different dental regions. Above the age of 70 years, only 64% of the subjects presented 'not less than 20 natural teeth'.

Background

Levels of circulating vascular endothelial growth factor (VEGF) have widely been used as biomarker for angiogenic activity in cancer. For this purpose, non-standardized measurements in plasma and serum were used, without correction for artificial VEGF release by platelets activated ex vivo. We hypothesize that “true” circulating (c)VEGF levels in most cancer patients are low and unrelated to cancer load or tumour angiogenesis.

Methodology

We determined VEGF levels in PECT, a medium that contains platelet activation inhibitors, in citrate plasma, and in isolated platelets in 16 healthy subjects, 18 patients with metastatic non-renal cancer (non-RCC) and 12 patients with renal cell carcinoma (RCC). In non-RCC patients, circulating plasma VEGF levels were low and similar to VEGF levels in controls if platelet activation was minimized during the harvest procedure by PECT medium. In citrate plasma, VEGF levels were elevated in non-RCC patients, but this could be explained by a combination of increased platelet activation during blood harvesting, and by a two-fold increase in VEGF content of individual platelets (controls: 3.4 IU/106, non-RCC: 6.2 IU/106 platelets, p = 0.001). In contrast, cVEGF levels in RCC patients were elevated (PECT plasma: 64 pg/ml vs. 21 pg/ml, RCC vs. non-RCC, p<0.0001), and not related to platelet VEGF concentration.

Conclusions

Our findings suggest that “true” freely cVEGF levels are not elevated in the majority of cancer patients. Previously reported elevated plasma VEGF levels in cancer appear to be due to artificial release from activated platelets, which in cancer have an increased VEGF content, during the blood harvest procedure. Only in patients with RCC, which is characterized by excessive VEGF production due to a specific genetic defect, were cVEGF levels elevated. This observation may be related to limited and selective success of anti-VEGF agents, such as bevacizumab and sorafenib, as monotherapy in RCC compared to other forms of cancer.

Extremely low-frequency magnetic fields (from DC to 300 Hz) have been shown to affect pain sensitivity in snails, rodents and humans. Here, a functional magnetic resonance imaging study demonstrates how the neuromodulation effect of these magnetic fields influences the processing of acute thermal pain in normal volunteers. Significant interactions were found between pre- and post-exposure activation between the sham and exposed groups for the ipsilateral (right) insula, anterior cingulate and bilateral hippocampus/caudate areas. These results show, for the first time, that the neuromodulation induced by exposure to low-intensity low-frequency magnetic fields can be observed in humans using functional brain imaging and that the detection mechanism for these effects may be different from those used by animals for orientation and navigation. Magnetoreception may be more common than presently thought.

Pancreatic cancer has an extremely poor prognosis, only a small minority of patients undergo a resection with curative intent. Chemotherapy and/or radiochemotherapy may improve this by prolonging survival or disease-free interval and improving resectability and the proportion of microscopically complete (R0) resections. With regard to prolonging survival, both in the postoperative adjuvant setting and in locally advanced disease, chemotherapy has a positive but limited effect on survival and may be considered standard. The role of postoperative adjuvant radiochemotherapy remains debatable. For improving resectability/proportion of R0 resections, many studies suggest that the proportion of patients undergoing a resection during exploration and the proportion of R0 resections increase after neoadjuvant radiochemotherapy. This may improve the prognosis of patients with a resectable or borderline resectable pancreatic carcinoma. The effect of neoadjuvant radiochemotherapy, if any, is modest. The search for better combinations, including targeted therapy, must continue. The interpretation of single-arm studies is hampered by (selection) biases. The reporting of pathology and study endpoints should be internationally standardized. To avoid biases in studies of patients with (borderline) resectable tumours, prospective parallel registration of all patients referred for surgery would help. Ultimately, randomized controlled phase III trials should establish the role of neoadjuvant radiochemotherapy. Thus, neoadjuvant radiochemotherapy has a potential benefit in resectable and borderline resectable pancreatic cancer, but better combinations are warranted.

Objective. To describe prosthodontic production related to mutilated dentitions in Sofia, Bulgaria. Methods. Prosthodontic production from 5 dental laboratories was recorded during a 14-day period. Production was related to dentitions as noted from casts. Dentitions were classified as edentulous, interrupted/reduced, slightly interrupted, shortened, and complete. The representativeness of the laboratory sample was verified trough comparison with a Sofia population sample using proportions of crowned or replaced teeth per dental region. Results. The total production consisted of 243 crowns, 16 post and cores, 82 fixed dental prostheses, and 41 removable dentures. Proportions of crowned teeth were significantly different between the samples; proportions of replaced teeth were not. Of the 58 incomplete dentitions analyzed, 19 were restored to the level of completeness, 15 resulted in slightly interrupted, and 24 in shortened dentitions. Conclusions. Predominantly fixed restorations were provided to restore mutilated dentitions to a functional level and not necessarily to complete dentitions.

Background

Primary postpartum haemorrhage is an obstetrical emergency often causing acute anaemia that may require immediate red blood cell (RBC) transfusion. This anaemia results in symptoms such as fatigue, which may have major impact on the health-related quality of life. RBC transfusion is generally thought to alleviate these undesirable effects although it may cause transfusion reactions. Moreover, the postpartum haemoglobin level seems to influence fatigue only for a short period of time. At present, there are no strict transfusion criteria for this specific indication, resulting in a wide variation in postpartum policy of RBC transfusion in the Netherlands.

Methods/Design

The WOMB trial is a multicentre randomised non-inferiority trial. Women with acute anaemia due to postpartum haemorrhage, 12-24 hours after delivery and not initially treated with RBC transfusion, are eligible for randomisation. Patients with severe physical complaints are excluded. Patients are randomised for either RBC transfusion or expectant management. Health related quality of life (HRQoL) will be assessed at inclusion, at three days and one, three and six weeks postpartum with three validated measures (Multi-dimensional Fatigue Inventory, ShortForm-36, EuroQol-5D). Primary outcome of the study is physical fatigue three days postpartum. Secondary outcome measures are general and mental fatigue scores and generic health related quality of life scores, the number of RBC transfusions, length of hospital stay, complications and health-care costs.

The primary analysis will be by intention-to-treat. The various longitudinal scores will be evaluated using Repeated Measurements ANOVA. A costs benefit analysis will also be performed. The power calculation is based on the exclusion of a difference in means of 1.3 points or greater in favour of RBC transfusion arm regarding physical fatigue subscale. With missing data not exceeding 20%, 250 patients per arm have to be randomised (one-sided alpha = 0.025, power = 80%).

Discussion

This study will provide evidence for a guideline regarding RBC transfusion in the postpartum patient suffering from acute anaemia. Equivalence in fatigue score, remaining HRQoL scores and physical complications between both groups is assumed, in which case an expectant management would be preferred to minimise transfusion reactions and costs.

Trial registration

ClinicalTrials.gov NCT00335023, Nederlands Trial Register NTR335

Children with autism spectrum disorder (ASD) exhibit characteristic cognitive and behavioral differences, but no systematic pattern of neuroanatomical differences has been consistently found. Recent neurodevelopmental models posit an abnormal early surge in subcortical white matter growth in at least some autistic children, perhaps normalizing by adulthood, but other studies report subcortical white matter deficits. To investigate the profile of these alterations in 3D, we mapped brain volumetric differences using a relatively new method, tensor-based morphometry (TBM). 3D T1-weighted brain MRIs of 24 male children with ASD (age: 9.5 years ± 3.2 SD) and 26 age-matched healthy controls (age: 10.3 ± 2.4 SD) were fluidly registered to match a common anatomical template. Autistic children had significantly enlarged frontal lobes (by 3.6% on the left and 5.1% on the right), and all other lobes of the brain were enlarged significantly, or at trend level. By analyzing the applied deformations statistically point-by-point, we detected significant gray matter volume deficits in bilateral parietal, left temporal and left occipital lobes (p=0.038, corrected), trend-level cerebral white matter volume excesses, and volume deficits in the cerebellar vermis, adjacent to volume excesses in other cerebellar regions. This profile of excesses and deficits in adjacent regions may (1) indicate impaired neuronal connectivity, resulting from aberrant myelination and/or an inflammatory process, and (2) help to understand inconsistent findings of regional brain tissue excesses and deficits in autism.

Background

It is increasingly recognized that the impact of disease on quality of life should be taken into account when assessing health status. It is likely that tooth loss, in most cases being a consequence of oral diseases, affects Oral Health-Related Quality of Life (OHRQoL). The aim of the present study is to systematically review the literature and to analyse the relationship between the number and location of missing teeth and oral health-related quality of life (OHRQoL). It was hypothesized that tooth loss is associated with an impairment of OHRQoL. Secondly, it was hypothesized that location and distribution of remaining teeth play an important role in this.

Methods

Relevant databases were searched for papers in English, published from 1990 to July 2009 following a broad search strategy. Relevant papers were selected by two independent readers using predefined exclusion criteria, firstly on the basis of abstracts, secondly by assessing full-text papers. Selected studies were grouped on the basis of OHRQoL instruments used and assessed for feasibility for quantitative synthesis. Comparable outcomes were subjected to meta-analysis; remaining outcomes were subjected to a qualitative synthesis only.

Results

From a total of 924 references, 35 were eligible for synthesis (inter-reader agreement abstracts κ = 0.84 ± 0.03; full-texts: κ = 0.68 ± 0.06). Meta-analysis was feasible for 10 studies reporting on 13 different samples, resulting in 6 separate analyses. All studies showed that tooth loss is associated with unfavourable OHRQoL scores, independent of study location and OHRQoL instrument used. Qualitative synthesis showed that all 9 studies investigating a possible relationship between number of occluding pairs of teeth present and OHRQoL reported significant positive correlations. Five studies presented separate data regarding OHRQoL and location of tooth loss (anterior tooth loss vs. posterior tooth loss). Four of these reported highest impact for anterior tooth loss; one study indicated a similar impact for both locations of tooth loss.

Conclusions

This study provides fairly strong evidence that tooth loss is associated with impairment of OHRQoL and location and distribution of tooth loss affect the severity of the impairment. This association seems to be independent from the OHRQoL instrument used and context of the included samples.