Palladium-Catalyzed Cross-Coupling of Alkenyl Carboxylates.

Carboxylate esters have many desirable features as electrophiles for catalytic cross-coupling: they are easy to access, robust during multistep synthesis, and mass-efficient in coupling reactions. Alkenyl carboxylates, a class of readily prepared non-aromatic electrophiles, remain difficult to functionalize through cross-coupling. We demonstrate that Pd catalysis is effective for coupling electron-deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C-O bond activation. A Pd0/II catalytic cycle is viable when using a Pd0 precatalyst, with turnover-limiting C-O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and ß-carboxyl elimination is proposed for PdII precatalysts. This work provides a clear path toward engaging myriad oxygen-based electrophiles in Pd-catalyzed cross-coupling.

In silico identification and in vivo validation of miR-495 as a novel regulator of motivation for cocaine that targets multiple addiction-related networks in the nucleus accumbens.

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression and are implicated in the etiology of several neuropsychiatric disorders, including substance use disorders (SUDs). Using in silico genome-wide sequence analyses, we identified miR-495 as a miRNA whose predicted targets are significantly enriched in the Knowledgebase for Addiction Related Genes (ARG) database (KARG; http://karg.cbi.pku.edu.cn). This small non-coding RNA is also highly expressed within the nucleus accumbens (NAc), a pivotal brain region underlying reward and motivation. Using luciferase reporter assays, we found that miR-495 directly targeted the 3'UTRs of Bdnf, Camk2a and Arc. Furthermore, we measured miR-495 expression in response to acute cocaine in mice and found that it is downregulated rapidly and selectively in the NAc, along with concomitant increases in ARG expression. Lentiviral-mediated miR-495 overexpression in the NAc shell (NAcsh) not only reversed these cocaine-induced effects but also downregulated multiple ARG mRNAs in specific SUD-related biological pathways, including those that regulate synaptic plasticity. miR-495 expression was also downregulated in the NAcsh of rats following cocaine self-administration. Most importantly, we found that NAcsh miR-495 overexpression suppressed the motivation to self-administer and seek cocaine across progressive ratio, extinction and reinstatement testing, but had no effect on food reinforcement, suggesting that miR-495 selectively affects addiction-related behaviors. Overall, our in silico search for post-transcriptional regulators identified miR-495 as a novel regulator of multiple ARGs that have a role in modulating motivation for cocaine.

Clinical medical sciences for undergraduate dental students in the United Kingdom and Ireland - a curriculum.

The technical aspects of dentistry need to be practised with insight into the spectrum of human diseases and illnesses and how these impact upon individuals and society. Application of this insight is critical to decision-making related to the planning and delivery of safe and appropriate patient-centred healthcare tailored to the needs of the individual. Provision for the necessary training is included in undergraduate programmes, but in the United Kingdom and Ireland there is considerable variation between centres without common outcomes. In 2009 representatives from 17 undergraduate dental schools in the United Kingdom and Ireland agreed to move towards a common, shared approach to meet their own immediate needs and that might also be of value to others in keeping with the Bologna Process. To provide a clear identity the term 'Clinical Medical Sciences in Dentistry' was agreed in preference to other names such as 'Human Disease' or 'Medicine and Surgery'. The group was challenged to define consensus outcomes. Contemporary dental education documents informed, but did not drive the process. The consensus curriculum for undergraduate Clinical Medical Sciences in Dentistry teaching agreed by the participating centres is reported. Many of the issues are generic and it includes elements that are likely to be applicable to others. This document will act as a focus for a more unified approach to the outcomes required by graduates of the participating centres and act as a catalyst for future developments that ultimately aim to enhance the quality of patient care.

Competitive Drivers of Atrial Fibrillation: The Interplay Between Focal Drivers and Multiwavelet Reentry.

BACKGROUND: There is debate whether human atrial fibrillation is driven by focal drivers or multiwavelet reentry. We propose that the changing activation sequences surrounding a focal driver can at times self-sustain in the absence of that driver. Further, the relationship between focal drivers and surrounding chaotic activation is bidirectional; focal drivers can generate chaotic activation, which may affect the dynamics of focal drivers. METHODS AND RESULTS: In a propagation model, we generated tissues that support structural micro-reentry and moving functional reentrant circuits. We qualitatively assessed (1) the tissue's ability to support self-sustaining fibrillation after elimination of the focal driver, (2) the impact that structural-reentrant substrate has on the duration of fibrillation, the impact that micro-reentrant (3) frequency, (4) excitable gap, and (5) exposure to surrounding fibrillation have on micro-reentry in the setting of chaotic activation, and finally the likelihood fibrillation will end in structural reentry based on (6) the distance between and (7) the relative lengths of an ablated tissue's inner and outer boundaries. We found (1) focal drivers produced chaotic activation when waves encountered heterogeneous refractoriness; chaotic activation could then repeatedly initiate and terminate micro-reentry. Perpetuation of fibrillation following elimination of micro-reentry was predicted by tissue properties. (2) Duration of fibrillation was increased by the presence of a structural micro-reentrant substrate only when surrounding tissue had a low propensity to support self-sustaining chaotic activation. Likelihood of micro-reentry around the structural reentrant substrate increased as (3) the frequency of structural reentry increased relative to the frequency of fibrillation in the surrounding tissue, (4) the excitable gap of micro-reentry increased, and (5) the exposure of the structural circuit to the surrounding tissue decreased. Likelihood of organized tachycardia following termination of fibrillation increased with (6) decreasing distance and (7) disparity of size between focal obstacle and external boundary. CONCLUSION: Focal drivers such as structural micro-reentry and the chaotic activation they produce are continuously interacting with one another. In order to accurately describe cardiac tissue's propensity to support fibrillation, the relative characteristics of both stationary and moving drivers must be taken into account.

Neuronal RNA-binding protein HuD regulates addiction-related gene expression and behavior.

The neuronal RNA-binding protein HuD is involved in synaptic plasticity and learning and memory mechanisms. These effects are thought to be due to HuD-mediated stabilization and translation of target mRNAs associated with plasticity. To investigate the potential role of HuD in drug addiction, we first used bioinformatics prediction algorithms together with microarray analyses to search for specific genes and functional networks upregulated within the forebrain of HuD overexpressing mice (HuDOE ). When this set was further limited to genes in the knowledgebase of addiction-related genes database (KARG) that contains predicted HuD-binding sites in their 3' untranslated regions (3'UTRs), we found that HuD regulates networks that have been associated with addiction-like behavior. These genes included Bdnf and Camk2a, 2 previously validated HuD targets. Since addiction is hypothesized to be a disorder stemming from altered gene expression causing aberrant plasticity, we sought to test the role of HuD in cocaine conditioned placed preference (CPP), a model of addiction-related behaviors. HuD mRNA and protein were upregulated by CPP within the nucleus accumbens of wild-type C57BL/6J mice. These changes were associated with increased expression of Bdnf and Camk2a mRNA and protein. To test this further, we trained HuDOE and wild-type mice in CPP and found that HuDOE mice showed increased cocaine CPP compared with controls. This was also associated with elevated expression of HuD target mRNAs and proteins, CaMKIIα and BDNF. These findings suggest HuD involvement in addiction-related behaviors such as cocaine conditioning and seeking, through increased plasticity-related gene expression.

Resorbable versus titanium plates for orthognathic surgery.

BACKGROUND: Recognition of some of the limitations of titanium plates and screws used for the fixation of bones has led to the development of plates manufactured from bioresorbable materials. Whilst resorbable plates appear to offer clinical advantages over metal plates in orthognathic surgery, concerns remain about the stability of fixation and the length of time required for their degradation and the possibility of foreign body reactions. OBJECTIVES: To compare the effectiveness of bioresorbable fixation systems with titanium systems used during orthognathic surgery. SEARCH STRATEGY: We searched the following databases: Cochrane Oral Health Group Trials Register (to 26th January 2006); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 4); MEDLINE (without filter) (from 1966 to 26th January 2006); and EMBASE (without filter) (from 1980 to 26th January 2006). SELECTION CRITERIA: Randomised controlled trials comparing resorbable versus titanium fixation systems used for orthognathic surgery. DATA COLLECTION AND ANALYSIS: Clinical heterogeneity between the included trials precluded pooling of data, and only a descriptive summary is presented. MAIN RESULTS: This review included two trials, involving 103 participants, one compared titanium with resorbable plates and screws and the other titanium with resorbable screws, both provided very limited data for the primary outcomes of this review. All patients in one trial suffered mild to moderate postoperative discomfort with no statistically significant difference between the two plating groups at different follow-up times. Mean scores of patient satisfaction were 7.43 to 8.63 (range 0 to 10) with no statistically significant difference between the two groups throughout follow up. Adverse effects reported in one study were two plate exposures in each group occurring between the third and ninth months. Plate exposures occurred mainly in the posterior maxillary region, except for one titanium plate exposure in the mandibular premolar region. Known causes of infection were associated with loosened screws and wound dehiscence with no statistically significant difference in the infection rate between titanium (3/196), and resorbable (3/165) plates P = 0.83 (published as P = 0.67). AUTHORS' CONCLUSIONS: This review provides some evidence to show that there is no statistically significant difference in postoperative discomfort, level of patient satisfaction, plate exposure or infection for plate and screw fixation using either titanium or resorbable materials in orthognathic surgery.

Interventions for the treatment of oral and oropharyngeal cancers: surgical treatment.

BACKGROUND: Oral and oropharyngeal cancers can be managed by surgery alone or with any combination of radiotherapy, chemotherapy and immunotherapy/biotherapy. Opinions on the surgical treatment, the optimal combinational therapy and the sequence of treatments in combinational therapy varies enormously. OBJECTIVES: To determine which surgical treatment modalities for oral and oropharyngeal cancers lead to the best outcomes compared with other surgical, radiotherapy, chemotherapy or immunotherapy/biotherapy combinations. SEARCH STRATEGY: Electronic search of the Cochrane Oral Health Group Trials Register, CENTRAL, MEDLINE, OLDMEDLINE, EMBASE, AMED and the National Cancer Trials Database. Reference lists from relevant articles were searched and the authors of eligible trials were contacted. Date of the most recent searches: July 2007. SELECTION CRITERIA: Randomised controlled trials of surgery alone or in combination with chemotherapy, radiotherapy or immunotherapy/biotherapy for the treatment of primary oral or oropharyngeal cancer or both. DATA COLLECTION AND ANALYSIS: A minimum of two review authors conducted data extraction. Risk ratios were calculated for dichotomous outcomes at different time intervals, and hazard ratios were extracted or calculated for disease-free survival, total mortality, and disease-related mortality. Additional information from trial authors was sought. Data on adverse events were collected from the trial reports. MAIN RESULTS: Thirty-one trials satisfied the inclusion criteria, only 13 of which were assessed as low risk of bias. Trials were grouped into 12 main comparisons. There were no trials that compared different surgical modalities of the primary tumour itself. However, there were a number of trials comparing different approaches to managing the cervical lymph nodes. The majority of treatment regimens under evaluation were surgery in combination with other modalities. As individual treatment regimens within each comparison varied, meta-analysis was inappropriate in most instances. Only two trials could be pooled, comparing concomitant radio/chemotherapy (with surgery) versus radiotherapy (with surgery). A statistically significant difference was shown for disease-free survival (hazard ratio 0.77, 95% confidence interval (CI): 0.64 to 0.92) and total mortality (hazard ratio 0.78, 95% CI: 0.64 to 0.95) in favour of the concomitant chemotherapy and radiotherapy (with surgery) arm. No other treatment regimens showed consistent statistically significant results across the outcomes measured. AUTHORS' CONCLUSIONS: There is some evidence that concomitant radio/chemotherapy (with surgery) is more effective than radiotherapy (with surgery) and may benefit outcomes in patients with more advanced oral and oropharyngeal cancers. As these trials were based on head and neck studies, future studies should evaluate this treatment regimen specifically in oral and oropharyngeal cancers separately and also address tumour staging and its impact on outcomes. In general, future studies are encouraged to evaluate site-specific and stage-specific data for oral and oropharyngeal cancers. Future trials should include health-related quality of life assessment as an outcome measure. There is a need for a consolidated standardised approach to reporting adverse events.

Screening programmes for the early detection and prevention of oral cancer.

BACKGROUND: Screening programmes for major cancers, such as breast and cervical cancer have effectively decreased the mortality rate and helped to reduce the incidence of these cancers. Although oral cancer is a global health problem with increasing incidence and mortality rates, no national population-based screening programmes for oral cancer have been implemented. To date there is debate on whether to employ screening methods for oral cancer in the daily routine work of health providers. OBJECTIVES: To assess the effectiveness of current screening methods in decreasing oral cancer mortality. SEARCH STRATEGY: Electronic databases (MEDLINE, CANCERLIT, EMBASE, the Cochrane Central Register of Controlled Trials; 1966 to July 2005, The Cochrane Library - Issue 3, 2005), bibliographies, handsearching of specific journals and contact authors were used to identify published and unpublished data. SELECTION CRITERIA: Randomised controlled trials of screening for oral cancer or precursor oral lesions using visual examination, toluidine blue, fluorescence imaging or brush biopsy. DATA COLLECTION AND ANALYSIS: The search found 112 citations and these have been reviewed. One randomised controlled trial of screening strategies for oral cancer was identified as meeting the review's inclusion criteria. Validity assessment, data extraction and statistics evaluation were undertaken by two independent review authors. MAIN RESULTS: One 10-year randomised controlled trial has been included (n = 13 clusters: 191,873 participants). There was no difference in the age-standardised oral cancer mortality rates for the screened group (16.4/100,000 person-years) and the control group (20.7/100,000 person-years). Interestingly, a significant 34% reduction in mortality was recorded in high-risk subjects between the intervention cohort (29.9/100,000 person-years) and the control arm (45.4/100,000). However, this study has some methodological weaknesses. Additionally, the study did not provide any information related to costs, quality of life or even harms of screening from false-positive or false-negative findings. AUTHORS' CONCLUSIONS: Given the limitation of evidence (only one included randomised controlled trial) and the potential methodological weakness of the included study, it is valid to say that there is insufficient evidence to support or refute the use of a visual examination as a method of screening for oral cancer using a visual examination in the general population. Furthermore, no robust evidence exists to suggest that other methods of screening, toluidine blue, fluorescence imaging or brush biopsy, are either beneficial or harmful. Future high quality studies to assess the efficacy, effectiveness and costs of screening are required for the best use of public health resources. In addition, studies to elucidate the natural history of oral cancer, prevention methods and the effectiveness of opportunistic screening in high risk groups are needed. Future studies on improved treatment modalities for oral cancer and precancer are also required.

Classification of normal and male-sterile cytoplasms in maize. I. Electrophoretic analysis of variation in mitochondrially synthesized proteins.

Male-sterile cytoplasms of maize have previously been classified into three groups (T, S and C) according to their fertility ratings in various inbred backgrounds. In earlier studies, mitochondria from three male-sterile cytoplasms, representing each of these three groups, have been found to synthesize characteristic variant polypeptides that distinguish them from each other and from those of normal (N) cytoplasm. In order to determine the extent of cytoplasmic variation, we have now analyzed the translation products of mitochondria from 28 additional cytoplasmic sources. The results show that on this basis 18 of the cytoplasms are identical to the USDA (S) cytoplasm, three are identical to the Texas (T) cytoplasm and two are identical to the C cytoplasm. The five remaining cytoplasms are indistinguishable from normal, male-fertile (N) cytoplasm. Our classification of the cytoplasms is in general agreement with those based on fertility restoration. However, of three cytoplasms that have previously remained unclassified, two (B and D) have now been assigned to the S group and one (LF) to the N group. No heterogeneity in mitochondrial translation products was detected within the normal or any of the three male-sterile groups. The usefulness of the analysis of mitochondrial translation products as a method for classifying normal and male-sterile cytoplasms is discussed.

Structural defects lead to dynamic entrapment in cardiac electrophysiology.

Biological networks are typically comprised of many parts whose interactions are governed by nonlinear dynamics. This potentially imbues them with the ability to support multiple attractors, and therefore to exhibit correspondingly distinct patterns of behavior. In particular, multiple attractors have been demonstrated for the electrical activity of the diseased heart in situations where cardioversion is able to convert a reentrant arrhythmia to a stable normal rhythm. Healthy hearts, however, are typically resilient to abnormal rhythms. This raises the question as to how a healthy cardiac cell network must be altered so that it can support multiple distinct behaviors. Here we demonstrate how anatomic defects can give rise to multi-stability in the heart as a function of the electrophysiological properties of the cardiac tissue and the timing of activation of ectopic foci. This leads to a form of hysteretic behavior, which we call dynamic entrapment, whereby the heart can become trapped in aberrant attractor as a result of a transient change in tissue properties. We show that this can lead to a highly inconsistent relationship between clinical symptoms and underlying pathophysiology, which raises the possibility that dynamic entrapment may underlie other forms of chronic idiopathic illness.

Prospectively quantifying the propensity for atrial fibrillation: a mechanistic formulation.

The goal of this study was to determine quantitative relationships between electrophysiologic parameters and the propensity of cardiac tissue to undergo atrial fibrillation. We used a computational model to simulate episodes of fibrillation, which we then characterized in terms of both their duration and the population dynamics of the electrical waves which drove them. Monte Carlo sampling revealed that episode durations followed an exponential decay distribution and wave population sizes followed a normal distribution. Half-lives of reentrant episodes increased exponentially with either increasing tissue area to boundary length ratio (A/BL) or decreasing action potential duration (APD), resistance (R) or capacitance (C). We found that the qualitative form of fibrillatory activity (e.g., multi-wavelet reentry (MWR) vs. rotors) was dependent on the ratio of resistance and capacitance to APD; MWR was reliably produced below a ratio of 0.18. We found that a composite of these electrophysiologic parameters, which we term the fibrillogenicity index (Fb = A/(BL*APD*R*C)), reliably predicted the duration of MWR episodes (r2 = 0.93). Given that some of the quantities comprising Fb are amenable to manipulation (via either pharmacologic treatment or catheter ablation), these findings provide a theoretical basis for the development of titrated therapies of atrial fibrillation.

Prognostic value of facilitative glucose transporter Glut-1 in oral squamous cell carcinomas treated by surgical resection; results of EORTC Translational Research Fund studies.

Hypoxia in tumours of the oral cavity has not been extensively investigated with regard to clinical outcome and prognosis. The expression of the facilitative glucose transporter, Glut-1, has been shown to be related to hypoxia in tumours at other sites. The aim of the present study was to investigate the relationship between Glut-1 expression and clinical outcome in a series of oral squamous cell carcinomas. A retrospective series of 54 cases of oral squamous cell carcinomas with known clinical outcome and treated by one surgeon over a period of 6 years was used in the study. A representative section from each case was stained immunohistochemically with an antibody against Glut-1. The stained sections were then assessed independently by two observers using a semi-quantitative method. The relationship between these results and the clinical outcomes of local recurrence, regional lymph-node metastasis and disease-free survival were examined. Glut-1 staining was observed in most of the tissue specimens and all of the few sections with demonstrably necrotic areas histologically. Some showed more prominent staining in the epithelial islands of the tumour than others. However, the intensity of staining was variable. There was a significant relationship between those tumours which demonstrated intense staining and recurrence overall (chi(2)=6.18, P=0.032). This relationship was strongest in relation to regional lymph-node recurrence (chi(2)=10.19, P=0.005). A significant relationship between disease-related death and intense Glut-1 staining was also observed (chi(2)=11.67, P=0.002). In conclusion, the results of this study indicate a relationship between Glut-1 expression and disease progression of oral cancer and could indicate a need for neoadjuvant chemoradiotherapy for those tumours demonstrating intense Glut-1 expression.

Solitary adult myofibroma of the mandible simulating an odontogenic cyst.

The solitary adult myofibroma is a rare lesion but has a predilection for the head and neck. Intraosseous lesions are common in childhood but uncommon in adults. The lesion is considered to be completely benign but there is the potential for it being confused with more aggressive spindle cell tumours. Histologically it is characterised by two cell types arranged in a biphasic pattern; namely centrally positioned small rounded cells with pale staining nuclei and eosinophilic cytoplasm and peripherally elongated spindle cells. A case is reported of a 34-year-old female patient who presented with a solitary myofibroma in the lower third molar region of the mandible which clinically and radiographically simulated an odontogenic cyst.

Oral biopsies: methods and applications.

Biopsies are an important diagnostic tool for the diagnosis of lesions ranging from simple periapical lesions to malignancies. Planning prior to performing a biopsy is essential. It will be beneficial to the receiving pathologist in reaching a helpful and meaningful diagnosis, and therefore ultimately and more importantly, to the patient. This paper presents an updated view of biopsies and discusses some of the potential problems with biopsy technique and specimens and how to overcome them.

Oral cancer in young adults: report of three cases and review of the literature.

Oral cancer in young adults is fortunately uncommon in the UK. However, since it is so rare, when cases present they are often misdiagnosed and inappropriately treated leading to delay in definitive treatment. This may, in turn, lead to a poorer prognosis for these patients. It is debatable if oral cancer in younger adults carries an inherently poor prognosis and presents with more aggressive tumours. Three cases of oral cancer in young adults, aged under 30 years are presented and the literature reviewed with respect to oral cancer in this group of patients.

Miconazole oral gel and drug interactions.

Miconazole oral gel is frequently prescribed for the treatment of oral Candidal infections. Its ability to be systemically absorbed and interact with other drugs has previously been recorded but is not universally known. As a reminder, a further case of derangement of anticoagulation following concomitant use of warfarin and miconazole is reported. Other potential drug interactions of miconazole and fluconazole are highlighted.

Persistent impairment of taste associated with terbinafine.

A second case of persistent taste disturbance associated with terbinafine is described. Taste disturbance associated with this drug is reviewed and a table is provided listing the more common drugs associated with taste disturbance.

Patterns of antifungal prescribing in general dental practice.

OBJECTIVE: To examine the current practice of antifungal prescribing by GDPs in the United Kingdom. Design A postal questionnaire circulated to a random selection of 400 dentists. OUTCOME MEASURES: The questionnaires were analysed and the responses expressed as absolute and relative frequencies. RESULTS: Responses to the questionnaire were received from 297 (74.3%) GDPs. Nystatin was the most popular choice of antifungal agent that GDPs would use, followed by miconazole, amphotericin B and fluconazole. The likelihood of use of miconazole was positively linked to recent date of graduation. Lack of knowledge regarding contraindications and problems with azole antibiotics was found in a significant minority of practitioners (36%). CONCLUSIONS: The present study indicates that azole antifungal agents (especially miconazole) are becoming more widely used by GDPs, but that knowledge regarding potential problems with their use is sub-optimal. Nystatin remains the most popular choice of antifungal agent.

Routine follow-up after periradicular operations: current practice in UK hospitals.

Questionnaires were circulated to all Fellows of the British Society of Oral and Maxillofacial Surgeons in 1999, 75% of whom replied (n = 194). There was a wide range of responses for both the timing of review appointments and the taking of radiographs. Most patients were first followed up 1 week after operation (46%), but 38% were reviewed in the second week. Five surgeons did not review patients at all and two did not review until 6 or 9 months, respectively. Nearly two-thirds routinely offered a second follow-up appointment but only 14% offered more than two, the maximum being seven. Most arranged postoperative radio-graphs but the timing ranged from immediately postoperatively to 1 year after the procedure. Less than one-third requested a second postoperative radiograph between 1 month and 1 year. The largest disparity was in the time of discharge to the general dental practitioner, which ranged from immediately to 5 years, the most popular time of discharge being at 3 months. The wide variations may reflect unnecessary recall of patients and misuse of valuable clinical time.

Update on precancerous lesions.

Oral cancer continues to be a serious problem in the UK and it is well known that prevention and early recognition of potentially malignant lesions will provide the best prognosis. This article discusses recent changes in the nomenclature of lesions and current concepts in diagnosis and management.