Opioids are efficacious and cost-effective analgesics, but tolerance limits their effectiveness. This paper does not present any new clinical or experimental data but demonstrates that there exist ascending sensory pathways that contain few opioid receptors. These pathways are located by brain PET scans and spinal cord autoradiography. These nonopioid ascending pathways include portions of the ventral spinal thalamic tract originating in Rexed layers VI–VIII, thalamocortical fibers that project to the primary somatosensory cortex (S1), and possibly a midline dorsal column visceral pathway. One hypothesis is that opioid tolerance and opioid-induced hyperalgesia may be caused by homeostatic upregulation during opioid exposure of nonopioid-dependent ascending pain pathways. Upregulation of sensory pathways is not a new concept and has been demonstrated in individuals impaired with deafness or blindness. A second hypothesis is that adjuvant nonopioid therapies may inhibit ascending nonopioid-dependent pathways and support the clinical observations that monotherapy with opioids usually fails. The uniqueness of opioid tolerance compared to tolerance associated with other central nervous system medications and lack of tolerance from excess hormone production is discussed. Experimental work that could prove or disprove the concepts as well as flaws in the concepts is discussed. Chronic pain is one of the greatest causes of human suffering. Chronic pain becomes intractable when standard therapies fail to control the pain , 2. In mFrom the first-order afferent receptor  through the ascending tracts to the thalamo, reticular, and mesencephalic relays to the final destination in the somatosensory cortices, anterior cingulated gyrus, and basal ganglia, pain is associated with a net excitatory stimulus. Numerous studies and clinical observations, including those from neural blockade, cordotomy, or rhizotomy, support this concept . DestrucOpioid tolerance can be defined as a decrease in analgesic response with increasing dose or frequency of administration. Tolerance is the greatest obstacle to the development of effective opioid treatment for intractable pain. Tolerance to endogenous opioids is often rapid, whereas tolerance to exogenous opioids is often delayed . OpioidsThe Human Thalamocortical and Spinothalamic Tracts Have Divisions That Are Not Modulated by Opioids. This observation has not been fully appreciated in the literature but is depicted in Figures (1) Sensory fibers of the thalamocortical tract project to the primary somatosensory cortex (S1) and secondary sensory cortex (S2) , 15. In As shown in Surgical Interruption of a Midline Dorsal Column Visceral Pain Pathway Produces Analgesia . Clinical reports confirm that a modified midline myelotomy can provide successful visceral pain relief especially in patients who have become tolerant to opioids. The analgesia produced by punctuate midline myelotomy that interrupts ascending fibers of the posterior columns has effectively controlled pain in patients suffering from pelvic pain secondary to malignancy [(2) lignancy . It is nWhen Compared to Other G-Protein Ligands, a Unique form of Tolerance Develops after Opioid Administration. Patients who suffer from hypersecretory states activated by G-protein receptors, such as hyperthyroidism, hyperparathyroidism, and pheochromocytoma, do not become tolerant to endogenous hormone ligands, and they need to be treated by lowering the production of these hormones. Although catecholamine tolerance has been reported in animal models, anecdotal reports from critical care physicians confirm that norepinephrine and dopamine administered as infusions rarely require major adjustments secondary to tolerance [(3) olerance –31. Opioolerance –34. ToleOpioid-induced hyperalgesia is a condition that may occur after chronic administration of large doses of an opioid. It is characterized by a lowering of the pain threshold with an exaggerated response to painful and nonpainful stimuli . One hypThe hypothesis that upregulation of non-opioid-dependent ascending sensory systems is a possible cause of opioid tolerance and opioid-induced hyperalgesia is novel, but recent reports have implied that this could be true . This hyMost pain practitioners acknowledge that opioid therapy in sufficient doses can ameliorate acute and chronic intractable pain, and addition of adjuvant medications such as antidepressants, anticonvulsants, and anti-inflammatory medication improves response. However, opioids alone cannot provide long-term relief because of tolerance, opioid-induced hyperalgesia, or side effects. Pain practitioners are also well aware that other nonopioid therapies, such as intravenous infusion of local anesthetics or ketamine, inhalation of nitrous oxide, or conduction block, provide reliable analgesia for patients suffering from intractable pain probably via a different mechanism than activation of opioid receptors. If upregulation of non-opioid-dependent ascending nociceptive pathways is shown to be a cause of pain from opioid tolerance or opioid-induced hyperalgesia, providers may consider adding GABA agonist to the medication regime of opioid-tolerant patients. Interestingly, our patients who suffer from intractable pain have learned that alcohol and benzodiazepines, both indirect GABA agonists, provide additional, but unsafe, analgesia when combined with opioids. In addition to increasing GABA, decreasing glutamate or blocking glutamate receptors could possibly attenuate the excitatory activity of non-opioid-dependent pathways. As espoused by most investigators, opioid tolerance is believed to be caused by ligand-receptor inefficiency . EvidencIntractable pain is one of the leading causes of worldwide suffering. Opioids are the most consistent, efficacious, and cost-effective analgesics available. Tolerance to opioids limits their effectiveness, and some aspects of this phenomenon are unique to opioids when compared to other G-protein receptor ligand systems. One hypothesis of this paper is that some aspect of opioid tolerance is caused by homeostatic upregulation of non-opioid-mediated ascending nociceptive pathways, including the thalamocortical and ventral spinothalamic tracts and possibly the midline dorsal column tract. Another hypothesis is that upregulation of these tracts may contribute to opioid-induced hyperalgesia. As one observes in clinical practice, therapy with adjuvant agents combined with opioids, rather than opioids alone, produced the best outcome for the treatment of intractable pain. Aside from presumed stimulation of descending inhibitory tracts from some adjuvants, one possible explanation for these outcomes is that these therapies inhibit nonopioid ascending dependent tracts as well as opioid-dependent tracts. This paper offers a hypothetical explanation based on neuroanatomic correlation as to why adjuvants plus opioid therapy are most successful and single-opioid therapy usually fails. When shown a comparison of opioid and non-opioid ascending nociceptive dependent tracts, physicians and patients may develop a better understanding of their therapy.


Prescription drugs are used in people with hypertension, diabetes, and cardiovascular disease to manage their illness. Patient cost sharing strategies such as copayments and deductibles are often employed to lower expenditures for prescription drug insurance plans, but the impact on health outcomes in these patients is unclear.To determine the association between drug insurance and patient cost sharing strategies on medication adherence, clinical and economic outcomes in those with chronic diseases .Studies were included if they examined various cost sharing strategies including copayments, coinsurance, fixed copayments, deductibles and maximum out-of-pocket expenditures. Value-based insurance design and reference based pricing studies were excluded. Two reviewers independently identified original intervention studies . MEDLINE, EMBASE, Cochrane Library, CINAHL, and relevant reference lists were searched until March 2013. Two reviewers independently assessed studies for inclusion, quality, and extracted data. Eleven studies, assessing the impact of seven policy changes, were included: 2 separate reports of one randomized controlled trial, 4 interrupted time series, and 5 controlled before-after studies.Outcomes included medication adherence, clinical events , quality of life, healthcare utilization, or cost. The heterogeneity among the studies precluded meta-analysis. Few studies reported the impact of cost sharing strategies on mortality, clinical and economic outcomes. The association between patient copayments and medication adherence varied across studies, ranging from no difference to significantly lower adherence, depending on the amount of the copayment.Lowering cost sharing in patients with chronic diseases may improve adherence, but the impact on clinical and economic outcomes is uncertain. Access and adherence to medications is important in the management of many chronic diseases, including cardiovascular conditions The type of drug insurance that is available to citizens varies internationally, as does the use of patient cost sharing strategies. Many patients lack drug insurance or make some form of direct payment for a portion of their prescriptions, which may constitute a financial barrier to drug access A prior Cochrane review of studies published before 2008 found low-quality evidence that fixed copayments and caps reduced adherence to medications Full drug insurance: a policy where the patient does not pay any out-of-pocket expenditure at the time the prescription is dispensed.Cap: a limit below which a patient does not pay or has reduced payments for prescriptions. After the cap is reached full payment is required by the patient.Coinsurance: a system where a patient pays a set percentage of the amount per drug or per prescription.Copayment: an amount per drug or per prescription that a patient pays.Coverage gap: a gap between a cap and catastrophic coverage where a patient is responsible for the full cost of the drug.Deductible: a limit up to which a patient pays the full cost of the drug. After the deductible is reached, the patient either does not pay or has reduced payments for prescriptions.Fixed copayment: a system where a patient pays a fixed, or set, amount per drug or per prescription.Maximum out-of-pocket limit: a limit that is set as a fixed dollar amount or as a percentage of income after which the insurer pays 100% of the drugs. Copayments and coinsurance are in place prior to the limit being reached. Some studies refer to this as catastrophic coverage limitcoronary artery disease, hypertension, dyslipidemia, diabetes, peripheral vascular disease, stroke, transient ischemic attack, heart failure, chronic kidney disease, insurance, pharmaceutical services, health or for-profit insurance plans, reimbursement, Medicare, single-payer system, copay, deductibles, coinsurance, and insurance coverage. No limitations were placed on patient characteristics, study duration or outcomes; the bibliographies of included studies were also searched independently by two reviewers (BSM and LB).A librarian assisted search was performed of electronic databases for English language studies, from inception until March 2013 and included: MEDLINE, EMBASE, CINAHL, Cochrane Controlled Trials Register, and Current Controlled Trials. The full search strategy is available in Two reviewers (BSM and LB) independently screened citations and determined eligibility in two stages. In the first stage, all identified citations were reviewed, while the second stage encompassed full-text review of selected abstracts to determine eligibility. Disagreements were resolved by consensus or through consultation with a third reviewer (BJM). Studies were included if they focused on: adult patients with chronic disease , and assessed the impact of full drug insurance without cost sharing, or with lower level of cost sharing as part of a drug insurance system against a comparator group.We included studies that examined various cost sharing strategies including copayments, coinsurance, fixed copayments, deductibles and maximum out-of-pocket expenditures, defined in Consistent with the Cochrane Effective Practice and Organisation of Care Group [EPOC] taxonomy of health care policy studies Two reviewers (BSM and LB) independently extracted data and disagreements were resolved by consensus or through consultation with a third reviewer (BJM). The quality of included studies was evaluated using the Cochrane risk of bias tool for randomized controlled trials a priori not to pool the studies. Individual study results are reported by type of intervention.As we anticipated substantial heterogeneity between the outcomes reported across studies, we developed broad categories of outcomes, and decided The search yielded 3,122 citations, 72 of which were selected for full-text review. Of these, 11 studies evaluating 7 different drug insurance policy changes met our inclusion criteria : 2 separThe randomized controlled trial was rated as moderate quality . The othThree studies compared those with no drug coverage to a group that had stable uncapped drug coverage that remained unchanged before and after the implementation of Medicare Part D Zhang 2009 Seven studies (assessing five different policy interventions) assessed the impact of varying levels of copayment, ranging from full coverage (no payment from patient) to 95% patient copayment on drug adherence .The RAND RCT compared full healthcare insurance with three different cost sharing strategies. In a sub-group analysis, they found that in patients with hypertension, full drug insurance led to higher use of antihypertensive medications at the exit screening examination (20% absolute increase) compared to each of the three cost sharing strategies Clinically relevant outcomes were reported in two studies. The sub-group analysis of the RAND trial reported that full insurance was associated with a statistically significant decrease in diastolic blood pressure , as compared to the three cost sharing strategies . The QueThe impact of deductibles was assessed in the studies from Quebec and British Columbia Few studies evaluated changes in the maximum out-of-pocket limit, outside of other policy changes. In a high risk group of US Veteran's Administration patients with coronary heart disease, there was a slight decline in adherence in patients without an annual maximum out-of-pocket expenditure, compared to those with a maximum out-of-pocket expenditure ($840 US per year)  [29]. InA study by Li et al examined the effect of a coverage gap in a group of elderly Part D enrollees who were ineligible for low-income subsidies with elderly Part D enrollees who were eligible for low-income subsidies. As of 2006, the standard Medicare Part D design has a coverage gap, where a beneficiary has to pay 100% of drug costs after total drug spending exceeds an annual threshold of $2250 in 2006 Our systematic review identified 11 studies, comparing 7 policy changes assessing drug insurance and patient cost sharing strategies  in patients with or at risk for cardiovascular disease. Although data on clinical outcomes was not widely reported, our review found that providing drug insurance to people with chronic diseases who have no drug insurance appears to increase appropriate use of and adherence to drugs.The proportion of the US gross domestic product that is spent on health care has more than tripled over the past 30 years Previous reviews have examined the relationship between drug insurance and health care utilization While the use of deductibles (up to $350 per year) does not appear to have a significant impact on medication adherence, one study reported that 100% copayment (i.e. those who had not yet reached the deductible level) was associated with a two-fold reduction in drug adherence Our review has some limitations: we limited our search to English language studies and may have missed non-English language studies. Furthermore, the heterogeneity of the studies prevented us from obtained pooled estimates of the overall effect of drug insurance on our outcomes of interest. Our review focused on patients with or at risk for cardiovascular diseases, and it is possible that the impact of some tools (such as maximum out-of-pocket limits) may be more important for patients receiving very high-cost drugs, such as those with cancer. While we attempted to assess the association between changes in drug policy and clinically relevant outcomes, studies rarely reported on these outcomes. Though we wished to explore any unwanted side effects of using less drugs as a result of these cost-sharing strategies, the studies included did not report specifically on this outcome. However, providing medication coverage appeared to improve medication adherence, though studies either did not find or did not report changes in clinically relevant outcomes such as myocardial infarction, heart failure, angina or death Our review shows that providing drug insurance to those with or at risk for cardiovascular disease who have no insurance improves drug adherence. The impact of cost sharing strategies is less certain, though patient cost sharing in people of lower socioeconomic status may adversely impact adherence. Policy makers should be aware that copayments and deductibles, while reducing cost for the payer, may influence medication adherence and ultimately health outcomes – especially for those of lower socioeconomic status.Appendix S1Search strategy.(DOCX)Click here for additional data file.Appendix S2Risk of bias summary table.(DOCX)Click here for additional data file.


Feynman’s early vision in 1959 gave birth to the concept of nanotechnology. He saw it as an unavoidable development in the progress of science and said that there is plenty of room at the bottom. Since then, nanotechnology has been part of mainstream scientific theory with potential medical and dental applications. Numerous theoretical predictions have been made based on the potential applications of nanotechnology in dentistry, with varying levels of optimism. While a few layers of nanotechnologic capability have become a reality for oral health in the last decade, many of these applications are still in their puerile stage .The most substantial contribution of nanotechnology to dentistry till date, is the more enhanced restoration of tooth structure with nanocomposites. The field of nanotechnology has tremendous potential, which if harnessed efficiently, can bring out significant benefits to the human society such as improved health, better use of natural resources, and reduced environmental pollution. The future holds in store an era of dentistry in which every procedure will be performed using equipments and devices based on nanotechnology. This article reviews the current status and the potential clinical applications of nanotechnology in dentistry. Key words:Nanotechnology, nanodentistry, nanocomposites. Last decade witnessed an unparalleled growth in all the fields of research in medicine. But there is little doubt that nanotechnology has the potential to change all aspects of medicine, health care and human life more profoundly than many other developments of the past taken together. Nanotechnology has revolutionized all aspects of health care into a new paradigm of state-of-the-art patient care beyond traditional, and dentistry is no exception.The conceptual underpinnings of nanotechnologies were first laid out in 1959 by the noble prize winning physicist Richard Feynman in his lecture, “There’s plenty of room at the bottom”. In his historic lecture, he concluded saying, “this is a development which I think cannot be avoided”. -3 biotecThis purpose of this article is to review current status of nanotechnology in dentistry and to provide an insight into what the future holds, highlighting the ethical and safety concerns associated with the use of nanotechnology.- Bottom-up approaches- Top-down approachesBottom-up approaches - To arrange smaller components into more complex assemblies.- DNA Nanotechnology utilizes the specificity of Watson-Crick base pairing to construct well-defined structures out of DNA and other nucleic acids.Top-down approaches - To create smaller devices by using larger ones to direct their assembly.- Inducing anesthesia- Major Tooth Repair- Hypersensitivity Cure- Dental Durability and Cosmetics- Nanorobotic Dentifrice (dentifrobots)- Tooth repositioning- Local drug delivery - Nanodiagnostics- Therapeutic aid in oral diseases.Local NanoanaesthesiaDental treatment often involves injection of local anesthetic, which in turn comes with its longer duration of action and varying degrees of efficacy, patient discomfort and complications. Well-known alternatives, such as transcutaneous electronic nerve stimulation (TENS), cell demodulated electronic targeted anesthesia and other transmucosal, intraosseous or topical techniques, have proved to be of limited clinical efficacy.Ongoing research to induce local anesthesia in the era of nanodentistry, is working on colloidal suspension containing millions of active analgesic dental nanorobotic particles that could be instilled on the patient’s gingivae. These nanorobots, after contacting the surface of the crown or mucosa, reach the dentin by migrating into the gingival sulcus and pass painlessly to the target site. On reaching the dentin, the nanorobots enter dentinal tubule holes that are 1 to 4 Am in diameter -12 and pMajor tooth repairNanodental techniques for major tooth repair may evolve through several stages of technological development, first using genetic engineering, tissue engineering and tissue regeneration, and later involving the growth of whole new teeth in vitro and their installation. Ultimately, the nanorobotic manufacture and installation of a biologically autologous whole-replacement tooth that includes both mineral and cellular components— that is, complete dentition replacement therapy—should become feasible within the time and economic constraints of a typical office visit, through the use of an affordable desktop manufacturing facility, which would fabricate the new tooth, in the dentist’s office. Nanodentistry could also play a vital role in natural tooth maintenance.Tooth RepositioningOrthodontic nanorobots could directly manipulate the periodontal tissues, including gingivae, periodontal ligament, cementum and alveolar bone, allowing rapid and painless tooth straightening, rotating and vertical repositioning within minutes to hours.  This offDentin HypersensitivityAnother pathological phenomenon that may be benefited by nanodental treatment is dentin hypersensitivity.  Dentin hDurability and AppearanceThe appearance and durability of teeth may be improved by replacing upper enamel layers with covalently bonded artificial materials such as sapphire  or diamoNanorobotic dentifrice (Dentifrobots)A subocclusal-dwelling nanorobotic dentifrice delivered by mouthwash or toothpaste could patrol all supragingival and subgingival surfaces at least once a day, metabolizing trapped organic matter into harmless and odorless vapors and performing continuous calculus debridement.NanodiagnosticsNanotechnologies already afford the possibility of intracellular imaging through attachment of quantum dots (QDs) or synthetic chromophores to selected molecules, for example proteins, or by the incorporation of naturally occurring fluorescent proteins that, with optical techniques such as confocal microscopy and correlation imaging, allow intracellular biochemical processes to be investigated directly.-24Even though microarray/ biochip methods making use of the detection of specific biomolecular interactions are now an indispensable tool for molecular diagnostics, there are some limitations. Nanotechnology is being applied to overcome some of the limitations of biochip technology. -26Therapeutic aid in oral diseasesDrug delivery Nanotechnology is opening new therapeutic opportunities for many agents that cannot be used effectively as conventional oral formulations because of their poor bioavailability. In some cases, reformulation of a drug with smaller particle size may improve oral bioavailability. NanopartGene TherapyGene therapy is a recently introduced method for treatment or prevention of genetic disorders by correcting defective genes responsible for disease development based on the delivery of repaired genes or the replacement of incorrect ones.Three mai - Nanocomposites - Nano Light-Curing Glass Ionomer Restorative- Nano Impression Materials- Nano-Composite Denture Teeth- Nanosolutions - Nanoencapsulation - Plasma Laser application - Prosthetic Implants- Nanoneedles - Bone replacement materialsNanocomposites:Currently, nanotechnology has had its greatest impact on restorative dentistry by offering refinements to already clinically proven resin based composite systems. Nanohybrid and nanofilled resin-based composites are generally the two types of composite restorative materials referred to under the term “nanocomposite”, usually in a context of particle size. Characterized by filler-particle sizes of ≤100 nm, these materials can offer esthetic and strength advantages over conventional microfilled and hybrid resin-based composite systems, primarily in terms of smoothness, polishability and precision of shade characterization, plus flexural strength and microhardness similar to those of the better-performing posterior resin-based composites. Beun and colleagues compared the physical properties of nanofilled, universal hybrid and microfilled composites, and observed a higher elastic modulus with the nanofilled RBC than most of the hybrids tested.Advantages:- Superior hardness.- Superior Flexural strength, modulus of elasticity and translucency.- Reduced filling shrinkage.- Excellent handling properties.Nano Light-curing glass ionomer restorativeBlends Nanotechnology originally developed for Filtek™ Supreme Universal Restorative with fluoraluminosilicate (FAS) technology.Advantages:1. Superb polish.2. Excellent esthetics.3. Improved wear resistanceClinical Indications:- Primary teeth restorations.- Transitional restorations.- Small Class I restorations.- Sandwich restorations.- Class III and V restorations.- Core buildups.Impression MaterialsNanofillers are integrated in vinylpolysiloxanes, producing a unique addition of siloxane impression materials. The material has better flow, improved hydrophilic properties and enhanced detail precision. Nanofillers are integrated in the vinylsiloxanes, producing a unique addition siloxane impression material that offers better flow, improved hydrophilic properties, hence fewer voids at margin and better model pouring, enhanced detail precision.Advantages:1. Increased fluidity2. High tear resistance,3. Hydrophilic properties4. Resistance to distortion and heat resistance 5. Snap set that consequently reduces errors caused by micro movements Nano-composite denture teeth Wear resistance is the most important physical properties of denture teeth .Porcelain denture teeth are most wear resistant, but they are brittle, lack bonding to the denture base, and difficult to polish. Acrylic resin denture teeth are easier to recontour, but undergo excessive wear. NanocompAdvantages:- Highly polishable, stain and impact resistant material - Lively surface structure - Superior surface hardness and wear resistanceNanosolutionNanosolutions produce unique and dispersible nanoparticles, which can be used in bonding agents. This ensures homogeneity and ensures that the adhesive is perfectly mixed everytime.NanoencapsulationSWRI (South West Research Institute) has developed targeted release systems that encompass nanocapsules including novel vaccines, antibiotics and drug delivery with reduced side effects. At present, targeted delivery of genes and drugs to human liver has been developed by Osaka University in Japan 2003. Engineered Hepatitis B virus envelope L particles were allowed to form hollow nanoparticles displaying a peptide that is indispensable for liver-specific entry by the virus in humans. Future specialized nanoparticles could be engineered to target oral tissues, including cells derived from the periodontium.Laser Plasma Application for periodontia When TiO2 particle sizes are reduced to nanoscale (20-50 nm), and present on human skin in the form of a gel-like emulsion, it has some interesting properties such that when irradiated with laser pulses, these particles can be optically broken down with accompanying effects. - Shock wave- Micro-abrasion hard tissue- Stimulation of collagen productionClinical applications:1. Periodontal treatments 2. Melanin removal 3. Incision of soft tissue without anesthesia 4. Caries preparation 5. Cutting of enamel & dentin.Prosthetic Implant Nanotechnologies may produce surfaces with controlled topography and chemistry that would help understan-ding biological interactions and developing novel implant surfaces with predictable tissue-integrative properties. Nanostructured surfaces may control the differentiation pathways into specific lineages and ultimately direct the nature of peri-implant tissues. Furthermore, it is possible to incorporate biologically active drugs such as antibiotics or growth factors during the precipitation of CaP coatings on Ti implants.,35 CompaNano NeedlesSuture needles incorporating nano-sized stainless steel crystals have been developed. . Nanotweezers are also under development, which will make cell surgery possible in near future.Bone replacement MaterialsChen et al.  took advHydroxyapatite nanoparticles used to treat bone defects are;- Ostim ® (osartis GmbH Germany) HA.- VITOSS ®  HA+ TCP.- NanOssTM  HABarriers to overcome- Precise positioning and assembly of molecular scale part.- Economical nanorobot mass production technique.- Simultaneous coordination of activities of large numbers of independent micron scale robots.- Biocompatibility issue.- Funding and strategic issues.- Insufficient integration of clinical research.- Inefficient translation of concept to product because of inadequate venture capital, excessive bureaucracy and lack of medical input- Social issues of public acceptance, ethics, regulation and human safety.The aim of ‘Nanomedicine’ may be broadly defined as the comprehensive monitoring, control, construction, repair, defence and improvement of all human biological systems, working from the molecular level using engineered devices and nanostructures, ultimately to achieve medical benefit. Nanotechnology has a potential to transform the field of medicine, because it offers novel opportunities for sensing clinically relevant markers, molecular disease imaging, and tools for therapeutic intervention However, many challenges must be overcome if the application of Nanomedicine is to realise the improved understanding of the pathophysiological basis of disease, bring more sophisticated diagnostic opportunities, and yield more effective therapies and preventive measures.Nanomedicine is clearly multidisciplinary and builds on the existing expertise in a large number of different scientific fields. Formal interdisciplinary training programmes should be instituted, focusing on basic scientific topics; for example molecular biology, colloidal chemistry, cell physiology, surface chemistry, and membrane biophysics towards a common goal of developing newer non invasive technologies that will benify oral health and general health at large. Nanotechnology is destined to become the core technology underlying all of 21st century medicine and dentistry.


Pseudomonas protegens (formerly Pseudomonas fluorescens) CHA0, a model organism used in plant-microbe interactions, biological control of phytopathogens, and bacterial genetics.We report the complete genome sequence of the free-living bacterium  Pseudomonas protegens, formerly part of the Pseudomonas fluorescens complex  clusters, suggesting that interactions with phages contributed to shaping the genome. It encodes only one predicted functional bacteriocin, which is in line with its relatively low antagonistic activity against other pseudomonads , confirming that P. protegens is an independent taxon well separated from other pseudomonads (The genome is very close to that of domonads .CP003190.The nucleotide sequence is deposited in NCBI under the accession no.


During the last decades, schizophrenia has been regarded as a developmental disorder. The neurodevelopmental hypothesis proposes schizophrenia to be related to genetic and environmental factors leading to abnormal brain development during the pre- or postnatal period. First disease symptoms appear in early adulthood during the synaptic pruning and myelination process. Meta-analyses of structural MRI studies revealing hippocampal volume deficits in first-episode patients and in the longitudinal disease course confirm this hypothesis. Apart from the influence of risk genes in severe psychiatric disorders, environmental factors may also impact brain development during the perinatal period. Several environmental factors such as antenatal maternal virus infections, obstetric complications entailing hypoxia as common factor or stress during neurodevelopment have been identified to play a role in schizophrenia and bipolar disorder, possibly contributing to smaller hippocampal volumes. In major depression, psychosocial stress during the perinatal period or in adulthood is an important trigger. In animal studies, chronic stress or repeated administration of glucocorticoids have been shown to induce degeneration of glucocorticoid-sensitive hippocampal neurons and may contribute to the pathophysiology of affective disorders. Epigenetic mechanisms altering the chromatin structure such as histone acetylation and DNA methylation may mediate effects of environmental factors to transcriptional regulation of specific genes and be a prominent factor in gene-environmental interaction. In animal models, gene-environmental interaction should be investigated more intensely to unravel pathophysiological mechanisms. These findings may lead to new therapeutic strategies influencing epigenetic targets in severe psychiatric disorders. Schizophrenia is a severe mental disorder starting at young adulthood  in the hippocampus and amygdala have been reported to result from prenatal stress and may be related to increased anxiety and depression-related behavior  also confer an increased risk of schizophrenia (Hagberg et al., As to offspring of mothers exposed to influenza, several epidemiological studies have demonstrated an increased risk for schizophrenia. However, infections with other viruses such as measles, rubella, varicella-zoster, polio, and herpes as well as bacteria and parasites (Many efforts have been made to unravel the genetic background of severe psychiatric disorders. Recent GWAS point toward a partial overlap in susceptibility between schizophrenia and affective disorders (Cross-Disorder Group of the Psychiatric Genomics Consortium et al., Berend Malchow declares no conflicts of interest. Alkomiet Hasan has been invited to scientific conferences by Janssen Cilag, Pfizer, and Lundbeck. He received paid speakership by Desitin and is member of the Roche advisory board. Andrea Schmitt was honorary speaker for TAD Pharma and Roche and has been member of the Roche advisory board. Peter Falkai until 12/2011 has been member of the advisory boards of Janssen-Cilag, BMS, Lundback, Pfizer, Lilly, and AstraZeneca and received an educational grant from AstraZeneca and honoraria as lecturer from Janssen-Cilag, BMS, Lundbeck, Pfizer, Lilly, and AstraZeneca.


Previous efforts to characterize conservation between the human and mouse genomes focused largely on sequence comparisons. These studies are inherently limited because they don't account for gene structure differences, which may exist despite genomic sequence conservation. Recent high-throughput transcriptome studies have revealed widespread and extensive overlaps between genes, and transcripts, encoded on both strands of the genomic sequence. This overlapping gene organization, which produces sense-antisense (SAS) gene pairs, is capable of effecting regulatory cascades through established mechanisms. We present an evolutionary conservation assessment of SAS pairs, on three levels: genomic, transcriptomic, and structural. From a genome-wide dataset of human SAS pairs, we first identified orthologous loci in the mouse genome, then assessed their transcription in the mouse, and finally compared the genomic structures of SAS pairs expressed in both species. We found that approximately half of human SAS loci have single orthologous locations in the mouse genome; however, only half of those orthologous locations have SAS transcriptional activity in the mouse. This suggests that high human-mouse gene conservation overlooks widespread distinctions in SAS pair incidence and expression. We compared gene structures at orthologous SAS loci, finding frequent differences in gene structure between human and orthologous mouse SAS pair members. Our categorization of human SAS pairs with respect to mouse conservation of expression as well as structure points to limitations of mouse models. Gene structure differences, including at SAS loci, may account for some of the phenotypic distinctions between primates and rodents. Genes in non-conserved SAS pairs may contribute to evolutionary lineage-specific regulatory outcomes. D. melanogaster and C. elegans genomes have abnormally high and low SAS pair content respectively; pair incidence is more uniform in vertebrates  gene pair is defined as two genes that reside on opposite genomic strands within the same locus and share exonic sequence overlap. Until recently, the genome was thought to be organized into discrete transcriptional units (TUs). This assumption contrasts with the unanticipated complexity of gene structure revealed by large-scale transcriptome sequencing projects , each of which regulates multiple mRNAs encoded outside of its own locus, and endogenous small-interfering RNAs (siRNA) , in-trans regulation of mRNAs by antisense lncRNAs is also important, particularly in mRNA degradation  and we also mapped the genomic span of both genes and the overlap (pair-level LiftOver)  Figure . The “muAfter identifying mouse regions putatively orthologous to human SAS gene pairs, we searched for biological evidence of transcription at these sites. First, we tested whether any mouse mRNA/cDNA sequences from Genbank mapped to these loci. Mouse mRNAs were obtained from the all_mRNA (mm9) table of the UCSC database. We used only those mouse mRNAs which mapped unambiguously to single loci in the mouse genome. Human and mouse genes at orthologous loci were checked for gene-name identity (using RefSeq gene names from the UCSC Ref Seq RefFlatTable) and non-matching gene names were discarded. Human SAS pairs could retain their SAS structure classification  or be structurally different in mouse. In order to assess the incidence of transcription from orthologous loci in which structure is conserved in human and mouse, we used the UCSC Human Genome Browser Assembly hg19 to annotate the loci in human and in mouse.http://www.repeatmasker.org) to mask repetitive elements. We used the repeatmasked cDNAs as UCSC BLAT queries and manually annotated the visual browser results.After our LiftOver genome-wide analysis, we performed a manual annotation of a subset of resulting data Table . Gene paTo characterize the genomic structure of mouse orthologs of human SAS genes, we assigned a specific structure to each antisense pair. The structural characterization had to be supported by the majority of mRNAs at each locus; more than half of the mRNAs were required to support the declared structure type. Four structures were possible: convergent, divergent, complex, and no alignment  lacked unambiguous genomic sequence conservation in mouse, and the other 51% , and whether the unnamed genes had protein-coding capacity. Only five pairs were comprised of two functionally named genes in the pair (nine genes were protein-coding and one was an expressed pseudogene), 47 contained one functionally named gene and one non-descriptive alphanumeric identifier, and 14 pairs were comprised of two non-descriptively named  genes. Next we examined the longest same-strand open reading frame (ORF) for the 75 genes which had only non-descriptive alpha-numeric identifiers; 24 had ORFs under 100 amino acids (aa) and no BLASTP hits, indicating that they may encode lncRNAs. Further, 17 of those genes had ORFs greater than 100 aa but no conserved domains, putative protein motifs or homology to known proteins. Although these SAS pair members may encode novel non-conserved proteins, the protein-coding potential of these transcripts was not pursued further , while partial gene structure conservation (n = 27) and gene structure non-conservation were more common (n = 7).Our manual annotation of this subset of loci  human SAS loci had unambiguous mouse orthologs and preliminary evidence of SAS transcription. For each such SAS locus, mRNAs with opposite transcriptional orientation resided within the mouse genomic intervals corresponding to the two individual human paired genes. We proceeded to more precisely interrogate the genomic structure of these 1261 loci. Of these 1261 mouse loci, 186 lacked mRNA-level evidence that gene boundaries of the oppositely oriented transcripts overlapped  in almost half of cases. The existence of SAS gene pairs is a remarkable and non-random phenomenon; it is statistically unlikely for genes to overlap even on a very gene-dense chromosome  from the dataset of 66 above. Surprisingly, we found that half of these pairs were parts of longer complex loci, gene chains . In these situations, mouse loci orthologous to human SAS pairs contained only one gene, as a possible result of either a gene birth on the primate or a gene loss on the rodent lineage. Positional equivalency [the presence of SAS pairing at an orthologous locus in two species, where one member of the pair is a conserved protein-coding gene while the other lacks any sequence conservation outside of the actual SAS overlap . Interestingly, three of these seven loci encode known protein-coding genes whose products have DNA-binding domains, suggesting that complex loci containing positional equivalents may impact transcriptional regulation in both human and mouse. Manual annotation using the UCSC Genome Browser for visual interrogation of complex loci was integral to this analysis. Even though our manual annotation focused on a minority of pairs, these 66 pairs represent a microcosm of the evolutionary complexity of the mammalian SAS transcriptome.The most common situation in our cross-species analysis was a human locus, composed of a single SAS pair or containing a SAS pair as part of a gene chain, where one or both genes in the mouse locus orthologous to that SAS pair lacked any evidence of transcriptional activity in Genbank cDNAs , a protein associated with cell division as well as with chromatin states in the interphase nucleus (NUMA1), and a tumor suppressor originally discovered from a B-cell lymphoma translocation breakpoint (BCL7A). However, the most common category of human-mouse gene structure relationships was non-conservation Figure . This reWe identified only 986 mouse orthologs of 4511 human SAS loci such that both the genomic sequence of the two genes in each SAS pair and their bidirectional transcription, including the SAS overlap itself, were conserved in mouse Figure . To inveWhen we compared genomic structure categories between complete SAS orthologs, we found that when the human pair was divergent , its orthologous pair was most often in the complex, “other,” category (48%) in the mouse. This is unexpected because, if genomic structure were to be as consistently conserved as sequence and transcriptional activity in this subset of pairs, then we would expect the orthologs of human divergent pairs to be divergent in mouse as well. In fact, none of the three SAS genomic structure categories was found in more than half of the mouse orthologs of the human SAS pairs that had been assigned to that category Figure . Aside fSAS pairs reflect considerable and non-conserved gene structure complexity, which is particularly interesting as a source of interspecies regulatory differences at the 3′ends of protein-coding SAS pair member genes: antisense lncRNA binding to a sense mRNA 3′UTR may obstruct a miRNA binding site in that UTR, potentially protecting the mRNA from miRNA-induced post-transcriptional suppression. This process, by which the 3′ends of SAS pair member genes' mRNAs may compete with cognate lncRNAs, and/or with trans-encoded mRNAs, for miRNA binding has been characterized as “competing endogenous RNA” regulation , 42% of pairs display the same pair structure. The lack of pair structure conservation in the remaining group hints at a diversity of regulatory mechanisms through which lncRNAs at orthologous loci may exert regulation, and be regulated, in different evolutionary lineages. We also identified SAS pairs with both genomic conservation and transcriptional activity conservation, but with an apparently flipped region of exonic SAS overlap: for example, a SAS pair is divergent in human, but its putative ortholog is convergent in mouse. These SAS pairs may harbor conserved protein-coding genes overlapped by non-conserved terminal-end-overlapping antisense lncRNAs, pointing to different antisense mechanisms of regulating an orthologous protein-coding gene in different species. We provide a resource that can be used to identify non-conserved terminal-end-overlapping antisense transcripts (Supplementary Dataset In bacteria, riboswitches change the 5′end structure of mRNAs in response to specific conditions, altering translational competence. Riboswitch sequences are contained within these mRNAs Breaker, . WidesprDifferent regulatory modalities may be used by antisense lncRNAs based on nuclear versus cytoplasmic localization. It is not clear whether cytoplasmic lncRNAs possess sufficient stability or half-life to harbor regulatory potential. Evidence is emerging for a large repertoire of lncRNA mechanisms, some of which are nuclear and some cytoplasmic. Long RNAseq data being generated by the ENCODE Consortium enables transcript localization and nuclear to cytoplasmic ratio approximation in any profiled cell type, providing a first step toward distinguishing lncRNA, including antisense, mechanisms based on subcellular localization. In this study, we have focused on SAS gene pairs with shared sense and antisense exonic sequence. These pairs may exert their regulatory potential through both epigenetic and cytoplasmic mechanisms, whereas intronic SAS overlaps are more suggestive of nuclear function, since all pre-mRNAs prior to splicing in the nucleus contain these sequences while relatively few retained introns are observed in transcripts exported to the cytoplasm. The same antisense transcript might act through different mechanisms in different tissues and time points.Genomic regions with non-conserved sequences between human and mouse display higher potential for secondary structure conservation of their encoded RNAs than what would be expected by chance (Torarinsson et al., de novo genes at SAS loci in human may have arisen through gene birth including co-option of transposable elements or other processes (Lipovich, In 1975 King and Wilson (King and Wilson, SAS gene pairs may arise as a consequence of retroposition (Zhu et al., An early study of well-annotated protein-coding genes showed that less than half of human SAS pairs had mouse homologs for both genes in the pair, and that over half of the latter were not conserved structurally, as mouse lacked a SAS overlap of the homologous genes (Veeramachaneni et al., Numerous lncRNAs regulate protein-coding target genes, both in-cis and in-trans, though epigenetic mechanisms. Thousands of mammalian lncRNAs have been documented by a high-throughput RIPseq strategy to bind the PRC2 complex Lee, , and theThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Several risk factors for the development of running injuries have been identified, however, the etiology is still not completely clear . A numbePrior to and after a 20 km run, force distribution underneath the feet of 52 participants was registered using Footscan® pressure plates while the participants ran shod at a constant self-selected pace. Peak force, mean force and impulse were registered underneath different zones of the foot. In addition, temporal data were derived and a medio-lateral force ratio was calculated during the roll-off.After the run, increases in the loading of the forefoot, midfoot and medial heel were noted and decreases in loading of the lateral toes. Significant differences are presented in Figure Several of the significantly increased variables have been identified as risk factors for running injuries as stress fractures, patella-femoral pain syndrome and exercise-related lower leg pain. The results of this study demonstrated plantar pressure alterations after long-distance running which could give additional information related to several running injuries.


Additionally, an in-depth description of the mechanisms that disrupt the delicate balance between endothelial damage and repair will be given. Finally, the effects of lifestyle interventions and pharmacotherapy on endothelial dysfunction will be reviewed.The association of obesity with noncommunicable diseases, such as cardiovascular complications and diabetes, is considered a major threat to the management of health care worldwide. Epidemiological findings show that childhood obesity is rapidly rising in Western society, as well as in developing countries. This pandemic is not without consequences and can affect the risk of future cardiovascular disease in these children. Childhood obesity is associated with endothelial dysfunction, the first yet still reversible step towards atherosclerosis. Advanced research techniques have added further insight on how childhood obesity and associated comorbidities lead to endothelial dysfunction. Techniques used to measure endothelial function were further brought to perfection, and novel biomarkers, including endothelial progenitor cells, were discovered. The aim of this paper is to provide a critical overview on both  Society is faced with a new pandemic. Obesity and its associated non-communicable diseases, such as cardiovascular (CV) complications, diabetes , sleep ain vivo evaluation of endothelial dysfunction, which is considered the earliest demonstrable feature of atherosclerosis, rapidly advanced pathophysiological insights. Recently, more fundamental research into disrupted bone-marrow-related endothelial repair mechanisms , as well as the identification of novel markers of endothelial damage , has created an entirely new line of research . T. T143]. in vivo . Furtherin vivo , even noin vivo .The mechanism by which EPCs are released from the bone marrow is not fully understood but is the result of Matrix MetalloProteinase (MMP)-9 activation , in a NOThe technique most commonly used to quantify EPC is flow cytometry. Although this method is technically challenging due to very low numbers of circulating EPC, it is minimally invasive (blood sample via venipuncture) and therefore very convenient in children. Since there is no single, specific marker to identify EPC , a combiin vivo evidence is provided by the fact that lower numbers of circulating EPC predict CV events and death in adults [Since mature endothelial cells have limited regenerative capacity, EPC are necessary for endothelial repair. This notion is supported by a mathematical model of endothelial maintenance, which predicted a critical phase of endothelial cell defects that causes serious vascular damage. Such devastating consequences can be significantly delayed by incorporation of EPC . Furthern adults , 156 andn adults .Using flow cytometry it was demonstrated that EPC numbers correlate with endothelial function in CAD patients , in patiMüller-Ehmsen J et al. noted lower numbers of EPC in obese volunteers compared to healthy participants, while they observed a significant increase in EPC levels after weight loss . BesidesResearch in obese children has shown conflicting results. To our knowledge, there are only two papers comparing numbers of endothelial progenitor cells in obese children and lean controls. Unfortunately, each group used different protocols and different markers to detect these cells. Jung et al. were the first to investigate numbers of EPC in obese adolescents. They did not find significant differences in CD34+/KDR+/CD133+-cells, but did mention higher numbers of CD34-/KDR+CD133+-cells in overweight adolescents . Howeverr = 0.458) and CD133+/CD34+ cells (r = 0.456) in this population, yet the endothelial marker (KDR) was not assessed in this study [Arnold C et al. investigated whether numbers of circulating EPC related to physical fitness in obese children. Maximal oxygen uptake significantly correlated with CD34+  are grown from peripheral blood mononuclear cells after 4 to 7 days of culture in endothelial promoting media and fibronectin-coated plates. CACs have a low proliferative capacity and do not incorporate into endothelium, yet these cells restore damaged endothelium in a paracrine fashion by aiding in the recruitment and proliferation of, respectively, EPC and endothelial cells. CACs do not demonstrate an endothelial phenotype , but arecultures . Both VE tissues . After a tissues , and thuNumbers of CAC and their migratory capacity correlate with endothelial function . Obese aNO is necessary for the migration of CAC towards VEGF , and theLeptin stimulates the migratory capacity of CAC, yet CACs of obese patients display a resistance against the leptin associated pro-angiogenic effect, which again is reversed by weight loss. Leptin resistance has been attributed to higher concentrations of Protein Tyrosine Phosphatase 1B (PTP-1B), a known inhibitor of the leptin signaling cascade. Higher levels of PTP-1B were seen in obese individuals, which returned to levels comparable to lean subjects after weight loss. Furthermore, blocking PTP-1B activity pharmacologically restored responsiveness to leptin in CAC of obese patients .α [α, C-X-C Chemokine Receptor type 4 (CXCR-4) on CAC. Lower concentrations of adiponectin, seen in obese, could therefore further contribute to the functional deficit of CAC.Adiponectin similarly enhances the migratory capacity of CAC towards SDF-1α . This fiμm) shed from the plasma membrane by endothelial cells upon damage, activation, or apoptosis [Endothelial MicroParticles (EMP) are small particles , DNA, and proteins to target cells . Severalin vivo are not completely understood, but involve an end in membrane phospholipid asymmetry and the expression of phosphatidylserine on the outside of the cell membrane, membrane budding, and eventually microparticle release.The exact mechanisms that regulate the release of EMP EMPs are widely identified by their constitutive expression of CD31 , but not CD42b. The absence of the CD42b (platelet-specific glycoprotein Ib marker) marker is used to avoid potential contamination with platelet microparticles that have the same size range as EMP. EMPs are to be detected in platelet poor plasma that was subjected to sequential centrifugation. In fact, careful attention has to be paid to all preanalytical and analytical steps, as variables in both phases may affect accurate microparticle enumeration and could be an important source of variability, interlaboratory discrepancies, and artifacts , 187.μL blood in healthy volunteers [Numbers of EMP are elevated in obese women and inversely correlate with endothelial function . Van Ierlunteers , yet numData on EMP in children are scarce. Siklar et al.  providedThe ultimate goal of therapy remains improvement of long-term physical health through permanent healthy lifestyle habits. Although weight maintenance is advised for younger children and a decline in BMI is achieved through growth, weight loss remains the cornerstone of therapy for obesity in adolescents .Weight loss leads to an improvement of CV risk factors associated with endothelial dysfunction in childhood obesity , 194. BeP = 0.01).Woo et al.  comparedExercise training appears more effective than weight loss alone to improve endothelial function in obese children. As little as eight weeks of exercise training consisting of three 1-hour sessions of circuit training each week led to a significant improvement in endothelial function, even without weight loss in a randomized cross-over study involving 19 obese adolescents . Two othIn addition to the effect on factors leading to endothelial dysfunction , exercis4 [On top of increasing NO synthesis, exercise decreases production of ROS by reducing Nicotinamide Adenine Dinucleotide Phosphate (NAD(P)H) oxidase activity  and by e4  and therExercise training has a significant effect on endothelial repair mechanisms, including both EPC and CAC. In adults with metabolic syndrome, 8 weeks of exercise training led to a significant increase in repair capacity of CAC . These fStudies on the effect of pharmacological therapy in reversing endothelial dysfunction in children are very scarce. Therefore, potential candidates investigated in obese adults will be briefly discussed.Since the withdrawal of both rimonabant and sibutramine, due the increased risk of psychiatric adverse events  and incrMetformin is approved in many countries to treat insulin resistance in obese children. Although 3 months of metformin ingestion significantly improved both endothelial function and insulin resistance in adults with metabolic syndrome , adding Dietary components have recently gained significant interest because of their potential benefit on endothelial function and presumed prevention of CV disease.Adding vitamins C (500 mg/d) and E (400 IU/d) for 6 weeks to a program of diet and exercise further improved endothelial function in hyperlipidemic children . DangardAlthough results from several randomized controlled trials with dietary components are quite promising, effects need to be confirmed in larger population-based studies.As mentioned earlier in the paper, children are not just small adults and the speed by which physiological changes occur during puberty is tremendous. Puberty modulates endothelial function, and this improvement seems to be mediated through hormonal changes. The underlying mechanisms are not yet completely understood and deserve further investigation, as it may reveal key factors capable of ameliorating endothelial function later in life.Further observation and perfectioning of flow cytometry and culture techniques have made EPC enumeration even more reliable. Yet studies on childhood and adolescent obesity that have adequately implemented these optimized strategies are lacking. In addition, the relationship of EPC and EMP with endothelial function also needs to be fully addressed in obese and overweight children.And last but not least, whereas pharmacological interventions in obese children have been largely disappointing, inclusion of specific dietary components has shown to be highly effective in improving endothelial function in the short term. Further research, however, is needed to confirm whether these beneficial effects still remain at long-term followup.Recent research has demonstrated the relevance of obesity-induced endothelial dysfunction, both in adults and in children. Fundamental and translational studies have led to significant understanding of cellular and molecular alterations held responsible for endothelial disruption. Unfortunately, research has until now mainly focused on the progression of atherosclerosis in obese adults, who have been exposed to the consequences of endothelial dysfunction during many years. Despite technical difficulties and ethical concerns, the investigation of endothelial function in obese children is a necessary step to further examine the initiation and progression of endothelial dysfunction, which is crucial to the development of treatment strategies.Use of novel circulating markers can further unravel the delicate balance between endothelial damage and repair that causes endothelial dysfunction in obese subjects. Health care management should aim to avoid the catastrophic rise in CV morbidity and mortality, which will accompany obese children into adulthood. Therefore, multi-disciplinary prevention programs need to be set up and tested for their clinical effect. In order to speed up advances achieved in this domain, clinical research will largely depend on the effect of such interventions on the so-called surrogate endpoints, such as the correction of endothelial function.


Bipolar depression is often refractory to treatment and is frequently associated with anxiety symptoms and elevated suicide risk. There is a great need for adjunctive psychotherapeutic interventions. Treatments with effectiveness for depressive and anxiety symptoms as well as suicide-related thoughts and behaviors would be particularly beneficial. Mindfulness-based interventions hold promise, and studies of these approaches for bipolar disorder are warranted. The aim of this paper is to provide a conceptual background for such studies by reviewing key findings from diverse lines of investigation. Results of that review indicate that cortical midline structures (CMS) appear to link abnormal self-referential thinking to emotional dysregulation in mood disorders. Furthermore, CMS and striatal dysfunction may play a role in the neuropathology underlying suicide-related thoughts and behaviors. Thus, combining studies of mindfulness interventions targeting abnormal self-referential thinking with functional imaging of CMS and striatal function may help delineate the neurobiological mechanisms of action of these treatments. The neurobiology of bipolar spectrum disorders is incompletely characterized . FurtherMindfulness interventions target aberrant self-referential thinking . IncreasThere is evidence that the processing of self-referent information is abnormal in both unipolar and bipolar spectrum illness , 58, 59.In addition to abnormalities of self-concept, other facets of self-referential thinking are associated with affective disorders. One of these is the amount of time spent thinking about self. Individuals with unipolar illness have increased self-focused thinking , 79. TheIn contrast to the extent of self-referential thinking, there is strong evidence that a particular type of thinking about self contributes to dysphoria in general and unipolar depression. Specifically, analytical self-focused rumination  is maladaptive . This coIn summary, considerable evidence indicates that alterations of self-referential thinking are associated with both unipolar and bipolar spectrum illness. One component is negative self-concept, which is likely associated with depression, regardless of diagnosis. Another facet is rumination about self. In particular, analytic self-focused rumination is maladaptive and may represent a treatment target for bipolar spectrum depression. The implications of this will be discussed in the sections that follow.As described above, cognitive theories suggest that suicidal ideation, and other psychological symptoms, can occur as a result of dysfunctional self-schemas and thus negative self-focused thinking –63. As wIn addition to low self-esteem, other aspects of self-referential thinking patterns have been shown to be associated with suicide. For example, suicide has been posited to serve as an escape from awareness of self  and reseAutomatic self-associations are another important facet of self-referential thinking. Both automatic associations and explicit beliefs reflect aspects of dysfunctional self-schemas likely related to suicidal thinking. Automatic associations reflect simple associations in memory that activate links between self and specific concepts as opposed to the more complex development of explicit beliefs . It has Automatic self-associations are clinically relevant because they are associated with both symptom expression , 109 andFinally as is the case for depressive symptoms, there is compelling evidence that rumination is directly associated with suicidal ideation –118. FurThe literature reviewed above provides strong evidence that aspects of self-referential thinking are related to suicidal ideations and behaviors in a variety of populations. Few studies have directly addressed this topic among subjects with bipolar spectrum disorders. However, some evidence indicates that facets of self-focused thinking are relevant to suicide in these conditions. For example, low self-esteem lasting into remission seems related to the expression of suicidality during depressive episodes of bipolar patients . AnotherMost of the anterior and posterior midline cortex has been characterized as an anatomical and functional unit known collectively as the cortical midline structures (CMS) . The CMSStudies using a variety of methodologies suggest that functional alterations exist in the CMS in both unipolar –145 and The potential role of the CMS in emotional dysregulation and self-referential thinking is not as well characterized in bipolar spectrum disorders. However, a number of function imaging studies using emotional activation paradigms suggest a relationship between CMS function and emotional dysregulation in depression , 155, maIn summary, compelling functional imaging evidence indicates that CMS dysfunction in unipolar illness is associated with self-referential thinking and emotional regulation in unipolar illness. Further, the CMS likely mediates interactions between self-focused cognitions and emotional symptom expression. In bipolar disorders, considerable evidence indicates that CMS function is related to emotional dysregulation. Neuroimaging studies of self-referential processing in bipolar spectrum conditions are warranted.A large literature documents the role of striatal and associated corticobasal ganglia circuitry dysfunction in affective disorders, see , 167 forThe striatum and CMS have extensive anatomical , 173 andTaken together, these studies suggest that both CMS and striatal dysfunction may be relevant for suicide. Future investigations of the potential role of these regions in suicide-related behaviors are warranted. In particular, additional investigations of functional connectivity between the two regions may provide important insights.A primary aim of this manuscript is to integrate results of diverse key studies in order to provide a conceptual framework for future investigations of bipolar depression. Conclusions from the investigations reviewed herein are summarized in It is now well established that aspects of aberrant self-referential thinking contribute to the symptoms of unipolar depression. The strongest evidence is for analytical self-focused rumination. However, the amount of time spent thinking about the self may also be relevant. Studies clearly demonstrate that CMS play primary role in self-referential thinking. Additionally, there is strong evidence the CMS dysfunction plays a direct role in emotional dysregulation in unipolar depression and likely mediates the relationship between self-focused thinking and emotional dysregulation in this disorder. Finally, abnormalities of both the striatum and CMS may contribute to suicide risk in affective illness and the functional connectivity between the new regions may be of particular relevance.In regard to bipolar disorder, there is relatively strong evidence of aberrations of both self-referential thinking and CMS function. Further, CMS dysfunction appears to be associated with deficits of emotional regulation. It is unclear if self-focused thinking and emotion dysregulation are linked by the CMS, as is the case for unipolar depression. However, this possibility clearly warrants investigation. Studies of the potential roles of both the striatum and CMS in suicide are indicated as well.Future studies, as suggested above, may enhance our understanding of the neurobiology of bipolar depression. More importantly, it is possible that a subregion of the CMS might mediate relationships between self-referential thinking, emotional dysregulation, and suicidality. Such a finding would likely be very relevant for the development of biomarkers as well as treatment interventions.The studies reviewed herein have implications for studying neurobiological mechanisms in bipolar depression as described above. More importantly, these investigations support studies of mindfulness-based treatment interventions that specifically focus on altered self-referential processing.There is not yet complete consensus as to how the concept of mindfulness should be properly operationalized in Western psychology, and such lack of consensus is reflected into the multiplicity of definitions of mindfulness employed by different authors concerned with mindfulness-based interventions, for example . HoweverAlthough an increasing number of mindfulness-based interventions are currently employed for a large variety of psychiatric disorders, two such interventions, mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT), have proven to be particularly fruitful approaches for many of these conditions. The concept of mindfulness originated in Buddhist spiritual practices ; howeverA very large literature supports the effectiveness of MBSR on several psychological outcomes. Examples include studies of social anxiety disorder , generalThese studies suggest that both MBSR and MBCT have broad-spectrum antidepressant and antianxiety effectiveness. Furthermore, preliminary evidence suggests that MBCT is feasible for use in bipolar disorder and may decrease symptoms of anxiety and depression –19. Of nThe studies citied above indicate that additional trials of mindfulness interventions for bipolar spectrum disorders are warranted. In particular, studies of acute and maintenance treatment of depressive and anxiety symptoms as well as suicide prevention are warranted.The possibility that mindfulness interventions may help prevent suicide is particularly intriguing. In bipolar spectrum disorders, severity of affective episodes  comorbidNeuroimaging studies of mindfulness add to the evidence supporting trials of mindfulness interventions for bipolar depression. Furthermore, these studies suggest specific investigations that could be aimed at exploring the neural mechanisms underlying any observed benefits.As described above, the CMS play a key role in both self-referential and emotional processing , 128. FuZen meditation is a mindfulness practice that has been studied using neuroimaging methods. Zen is a traditional Buddhist approach to mindfulness , 220. ZeA number of investigations indicate that Zen meditation induces changes in brain function measurable by both functional MRI (fMRI) and EEG –228. OneIn addition to functional changes, evidence also indicates that extended Zen practice is associated with changes in brain morphology. In one study , structuSeveral studies of mindfulness and other meditation practices also indicate these methods impact CMS function –235. ForIn addition to the investigations described above, MBSR has also been studied using functional and structural neuroimaging. One study  found thAs described above, compelling evidence now exists demonstrating that mindfulness practices impact both the structure and function of the CMS as well as other regions. Furthermore, sadness is associated with CMS activation and mindfulness training changes the neural response associated with this emotion . Taken tBipolar disorder is a disabling –244 and Converging lines of clinical evidence reviewed herein indicate that mindfulness-based interventions, such as MBSR and MBCT, hold great promise as psychotherapeutic interventions for bipolar depression. From the clinical perspective, there is compelling evidence that MBSR and MBCT have broad-spectrum effectiveness for anxiety and depressive symptoms , 179–209In addition to the clinical evidence, psychological and neurobiological studies come together suggesting a hypothetical mechanism of action for mindfulness practices in the treatment of bipolar disorders. Specifically, the processing of self-referent information is abnormal in affective disorders , 58, 59.


Stem and progenitor cells are characterized by their ability to self-renew and produce differentiated progeny. A fine balance between these processes is achieved through controlled asymmetric divisions and is necessary to generate cellular diversity during development and to maintain adult tissue homeostasis. Disruption of this balance may result in premature depletion of the stem/progenitor cell pool, or abnormal growth. In many tissues, including the brain, dysregulated asymmetric divisions are associated with cancer. Whether there is a causal relationship between asymmetric cell division defects and cancer initiation is as yet not known. Here, we review the cellular and molecular mechanisms that regulate asymmetric cell divisions in the neural lineage and discuss the potential connections between this regulatory machinery and cancer. Asymmetric cell division (ACD) is a fundamental process whereby the asymmetric inheritance of cellular components  during mitosis defines distinct fates for each daughter cell. This evolutionarily conserved division mode is used by stem and progenitor cells in different tissues. In a typical outcome of an asymmetric division, the stem or progenitor cell generates a copy of itself, which retains self-renewal ability and differentiation potential, and one daughter that enters the path of differentiation. Thus, by balancing self-renewal with differentiation, asymmetric divisions maintain the stem and progenitor cell pool while allowing the generation of diverse functional cells.Drosophila, the neuroblasts (NBs). These studies in Drosophila have shown that disruption of ACD leads to abnormal proliferation and genomic instability, indicating that ACD may operate as a tumor suppressor mechanism during normal development . S. S162]. Transforming growth factor beta (TGF-β) signaling has long been implicated in EMT  and is fDysregulation of the EGFR family of RTKs is very common in many cancers, including astrocytoma and oligodendroglioma. In epithelial tissues, EGFR family members have been implicated in regulation of polarity, which is an essential component of ACD. Activation of ErbB2  or EGFR Moreover, the archetypal tumor suppressor PTEN, which is a negative regulator of RTK signaling, has also been implicated in the maintenance of epithelial polarity. Polarized localization of PTEN to the apical membrane dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3), antagonizing phosphatidylinositol 3-kinase (PI3K) signaling at the apical domain of the cell. This restriction of PI3K activity at the apical surface appears to play a key role in establishing polarity, as localization of PTEN to the baso-lateral membrane results in the recruitment of apical protein Cdc42 to the lateral wall, while ablation of PTEN activity disrupts apical polarity .There is an intimate relationship between polarity and maintenance of AJs. Indeed, loss of Par3, Par6, or Cdc42 individually destabilize tight junctions, leading to disruption of epithelial polarity –175. StuThe temporal regulation of polarity defects and how they arise to impact tumor initiation and progression in human cancer is still unclear. In particular, the causal relationship between disruption of ACD and associated loss of cellular polarity is not yet known.Glioblastoma multiforme (GBM) are fast-growing grade IV astrocytomas and extremely resistant to radiation- and chemotherapy. Oligodendrogliomas, on the other hand, are slow-growing cancers that are very responsive to chemotherapy , 146. YeAt least two models attempt to explain how a single cell of origin can lead to a heterogeneous tumor, displaying expression of markers of distinct brain cell types at various stages of differentiation. The stochastic model has long been established and claims that cancer cells acquire mutations stochastically and those mutations that provide a survival benefit will expand the affected cell population. In this model, cancer evolves from a single mutated cell (clone), through clonal expansions. On the other hand, the cancer stem cell (CSC) model postulates that only some cancer cells, namely those with stem cell properties, are tumorigenic. These CSCs are proposed to generate cellular hierarchies similar to NSCs by self-renewing and giving rise to progeny that then “differentiates” into heterogeneous tumor cells. Recently, an extended model of cancer development has been provided, which combines the stochastic and the CSC hypothesis by claiming that different cancer cell populations may evolve and these interact with each other and with the cancer microenvironment, thereby promoting cancer growth and development of therapy-resistant subpopulations . Several+ neural progenitor population survives treatment with the alkylating agent temozolomide, while the tumor bulk shrinks. Moreover, the Nestin+ population significantly contributes to tumor re-growth [CSCs are common in anaplastic astrocytoma and GBM –183 and e-growth .+ CSCs indeed asymmetrically segregate CD133 during mitosis [high-expressing GBM cells and to specify their stem cell fate [+ TPCs isolated from human surgical glioma specimens from patients prior to treatment revealed that these cells divide predominantly symmetrically [The resemblance to stem and progenitor cells by CSCs and some TPCs, respectively, has raised the question of whether they undergo ACDs. CD133 is a surface marker for CSCs in GBM  and cult mitosis . Molecul mitosis . The celell fate . Interesell fate . This in+ OPCs [A major open question with regards to glioma CSCs and TPCs and in relation to cell division modes is about their predecessor in humans. Do CSCs have a common predecessor, such as a NSC, and do TPCs arise from progenitor cells instead? Such a direct lineage relationship of the CSCs and TPCs and their non-neoplastic counterpart is suggested by their biological similarities. Indeed, studies with GEMMs of glioma have suggested that NSCs can act as cellular origin of astrocytoma , 192. Al+ OPCs  and even+ OPCs . These s+ OPCs , but ast+ OPCs , these dIn summary, in glioma, the capacity for tumor propagation is not restricted to NSC-like cells, but can also be kept by progenitor-like cells, which are more accurately referred to as TPCs. Regardless of how these distinct phenotypes are acquired, it is clear that tumors are comprised of multiple cellular populations that may not be equally impacted by conventional therapies. Understanding why some populations of cells acquire and/or retain ACD, while others expand symmetrically, may prove useful in understanding why distinct cancer cell types are unequally affected by treatment.Drosophila has helped to uncover many of the molecular mechanisms and cellular processes underlying ACD regulation in mammalian cells. Recent questions have begun to push the limits of invertebrate model systems, in particular with respect to the great variety of progenitor cell types and ACD mechanisms present in mammals.Groundbreaking work in As evidence mounts for adult progenitor cells as a likely cellular origin of distinct human cancers, the importance of understanding the molecular mechanisms underlying ACD regulation in different types of progenitor cells become more urgent. In-depth cellular analyses of complex and difficult-to-treat tumors, such as high-grade astrocytoma, constantly reveal new types of subpopulations that may be resistant to traditional therapy. New research will allow therapeutics to target defects in ACD, and associated changes in polarity, spindle orientation, and cell-fate decision, in different types of cancer cells.