The impact of targeted cathodal transcranial direct current stimulation on reward circuitry and affect in Bipolar Disorder.

Bipolar Disorder is costly and debilitating, and many treatments have side effects. Transcranial Direct Current Stimulation (tDCS) is a well-tolerated neuromodulation technique that may be a useful treatment for Bipolar Disorder if targeted to neural regions implicated in the disorder. One potential region is the left ventrolateral prefrontal cortex (vlPFC), which shows abnormally elevated activity during reward expectancy in individuals with Bipolar Disorder. We used a counterbalanced repeated measures design to assess the impact of cathodal (inhibitory) tDCS over the left vlPFC on reward circuitry activity, functional connectivity, and affect in adults with Bipolar Disorder, as a step toward developing novel interventions for individuals with the disorder. -1mA cathodal tDCS was administered over the left vlPFC versus a control region, left somatosensory cortex, concurrently with neuroimaging. Affect was assessed pre and post scan in remitted Bipolar Disorder (n = 27) and age/gender-matched healthy (n = 31) adults. Relative to cathodal tDCS over the left somatosensory cortex, cathodal tDCS over the left vlPFC lowered reward expectancy-related left ventral striatal activity (F(1,51) = 9.61, p = 0.003), and was associated with lower negative affect post scan, controlling for pre-scan negative affect, (F(1,49) = 5.57, p = 0.02) in all participants. Acute cathodal tDCS over the left vlPFC relative to the left somatosensory cortex reduces reward expectancy-related activity and negative affect post tDCS. Build on these findings, future studies can determine whether chronic cathodal tDCS over the left vlPFC has sustained effects on mood in individuals with Bipolar Disorder, to guide new treatment developments for the disorder.

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

American dental hygienists' attitudes towards chairside medical screening in a dental setting.

OBJECTIVES: Targeted screening for medical conditions in a dental setting can be an effective strategy for early identification of individuals at increased disease risk. Dentists, patients and physicians have a favourable attitude towards this strategy. Given that dental hygienists (DHs) are involved in preventive and educational activities, this seems like a natural extension to their roles. We report on the attitudes of American DHs towards chairside medical screening. METHODS: A 5-point Likert scale (1 = very important/willing, 5 = very unimportant/unwilling) survey was mailed to a nationwide random sample of US practicing DHs. Descriptive statistics were used for all questions, and the Friedman nonparametric analysis of variance was used for multi-element questions. RESULTS: A total of 3133 respondents returned the completed questionnaires for an effective response rate of 49.2% and a margin of error 1.8%. The majority of respondents felt it was important to perform/conduct chairside screening for hypertension (94%), diabetes mellitus (89%), cardiovascular disease (85%), HIV (79%) and hepatitis infection (78%); were willing to refer a patient for medical consult (94%), conduct screening that yields immediate results (85%); and were willing to collect the data/samples needed (57-95%). The most important considerations were dentist/owner support (98%), training (97%), patient willingness (98%) and time (98%). CONCLUSION: Similar to dentists, physicians and patients, the majority of the DHs had a favourable attitude towards chairside medical screening. Integrating the DH into screening activities is likely to require additional training and education regarding the diseases of interest, something that could be accomplished through continuing education courses and eventually incorporation into the educational curriculum.

Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure.

Adeno-associated virus serotype 1 (AAV1) has many advantages as a gene therapy vector, but the presence of pre-existing neutralizing antibodies (NAbs) is an important limitation. This study was designed to determine: (1) characteristics of AAV NAbs in human subjects, (2) prevalence of AAV1 NAbs in heart failure patients and (3) utility of aggressive immunosuppressive therapy in reducing NAb seroconversion in an animal model. NAb titers were assessed in a cohort of heart failure patients and in patients screened for a clinical trial of gene therapy with AAV1 carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a). AAV1 NAbs were found in 59.5% of 1552 heart failure patients. NAb prevalence increased with age (P=0.001) and varied geographically. The pattern of NAb titers suggested that exposure is against AAV2, with AAV1 NAb seropositivity due to crossreactivity. The effects of immunosuppression on NAb formation were tested in mini-pigs treated with immunosuppressant therapy before, during and after a single AAV1/SERCA2a infusion. Aggressive immunosuppression did not prevent formation of AAV1 NAbs. We conclude that immunosuppression is unlikely to be a viable solution for repeat AAV1 dosing. Strategies to reduce NAbs in heart failure patients are needed to increase eligibility for gene transfer using AAV vectors.

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.

Neuromyelitis optica and multiple sclerosis: Seeing differences through optical coherence tomography.

Neuromyelitis optica (NMO) is an inflammatory autoimmune disease of the central nervous system that preferentially targets the optic nerves and spinal cord. The clinical presentation may suggest multiple sclerosis (MS), but a highly specific serum autoantibody against the astrocytic water channel aquaporin-4 present in up to 80% of NMO patients enables distinction from MS. Optic neuritis may occur in either condition resulting in neuro-anatomical retinal changes. Optical coherence tomography (OCT) has become a useful tool for analyzing retinal damage both in MS and NMO. Numerous studies showed that optic neuritis in NMO typically results in more severe retinal nerve fiber layer (RNFL) and ganglion cell layer thinning and more frequent development of microcystic macular edema than in MS. Furthermore, while patients' RNFL thinning also occurs in the absence of optic neuritis in MS, subclinical damage seems to be rare in NMO. Thus, OCT might be useful in differentiating NMO from MS and serve as an outcome parameter in clinical studies.

Requirement for safety monitoring for approved multiple sclerosis therapies: an overview.

During the last two decades, treatment options for patients with multiple sclerosis (MS) have broadened tremendously. All agents that are currently approved for clinical use have potential side effects, and a careful risk-benefit evaluation is part of a decision algorithm to identify the optimal treatment choice for an individual patient. Whereas glatiramer acetate and interferon beta preparations have been used in MS for decades and have a proven safety record, more recently approved drugs appear to be more effective, but potential risks might be more severe. The potential complications of some novel therapies might not even have been identified to their full extent. This review is aimed at the clinical neurologist in that it offers insights into potential adverse events of each of the approved MS therapeutics: interferon beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide, as well as recently approved therapeutics such as dimethyl fumarate and alemtuzumab. It also provides recommendations for monitoring the different drugs during therapy in order to avoid common side effects.

The OHStat Guidelines for Reporting Observational Studies and Clinical Trials in Oral Health Research: Manuscript Checklist.

Adequate and transparent reporting is necessary for critically appraising published research. Yet, ample evidence suggests that the design, conduct, analysis, interpretation, and reporting of oral health research could be greatly improved. Accordingly, the Task Force on Design and Analysis in Oral Health Research-statisticians and trialists from academia and industry-identified the minimum information needed to report and evaluate observational studies and clinical trials in oral health: the OHStat Guidelines. Drafts were circulated to the editors of 85 oral health journals and to Task Force members and sponsors and discussed at a December 2020 workshop attended by 49 researchers. The guidelines were subsequently revised by the Task Force's writing group. The guidelines draw heavily from the Consolidated Standards for Reporting Trials (CONSORT), Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), and CONSORT harms guidelines and incorporate the SAMPL guidelines for reporting statistics, the CLIP principles for documenting images, and the GRADE indicating the quality of evidence. The guidelines also recommend reporting estimates in clinically meaningful units using confidence intervals, rather than relying on P values. In addition, OHStat introduces 7 new guidelines that concern the text itself, such as checking the congruence between abstract and text, structuring the discussion, and listing conclusions to make them more specific. OHStat does not replace other reporting guidelines; it incorporates those most relevant to dental research into a single document. Manuscripts using the OHStat guidelines will provide more information specific to oral health research.

The OHStat Guidelines for Reporting Observational Studies and Clinical Trials in Oral Health Research: Manuscript Checklist.

Adequate and transparent reporting is necessary for critically appraising published research. Yet, ample evidence suggests that the design, conduct, analysis, interpretation, and reporting of oral health research could be greatly improved. Accordingly, the Task Force on Design and Analysis in Oral Health Research-statisticians and trialists from academia and industry-identified the minimum information needed to report and evaluate observational studies and clinical trials in oral health: the OHStat Guidelines. Drafts were circulated to the editors of 85 oral health journals and to Task Force members and sponsors and discussed at a December 2020 workshop attended by 49 researchers. The guidelines were subsequently revised by the Task Force's writing group. The guidelines draw heavily from the Consolidated Standards for Reporting Trials (CONSORT), Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), and CONSORT harms guidelines and incorporate the SAMPL guidelines for reporting statistics, the CLIP principles for documenting images, and the GRADE indicating the quality of evidence. The guidelines also recommend reporting estimates in clinically meaningful units using confidence intervals, rather than relying on P values. In addition, OHStat introduces 7 new guidelines that concern the text itself, such as checking the congruence between abstract and text, structuring the discussion, and listing conclusions to make them more specific. OHStat does not replace other reporting guidelines; it incorporates those most relevant to dental research into a single document. Manuscripts using the OHStat guidelines will provide more information specific to oral health research.

The OHStat Guidelines for Reporting Observational Studies and Clinical Trials in Oral Health Research: Explanation and Elaboration.

Adequate and transparent reporting is necessary for critically appraising research. Yet, evidence suggests that the design, conduct, analysis, interpretation, and reporting of oral health research could be greatly improved. Accordingly, the Task Force on Design and Analysis in Oral Health Research-statisticians and trialists from academia and industry-empaneled a group of authors to develop methodological and statistical reporting guidelines identifying the minimum information needed to document and evaluate observational studies and clinical trials in oral health: the OHstat Guidelines. Drafts were circulated to the editors of 85 oral health journals and to Task Force members and sponsors and discussed at a December 2020 workshop attended by 49 researchers. The final version was subsequently approved by the Task Force in September 2021, submitted for journal review in 2022, and revised in 2023. The checklist consists of 48 guidelines: 5 for introductory information, 17 for methods, 13 for statistical analysis, 6 for results, and 7 for interpretation; 7 are specific to clinical trials. Each of these guidelines identifies relevant information, explains its importance, and often describes best practices. The checklist was published in multiple journals. The article was published simultaneously in JDR Clinical and Translational Research, the Journal of the American Dental Association, and the Journal of Oral and Maxillofacial Surgery. Completed checklists should accompany manuscripts submitted for publication to these and other oral health journals to help authors, journal editors, and reviewers verify that the manuscript provides the information necessary to adequately document and evaluate the research.

Expansion of CD27high plasmablasts in transverse myelitis patients that utilize VH4 and JH6 genes and undergo extensive somatic hypermutation.

Patients with the autoimmune disease multiple sclerosis (MS) typically present with the clinically isolated syndromes (CIS) transverse myelitis (TM) or optic neuritis (ON). B-cell disturbances have been well documented in patients with MS and CIS patients with ON, but not in CIS patients with TM, despite the fact that these patients have the worst clinical outcome of all CIS types. The goal of this study was to characterize the B-cell populations and immunoglobulin genetics in TM patients. We found a unique expansion of CD27(high) plasmablasts in both the cerebrospinal fluid and periphery of TM patients that is not present in ON patients. Additionally, plasmablasts from TM patients show evidence for positive selection with increased somatic hypermutation accumulation in VH4(+) B cells and receptor editing that is not observed in ON patients. These characteristics unique to TM patients may impact disease severity and progression.

Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1.

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.

Disconnect between the effects of serelaxin on renal function and outcome in acute heart failure.

BACKGROUND: We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes. METHODS: We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure. RESULTS: Improvement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64-2.15, p < 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60-0.83, p < 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99-1.04), ACM HR 1.01 (0.99-1.03), HF/renal failure hospitalization HR 0.99 (0.97-1.00)]. CONCLUSIONS: Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF. Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.

Gamma knife capsulotomy for intractable OCD: Neuroimage analysis of lesion size, location, and clinical response.

Obsessive-compulsive disorder (OCD) affects 2-3% of the population. One-third of patients are poorly responsive to conventional therapies, and for a subgroup, gamma knife capsulotomy (GKC) is an option. We examined lesion characteristics in patients previously treated with GKC through well-established programs in Providence, RI (Butler Hospital/Rhode Island Hospital/Alpert Medical School of Brown University) and São Paulo, Brazil (University of São Paolo). Lesions were traced on T1 images from 26 patients who had received GKC targeting the ventral half of the anterior limb of the internal capsule (ALIC), and the masks were transformed into MNI space. Voxel-wise lesion-symptom mapping was performed to assess the influence of lesion location on Y-BOCS ratings. General linear models were built to compare the relationship between lesion size/location along different axes of the ALIC and above or below-average change in Y-BOCS ratings. Sixty-nine percent of this sample were full responders (≥35% improvement in OCD). Lesion occurrence anywhere within the targeted region was associated with clinical improvement, but modeling results demonstrated that lesions occurring posteriorly (closer to the anterior commissure) and dorsally (closer to the mid-ALIC) were associated with the greatest Y-BOCS reduction. No association was found between Y-BOCS reduction and overall lesion volume. GKC remains an effective treatment for refractory OCD. Our data suggest that continuing to target the bottom half of the ALIC in the coronal plane is likely to provide the dorsal-ventral height required to achieve optimal outcomes, as it will cover the white matter pathways relevant to change. Further analysis of individual variability will be essential for improving targeting and clinical outcomes, and potentially further reducing the lesion size necessary for beneficial outcomes.

Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective.

BACKGROUND: Experts have proposed removing obsessive-compulsive disorder (OCD) from the anxiety disorders section and grouping it with putatively related conditions in DSM-5. The current study uses co-morbidity and familiality data to inform these issues. METHOD: Case family data from the OCD Collaborative Genetics Study (382 OCD-affected probands and 974 of their first-degree relatives) were compared with control family data from the Johns Hopkins OCD Family Study (73 non-OCD-affected probands and 233 of their first-degree relatives). RESULTS: Anxiety disorders (especially agoraphobia and generalized anxiety disorder), cluster C personality disorders (especially obsessive-compulsive and avoidant), tic disorders, somatoform disorders (hypochondriasis and body dysmorphic disorder), grooming disorders (especially trichotillomania and pathological skin picking) and mood disorders (especially unipolar depressive disorders) were more common in case than control probands; however, the prevalences of eating disorders (anorexia and bulimia nervosa), other impulse-control disorders (pathological gambling, pyromania, kleptomania) and substance dependence (alcohol or drug) did not differ between the groups. The same general pattern was evident in relatives of case versus control probands. Results in relatives did not differ markedly when adjusted for demographic variables and proband diagnosis of the same disorder, though the strength of associations was lower when adjusted for OCD in relatives. Nevertheless, several anxiety, depressive and putative OCD-related conditions remained significantly more common in case than control relatives when adjusting for all of these variables simultaneously. CONCLUSIONS: On the basis of co-morbidity and familiality, OCD appears related both to anxiety disorders and to some conditions currently classified in other sections of DSM-IV.

Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study.

Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj) = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.

Homeobox genes in obsessive-compulsive disorder.

BACKGROUND: Despite evidence that obsessive-compulsive disorder (OCD) is a familial neuropsychiatric condition, progress aimed at identifying genetic determinants of the disorder has been slow. The OCD Collaborative Genetics Study (OCGS) has identified several OCD susceptibility loci through linkage analysis. METHODS: In this study we investigate two regions on chromosomes 15q and 1q by first refining the linkage region using additional short tandem repeat polymorphic (STRP) markers. We then performed association analysis on single nucleotide polymorphisms (SNP) genotyped (markers placed every 2-4 kb) in the linkage regions in the OCGS sample of 376 rigorously phenotyped affected families. RESULTS: Three SNPs are most strongly associated with OCD: rs11854486 (P = 0.00005 [0.046 after adjustment for multiple tests]; genetic relative risk (GRR) = 11.1 homozygous and 1.6 heterozygous) and rs4625687 [P = 0.00007 (after adjustment = 0.06); GRR = 2.4] on 15q; and rs4387163 (P = 0.0002 (after adjustment = 0.08); GRR = 1.97) on 1q. The first SNP is adjacent to NANOGP8, the second SNP is in MEIS2, and the third is 150 kb between PBX1 and LMX1A. CONCLUSIONS: All the genes implicated by association signals are homeobox genes and are intimately involved in neurodevelopment. PBX1 and MEIS2 exert their effects by the formation of a heterodimeric complex, which is involved in development of the striatum, a brain region involved in the pathophysiology of OCD. NANOGP8 is a retrogene of NANOG, a homeobox transcription factor known to be involved in regulation of neuronal development. These findings need replication; but support the hypothesis that genes involved in striatal development are implicated in the pathogenesis of OCD.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience.

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a 'learning curve' both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior-posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Nanostructure of vortex during explosion welding.

The microstructure of a bimetallic joint made by explosion welding of orthorhombic titanium aluminide (Ti-30Al-16Nb-1Zr-1Mo) with commercially pure titanium is studied. It is found that the welded joint has a multilayered structure including a severely deformed zone observed in both materials, a recrystallized zone of titanium, and a transition zone near the interface. Typical elements of the transition zone-a wavy interface, macrorotations of the lattice, vortices and tracks of fragments of the initial materials-are determined. It is shown that the observed vortices are formed most probably due to local melting of the material near the contact surface. Evidence for this assumption is deduced from the presence of dipoles, which consist of two vortices of different helicity and an ultrafine duplex structure of the vortex. Also, high mixing of the material near the vortex is only possible by the turbulent transport whose coefficient is several orders of magnitude larger than the coefficient of atomic diffusion in liquids. The role played by fragmentation in both the formation of lattice macrorotations and the passage of coarse particles of one material through the bulk of the other is determined.

Saliva, diagnostics, and dentistry.

Saliva, a scientific and clinical entity familiar to every oral health researcher and dental practitioner, has emerged as a translational and clinical commodity that has reached national visibility at the National Institutes of Health and the President's Office of Science and Technology. "Detecting dozens of diseases in a sample of saliva" was issued by President Obama as one of the 14 Grand Challenges for biomedical research in the 21(st) Century (National Economic Council, 2010). In addition, NIH's 2011 Government Performance Report Act (GPRA) listed 10 initiatives in the high-risk long-term category (Collins, 2011). The mandate is to determine the efficacy of using salivary diagnostics to monitor health and diagnose at least one systemic disease by 2013. The stage is set for the scientific community to capture these national and global opportunities to advance and substantiate the scientific foundation of salivary diagnostics to meet these goals. A specific calling is to the oral, dental, and craniofacial health community. Three areas will be highlighted in this paper: the concept of high-impact diagnostics, the role of dentists in diagnostics, and, finally, an infrastructure currently being developed in the United Kingdom--The UK Biobank--which will have an impact on the translational and clinical utilizations of saliva.