The resection angle in apical surgery: a CBCT assessment.

OBJECTIVES The primary objective of the present radiographic study was to analyse the resection angle in apical surgery and its correlation with treatment outcome, type of treated tooth, surgical depth and level of root-end filling. MATERIALS AND METHODS In the context of a prospective clinical study, cone beam computed tomography (CBCT) scans were taken before and 1 year after apical surgery to measure the angle of the resection plane relative to the longitudinal axis of the root. Further, the surgical depth (distance from the buccal cortex to the most lingual/palatal point of the resection plane) as well as the level of the root-end filling relative to the most coronal point of the cut root face was determined. Treated teeth were categorized into four groups (maxillary and mandibular anterior and posterior teeth). The final material comprised 62 treated roots in 55 teeth. RESULTS The mean calculated resection angle of all roots was 17.7° ± 11.4° (range -9.6° to 43.4°). Anterior maxillary roots presented the highest mean angle (25.8° ± 10.3°) that was significantly different from the mean angle in posterior maxillary roots (10.7° ± 9.4°; p 20°), however without reaching statistical significance (p = 0.0905). Angles did not correlate either with the surgical depth or with the retrofilling length. CONCLUSIONS Statistically significant differences were observed comparing resection angles of different tooth groups. However, the angle had no significant effect on treatment outcome. CLINICAL RELEVANCE Contrary to common belief, the resection angle in maxillary anterior teeth was greater than in the other teeth. The surgeon is advised to pay attention to the resection angle when bevelling maxillary anterior teeth in apical surgery

Extra-Legal Factors and Product Liability: The Influence of Mock Jurors’ Demographic Characteristics and Intuitions about the Cause of an Injury

Two experiments were performed to investigate the role of extra-legal factors in a simulated product liability trial. In cases where the factual evidence was identical, subjects’ liability judgments varied as a function of the case-specific factor of the alleged source of the plaintiff’s injury. In deciding cases differently depending on the alleged cause, subjects relied on intuitions about what injury sources are more or less likely to cause a certain kind of injury. Juror- specific factors also influenced subjects’ verdicts. There was no difference between students and non-students, but race and SES—factors that are often correlated with student status—did affect subjects’ verdicts. Low-SES and minority subjects were more likely to find the defendant liable than high-SES and white subjects. The results are considered in terms of general decision-making processes, and the implications for jury selection and mock jury research are discussed

Identifying predictors of attitudes towards local onshore wind development with reference to an English case study

The threats posed by climate change are placing governments under increasing pressure to meet electricity demand from low-carbon sources. In many countries, including the UK, legislation is in place to ensure the continued expansion of renewable energy capacity. Onshore wind turbines are expected to play a key role in achieving these aims. However, despite high levels of public support for onshore wind development in principle, specific projects often experience local opposition. Traditionally this difference in general and specific attitudes has been attributed to NIMBYism (not in my back yard), but evidence is increasingly calling this assumption into question. This study used multiple regression analysis to identify what factors might predict attitudes towards mooted wind development in Sheffield, England. We report on the attitudes of two groups; one group (target) living close to four sites earmarked for development and an unaffected comparison group (comparison). We found little evidence of NIMBYism amongst members of the target group; instead, differences between general and specific attitudes appeared attributable to uncertainty regarding the proposals. The results are discussed with respect to literature highlighting the importance of early, continued and responsive community involvement in combating local opposition and facilitating the deployment of onshore wind turbines. (C) 2009 Elsevier Ltd. All rights reserved

Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy

Genetic mitochondrial diseases are the most frequent cause of inherited metabolic disorders and one of the most prevalent causes of heritable neurological disease. Leigh syndrome is the most common clinical presentation of pediatric mitochondrial disease, typically appearing in the first few years of life, and involving severe multisystem pathologies. Clinical care for Leigh syndrome patients is difficult, complicated by the wide range of symptoms including characteristic progressive CNS lesion, metabolic sequelae, and epileptic seizures, which can be intractable to standard management. While no proven therapies yet exist for the underlying mitochondrial disease, a ketogenic diet has led to some reports of success in managing mitochondrial epilepsies, with ketosis reducing seizure risk and severity. The impact of ketosis on other aspects of disease progression in Leigh syndrome has not been studied, however, and a rigorous study of the impact of ketosis on seizures in mitochondrial disease is lacking. Conversely, preclinical efforts have identified the intracellular nutrient signaling regulator mTOR as a promising therapeutic target, with data suggesting the benefits are mediated by metabolic changes. mTOR inhibition alleviates epilepsies arising from defects in TSC, an mTOR regulator, but the therapeutic potential of mTOR inhibition in seizures related to primary mitochondrial dysfunction is unknown. Given that ketogenic diet is used clinically in the setting of mitochondrial disease, and mTOR inhibition is in clinical trials for intractable pediatric epilepsies of diverse causal origins, a direct experimental assessment of their effects is imperative. Here, we define the impact of dietary ketosis on survival and CNS disease in the Ndufs4(KO) mouse model of Leigh syndrome and the therapeutic potential of both dietary ketosis and mTOR inhibition on seizures in this model. These data provide timely insight into two important clinical interventions

Three-Year Follow-up of 2-Dose Versus 3-Dose HPV Vaccine

BACKGROUND AND OBJECTIVES: Human papillomavirus (HPV) antibody responses to the 9-valent abstract human papillomavirus (9vHPV) vaccine among girls and boys (aged 9–14 years) receiving 2- dose regimens (months 0, 6 or 0, 12) were noninferior to a 3-dose regimen (months 0, 2, 6) in young women (aged 16–26 years) 4 weeks after last vaccination in an international, randomized, open-label trial (NCT01984697). We assessed response durability through month 36. METHODS: Girls received 2 (months 0 and 6 [0, 6]: n = 301; months 0 and 12 [0, 12]: n = 151) or 3 doses (months 0,2, and 6 [0, 2, 6]: n = 301); boys received 2 doses ([0, 6]: n = 301; [0, 12]: n = 150); and young women received 3 doses ([0, 2, 6]: n = 314) of 9vHPV vaccine. Anti-HPV geometric mean titers (GMTs) were assessed by competitive Luminex immunoassay (cLIA) and immunoglobulin G-Luminex immunoassay (IgG-LIA) through month 36. RESULTS: Anti-HPV GMTs were highest 1 month after the last 9vHPV vaccine regimen dose, decreased sharply during the subsequent 12 months, and then decreased more slowly. GMTs 2 to 2.5 years after the last regimen dose in girls and boys given 2 doses were generally similar to or greater than GMTs in young women given 3 doses. Across HPV types, most boys and girls who received 2 doses (cLIA: 81%–100%; IgG-LIA: 91%–100%) and young women who received 3 doses (cLIA: 78%–98%; IgG-LIA: 91%–100%) remained seropositive 2 to 2.5 years after the last regimen dose. CONCLUSIONS: Antibody responses persisted through 2 to 2.5 years after the last dose of a 2-dose 9vHPV vaccine regimen in girls and boys. In girls and boys, antibody responses generated by 2 doses administered 6 to 12 months apart may be sufficient to induce high-level protective efficacy through at least 2 years after the second dose.Medicin

Responses to systemic therapy in metastatic pheochromocytoma/paraganglioma: a retrospective multicenter cohort study

OBJECTIVE The therapeutic options for metastatic pheochromocytomas/paragangliomas (mPPGLs) include chemotherapy with cyclophosphamide/vincristine/dacarbazine (CVD), temozolomide monotherapy, radionuclide therapies, and tyrosine kinase inhibitors such as sunitinib. The objective of this multicenter retrospective study was to evaluate and compare the responses of mPPGLs including those with pathogenic variants in succinate dehydrogenase subunit B (SDHB), to different systemic treatments. DESIGN This is a retrospective analysis of treatment responses of mPPGL patients (n = 74) to systemic therapies. METHODS Patients with mPPGLs treated at 6 specialized national centers were selected based on participation in the ENSAT registry. Survival until detected progression (SDP) and disease-control rates (DCRs) at 3 months were evaluated based on imaging reports. RESULTS For the group of patients with progressive disease at baseline (83.8% of 74 patients), the DCR with first-line CVD chemotherapy was 75.0% (n = 4, SDP 11 months; SDHB [n = 1]: DCR 100%, SDP 30 months), with somatostatin peptide receptor-based radionuclide therapy (PPRT) 85.7% (n = 21, SDP 17 months; SDHB [n = 10]: DCR 100%, SDP 14 months), with 131I-meta-iodobenzylguanidine (131I-MIBG) 82.6% (n = 23, SDP 43 months; SDHB [n = 4]: DCR 100%, SDP 24 months), with sunitinib 100% (n = 7, SDP 18 months; SDHB [n = 3]: DCR 100%, SDP 18 months), and with somatostatin analogs 100% (n = 4, SDP not reached). The DCR with temozolomide as second-line therapy was 60.0% (n = 5, SDP 10 months; SDHB [n = 4]: DCR 75%, SDP 10 months). CONCLUSIONS We demonstrate in a real-life clinical setting that all current therapies show reasonable efficacy in preventing disease progression, and this is equally true for patients with germline SDHB mutations

Adrenal cortical and chromaffin stem cells: Is there a common progeny related to stress adaptation?

The adrenal gland is a highly plastic organ with the capacity to adapt the body homeostasis to different physiological needs. The existence of stem-like cells in the adrenal cortex has been revealed in many studies. Recently, we identified and characterized in mice a pool of glia-like multipotent Nestin-expressing progenitor cells, which contributes to the plasticity of the adrenal medulla. In addition, we found that these Nestin progenitors are actively involved in the stress response by giving rise to chromaffin cells. Interestingly, we also observed a Nestin-GFP-positive cell population located under the adrenal capsule and scattered through the cortex. In this article, we discuss the possibility of a common progenitor giving rise to subpopulations of cells both in the adrenal cortex and medulla, the isolation and characterization of this progenitor as well as its clinical potential in transplantation therapies and in pathophysiology

Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. OBJECTIVE: Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. METHODS: Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs. RESULTS: Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx). CONCLUSION: SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS. Depleting leukocytes with a colony-stimulating factor 1 receptor inhibitor disrupted disease progression, including suppression of CNS lesion formation and a substantial extension of survival. Leukocyte depletion rescued diverse symptoms, including seizures, respiratory center function, hyperlactemia, and neurologic sequelae. These data reveal a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement is causal in disease. This work has important implications for the mechanisms of mitochondrial disease and may lead to novel therapeutic strategies