Cyclooxygenase inhibition in early onset of tumor growth and related angiogenesis evaluated in EP1 and EP3 knockout tumor-bearing mice

It is well established that prostanoids are essential for local inflammation including cell proliferation and apoptosis. Accordingly, prostaglandin E2 (PGE₂) is a critical factor in wound healing, tumor invasiveness and progression. Therefore, the aim of the present work was to evaluate effects by PGE₂ on tumor vascular density at early onset of tumor growth where hypoxia is limited. Wild-type mice (C57Bl, C3H/HeN) bearing either MCG-101 tumors or a malignant melanoma (K1735-M2) with either high or insignificant PGE₂ production and subsequently different in sensitivity to cyclooxygenase (COX) inhibition were used. Tumor angiogenesis was estimated by intravital microscopy and immune histochemical analysis in wild type and EP₁ or EP₃ subtype receptor knockout mice (C57Bl). Both MCG-101 and K1735-M2 tumor cells stimulated early outgrowth of tumor vessels in proportion to intrinsic growth rate of tumor cells. Indomethacin had no effects on tumor growth or tumor related vascular area in K1735-M2 bearing mice. By contrast, indomethacin decreased tumor cell proliferation and increased apoptosis in MCG-101 tumors with subsequent adaptation in tumor vascular density. Effects of indomethacin on early growth of MCG-101 tumors were not related to tumor content of bFGF protein, while our earlier studies on long-term tumor growth have shown decreased mRNA levels of bFGF during indomethacin treatment. Early onset of tumor growth was significantly promoted in EP₃- but not in EP₁-knockouts, although long-term tumor growth is attenuated in EP₁-knockouts as reported elsewhere. Our results demonstrate that tumor production of PGE₂ promotes primarily net growth of tumor cells with subsequent adaptations in development of the tumor vasculature. Therefore, it is likely that angiogenesis is not a limiting step at the early onset of tumor growth.     

Intra‐oral pattern of tooth and periodontal bone loss between the age of 50 and 60 years. A longitudinal prospective study

Objective: In a 10‐year prospective study we analyzed (i) the intra‐oral pattern of and (ii) potential risk factors for tooth and periodontal bone loss in 50‐year‐old individuals. Methods: A randomized subject sample of 50‐year‐old inhabitants in the County of Värmland, Sweden, was examined at baseline and after 10 years. Data from full‐mouth clinical and radiographic examinations and questionnaire surveys of 309 (72%) of the individuals who were dentate at baseline were available for analysis. Non‐parametric tests and binary logistic multiple regression models were used for statistical analysis of the data. Results: 4.1% of the 7,101 teeth present at baseline, distributed among 39% of the subjects, were lost during the 10‐year interval. The incidence of tooth loss was highest among mandibular molars (7.5%) and lowest among canines (1.8%). The relative risk (RR) for tooth loss for endodontically compromised teeth was 4.1 and for furcation‐involved molars 2.4–6.5, depending on tooth position. Logistic regression analysis identified baseline alveolar bone level (ABL), endodontic conditions, CPITN score (Community Periodontal Index of Treatment Needs), tooth position, caries, and educational level as risk factors for tooth loss. The overall mean 10‐year ABL change was ?0.54?mm (S.E. 0.01). On a tooth level the ABL change varied between ?0.35?mm (mandibular molars) and ?0.79?mm (mandibular incisors). Smokers experienced a greater (20–131% depending on tooth type) mean bone loss than non‐smokers. The logistic regression model revealed that tooth position, smoking, and probing pocket depth ≥4?mm were risk factors for bone loss of >1?mm. No pertinent differences were observed with respect to risk factors for ABL change in the subgroup of non‐smokers compared to the results of the analysis based on the entire subject sample. Conclusion: Tooth loss was more common in the molar than in the anterior tooth regions, while periodontal bone loss had a random distribution in the dentition. The predominant risk factors identified with regard to further radiographic bone loss were ‘probing pocket depth ≥6?mm’ and ‘smoking’.     

Diagnosis of the condition of the dental pulp: a systematic review

The aim of this systematic review was to appraise the diagnostic accuracy of signs/symptoms and tests used to determine the condition of the pulp in teeth affected by deep caries, trauma or other types of injury. Radiographic methods were not included. The electronic literature search included the databases PubMed, EMBASE, The Cochrane Central Register of Controlled Trials and Cochrane Reviews from January 1950 to June 2011. The complete search strategy is given in an Appendix S1 (available online as Supporting Information). In addition, hand searches were made. Two reviewers independently assessed abstracts and full-text articles. An article was read in full text if at least one of the two reviewers considered an abstract to be potentially relevant. Altogether, 155 articles were read in full text. Of these, 18 studies fulfilled pre-specified inclusion criteria. The quality of included articles was assessed using the QUADAS tool. Based on studies of high or moderate quality, the quality of evidence of each diagnostic method/test was rated in four levels according to GRADE. No study reached high quality; two were of moderate quality. The overall evidence was insufficient to assess the value of toothache or abnormal reaction to heat/cold stimulation for determining the pulp condition. The same applies to methods for establishing pulp status, including electric or thermal pulp testing, or methods for measuring pulpal blood circulation. In general, there are major shortcomings in the design, conduct and reporting of studies in this domain of dental research.     

Specific impairments in instrumental learning following chronic intermittent toluene inhalation in adolescent rats

Rationale

Inhalant abuse is prevalent in adolescent populations, with chronic use resulting in neurobiological and cognitive abnormalities in adulthood. However, the nature and persistence of cognitive dysfunction, particularly following adolescent inhalant abuse, remain equivocal.

Objective

The present study assessed specific cognitive processes beginning in late adolescence and adulthood following adolescent inhalation of toluene, a main component of many compounds readily abused.

Methods

Adolescent male Wistar rats (postnatal day (PN) 27) were exposed to chronic intermittent inhaled toluene (10,000 ppm) for 1 h/day, 3 days/week for 4 weeks (PN 27–52) to mimic the patterns observed in human adolescent inhalant abusers. Following toluene exposure, motor and cognitive function was assessed.

Results

Adolescent toluene exposure did not alter motor learning in the Rotarod task (PN 58) or acquisition, reversal, or retention of spatial learning in the Morris water maze (PN 55–64). In contrast, it delayed acquisition of instrumental responding for sucrose (5 % w/v) and impaired operant reversal learning and cue-induced reinstatement of sucrose seeking in adulthood (PN 57–100).

Conclusion

This study demonstrates that exposure to toluene at an abuse concentration during adolescence results in specific impairments in aspects of instrumental learning, without altering motor function and spatial learning in late adolescence/early adulthood. Our data imply that persistent alterations in reward processing may occur following adolescent inhalant misuse.     

Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory

D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [¹¹C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.Dopamine (DA) plays a key role in several cognitive processes (1–4). Reductions of D1 and D2 DA receptors (D1DRs and D2DRs) in aging (5–7) have been linked to age-related cognitive deficits (8, 9). The D1DR system has been related to functions supported by the prefrontal cortex (PFC), such as working memory and executive functions (10–12), which may reflect the relatively high density of D1DRs in the PFC (13). However, the role of D2DRs is far less clear. D2DRs are present in the PFC at very low densities (13), and evidence supporting a role for the D2DR system in working memory and executive functions is elusive (10). Pharmacological (14, 15) and PET studies assessing striatal D2DR availability (or binding potential to nondisplacable tissue uptake; BP_ND) with [¹¹C]raclopride (16, 17) have yielded mixed findings in relation to cognition. It has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions (10, 18, 19). Supporting these claims, positive links between D2DR BP_ND and episodic memory are commonly observed (20–23). PET imaging of hippocampal D2DR BP_ND also provides support for this hypothesis, although some studies indicate that hippocampal D2DRs may be related to both episodic memory and PFC-based executive functions (22, 23), including verbal working memory (24). Medial temporal lobe regions have been implicated in working memory (25, 26), and D2DR-mediated modulation may be exerted via hippocampal–cortical pathways (27). In addition, a [¹¹C]raclopride task-activation PET study demonstrated contributions of striatal D2DRs to a verbal working-memory task (11).Taken together, the specific role of the D2DR system in cognition remains unclear, likely due to the fact that past studies included small and age-heterogeneous samples and lacked comprehensive test batteries that allowed systematic comparison of the role of D2DRs in different cognitive functions. Here we present results from the Cognition, Brain, and Aging (COBRA) study that include assessment of episodic memory, working memory, and processing speed, in combination with [¹¹C]raclopride PET and MRI of 181 healthy adults between 64 and 68 y of age (28). The main analyses concerned caudate D2DR–cognition associations, as this striatal region has been implicated in cognitive functioning (11, 12, 29, 30). Subsequently, whole-brain analyses were conducted to examine extrastriatal (especially hippocampal) D2DRs in relation to cognition. Finally, resting-state functional connectivity patterns were analyzed in relation to D2DR BP_ND, with special focus on interactions between the ventral caudate (31) and medial temporal cortex regions (32, 33).