Aptamers as Therapeutic Agents: Has the Initial Euphoria Subsided?

Aptamers are synthetic DNA or RNA oligonucleotide ligands with great potential for therapeutic applications. A vast number of disease-related targets have been used to identify agonistic, antagonistic, or inhibitory aptamers, or aptamer-based targeting ligands. However, only a few aptamers have reached late-stage clinical trials so far and the commercial infrastructure is still far behind that of other therapeutic agents such as monoclonal antibodies. The desirable properties of aptamers such as selectivity, chemical flexibility, or cost-efficiency are faced by challenges, including a short half-life in vivo, immunogenicity, and entrapment in cellular organelles. Aptamer research is still in an early stage, and a deeper understanding of their structure, target interactions, and pharmacokinetics is necessary to catch up to the clinical market. In this review, we will discuss the benefits and limitations in the development of therapeutic aptamers, as well as the advances and future directions of aptamer research. The progress towards effective therapies seems to be slow, but it has not stopped and the best is yet to come.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Differential patterns of activity and functional connectivity in emotion processing neural circuitry to angry and happy faces in adolescents with and without suicide attempt.

BACKGROUND: Neural substrates of emotion dysregulation in adolescent suicide attempters remain unexamined. METHOD: We used functional magnetic resonance imaging to measure neural activity to neutral, mild or intense (i.e., 0%, 50% or 100% intensity) emotion face morphs in two separate emotion-processing runs (angry and happy) in three adolescent groups: (1) history of suicide attempt and depression (ATT, n=14) ; (2) history of depression alone (NAT, n=15) ; and (3) healthy controls (HC, n=15). Post-hoc analyses were conducted on interactions from 3 group x 3 condition (intensities) whole-brain analyses (p<0.05, corrected) for each emotion run. RESULTS: To 50% intensity angry faces, ATT showed significantly greater activity than NAT in anterior cingulate gyral­dorsolateral prefrontal cortical attentional control circuitry, primary sensory and temporal cortices; and significantly greater activity than HC in the primary sensory cortex, while NAT had significantly lower activity than HC in the anterior cingulate gyrus and ventromedial prefrontal cortex. To neutral faces during the angry emotion processing run, ATT had significantly lower activity than NAT in the fusiform gyrus. ATT also showed significantly lower activity than HC to 100% intensity happy faces in the primary sensory cortex, and to neutral faces in the happy run in the anterior cingulate and left medial frontal gyri (all p<0.006,corrected). Psychophysiological interaction analyses revealed significantly reduced anterior cingulate gyral­insula functional connectivity to 50% intensity angry faces in ATT v. NAT or HC. CONCLUSIONS: Elevated activity in attention control circuitry, and reduced anterior cingulate gyral­insula functional connectivity, to 50% intensity angry faces in ATT than other groups suggest that ATT may show inefficient recruitment of attentional control neural circuitry when regulating attention to mild intensity angry faces, which may represent a potential biological marker for suicide risk.

Radiation-induced suppression of the Bmp2 signal transduction pathway in the pluripotent mesenchymal cell line C2C12: an in vitro model for prevention of heterotopic ossification by radiotherapy.

Heterotopic ossification is a common complication after total hip replacement. Clinical studies showed the effectiveness of radiation for prevention of heterotopic ossification. The mechanism of radiotherapy responsible for the reduction of heterotopic ossification is unclear. The purpose of this study was to study an analogue model showing a time- and dose-dependent effect of radiation. Using cells of the defined embryonic mouse cell line C2C12, the influence of ionizing radiation on the Bmp-induced signal cascade leading to osteogenic differentiation was analyzed. Binding of iodinated Bmp2 to the receptors, Smad1 activation, and alkaline phosphatase (ALP) activity were determined in cells with or without irradiation. The cytotoxic effect of radiotherapy was evaluated using viability tests. Radiotherapy reduced formation of the Bmp2/Bmp receptor complex. This effect was dependent on dose. The phosphorylation (activation) of Smad1 decreased after irradiation in a time-dependent manner, whereas the level of total Smads was not influenced by radiotherapy. The ALP activity decreased after radiotherapy. A dose of 7 Gy delivered 6 h before or after incubation with Bmp resulted in about a 30% decrease in ALP activity. No signs of cytotoxic effects were observed within the time window studied using doses of 0 to 20 Gy. The time- and dose-dependent effect of radiotherapy for prevention of heterotopic ossification known from the results of clinical studies has an analogue in the C2C12 cell model. The primary mechanism of radiotherapy seems to be an influence on cellular responsiveness to the Bmp2-induced osteoblastic differentiation. The results suggest a down-regulation of the Bmp2/receptor complex.

Bacterial filters in anesthesia: results of 9 years of surveillance.

In 9 years of surveillance of postoperative lower respiratory infections, the infection rate in patients following regional anesthesia was 0.2% and 0.1% in patients following general anesthesia. No bacterial filters in the breathing circuit were used. Infected patients had risk factors such as type of surgery, American Society of Anesthesiologists class > or =2, old age, chronic obstructive pulmonary disease, or smoking habits. Infections were not clustered. This suggests that, in our setting, patient factors are most important in the development of postoperative lower respiratory infections and that the role of bacterial filters as a preventive measure is negligible.

Close-following drivers on two-lane highways.

This study was intended first to replicate, on two-lane highways, of the Evans and Wasielewski (Accident Analysis & Prevention 14, 57-64, 1982; 15, 121-136, 1983) results on the connection between close-following driving and traffic offenses and, second, to reveal reasons for close-following. A sample of close-following drivers (N = 157) and control drivers (N = 178) was picked from the flow on two-lane main highways. The driver records of the past 3 years showed retrospectively that the close-followers had accumulated 2.3 times more traffic offenses than had the control drivers and 2.0 times more when mileage was taken into account. The result is in agreement with the Evans and Wasielewski results for multi-lane highways, with the additional check for mileage in these data. However, the effect only occurred in males and was more marked in young males. Close-following females even indicated a tendency of having fewer offenses than their controls when their higher mileage was taken into account. Another sample of close-followers interviewed on the road revealed that hurry or desire to overtake the car ahead was the justification for the close-following in the majority of cases. It was suggested that on two-lane highways close-following substantially stems from overtaking needs and maneuvering connected to higher target speeds. This study partly confirms the connection between close-following and an increased number of offenses in comparisons between drivers. However, the suggested connection between close-following and accident involvement, as based on interindividual comparisons, still remains somewhat open.