Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals

Neuronal death is often preceded by functional alterations at nerve terminals. Anti- and proapoptotic BCL-2 family proteins not only regulate the neuronal death pathway but also affect excitability of healthy neurons. We found that exposure of squid stellate ganglia to hypoxia, a death stimulus for neurons, causes a cysteine protease-dependent loss of full-length antiapoptotic BCL-xL, similar to previous findings in mammalian cells. Therefore, to determine the direct effect of the naturally occurring proapoptotic cleavage product of BCL-xL on mitochondria, recombinant N-truncated BCL-xL was applied to mitochondria inside the squid presynaptic terminal and to purified mitochondria isolated from yeast. N-truncated BCL-xL rapidly induced large multi-conductance channels with a maximal conductance significantly larger than those produced by full-length BCL-xL. This activity required the hydrophobic C terminus and the BH3 domain of BCL-xL. Moreover, N-truncated BCL-xL failed to produce any channel activity when applied to plasma membranes, suggesting that a component of the mitochondrial membrane is necessary for its actions. Consistent with this idea, the large channels induced by N-truncated BCL-xL are inhibited by NADH and require the presence of VDAC, a voltage-dependent anion channel present in the outer mitochondrial membrane. These observations suggest that the mitochondrial channels specific to full-length and N-truncated BCL-xL contribute to their opposite effects on synaptic transmission, and are consistent with their opposite effects on the cell death pathway.     

Navigating federalwide assurance requirements when conducting research in community-based care settings

There is an urgent need for research on quality of life and healthcare delivery for older adults living in community-based care settings, yet implementing current federalwide assurance (FWA) requirements can be a challenge in these settings. This paper discusses FWA requirements for engagement in federally funded research as the requirements pertain to community-based care settings. Factors that impede community facilities in achieving FWA approval include lack of organizational structure to provide oversight for the ethical conduct of research, administrator concerns regarding potential liability associated with obtaining the FWA, lack of resources to complete required paperwork, and lack of staff knowledge about human subjects protection and federal requirements for participating in research. Effects of the FWA process on investigators include the burden of extra time needed to support community-based facilities to acquire a FWA and concerns that studies may be limited to only those community facilities with the resources to complete the FWA process. Investigator-initiated strategies for conducting research in community-based settings include considering study designs that are exempt from the FWA process and proactively assisting community-based facilities to acquire FWA status. Investigators need to work with potential research sites and the office for human research protections to ensure that subjects are protected without shifting the burden of protection to ill-prepared community administrators.     

Improving sensitivity of cervical cytology by removal of cervical secretions before sampling: a prospective study in Mexico

Sensitivity of cervical cytology is suboptimal, especially in developing countries such as Mexico, despite available guidelines aimed at improving this. When obtaining cervical samples, whether the samples are taken from the transformation zone and whether abnormal cells are missing must be considered. Cervical secretions (CS) are always present in variable proportions, and when cleaning the cervix, better samples may be obtained. In this study, we analyzed samples obtained with or without cleaning the cervix, and compared their contents in order to determine the sensitivity and specificity of these two methods. Methods: Of 500 patients who underwent cytology and colposcopy, 271 (54.2%) required a second opinion due to a diagnosis of cervical intraepithelial neoplasia (CIN). CS was removed and compared with the clean, second sample (SS) using in both liquid-based cytology. The quality of samples according to the Bethesda System, the presence of CIN, and inflammatory reactions were recorded. The sensitivity and specificity were calculated using biopsy as the gold standard. Results: The SS resulted in a higher proportion of adequate samples being obtained (97.6% vs. 44.8%), and in increased sensitivity (88.2% vs. 58.8%). CIN was detected in the SS 26% more often than in the CS (34 vs. 27 samples), whereas inflammatory reactions were noted more often in the CS (91.4% vs. 74%). Conclusion: Cervical sampling including CS results in lower sensitivity and CIN detection rates, and in more inflammatory reactions. By excluding CS from cervical samples, the sensitivity could be improved and the false negative rate could be reduced.     

Intracranial infectious aneurysms: a comprehensive review

Intracranial infectious aneurysms, or mycotic aneurysms, are rare infectious cerebrovascular lesions which arise through microbial infection of the cerebral arterial wall. Due to the rarity of these lesions, the variability in their clinical presentations, and the lack of population-based epidemiological data, there is no widely accepted management methodology. We undertook a comprehensive literature search using the OVID gateway of the MEDLINE database (1950–2009) using the following keywords (singly and in combination): “infectious,” “mycotic,” “cerebral aneurysm,” and “intracranial aneurysm.” We identified 27 published clinical series describing a total of 287 patients in the English literature that presented demographic and clinical data regarding presentation, treatment, and outcome of patients with mycotic aneurysms. We then synthesized the available data into a combined cohort to more closely estimate the true demographic and clinical characteristics of this disease. We follow by presenting a comprehensive review of mycotic aneurysms, highlighting current treatment paradigms. The literature supports the administration of antibiotics in conjunction with surgical or endovascular intervention depending on the character and location of the aneurysm, as well as the clinical status of the patient. Mycotic aneurysms comprise an important subtype of potentially life-threatening cerebrovascular lesions, and further prospective studies are warranted to define outcome following both conservative and surgical or endovascular treatment.     

Comparison of brief interventions in primary care on smoking and excessive alcohol consumption: a population survey in England

Background

Brief interventions have a modest but meaningful effect on promoting smoking cessation and reducing excessive alcohol consumption. Guidelines recommend offering such advice opportunistically and regularly but incentives vary between the two behaviours.

Aim

To use representative data from the perspective of patients to compare the prevalence and characteristics of people who smoke or drink excessively and who receive a brief intervention.

Design and setting

Data was from a representative sample of 15 252 adults from household surveys in England.

Method

Recall of brief interventions on smoking and alcohol use, sociodemographic information, and smoking and alcohol consumption patterns were assessed among smokers and those who drink excessively (AUDIT score of ≥8), who visited their GP surgery in the previous year.

Results

Of 1775 smokers, 50.4% recalled receiving brief advice on smoking in the previous year. Smokers receiving advice compared with those who did not were more likely to be older (odds ratio [OR] 17-year increments 1.19, 95% confidence interval [CI] =1.06 to 1.34), female (OR 1.35, 95% CI =1.10 to 1.65), have a disability (OR 1.44, 95% CI = 1.11 to 1.88), have made more quit attempts in the previous year (compared with no attempts: one attempt, OR 1.65, 95% CI = 1.32 to 2.08; ≥2 attempts, OR 2.02, 95% CI =1.49 to 2.74), and have greater nicotine dependence (OR 1.17, 95% CI =1.05 to 1.31) but were less likely to have no post-16 qualifications (OR 0.81, 95% CI = 0.66 to 1.00). Of 1110 people drinking excessively, 6.5% recalled receiving advice in their GP surgery on their alcohol consumption in the previous year. Those receiving advice compared with those who did not had higher AUDIT scores (OR 1.17, 95% CI =1.12 to 1.23) and were less likely to be female (OR 0.44, 95% CI = 0.23 to 0.87).

Conclusion

Whereas approximately half of smokers in England visiting their GP in the past year report having received advice on cessation, <10% of those who drink excessively report having received advice on their alcohol consumption.