Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory

Growing evidence suggests serotonin's role in anxiety and depression is mediated by its effects on learned fear associations. Pharmacological and genetic manipulations of serotonin signaling in mice alter the retention of fear extinction learning, which is inversely associated with anxious temperament in mice and humans. Here, we test whether genetic variation in serotonin signaling in the form of a common human serotonin transporter polyadenylation polymorphism (STPP/rs3813034) is associated with spontaneous fear recovery after extinction. We show that the risk allele of this polymorphism is associated with impaired retention of fear extinction memory and heightened anxiety and depressive symptoms. These STPP associations in humans mirror the phenotypic effects of serotonin transporter knockout in mice, highlighting the STPP as a potential genetic locus underlying interindividual differences in serotonin transporter function in humans. Furthermore, we show that the serotonin transporter polyadenylation profile associated with the STPP risk allele is altered through the chronic administration of fluoxetine, a treatment that also facilitates retention of extinction learning. The propensity to form persistent fear associations due to poor extinction recall may be an intermediate phenotype mediating the effects of genetic variation in serotonergic function on anxiety and depression. The consistency and specificity of these data across species provide robust support for this hypothesis and suggest that the little-studied STPP may be an important risk factor for mood and anxiety disorders in humans.     

Multiple self-splicing introns in the 16S rRNA genes of giant sulfur bacteria

The gene encoding the small subunit rRNA serves as a prominent tool for the phylogenetic analysis and classification of Bacteria and Archaea owing to its high degree of conservation and its fundamental function in living organisms. Here we show that the 16S rRNA genes of not-yet-cultivated large sulfur bacteria, among them the largest known bacterium Thiomargarita namibiensis, regularly contain numerous self-splicing introns of variable length. The 16S rRNA genes can thus be enlarged to up to 3.5 kb. Remarkably, introns have never been identified in bacterial 16S rRNA genes before, although they are the most frequently sequenced genes today. This may be caused in part by a bias during the PCR amplification step that discriminates against longer homologs, as we show experimentally. Such length heterogeneity of 16S rRNA genes has so far never been considered when constructing 16S rRNA-based clone libraries, even though an elongation of rRNA genes due to intervening sequences has been reported previously. The detection of elongated 16S rRNA genes has profound implications for common methods in molecular ecology and may cause systematic biases in several techniques. In this study, catalyzed reporter deposition-fluorescence in situ hybridization on both ribosomes and rRNA precursor molecules as well as in vitro splicing experiments were performed and confirmed self-splicing of the introns. Accordingly, the introns do not inhibit the formation of functional ribosomes.     

Clinical outcomes of percutaneous interventions in saphenous vein grafts using drug-eluting stents compared to bare-metal stents: a comprehensive meta-analysisof all randomized clinical trials

Background:

Clinical outcomes of percutaneous coronary intervention (PCI) in patients with saphenous vein grafts (SVGs) remain poor despite the use of drug‐eluting stents (DES). There is a disparity in clinical outcomes in SVG PCI based on various registries, and randomized clinical data remain scant. We conducted a meta‐analysis of all existing randomized controlled trials (RCTS) comparing bare‐metal stents (BMS) and DES in SVGPCIs.

Hypothesis:

PCI in patients with SVG disease using DES may reduce need for repeat revascularization without an excess mortality when compared to BMS.

Methods:

An aggregate data meta‐analysis of clinical outcomes in RCTs comparing PCI with DES vs BMS for SVGs reporting at least 12 months of follow‐up was performed. A literature search between Janurary 1, 2003 and September 30, 2011 identified 4 RCTs (812 patients; DES = 416, BMS = 396). Summary odds ratio (OR) and 95% confidence interval (CI) were calculated using the random‐effects model. The primary endpoint was all‐cause mortality. Secondary outcomes included nonfatal myocardial infarction (MI), repeat revascularization, and major adverse cardiac events (MACE). These outcomes were assessed in a cumulative fashion at 30 days, 18 months, and 36 months.

Results:

There were no intergroup differences in baseline clinical and sociodemographic characteristics. At a median follow‐up of 25 months, patients in the DES and BMS group had similar rates of death (OR: 1.63, 95% CI: 0.45–5.92), MI (OR; 0.83, 95% CI: 0.27‐2.60), and MACE (OR: 0.58, 95% CI: 0.25–1.32). Patients treated with DES had lower rates of repeat revascularization (OR: 0.40, 95% CI: 0.22–0.75).

Conclusions:

In this comprehensive meta‐analysis of all RCTs comparing clinical outcomes of PCI using DES vs BMS in patients with SVG disease, use of DES was associated with a reduction in rate of repeat revascularization and no difference in rates of all‐cause death and MI. Clin. Cardiol. 2012 DOI: 10.1002/clc.21984 Dr. Virani is supported by a Department of Veterans Affairs Health Services Research and Development Service (HSR&D) Career Development Award (CDA‐09‐028), and has research support from Merck and National Football League Charities (all grants to the institution and not individual). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The authors have no other funding, financial relationships, or conflicts of interest to disclose.     

Outcomes of preoperative Angiotensin-converting enzyme inhibitor therapy in patients undergoing isolated coronary artery bypass grafting

The association between preoperative use of angiotensin-converting enzyme (ACE) inhibitors and outcomes after coronary artery bypass grafting (CABG) remain controversial. Our aim was to study in-hospital outcomes after isolated CABG in patients on preoperative ACE inhibitors. A retrospective analysis of 8,889 patients who underwent isolated CABG from 2000 through 2011 was conducted. The primary outcome of interest was the incidence of major adverse events (MAEs) defined as a composite of mortality, postoperative renal dysfunction, myocardial infarction, stroke, and atrial fibrillation during index hospitalization. The secondary outcome was the incidence of individual outcomes included in MAEs. Logistic regression analyses were performed. Of 8,889 patients, 3,983 (45%) were on preoperative ACE inhibitors and 4,906 (55%) were not. Overall incidence of MAEs was 38.1% (n = 1,518) in the ACE inhibitor group compared to 33.6% (n = 1,649) in the no-ACE inhibitor group. Preoperative use of ACE inhibitors was independently associated with MAEs (odds ratio 1.13, 95% confidence interval 1.03 to 1.24), most of which was driven by a statistically significant increase in postoperative renal dysfunction (odds ratio 1.18, 95% confidence interval 1.03 to 1.36) and atrial fibrillation (odds ratio 1.15, 95% confidence interval 1.05 to 1.27). In-hospital mortality, postoperative myocardial infarction, and stroke were not significantly associated with preoperative ACE inhibitor use. Analyses performed after excluding patients with low ejection fractions yielded similar results. In conclusion, preoperative ACE inhibitor use was associated with an increased risk of MAEs after CABG, in particular postoperative renal dysfunction and atrial fibrillation.     

Serum adipokines and low density lipoprotein subfraction profile in hypopituitary patients with growth hormone deficiency

The aim was to evaluate the concentrations of lipid subfractions in relation to adipokines and metabolic parameters in adult growth hormone (GH)-deficient hypopituitary patients on conventional replacement therapy. The study included 21 GH deficient-hypopituitary patients (age: 36.0 ± 15.1 years, male/female: 7/14) on conventional replacement therapy other than GH and 20 comparable controls (age: 37.3 ± 14.0 years, male/female: 6/14). Lipid subfractions (Lipoprint system), serum adipokine (leptin, adiponectin, resistin) concentrations, body composition, a surrogate marker for insulin resistance (HOMA) and conventional lipid profile were evaluated. No statistically significant difference was found with respect to HOMA, adipokine concentrations and anthropometric parameters between patients and controls except for significantly increased waist-to-hip ratio in hypopituitary group. Total and LDL cholesterol concentrations were significantly higher in the patients. LDL particle size (268.88 ± 3.16 vs. 271.31 ± 3.11 ?, P = 0.151) and small-dense LDL subfraction did not differ significantly. According to logistic regression analysis, triglyceride concentrations ≥1.69 mmol/L was the sole parameter significantly and independently predicted small (<268 ?) LDL particle size (P = 0.019) in the whole group. Increased triglyceride concentrations affect LDL particle size in GH-deficient hypopituitary patients. Small dense LDL seems not directly contribute to atherogenic potential in hypopituitarism.     

Nocturnal Medications Dosing: Does It Really Make a Difference in Blood Pressure Control Among Patients with Chronic Kidney Disease?

Ambulatory blood pressure (BP) monitoring is superior to clinic BP monitoring in predicting long-term consequences of hypertension. This has raised interest in diurnal variation in BP and elevation in nighttime BP as a prognostic and therapeutic target. Several studies have identified prevalence of nocturnal hypertension in patients with accelerated progression of chronic kidney disease and target organ damage. Some studies suggest that nocturnal BP can be lowered by changing administration of antihypertensive medication to bed time; whether that results in retarding kidney disease progression is not very clear. Further research is needed to determine if certain classes of medications or interventions are superior in controlling nocturnal hypertension, and protocols need to be developed to screen patients for monitoring nocturnal BP. Further studies are needed to evaluate long-term renal outcomes of evening dosing in patients with nocturnal hypertension and chronic kidney disease.     

Impact of azole drugs on energetics,kinetics, and ligand migration pathways of CO photo-dissociation in bacterial flavohemoglobins

Flavohemoglobins (fHbs) are heme proteins found in prokaryotic and eukaryotic microbes. They are involved in NO detoxification through an NO˙ dioxygenase mechanism. The N-terminal heme globin domain allows for binding of gaseous ligands whereas a C-terminal NADH/FADH binding domain facilitates association of redox cofactors necessary for ligand reduction. The NO˙ dioxygenase function is important in facilitating immune resistance by protecting the cell from nitrosative stress brought about by a host organism; as a result, bacterial flavoHbs have recently been considered as targets for the development of new antibiotics. Here, photoacoustic calorimetry and transient absorption spectroscopy have been used to characterize energetics, structural dynamics, and kinetics of CO migration within bacterial flavoHbs from Ralstonia eutropha (FHP) and Staphylococcus aureus (HMP_Sa) in the presence and absence of antibiotic azole compounds. In FHP, the ligand photo-release is associated with ΔH = 26.2 ± 7.0 kcal mol⁻¹ and ΔV = 25.0 ± 1.5 mL mol⁻¹ while in HMP_Sa, ΔH = 34.7 ± 8.0 kcal mol⁻¹ and ΔV = 28.6 ± 17 mL mol⁻¹ were observed, suggesting distinct structural changes associated with ligand escape from FHP and HMP_Sa. In the presence of ketoconazole, the CO escape leads to a more negative enthalpy change and volume change whereas association of miconazole to FHP or HMP_Sa does not impact the reaction volume. These data are in agreement with the computational results that propose distinct binding sites for ketoconazole and miconazole on CO bound FHP. Miconazole or ketoconazole binding to either protein has only a negligible impact on the CO association rates, indicating that azole drugs do not impact flavoHbs interactions with gaseous ligands but may inhibit the NOD activity through preventing the electron transfer between FAD and heme cofactors.

Impact of ketoconalzole and miconazole on structural dynamics of flavohemoglobin.     

Anesthesia for children with mitochondrial disorders: a national survey and review

Purpose

Mitochondrial diseases are a heterogeneous group of disorders. Patients with such diseases often need general anesthesia for diagnostic procedures and surgery; guidelines are lacking for the anesthetic care of these patients.

Methods

We conducted a survey to investigate the current practices of pediatric anesthesiologists in the US in order to determine and document current practice. The survey consisted of twenty questions, including two demographic questions. A link to the survey was sent via email to members of the Society for Pediatric Anesthesia (2440), and was available online for 14 weeks.

Results

Only 503 completed the survey: a response rate of 20.61 %. Among the responders, 93.2 % had children with mitochondrial disorders among their patients, but only 11 % had institutional guidelines for such cases in place. Among the responders, 80.3 % used the standard nil per os (NPO) status guidelines, while the rest give intravenous dextrose solution once NPO was in effect. Only 18.3 % took precautions for malignant hyperthermia during treatment. The majority of the practitioners chose sevoflurane as the safest inhaled agent for induction and maintenance (89.7 and 78.5 %, respectively). Regional anesthesia was deemed safe by 97.3 % of the responders. Lactated Ringer’s solution was considered safe for these children by 49 %; only 47.8 % used dextrose-containing fluids for fluid replacement. The blood glucose was monitored by 72.7 %, and the majority (85 %) of this monitoring was done in a postanesthesia care unit.

Conclusion

Although the response rate was low, the majority of the responders provide care to these children routinely, so it can be inferred that the results of this survey are the closest published results to the true trend.     

Long-term outcomes following single-bundle transtibial arthroscopic posterior cruciate ligament reconstruction

Purpose

Posterior cruciate ligament (PCL) injury has a reported incidence of 3–20 %. PCL reconstruction is aimed at reducing onset of premature articular degeneration and improving function. Numerous operative techniques have been described with varying degrees of result consistency.

Methods

We evaluated 15 patients treated for isolated primary posterior cruciate ligament injury with a mean follow-up of 4.1 years (range one to nine). Post-reconstruction clinical assessment included the Lysholm and Tegner knee scoring scale, international knee documentation committee (IKDC) ligament evaluation, and KT2000 arthrometer assessment.

Results

On the Lysholm knee score 11 patients (73 %) had excellent results, three patients (20 %) had good results and one patient (7 %) had a poor result. On the Tegner activity score the majority of patients scored 7–8 with a return to high level sports. At the final follow-up, the post-reconstruction IKDC score was normal or nearly normal (A and B) in 14 (93 %) patients, and abnormal (C) in one (7 %) patient. According to KT-2000 arthrometer measurements at final follow-up review, 11 patients (73 %) were rated as normal (A, 0–2 mm), and four patients (27 %) as nearly normal (B, 3–5 mm). These results were independent of age, mechanism of injury, time elapsed to surgical reconstruction, and length of follow-up.

Conclusions

Despite being a technically demanding procedure, the outcomes reported in this study show that single bundle transtibial arthroscopic PCL repair using four strands hamstring autograft provides satisfactory and consistent functional outcomes.