R6/2 neurons with intranuclear inclusions survive for prolonged periods in the brains of chimeric mice

The R6/2 mouse possesses mutant exon 1 of human Hdh, and R6/2 mice with 150 CAG repeats show neurological abnormalities by 10 weeks and die by 15 weeks. Few brain abnormalities, however, are evident at death, other than widespread ubiquitinated neuronal intranuclear inclusions (NIIs). We constructed R6/2t+/t- <--> wildtype (WT) chimeric mice to prolong survival of R6/2 cells and determine if neuronal death and/or neuronal injury become evident with longer survival. ROSA26 mice (which bear a lacZ transgene) were used as WT to distinguish between R6/2 and WT neurons. Chimeric mice consisting partly of R6/2 cells lived longer than pure R6/2 mice (up to 10 months), with the survival proportional to the R6/2 contribution. Genotypically R6/2 cells formed NIIs in the chimeras, and these NIIs grew only slightly larger than in 12-week pure R6/2 mice, even after 10 months. Additionally, neuropil aggregates formed near R6/2 neurons in chimeric mice older than 15 weeks. Thus, R6/2 neurons could survive well beyond 15 weeks in chimeras. Moreover, little neuronal degeneration was evident in either cortex or striatum by routine histological stains. Nonetheless, striatal shrinkage and ventricular enlargement occurred, and striatal projection neuron markers characteristically reduced in Huntington's disease were diminished. Consistent with such abnormalities, cortex and striatum in chimeras showed increased astrocytic glial fibrillary acidic protein. These results suggest that while cortical and striatal neurons can survive nearly a year with nuclear and extranuclear aggregates of mutant huntingtin, such lengthy survival does reveal cortical and striatal abnormality brought on by the truncated mutant protein.     

Psychosocial Predictors of Sexual HIV Transmission Risk Behavior among HIV-Positive Adults with a Sexual Abuse History in Childhood

Childhood sexual abuse (CSA) is associated with HIV sexual risk behavior. Although many psychosocial correlates of sexual risk among HIV-positive persons have been identified, studies predicting continued risk among HIV-positive adults with histories of CSA are limited. This cross-sectional study identified variables predictive of sexual transmission risk behavior among an ethnically diverse sample of 256 HIV-positive adults (women and men who have sex with men; MSM) with CSA histories. Participants were assessed for trauma symptoms, shame related to HIV and sexual trauma, substance use, coping style, and sexual risk behavior. Logistic regression analyses were conducted to identify variables predictive of unprotected sexual behavior in the past 4 months. Unprotected sex was significantly associated with substance use and trauma-related behavioral difficulties among women and men, and less spiritual coping among men. Unprotected sex with HIV negative or serostatus unknown partners was significantly associated with greater trauma-related behavioral difficulties, more HIV-related shame, and fewer active coping strategies. Thus, trauma symptoms, shame, coping style, and substance use were significantly associated with sexual risk behavior among HIV-positive adults with histories of CSA, with models of prediction differing by gender and partner serostatus. HIV prevention intervention for persons with HIV and CSA histories should address trauma-related behavioral difficulties and enhance coping skills to reduce sexual transmission risk behavior.     

Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors

Background

Critically ill patients with renal insufficiency are predisposed to both deep vein thrombosis (DVT) and bleeding. The objective of the present study was to evaluate the prevalence, incidence and predictors of DVT and the incidence of bleeding in intensive care unit (ICU) patients with estimated creatinine clearance <30 ml/min.

Methods

In a multicenter, open-label, prospective cohort study of critically ill patients with severe acute or chronic renal insufficiency or dialysis receiving subcutaneous dalteparin 5,000 IU once daily, we estimated the prevalence of proximal DVT by screening compression venous ultrasound of the lower limbs within 48 hours of ICU admission. DVT incidence was assessed on twice-weekly ultrasound testing. We estimated the incidence of major and minor bleeding by daily clinical assessments. We used Cox proportional hazards regression to identify independent predictors of both DVT and major bleeding.

Results

Of 156 patients with a mean (standard deviation) creatinine clearance of 18.9 (6.5) ml/min, 18 had DVT or pulmonary embolism within 48 hours of ICU admission, died or were discharged before ultrasound testing – leaving 138 evaluable patients who received at least one dose of dalteparin. The median duration of dalteparin administration was 7 days (interquartile range, 4 to 12 days). DVT developed in seven patients (5.1%; 95% confidence interval, 2.5 to 10.1). The only independent risk factor for DVT was an elevated baseline Acute Physiology and Chronic Health Evaluation II score (hazard ratio for 10-point increase, 2.25; 95% confidence interval, 1.03 to 4.91). Major bleeding developed in 10 patients (7.2%; 95% confidence interval, 4.0 to 12.8), all with trough anti-activated factor X levels ≤ 0.18 IU/ml. Independent risk factors for major bleeding were aspirin use (hazard ratio, 6.30; 95% confidence interval, 1.35 to 29.4) and a high International Normalized Ratio (hazard ratio for 0.5-unit increase, 1.68; 95% confidence interval, 1.07 to 2.66).

Conclusion

In ICU patients with renal insufficiency, the incidence of DVT and major bleeding are considerable but appear related to patient comorbidities rather than to an inadequate or excessive anticoagulant from thromboprophylaxis with dalteparin.

Clinical Trial Registration

Number NCT00138099.     

The N400 elicited by homonyms in puns: Two primes are not better than one

To comprehend a pun involving a homonym (e.g., The prince with a bad tooth got a crown), both meanings of the homonym must be accessed and selected. Previous ERP studies have shown that the N400 reflects lexicosemantic processing, but none have directly investigated the N400 elicited by homonyms in the unique context of puns. Here, N400 priming effects showed that the dual context of puns (e.g., the primes prince and tooth) did not facilitate homonym processing in comparison to single dominant biasing (e.g., The prince with a bad leg got a crown) or subordinate biasing (e.g., The adult with a bad tooth got a crown) conditions. However, homonyms did elicit a less negative N400 (i.e., priming) in the pun condition in comparison to the neutral context condition (e.g., The adult with a bad leg got a crown). These findings are interpreted in terms of the dominant advantage and subordinate bias effect posited by the reordered access model of homonym processing, and in terms of N400 amplitude as an index of how consistently various sources of semantic featural information converge on one lexical item, even when two lexical items must be activated for comprehension.     

Initial assessment on the impact of crystalloids versus colloids during damage control resuscitation

Background

High ratios of fresh frozen plasma:packed red blood cells in damage control resuscitation (DCR) are associated with increased survival. The impact of volume and type of resuscitative fluid used during high ratio transfusion has not been analyzed. We hypothesize a difference in outcomes based on the type and quantity of resuscitative fluid used in patients that received high ratio DCR.

Methods

A matched case control study of patients who received transfusions of ≥ four units of PRBC during damage control surgery over 4 1/2 y, was conducted at a Level I Trauma Center. All patients received a high ratio DCR, >1:2 of fresh frozen plasma:packed red blood cells. Demographics and outcomes of the type and quantity of resuscitative fluids used in combination with high ratio DCR were compared and analyzed. A Kaplan-Meier survival analysis was computed among four groups: colloid (median quantity = 1.0 L), <3 L crystalloid, 3–6 L crystalloid, and >6 L crystalloid.

Results

There were 56 patients included in the analysis (28 in the crystalloid group and 28 in the colloid group). Demographics were statistically similar. Intraoperative median units of PRBC: crystalloid versus colloid groups was 13 (IQR 8-21) versus 16 (IQR 12–19), P = 0.135; median units of FFP: 12 (IQR 7–18) versus 12 (IQR 10–18), P = 0.440. OR for 10-d mortality in the crystalloid group was 8.41 [95% CI 1.65–42.76 (P = 0.01)]. Kaplan-Meier survival analysis demonstrated lowest mortality in the colloid group and higher mortality with increasing amounts of crystalloid (P = 0.029).

Conclusions

During high ratio DCR, resuscitation with higher volumes of crystalloids was associated with an overall decreased survival, whereas low volumes of colloid use were associated with increased survival. In order to improve outcomes without diluting the survival benefit of hemostatic resuscitation, guidelines should focus on effective low volume resuscitation when high ratio DCR is used. A multi-institutional analysis is needed in order to validate these results.     

Pharmacology podcasts: a qualitative study of non-medical prescribing students' use,perceptions and impact on learning

Background  

There is growing research on student use of podcasts in academic settings. However, there is little in-depth research focusing on student experience of podcasts, in particular in terms of barriers to, and facilitators of, podcast use and students' perceptions of the usefulness of podcasts as learning tools. This study aimed to explore the experiences of non-medical prescribing students who had access to podcasts of key pharmacology lectures as supplementary learning tools to their existing course materials.     

Evaluation of a comprehensive algorithm for blunt and penetrating thoracic and abdominal trauma.

The objective was to develop a single branched-chain decision tree for both blunt and penetrating thoracic and abdominal trauma and to test its feasibility to track clinical decisions. The algorithm consisted of 14 specific patient management loops and 31 decision nodes. During a 4-month period, the management decisions and clinical course of 434 trauma patients were prospectively observed. Thirty-four patients had no signs of life on arrival to the emergency department (ED) and were excluded from the statistical evaluation; the remaining 400 patients constituted the study group. The mean Injury Severity Score (ISS), Penetrating Abdominal Trauma Index (PATI), and Trauma Score (TS) scores in the series were 21 +/- 10, 34 +/- 12, and 13 +/- 3. The overall patient mortality of the study group was 17 per cent; it was 61 per cent in those patients with major deviations from the algorithm and 6 per cent in patients who complied with the algorithm. The ISS, PATI, and TS scores were 29 +/- 9, 32 +/- 12, and 13 +/- 2 in patients with deviations and 20 +/- 10, 37 +/- 12, and 14 +/- 2 in patients who complied with the algorithm. Of the 37 patients who died with major deviations from the algorithm, the deviation was directly contributory to death in 21 cases (57%) and probably contributory in another 14 cases (38%). There were 108 patients with ISS scores between 20 and 50. In this group, mortality was 55 per cent when a major deviation occurred and 5 per cent without major deviations from the algorithm. The authors conclude that the survival of trauma patients may be improved by following the specific management criteria outlined by the algorithm.