Deficits in motor performance after pedunculopontine lesions in rats – impairment depends on demands of task

Anatomically and functionally located between basal ganglia and brainstem circuitry, the pedunculopontine tegmental nucleus (PPTg) is in a pivotal position to contribute to motor behavior. Studies in primates have reported akinesia and postural instability following destruction of the PPTg. In humans, the PPTg partially degenerates in Parkinson's disease and stimulation of this region is under investigation as a possible therapeutic. Studies in rats report no crude motor impairment following PPTg lesion, although a detailed assessment of the role of the PPTg in rat motor function has not been reported. Our studies applied motor tests generally used in rodent models of Parkinson's disease to rats bearing either excitotoxic damage to all neuronal populations within PPTg, or selective destruction of the cholinergic subpopulation created with the toxin Dtx‐UII. Neither lesion type altered baseline locomotion. On the rotarod, excitotoxic lesions produced a persistent impairment on the accelerating, but not fixed speed, conditions. In the vermicelli handling task (a quantitative measure of fine motor control and effective behavioral sequencing) excitotoxic lesions produced no single impairment, but globally increased the number of normal and abnormal behaviors. In contrast, depletion of cholinergic PPTg neurons produced impairment on the accelerating rotarod but no changes in vermicelli handling. Together, these results show that while PPTg lesions produce no impairment in the execution of individual motor actions, impairments emerge when the demands of the task increase. Results are discussed in terms of PPTg acting as part of a rapid action selection system, which integrates sensory information into motor output.     

Risk of AKI with Gentamicin as Surgical Prophylaxis

In 2009, the Scottish government issued a target to reduce Clostridium difficile infection by 30% in 2 years. Consequently, Scottish hospitals changed from cephalosporins to gentamicin for surgical antibiotic prophylaxis. This study examined rates of postoperative AKI before and after this policy change. The study population comprised 12,482 adults undergoing surgery (orthopedic, urology, vascular, gastrointestinal, and gynecology) with antibiotic prophylaxis between October 1, 2006, and September 30, 2010 in the Tayside region of Scotland. Postoperative AKI was defined by the Kidney Disease Improving Global Outcomes criteria. The study design was an interrupted time series with segmented regression analysis. In orthopedic patients, change in policy from cefuroxime to flucloxacillin (two doses of 1 g) and single-dose gentamicin (4 mg/kg) was associated with a 94% increase in AKI (P=0.04; 95% confidence interval, 93.8% to 94.3%). Most patients who developed AKI after prophylactic gentamicin had stage 1 AKI, but some patients developed persistent stage 2 or stage 3 AKI. The antibiotic policy change was not associated with a significant increase in AKI in the other groups. Regardless of antibiotic regimen, however, rates of AKI were high (24%) after vascular surgery, and increased steadily after gastrointestinal surgery. Rates could only be ascertained in 52% of urology patients and 47% of gynecology patients because of a lack of creatinine testing. These results suggest that gentamicin should be avoided in orthopedic patients in the perioperative period. Our findings also raise concerns about the increasing prevalence of postoperative AKI and failures to consistently measure postoperative renal function.Reported rates of postoperative AKI vary because of the heterogeneity of the populations studied. Uncomplicated AKI is associated with a mortality of 10%, rising to 50% in the context of multiorgan failure and up to 80% if RRT is required.^1,2 It was thought that the presence of AKI was a marker of coexisting pathology that increased mortality risk, but recent reports demonstrate AKI as an independent risk factor for mortality.^3,4 The increasing incidence of AKI and its long-term consequences have significant socioeconomic and public health effects globally.⁵Clostridium difficile infection (CDI) is an important healthcare-associated infection. Antibiotic use increases the risk of CDI for at least 3 months⁶ and short courses of perioperative antibiotic prophylaxis have also been associated with an increased risk of CDI, particularly in the context of an established outbreak.⁷In 2009, the Scottish government issued a new target for all health boards to reduce CDI by at least 30% over 2 years.⁸ The Scottish Antimicrobial Prescribing Group also produced recommendations for all National Health Service (NHS) boards to restrict the use of antibiotics associated with a high risk of CDI.⁹ As part of a widespread antibiotic policy change at NHS Tayside, orthopedic antibiotic prophylaxis was changed from cefuroxime to gentamicin and flucloxacillin. After concerns raised by nephrologists and a small uncontrolled study in the Dumfries and Galloway region of Scotland that described an increased rate of AKI in patients after orthopedic surgery after this policy change,¹⁰ it was felt that further investigation was required.This study aimed to use robust methodology, in a larger, population-based study of adult patients undergoing orthopedic implant surgery, to evaluate the effect of the policy change on postoperative AKI. It is noteworthy that patients who underwent repair of a neck of femur (NOF) fracture received coamoxiclav as antibiotic prophylaxis after the policy change because of concerns raised by orthopedic surgeons with regard to administering gentamicin in this particular patient group. This analysis was then extended to evaluate postoperative AKI in other surgical specialties (urology, vascular, gastrointestinal, and gynecology) that had changed to a gentamicin-based regimen.     

Molecular determinants of susceptibility to oncolytic vesicular stomatitis virus in pancreatic adenocarcinoma

Background

M protein mutant vesicular stomatitis virus (M51R-VSV) has oncolytic properties against many cancers. However, some cancer cells are resistant to M51R-VSV. Herein, we evaluate the molecular determinants of vesicular stomatitis virus (VSV) resistance in pancreatic adenocarcinoma cells.

Methods

Cell viability and the effect of β-interferon (IFN) were analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Gene expression was evaluated via microarray analysis. Cell infectability was measured by flow cytometry. Xenografts were established in athymic nude mice and treated with intratumoral M51R-VSV.

Results

Four of five pancreatic cancer cell lines were sensitive to M51R-VSV, whereas Panc 03.27 cells remained resistant (81 ± 3% viability 72 h after single-cycle infection). Comparing sensitive MiaPaCa2 cells with resistant Panc 03.27 cells, significant differences in gene expression were found relating to IFN signaling (P = 2 × 10⁻⁵), viral entry (P = 3 × 10⁻⁴), and endocytosis (P = 7 × 10⁻⁴). MiaPaCa2 cells permitted high levels of VSV infection, whereas Panc 03.27 cells were capable of resisting VSV cell entry even at high multiplicities of infection. Extrinsic β-IFN overcame apparent defects in IFN-mediated pathways in MiaPaCa2 cells conferring VSV resistance. In contrast, β-IFN decreased cell viability in Panc 3.27 cells, suggesting intact antiviral mechanisms. VSV-treated xenografts exhibited reduced tumor growth relative to controls in both MiaPaCa2 (1423 ± 345% versus 164 ± 136%; P < 0.001) and Panc 3.27 (979 ± 153% versus 50 ± 56%; P = 0.002) tumors. Significant lymphocytic infiltration was seen in M51R-VSV–treated Panc 03.27 xenografts.

Conclusions

Inhibition of VSV endocytosis and intact IFN-mediated defenses are responsible for M51R-VSV resistance in pancreatic adenocarcinoma cells. M51R-VSV treatment appears to induce antitumor cellular immunity in vivo, which may expand its clinical efficacy.     

Cross-sectional area of the abdomen predicts complication incidence in patients undergoing sternal reconstruction

Background

Sternal reconstruction with vascularized flaps is central to the management of sternal wound infections and mediastinitis but carries a high risk of complications. There is a need to identify reliable predictors of complication risk to help inform patients and clinicians in preparation for surgery. Unfortunately, body mass index and serum albumin may not be reliable predictors of complication rates. Analytic morphomics provides a robust quantitative method to measure patients' obesity as it pertains to their risk of complications in undergoing sternal reconstruction.

Methods

We identified 34 patients with preoperative computed tomography scans of the abdomen from a cohort of sternal reconstructions performed between 1997 and 2010. Using semiautomated analytic morphomics, we identified the patients' skin and fascia layers between the ninth and 12th thoracic spine levels; from these landmarks, we calculated morphomic measurements of the patients' abdomens, including their total body cross sectional area and the cross sectional area of their subcutaneous fat. We obtained the incidence of complications from chart review and correlated the incidence of complications (including seroma, hematoma, recurrent wounds, mediastinitis, tracheostomy, and death) with patients' morphomic measurements.

Results

Sixty-two percent of patients (n = 21) suffered complications after their operation. Those who suffered from complications, relative to those who did not have complications, had increased visceral fat area (12,547.2 mm²versus 6569.9 mm², P = 0.0080), subcutaneous fat area (16,520.2 mm²versus 8020.1 mm², P = 0.0036), total body area (91,028.6 mm²versus 67,506.5 mm², P = 0.0022), fascia area (69,238.4 mm²versus 56,730.9 mm², P = 0.0118), total body circumference (1101.8 mm versus 950.2 mm, P = 0.0017), and fascia circumference (967.5 mm versus 868.1 mm, P = 0.0077). We also demonstrated a significant positive correlation between the previously mentioned morphomic measurements and the incidence of complications in multivariate logistic regression models, with odds ratios ranging from 1.19–3.10 (P values ranging from 0.010–0.022).

Conclusions

Increases in abdominal morphomic measurements correlate strongly with the incidence of complications in patients undergoing sternal reconstruction. This finding may influence preoperative risk stratification and surgical decision making in this patient population.