Progesterone improves acute recovery after traumatic brain injury in the aged rat

Recent evidence has demonstrated that treatment with progesterone can attenuate many of the pathophysiological events following traumatic brain injury (TBI) in young adult rats, but this effect has not been investigated in aged animals. In this study, 20-month-old male Fischer 344 rats with bilateral contusions of the frontal cortex (n = 4 per group) or sham operations received 8, 16, or 32 mg/kg of progesterone or vehicle. Locomotor activity was measured at 72 h to assess behavioral recovery. Brain tissue was harvested at 24, 48, and 72 h, and Western blotting was performed for inflammatory and apoptotic factors. Edema was assessed at 48 h by measuring brain water content. Injured animals treated with 8 and 16 mg/kg progesterone showed decreased expression of COX-2, IL-6, and NFkappaB at all time points, indicating a reduction in the acute inflammatory process compared to vehicle. The 16 mg/kg group also showed reduced apoptosis at all time points as well as decreased edema and improved locomotor outcomes. Thus, in aged male rats, treatment with 16 mg/kg progesterone improves short-term motor recovery and attenuates edema, secondary inflammation, and cell death after TBI.     

Laparoscopic Heller myotomy with anterior fundoplication ameliorates symptoms of achalasia in pediatric patients

BACKGROUND: This study was undertaken to define outcomes after laparoscopic Heller myotomy with anterior fundoplication in pediatric patients and compare their outcomes with those in adults. STUDY DESIGN: A total of 337 patients have undergone laparoscopic Heller myotomy with anterior fundoplication since 1992, and were prospectively followed; 14 were pediatric patients of median age 17 years (range 11 to 19 years). Symptoms noted by pediatric patients before and after myotomy were compared with symptoms of 56 concurrently treated adults (4 treated adults for each pediatric patient) of median age 48 years. Among many symptoms, patients scored the severity and frequency of dysphagia, chest pain, regurgitation, choking, vomiting, and heartburn before and after myotomy using a Likert scale, ranging from 0 (never/not bothersome) to 10 (always/very bothersome). Followups were 38 months, 42 months+/-33.1. Data are reported as median, mean +/- SD. RESULTS: For pediatric patients, length of stay after myotomy was 2 days, 3 days+/-2.9 versus 2 days, 2+/-2.1 for adults. Before myotomy, symptom frequency and severity were similar between groups. After myotomy, symptom frequency and severity were similar between pediatric and adult patients, except for the frequency of chest pain. CONCLUSIONS: Achalasia can produce disabling symptoms, which were similar between pediatric and adult patients before myotomy. Laparoscopic Heller myotomy with anterior fundoplication ameliorated symptoms of achalasia in all patients, with postmyotomy symptoms similar between pediatric and adult patients. Laparoscopic Heller myotomy dramatically improved symptoms of achalasia in pediatric patients and its use is encouraged.     

Evaluation of anastomotic strength and drug safety after short-term sunitinib administration in rabbits

Background

Sunitinib (Sutent) is a Food and Drug Administration–approved receptor tyrosine kinase inhibitor found to reduce postoperative adhesion formation in animal models. The objective of the present study was to evaluate anastomotic healing and potential drug-related toxicities after short-term sunitinib administration in New Zealand White rabbits.

Materials and methods

Under an approved study protocol, 40 rabbits underwent a laparotomy followed by colonic transection and anastomosis. Animals were randomly assigned to treatment with oral sunitinib (10 mg/kg/d) or placebo, received one preoperative dose followed by 10 postoperative doses, and were divided into two groups following the procedure: group I animals were euthanized on completion of drug treatment and group II animals were euthanized 30 d after completion of treatment. Prior to study completion, animals underwent an echocardiogram and laboratory test results were obtained. At necropsy, intestinal bursting strength (in mmHg) was evaluated.

Results

All animals survived until designated euthanasia. There was no evidence of intra-abdominal sepsis or intestinal obstruction. Sunitinib-treated animals were found to have lower intestinal anastomotic strength compared with placebo-treated animals, as measured by bursting pressure at euthanasia, and a greater percentage of bursting at the anastomosis. On echocardiography, all ejection and shortening fractions were within established normal reference values. There were no significant differences in liver enzymes between animals. There were no wound infections, dehiscence, or delayed wound healing in any animal.

Conclusions

These results caution against the administration of sunitinib in cases involving intestinal anastomoses because of the elevated risk of anastomotic leak. No evidence of cardiotoxicity, hepatotoxicity, or detrimental effect on wound healing was found in any animal.     

Mid-Adulthood Risk Factor Profiles for CKD

Early identification of CKD risk factors may allow risk factor modification and prevention of CKD progression. We investigated the hypothesis that risk factors are present ≥30 years before the diagnosis of CKD in a case-control study using data from the Framingham Offspring Study. Patients with incident CKD (eGFR≤60 ml/min per 1.73 m²) at examination cycles 6, 7, and 8 were age- and sex-matched 1:2 to patients without CKD at baseline (examination 5). CKD risk factors were measured at each examination cycle. Logistic regression models, adjusted for age, sex, and time period, were constructed to compare risk factor profiles at each time point between cases and controls. During follow-up, 441 new cases of CKD were identified and matched to 882 controls (mean age 69.2 years, 52.4% women). Those who ultimately developed CKD were more likely to have hypertension (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.23 to 2.51), obesity (OR, 1.71; 95% CI, 1.14 to 2.59), and higher triglyceride levels (OR, 1.43; 95% CI, 1.12 to 1.83) 30 years before CKD diagnosis, and were more likely to have hypertension (OR, 1.38; 95% CI, 1.07 to 1.79), higher triglyceride levels (OR, 1.35; 95% CI, 1.11 to 1.64), lower HDL_c (OR, 0.89; 95% CI, 0.81 to 0.97), and diabetes (OR, 2.90; 95% CI, 1.59 to 5.29) 20 years before CKD diagnosis. These findings demonstrate that risk factors for CKD are identifiable ≥30 years before diagnosis and suggest the importance of early risk factor identification in patients at risk for CKD.     

Serum levels of 17-β-estradiol are not predictive of prostate cancer diagnosis and aggressiveness: Results from an Italian biopsy cohort

ObjectivesTo explore the association between serum levels of 17-β-estradiol (17BE) and prostate cancer (PCa) risk in men undergoing prostate biopsy.Methods and materialsBetween 2006 and 2012, we prospectively enrolled 894 patients, with no history of PCa, undergoing prostate biopsy. Before biopsy was performed, general data, digital rectal examination (DRE), body mass index, 17BE, and prostate-specific antigen (PSA) were recorded. The risk of detecting cancer and high-grade cancer was assessed as a function of 17BE using crude and adjusted logistic regressions.ResultsSerum levels of 17BE were not associated with an increased risk of PCa or high-grade disease. Age (odds ratio [OR] 1.05; 95% confidence interval [CI]: 1.03–1.07; P = 0.000), DRE(OR 2.81; 95% CI: 1.98–4.00; P = 0.000), and PSA(OR 1.07; 95% CI: 1.04–1.10; P = 0.000) were found to be independent predictors of PCa risk. Age (OR 1.05; 95% CI: 1.01–1.09; P = 0.007), DRE (OR 3.04; 95% CI: 1.79–5.17; P = 0.000), body mass index (OR 1.07; 95% CI: 1.01–1.150; P = 0.040), and PSA (OR 1.08; 95% CI: 1.03–1.12; P = 0.000) were found to be independent predictors of high-grade disease.ConclusionIn our cohort of patients, serum levels of 17BE are not predictive of PCa or high-grade disease. In patients at risk of PCa, 17BE should not be considered a reliable marker to predict poorly differentiated PCa in the setting of initial prostate biopsy.     

MALDI imaging–based identification of prognostically relevant signals in bladder cancer using large-scale tissue microarrays

ObjectiveAlthough most patients with urinary bladder cancer present with noninvasive and low-malignant stages of the disease, about 20% eventually develop life-threatening metastatic tumors. This study was designed to evaluate the potential of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify molecular markers predicting the clinical course of bladder cancer.Materials and methodsWe employed MALDI-MSI to a bladder cancer tissue microarray including paraffin-embedded tissue samples from 697 patients with clinical follow-up data to search for prognostically relevant associations.ResultsAnalysis of our MALDI imaging data revealed 40 signals in the mass spectra (m/z signals) associated with epithelial structures. The presence of numerous m/z signals was statistically related to one or several phenotypical findings including tumor aggressiveness (stage, grade, or nodal status; 30 signals), solid (5 signals) or papillary (3 signals) growth patterns, and increased (6 signals) or decreased (12 signals) cell proliferation, as determined by Ki-67 immunohistochemistry. Two signals were linked with tumor recurrence in noninvasive (pTa category) tumors, of which one was also related to progression from pTa-category to pT1-category disease. The absence of one m/z signal was linked with decreased survival in the subset of 102 muscle-invasive cancers.ConclusionOur data demonstrate the suitability of combining MSI and large-scale tissue microarrays to simultaneously identify and validate clinically useful molecular markers in urinary bladder cancer.     

The Effect of Perioperative Iron Therapy in Acute Major Non-cardiac Surgery on Allogenic Blood Transfusion and Postoperative Haemoglobin Levels: A Systematic Review and Meta-analysis

Background

Perioperative anaemia in relation to surgery is associated with adverse clinical outcomes. In an elective surgical setting, it is possible to optimize patients prior to surgery, often by iron supplementation with correction of anaemia. Possibilities for optimization prior to and during acute surgical procedures are limited. This review investigates whether iron treatment initiated perioperatively improves outcomes in patients undergoing major acute non-cardiac surgery.

Method

This systematic review was performed using PubMed, EMBASE (Ovid) and Scopus to identify current evidence on iron supplementation in acute surgery. Primary outcomes were allogenic blood transfusion (ABT) rate and changes in haemoglobin. Secondary outcomes were postoperative mortality, length of stay (LOS), and postoperative complications. Iron was administered at latest within 24 h after end of surgery.

Results

Of the 5413 studies screened, four randomized controlled trials and nine observational cohort studies were included. Ten studies included patients with hip fractures. A meta-analysis of seven studies showed a risk reduction of transfusion (OR = 0.35 CI 95% (0.20–0.63), p = 0.0004, I² = 66%). No influence on plasma haemoglobin was found. Postoperative mortality was reduced in the iron therapy group in a meta-analysis of four observational studies (OR 0.50 (CI 95% 0.26–0.96) p = 0.04). No effect was found on LOS, but a reduction in postoperative infection was seen in four studies.

Conclusions

This review examined perioperative iron therapy in acute major non-cardiac surgery. IV iron showed a lower 30-day mortality, a reduction in postoperative infections and a reduction in ABT largely due to the observational studies. The review primarily consisted of small observational studies and does not have the power to formally recommend this practice.

     

Nucleus accumbens core and shell are differentially involved in general and outcome‐specific forms of Pavlovian‐instrumental transfer with alcohol and sucrose rewards

Alcohol‐associated stimuli contribute to relapse risk. Therefore, understanding the behavioural and neural mechanisms underlying the ability of such stimuli to promote alcohol‐seeking is important for developing effective treatments for alcohol‐use disorders. The Pavlovian‐instrumental transfer (PIT) paradigm can be used to study the influence of Pavlovian cues on independently‐trained instrumental responses earning reward. The effects can be either general, increasing the vigour of reward‐related behaviours, or specific to responses that earn a common outcome. These different forms of PIT are mediated by distinct neural circuits involving the nucleus accumbens (NAC) core and shell, respectively. Here we examined the effects of pharmacological inactivation of either the NAC core or shell on PIT generated by alcohol‐predictive and sucrose‐predictive stimuli in rats. We found that presentations of a stimulus predicting sucrose enhanced responding for sucrose but not alcohol, suggesting an outcome‐specific effect. In contrast, presentations of an alcohol‐predictive stimulus enhanced responding for both alcohol and sucrose, suggesting a generally arousing effect. Inactivation of the NAC core reduced PIT and, in particular, the effect of the alcohol stimulus. Inactivation of the NAC shell reduced the specificity of the stimulus effects but left the ability of the stimuli to non‐specifically invigorate responding intact, consistent with a role in mediating the specificity of PIT. Together, these results suggest that the NAC core plays a particularly important role in mediating the influence of alcohol‐predictive cues on reward‐seeking behaviours.