A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast‐like cells

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue‐specific lesions associated with local double‐inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre‐expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1^flox/flox and Nf1^flox/? mice. The effects of the presence of Nf1^null cells were extensively examined. Cultured Nf1^null‐committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein‐2 (rhBMP‐2) treatment. Similarly, Nf1^null‐inducible osteoprogenitors obtained from Nf1 mouse muscle were also unresponsive to rhBMP‐2. In both closed and open fracture models in Nf1^flox/flox and Nf1^flox/? mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1^flox/flox and Nf1^flox/? mice. Histological analyses showed invasion of the Nf1^null fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10‐fold in Nf1^null fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1^null fractures, tartrate‐resistant acid phosphatase–positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds. © 2012 American Society for Bone and Mineral Research     

Late recovery of atrioventricular conduction after pacemaker implantation for complete heart block associated with surgery for congenital heart disease

OBJECTIVES: Pacemaker implantation is a standard recommendation for patients with persistent complete heart block following surgery for congenital heart disease. This study was performed to determine the incidence and clinical significance of late recovery of atrioventricular conduction following pacemaker implantation. METHODS: Between 1990 and 2001, 5662 open cardiac procedures for congenital heart defects were performed at our institution. The postoperative course of all patients with complete heart block in whom a permanent pacemaker was implanted was followed on a monthly basis, by either clinical or transtelephonic follow-up. RESULTS: A total of 72 patients with persistent postoperative complete heart block underwent pacemaker implantation. After insertion of the pacemaker, recovery of atrioventricular conduction was recognized in 7 of 72 patients (9.6%) at a median of 41 days (18-113 days) after the initial cardiac operation. These included 3 patients with ventricular septal defect, 2 with ventricular inversion or single ventricle, and 1 each with left ventricular outflow tract obstruction and atrioventricular septal defect. During a mean follow-up of 4.4 +/- 2.6 years, there was no late recurrence of heart block. Three patients had residual right bundle branch block and 1 had first-degree atrioventricular block. CONCLUSIONS: Atrioventricular conduction may return in a small but significant percentage of patients following pacemaker implantation for complete heart block associated with congenital heart surgery. When recovery of atrioventricular conduction occurs within the first months after surgery it appears reliable, which suggests that lifelong cardiac pacing may not be necessary in these individuals.     

Glomerular size and global glomerulosclerosis in normal Caucasian donor kidneys: effects of aging and gender

BACKGROUND: To assess the effects of aging and gender on glomerular size and global glomerulosclerosis (GS) and evaluate the relationship between glomerular size and GS in normal Caucasian donor kidneys. METHODS: All baseline graft biopsies between 1990 and 1998 were reviewed and sections with tissues containing at least 15 glomeruli were selected for morphometric analyses using a Digital Imaging Analyzer. Glomerular volumes (GV) were measured using the maximal profile area (MPA) method. The frequency of glomeruli with totally sclerotic lesions representing degree of global GS was expressed as a percentage of total number of glomeruli counted. RESULTS: 102 donor specimens (M/F, 46/56; mean age, 37.4 +/- 17.3 yrs) were analyzed showing mean MPA of 27.8 +/- 6.6 (x 10(-3)mm2), mean GV of 3.6 +/- 1.2 (x 10(6)microm3) and mean GS% of 6 +/- 10%. GV was increased with increasing age (r2 = 0.32, p < 0.0001). There was a progressive increase in glomerular size between infancy and adolescence (2-18 years old). The rate of MPA growth over childhood appeared to be linear (n = 13, r2 = 0.66, p = 0.0004). However, MPA increased with age at a slower rate (n = 99, r2 = 0.66, p = 0.0004) in adults (excluding data for patients < 18 years) than in infancy and adolescence. There wasn't significant gender difference in GV. Age (r = 0.47, p < 0.0001) and MPA (r = 0.31, p < 0.05) were both positively correlated with global GS. CONCLUSIONS: 1. Aging contributes to enlargement of glomerular size and global GS. 2. Gender had no significant effect on glomerular size. 3. Enlargement of glomerular size was associated with global GS in normal Caucasians.     

Poor sleep in adults with pediatric-onset spinal cord injury: associations with pain,health, and activity

Objective: To investigate medical complications that increase risk for poor sleep in adults with pediatric-onset spinal cord injury (SCI) and explore the relation of poor sleep to psychosocial outcomes.

Method: This was a cross-sectional study of individuals with pediatric-onset SCI interviewed between 2011–2015. Participants were recruited from a pediatric specialty hospital and answered questions about demographics, injury characteristics, pain, and medical complications and completed standardized outcome measures, including: Pittsburgh Sleep Quality Index, SF12v2 Health Survey, Craig Handicap Assessment and Recording Technique (CHART), and Subjective Happiness Scale.

Results: The study included 180 participants between the ages of 19 and 51 (M=34.20 y; SD=7.28) who sustained their SCI before the age of 19 (M=13.48y; SD=4.59). Participants were predominantly male (62%) and Caucasian (84%). A majority had tetraplegia (56%) and complete injuries (74%). Poor sleep occurred with greater frequency in those with tetraplegia and who were unemployed. Neck (OR=2.80, P?=?0.001), shoulder (OR=2.15, P?=?0.011), arm (OR=3.06, P?=?0.004), and lower extremity pain (OR=2.72, P?=?0.004) were associated with increased risk of poor sleep. In a logistic regression analysis, chronic medical conditions and continuous pain were most likely to be associated with poor sleep. Individuals with poor sleep reported lower levels of mobility, perceived health, and subjective happiness.

Conclusion: Pain and secondary complications significantly increase the odds of poor sleep. Furthermore, poor sleep is associated with decreased mobility and measures of well-being. Preventive measures to reduce risk factors and improve sleep quality after pediatric-onset SCI should be considered.     

Cardiovascular Health among Black and White Breast Cancer Patients Initiating Aromatase Inhibitor Therapy

The purpose of this study was to compare the cardiovascular health of Black and White breast cancer patients undergoing adjuvant treatment. Baseline data from a cohort study of Black (n = 45) and White (n = 101) breast cancer patients initiating aromatase inhibitor treatment were analyzed. Participants had a cardiovascular health assessment, including carotid intimal medial thickness measurement, donated a blood sample, and completed a questionnaire. Atherosclerotic cardiovascular disease (ASCVD) event risk scores were calculated. Compared to their White counterparts, the Black patients had a significantly higher median ASCVD risk score (p = 0.009) and had a higher number of CVD risk factors (p < 0.05). Black patients were also more likely to have hypertension, diabetes, or to be obese than the White participants. The prevalence of cardiovascular disease and cardiovascular disease risk factors among Black and White breast cancer patients is high, and racial disparities exist which may have treatment implications.     

Impact of modified-release opioid use on clinical outcomes following total hip and knee arthroplasty: a propensity score-matched cohort study

Modified-release opioids are often prescribed for the management of moderate to severe acute pain following total hip and knee arthroplasty, despite recommendations against their use due to increasing concerns regarding harm. The primary objective of this multicentre study was to examine the impact of modified-release opioid use on the incidence of opioid-related adverse events compared with immediate-release opioid use, among adult inpatients following total hip or knee arthroplasty. Data for total hip and knee arthroplasty inpatients receiving an opioid analgesic for postoperative analgesia during hospitalisation were collected from electronic medical records of three tertiary metropolitan hospitals in Australia. The primary outcome was the incidence of opioid-related adverse events during hospital admission. Patients who received modified with or without immediate-release opioids were matched to those receiving immediate-release opioids only (1:1) using nearest neighbour propensity score matching with patient and clinical characteristics as covariates. This included total opioid dose received. In the matched cohorts, patients given modified-release opioids (n = 347) experienced a higher incidence of opioid-related adverse events overall, compared with those given immediate-release opioids only (20.5%, 71/347 vs. 12.7%, 44/347; difference in proportions 7.8% [95%CI 2.3–13.3%]). Modified-release opioid use was associated with an increased risk of harm when used for acute pain during hospitalisation after total hip or knee arthroplasty.     

Laparoscopic cholecystectomy in a patient with a biventricular cardiac assist device.

Evaluation and management of abdominal pathology in patients with ventricular assist devices is likely to become increasingly important as the utilization of these devices expands. Ventricular assist devices represent a class of intracorporeal or paracorporeal mechanical devices that augment cardiac output in patients with congestive heart failure. Patients with ventricular assist devices supporting both right and left ventricles (biventricular assist devices) are uniquely challenging to the general surgeon because these devices restrict direct access to the abdominal cavity and because of the perioperative implications of biventricular heart failure. We describe herein the first reported successful laparoscopic cholecystectomy in a patient with a paracorporeal biventricular assist device. Cholecystectomy was performed in this patient for acute cholecystitis that occurred while the patient was awaiting heart transplantation. Our results add weight to the small body of evidence that laparoscopy is well tolerated in ventricular assist devices patients. The unique aspects of the biventricular assist device patient make laparoscopic abdominal intervention particularly suitable in this patient population.     

Resection of liver metastases from colorectal cancer: does preoperative chemotherapy affect the accuracy of PET in preoperative planning?

Background: Preoperative scanning for hepatic colorectal metastases surgery remains a challenge, especially in the age of preoperative chemotherapy, which has marked biochemical and physical effects on the liver. Integrated fluoro‐deoxyglucose positron emission tomography and computed tomography (FDG‐PET/CT) has applications for detecting extrahepatic disease. The aim of the present study was to investigate FDG‐PET/CT as a preoperative planning tool for detecting liver lesions in patients with and without preoperative chemotherapy. Methods: Patients who had resection of hepatic colorectal metastases between January 2004 and June 2006 were included. Patients were divided into those who received preoperative chemotherapy and those who did not. Malignant hepatic lesions found on each scan were compared with those found on histopathology, intraoperative examination and/or intraoperative ultrasound. Accurate scans (scan lesions corresponded to true lesions), false positives (scan lesions detected at least one non‐lesion) and false negatives (scan lesions missed at least one true lesions) were recorded. Results were also compared on a per lesion basis. Results: A total of 21 patients had preoperative FDG‐PET/CT scans with preoperative chemotherapy and 53 without. Accurate tests were six (29%) for the chemotherapy group versus 28 (53%) for the non‐chemotherapy group (P= 0.06). Notably, there were 11 (52%) underestimations in the chemotherapy group versus 18 (34%) in the non‐chemotherapy group. A total of 1.7 lesions were missed per patient in the chemotherapy group versus 0.7 in those who did not receive chemotherapy. Conclusion: Preoperative assessment with FDG‐PET/CT is not useful for hepatic colorectal metastases, particularly when preoperative chemotherapy is used, with a trend towards underestimation of lesions.