Inhalation of the Phosphodiesterase-3 Inhibitor Milrinone Attenuates Pulmonary Hypertension in a Rat Model of Congestive Heart Failure

Background: Most patients with congestive heart failure (CHF) develop pulmonary venous hypertension, but right ventricular afterload is frequently further elevated by increased pulmonary vascular resistance. To investigate whether inhalation of a vasodilatory phosphodiesterase-3 inhibitor may reverse this potentially detrimental process, the authors studied the effects of inhaled or intravenous milrinone on pulmonary and systemic hemodynamics in a rat model of CHF.

Methods: In male Sprague-Dawley rats, CHF was induced by supracoronary aortic banding, whereas sham-operated rats served as controls. Milrinone was administered as an intravenous infusion (0.2-1 [mu]g [middle dot] kg body weight-1 [middle dot] min-1) or by inhalation (0.2-5 mg/ml), and effects on pulmonary and systemic hemodynamics and lung water content were measured.

Results: In CHF rats, intravenous infusion of milrinone reduced both pulmonary and systemic arterial blood pressure. In contrast, inhalation of milrinone predominantly dilated pulmonary blood vessels, resulting in a reduced pulmonary-to-systemic vascular resistance ratio. Repeated milrinone inhalations in 20-min intervals caused a stable reduction of pulmonary artery pressure. No hemodynamic effects were detected when 0.9% NaCl was administered instead of milrinone or when milrinone was inhaled in sham-operated rats. No indications of potentially adverse effects of milrinone inhalation in CHF, such as left ventricular volume overload, were detected. Moreover, lung edema was significantly reduced by repeated milrinone inhalation.     

Continuous psoas and sciatic block after knee arthroplasty: good effects compared to epidural analgesia or i.v. opioid analgesia: a prospective study of 63 patients

Introduction For endoprosthetic knee surgery, intensive postoperative pain therapy is necessary. We therefore evaluated whether the combination of continuous psoas compartment and sciatic analgesia (PSC) is as effective as epidural analgesia (EPI) and whether it provides better analgesia than patient-controlled intravenous analgesia with piritramide (PCA).

Methods We studied 63 patients who underwent total knee arthroplasty (TKA). The PSC group received a combination of continuous psoas and sciatic nerve block, the EPI group an epidural analgesia, and the PCA group an intravenous patient-controlled piritramide pump. Pain scores, satisfaction, flexion and side effects were recorded.

Results Pain scores (0-10) were higher in the PCA group (on movement, day 1/day 2: 7.0/6.5) than in the EPI group (5.0/5.0) and the PSC group (4.0/3.5). Postoperative opioid consumption over 48 h was higher in the PCA group (51 mg) than in the EPI group (0 mg) and the PSC group (0 mg). There were no differences in functional recovery. Pruritus occurred more frequently in the PCA and EPI groups than in the PSC group. Patients receiving a PSC and EPI were more satisfied than those treated with PCA.

Interpretation Analgesia with PSC catheters or EPI catheter is superior to PCA regarding pain levels, analgesic requirements, and patient satisfaction. There was no difference in functional outcome between the 3 groups.     

Intraductal papillomas of the breast: diagnosis and management of 151 patients

Introduction

The assessment of papillary lesions continues to be a challenging area in breast radiology and pathology. The management of intraductal papillomas without atypia of the breast remains controversial. The purpose of the present study was to determine diagnostic accuracy of radiographical diagnosis, core biopsy, and surgical excision in papillary breast lesions.

Material and methods

By using files from 1995 to 2010, 151 cases of intraductal papilloma with or without atypia were identified. Patients were stratified as follows: core biopsy followed by surgical excision (n = 61), core biopsy alone (n = 19), and surgical excision alone (n = 71).

Results

The upstage rate of intraductal papillomas without atypia on core biopsy to atypia or malignancy on excision was 8.9%. Excision specimens revealed intraductal papillomas without atypia in 68 out of 71 cases, and atypical papillomas in 3 cases.

Conclusion

Our findings suggest that radiographic and histopathological diagnosis of intraductal papillomas show high accuracy and good concordance. In cases where the radiographic diagnosis reveals suspicious lesions core biopsy represents the first choice.     

Thromboembolism prophylaxis with dabigatran leads to lower perioperative blood loss than with dalteparin in primary knee arthroplasty

Introduction  

Low-molecular-weight heparins (LMWH) are commonly used in thrombosis prophylaxis after total knee arthroplasty. In contrast to LMWH, dabigatran etexilate is an oral and direct acting anticoagulant. The hypothesis of the present study was that blood loss occurring in total knee arthroplasty (TKA) is not greater after dabigatran etexilate than after dalteparin.     

Influence of the position of the fibular head after implantation of a total knee prosthesis on femorotibial rotation

A gold standard for the correct rotation of the tibial component has not been established in total knee arthroplasty (TKA). The target parameter of correct rotation is the facilitation of femorotibial rotation over the entire range of motion with no implant overhang. Although the origin of the lateral collateral ligament is a recognized landmark for determining the rotation of the femoral component (epicondylar axis), the attachment of the lateral collateral ligament has not been taken into consideration for adjusting tibial rotation until now. The objective of the current investigation was to examine whether the position of the fibular head, as the attachment of the lateral collateral ligament, influences femorotibial rotation. Seventy patients who underwent TKA were enrolled in this retrospective study. Computed tomography (CT) of the operated knee was performed 6 months postoperatively in all cases and the position of the lateral facet of the fibular head and the tibial tuberosity, and the geometric center of the tibia and the femoral epicondyles were determined. The angle between the lateral facet of the fibular head, the geometric center of the tibia, and the tibial tuberosity was 45.7°±6.9°. The angle between the surgical epicondylar axis and the line from tibial tuberosity to tibial center was 69°±8.3°. This close correlation (R=.73; P<.001) shows that the position of the fibular head determines femorotibial rotation. The fibular head may become a helpful landmark for establishing the rotation of the tibial component; it could be useful in interpretation of postoperative CT scans in knees suspected of tibial malrotation.     

Denosumab and changes in bone turnover markers during androgen deprivation therapy for prostate cancer

Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C‐telopeptide (sCTX), tartrate‐resistant alkaline phosphatase 5b (TRAP‐5b), and procollagen‐1 N‐terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double‐blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (< 70 years versus ≥ 70 years), prior duration of ADT (≤ 6 months versus >6 months), and baseline BTM (≤ median versus > median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was ?90% in the denosumab group and ?3% in the placebo group (p < 0.0001). The median change in TRAP‐5b levels at month 1 was ?55% in the denosumab group and ?3% in the placebo group (p < 0.0001). The maximal median change in P1NP was ?64% in the denosumab group and ?11% in the placebo group, (p < 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously. © 2011 American Society for Bone and Mineral Research     

Risk factors for well-differentiated thyroid carcinoma in patients with thyroid nodular disease.

OBJECTIVES: Evaluate current accepted risk factors for well-differentiated thyroid carcinoma, and develop a predictive model to determine one's risk of malignancy given a thyroid nodule. STUDY DESIGN: Retrospective analysis of 600 patients. SUBJECTS AND METHODS: Patients with benign thyroid nodular disease and with well-differentiated thyroid cancer were randomly selected. Patient, clinical, and investigational data were compared by means of univariate and multivariate regression analyses. RESULTS: Age, regional lymphadenopathy, ipsilateral vocal cord palsy, solid and/or calcified nodules, and an aspiration biopsy being malignant or suspicious predicted for cancer (P < 0.05). Regional lymphadenopathy and vocal cord palsy are perfect predictors of malignancy. Multivariate analysis indicated age, solid and/or calcified nodules, and all fine-needle aspiration biopsy results to be significant in assessing risk (P < 0.05). CONCLUSION: Taking individual risk factors in isolation is not always reliable. Using a predictive model, one can anticipate a patient's risk of malignancy when the diagnosis is unclear.     

Flexible non-fusion scoliosis correction systems reduce intervertebral rotation less than rigid implants and allow growth of the spine: a finite element analysis of different features of orthobiom™

The orthobiom™ non-fusion scoliosis correction system consists of two longitudinal rods, polyaxial pedicle screws, mobile and fixed connectors and a cross-connector. The mobile connectors can move along and around the rod, thus allowing length adaptation during growth. The aim of this study was to determine the effects of different features of this novel implant on intervertebral rotations, to calculate the movement of the mobile connectors along the rods for different loading cases and to compare the results with those of a rigid implant construct. A finite element analysis was performed using six versions (M1–M6) of a three-dimensional, nonlinear model of a spine ranging from T3 to L2. The models were loaded with pure moments of 7.5 N m in the three main anatomical planes. First, the validated intact model (M1) was studied. Then, the orthobiom™ implant system was inserted, bridging the segments between T4 and L1 (M2). The effect of pedicle screws only in every second vertebrae was investigated (M3). For comparison, three connection variations of screws and rods were investigated: (1) an implant with rigid screws and mobile connectors (M4), (2) an implant with non-locking polyaxial screws and fixed connectors (M5) and (3) a completely rigid implant construct (M6). For flexion, extension and lateral bending, intervertebral rotation was reduced at all implant levels due to the implants. A rigid implant construct (M6) and an implant with non-locking polyaxial screws and fixed connectors (M5) led to the strongest reduction of intervertebral rotation. The orthobiom™ non-fusion implant system (M2, M3) allowed much more intervertebral rotation than a rigid implant (M6). Differences in intervertebral rotations were small when polyaxial screws were placed at every second level only (M3) instead of at every level (M2). For axial rotation, intervertebral rotation was strongly reduced by a rigid implant construct (M6) and by an implant with rigid screws and mobile connectors (M4). For rotation, an implant with non-locking polyaxial screws (M2, M3, M5) led to nearly the same intervertebral rotations as in an intact spine without an implant (M1). The predicted maximum translation of the mobile connectors along the rod was 4.2 mm for extension, 3.1 mm for lateral bending, 1.6 mm for flexion and 0.8 mm for axial rotation. The movement of the connectors was highest for those closest to the ends of the rods. With rigid screws, the maximum translation was significantly reduced. This study, conducted under a load-controlled loading protocol, showed that intervertebral rotation was reduced much less by the non-fusion orthobiom™ system than by a rigid implant. The mobile connectors moved considerably along the rod when the spine was bent. It can be expected that the connectors also move along the rod as the adolescent grows, possibly leaving the discs intact until the patient is fully grown.     

Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes

Abstract: Background: Hyperacute rejection (HAR) and early graft failure (EGF) have been described in a minority of pig‐to‐baboon heart transplants using organs transgenic for human complement regulatory proteins (hCRP). Here we investigate the role of coagulation cascade activation in the pathogenesis of HAR and EGF in a consecutive series where a high incidence of these outcomes was observed. Methods: Twenty‐eight naïve wild‐caught Papio anubis baboons received heterotopic heart transplants from pigs transgenic for hDAF (n = 23) or hMCP (n = 5). Immunosuppression consisted of cyclosporine A, cyclophosphamide and MMF (n = 18) or anti‐CD154 mAb (IDEC‐131) and ATG (n = 10). Eleven received anti‐Gal carbohydrates (GAS914, n = 8, or NEX1285, n = 3), of which four also underwent extracorporeal immunoadsorption (EIA), and 12 also received pharmacologic complement inhibitors (C1 INH, n = 9, or APT070, n = 3). Results: Excluding one technical failure, 14 of 27 transplants (11 hDAF, 3 hMCP) exhibited either HAR (n = 10) or EGF (n = 4). Surprisingly, neither complement inhibition (with C1 INH or APT070) nor anti‐Gal antibody depletion with GAS914, NEX1285, or additional EIA consistently prevented HAR or EGF despite low or undetectable complement deposition. Strikingly, most grafts with HAR/EGF exhibited prominent fibrinogen and platelet deposition associated with systemic coagulation cascade activation, consistent with non‐physiologic intravascular coagulation, in many instances despite little evidence for antibody‐mediated complement activation. Conclusion: We conclude that dysregulated coagulation correlates closely with and probably causes primary failure of pig hearts transgenic for hCRP. These data support efforts to define effective strategies to prevent dysregulated coagulation in pig organ xenografts.     

Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not

Metabolic effects of the glucagon-like peptide-1 analog liraglutide and the dipeptidyl peptidase-IV inhibitor vildagliptin were compared in rats made obese by supplementary candy feeding. Female Sprague-Dawley rats were randomized to 12-week diets of chow or chow plus candy. The latter were randomized for 12 further weeks to continue their diet while receiving 0.2 mg/kg liraglutide twice daily subcutaneously, 10 mg/kg vildagliptin twice daily orally, or vehicle or to revert to chow-only diet. Energy expenditure was measured, and oral glucose tolerance tests (OGTTs) were performed. Body composition was determined by dual-energy X-ray absorptiometry scanning, and pancreatic beta-cell mass was determined by histology. Candy feeding increased weight, fat mass, and feeding-associated energy expenditure. Liraglutide or reversal to chow diet fully reversed weight and fat gains. Liraglutide was associated with decreased calorie intake and shifted food preference (increased chow/decreased candy consumption). Despite weight loss, liraglutide-treated rats did not decrease energy expenditure compared with candy-fed controls. Vildagliptin affected neither weight, food intake, nor energy expenditure. OGTTs, histology, and blood analyses indirectly suggested that both drugs increased insulin sensitivity. Liraglutide and vildagliptin inhibited obesity-associated increases in beta-cell mass. This was associated with weight and fat mass normalization with liraglutide, but not vildagliptin, where the ratio of beta-cell to body mass was low.