Matrix metalloproteinase protein expression profiles cannot distinguish between normal and early osteoarthritic synovial fluid

ABSTRACT: BACKGROUND: Osteoarthritis (OA) and Rheumatoid arthritis (RA) are diseases which result in the degeneration of the joint surface articular cartilage. Matrix Metalloproteinases (MMPs) are enzymes that aid in the natural remodelling of tissues throughout the body including cartilage. However, some MMPs have been implicated in the progression of OA and RA as their expression levels and activation states can change dramatically with the onset of disease. Yet, it remains unknown if normal and arthritic joints demonstrate unique MMPs expression profiles, and if so, can the MMP expression profile be used to identify patients with early OA. In this study, the synovial fluid protein expression levels for MMPs 1, 2, 3, 7, 8, 9, 12 & 13, as well as those for the Tissue Inhibitors of MMPs (TIMPs) 1, 2, 3, & 4 were examined in highly characterized normal knee joints, and knee joints with clinically diagnosed OA (early and advanced) or RA. The purpose of this study was to determine if normal, OA, and RA patients exhibit unique expression profiles for a sub-set of MMPs, and if early OA patients have a unique MMP expression profile that could be used as an early diagnostic marker. METHODS: Synovial fluid was aspirated from stringently characterized normal knee joints, and in joints diagnosed with either OA (early and advanced) or RA. Multiplexing technology was employed to quantify protein expression levels for 8 MMPs and 4 TIMPs in the synovial fluid of 12 patients with early OA, 17 patients diagnosed with advanced OA, 15 with RA and 25 normal knee joints. Principle component analysis (PCA) was used to reveal which MMPs were most influential in the distinction between treatment groups. K - means clustering was used to verify the visual grouping of subjects via PCA. RESULTS: Significant differences in the expression levels of MMPs and TIMPs were observed between normal and arthritic synovial fluids (with the exception of MMP 12). PCA demonstrated that MMPs 2, 8 & 9 can be used to effectively separate individuals diagnosed with advanced arthritis from early osteoarthritic and normal individuals, however, these MMP profiles do not separate early OA from normal synovial fluid. An apparent separation between advanced OA and RA subjects was also revealed through PCA. K-means clustering verified the presence of 3 clusters: normal joints clustered with early OA, and separate clusters of advanced OA or RA. CONCLUSIONS: This study demonstrates that unique MMP and TIMP expression profiles are present within normal, advanced OA and RA synovial fluid. These MMP profiles can be used to distinguish advanced OA & RA synovial fluid from early OA & normal synovial fluid, and even between synovial fluid samples from OA and RA joints. Although this methodology cannot be used for the diagnosis of early OA, high throughput multiplex technology of MMPs and TIMPs in synovial fluid may prove useful in determining the severity of the disease state, and/or quantifying the response of individuals to disease interventions.     

Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX

Denosumab has been shown to reduce the incidence of vertebral, nonvertebral, and hip fractures. The aim of the current study was to determine whether the antifracture efficacy of denosumab was dependent on baseline fracture probability assessed by FRAX. The primary data of the phase 3 FREEDOM study of the effects of denosumab in women with postmenopausal osteoporosis were used to compute country-specific probabilities using the FRAX tool (version 3.2). The outcome variable comprised all clinical osteoporotic fractures (including clinical vertebral fractures). Interactions between fracture probability and efficacy were explored by Poisson regression. At baseline, the median 10-year probability of a major osteoporotic fracture (with bone mineral density) was approximately 15% and for hip fracture was approximately 5% in both groups. In the simplest model adjusted for age and fracture probability, treatment with denosumab over 3 years was associated with a 32% (95% confidence interval [CI] 20% to 42%) decrease in clinical osteoporotic fractures. Denosumab reduced fracture risk to a greater extent in those at moderate to high risk. For example, at 10% probability, denosumab decreased fracture risk by 11% (p = 0.629), whereas at 30% probability (90th percentile of study population) the reduction was 50% (p = 0.001). The reduction in fracture was independent of prior fracture, parental history of hip fracture, or secondary causes of osteoporosis. A low body mass index (BMI) was associated with greater efficacy. Denosumab significantly decreased the risk of clinical osteoporotic fractures in postmenopausal women. Overall, the efficacy of denosumab was greater in those at moderate to high risk of fracture as assessed by FRAX.     

Repeated treatment of vestibular schwannomas after gamma knife radiosurgery

Purpose  When gamma knife radiosurgery (GKS) does not achieve control of the growth of a tumour, the need to repeat treatment is considered. The results and risks of repeat treatment of patients with a vestibular schwannoma were reviewed to assess its efficacy and safety. Methods  Between 1992 and 2001, we treated 351 patients with a vestibular schwannoma by GKS, control of the growth of the tumour was not achieved in 32. 26 patients underwntrepeat GKS and five patients had an open microsurgical operation and one stereotactic aspiration of a tumour cyst. Results  Twenty-four of 26 patients were followed up after the repeat GKS for a median of 43 months. 15 tumours became smaller, seven remained unchanged and two enlarged. After the second GKS one patient’s hearing deteriorated, one developed facial weakness and three facial spasms. One patient required insertion of ventriculo-peritoneal drainage. An operation to radically resect the tumour was performed in five patients after the first GKS and for a subtotal removal in one after repeated GKS. Conclusions  In the small proportion of patients (9%) in whom initial GKS does not control the growth of a vestibular schwannoma, most can be controlled by further GKS with a very low risk of a complications.     

Training general surgery residents in pediatric surgery: educational value vs time and cost

Background

This study evaluated the educational value of pediatric surgery rotations, the likelihood of performing pediatric operations upon completing general surgery (GS) residency, and time and cost of training GS residents in pediatric surgery.

Methods

A survey was administered to GS residents that evaluated the pediatric surgery rotation and anticipated practice intentions. A retrospective analysis (2005-2006) of operative times for unilateral inguinal hernia repair, bilateral inguinal hernia repair, and umbilical hernia repair was also performed. Procedure times were compared for operations performed by a pediatric surgeon with and without GS residents. Cost analysis was based on time differences.

Results

General surgery residents (n = 19) considered the pediatric surgery rotation to have high educational value (4.7 ± 0.6 of 5) with extensive teaching (4.6 ± 0.7) and operative experience (4.4 ± 0.8). Residents listed pediatric surgery exposure, operative technique, and observed work ethic as most valuable. Upon graduation, residents expect to perform pediatric operations 2 to 3 times annually. Thirty-seven percent of residents felt competent to perform appendectomy (patients >5 years), 32% appendectomy (3-5 years), 21% gastrostomy (>1 year), and 11% inguinal herniorrhaphy (>1 year). Operative times and costs were significantly higher in operative procedures performed with a GS resident.

Conclusion

General surgery residents considered pediatric surgery as a valuable educational experience. Residents anticipate performing pediatric operations a few times annually. Training GS residents in pediatric surgery increased operative time and cost. This information may be useful in determining the appropriate setting for resident education as well as budget planning for pediatric surgical practices.     

Establishing a regional pediatric surgical service in the setting of universal health care: a glimpse into the future

Purpose

Increasing health care expense and rising numbers of uninsured Americans have led many to propose a national health insurance. This study describes the process, rationale, and requirements in creating a regional pediatric surgical service in the setting of a single-payer system.

Methods

Our health care system consists of 10 medical centers providing comprehensive care to more than 3 million members. All services are provided by salaried physicians/practitioners to prepaid members. Before July 2004, pediatric surgical care was performed at multiple medical centers with many services contracted out. Starting July 2004, a multidisciplinary, comprehensive pediatric perioperative plan was established. Implementation has occurred in steps; current status and preliminary results are reviewed.

Results

Strict guidelines for pediatric anesthesia and requirements for support services, personnel, and equipment were defined. Pediatric surgery is now performed at 3 community medical centers and 1 tertiary, teaching hospital. Operative cases were assigned to each center based on age, complexity, level of postoperative care, and location. A single high-volume, center for complex care has been established. Access to care was excellent; more than 90% of outpatient consultations were seen within 2 weeks. Utilization of services was 94% in 2006 and 98% in 2007. Physician and patient satisfaction were high. Additional pediatric surgeons have been hired and nearly all care has been internalized. Given the proximity to a major children's hospital, specialty services have not been duplicated.

Conclusion

Establishing a multidisciplinary, comprehensive pediatric perioperative plan provided standards for supporting pediatric surgical services at community hospitals. This regional service may be a model for the future of specialty care, especially in the setting of a single-payer system.     

Endoscopic Vaporesection of the Prostate Using the Continuous-Wave 2-μm Thulium Laser: Outcome and Demonstration of the Surgical Technique

Background

The potential of a new continuous-wave (CW) 70-W, 2.013-μm thulium-doped yttrium aluminium garnet (Tm:YAG) laser for the endoscopic treatment of benign prostatic hyperplasia (BPH) is investigated.

Objective

The simultaneous combination of vaporisation and resection of prostatic tissue in a retrograde fashion is the main characteristic of this new laser technique. We provide a DVD that shows the main steps of this procedure.

Design, setting, and participants

We retrospectively evaluated 56 nonconsecutive patients who were treated by thulium laser vaporesection of the prostate in our institution between 2005 and 2007.

Surgical procedure

Vaporesection of the prostate is performed by moving the fibre semicircumferentially from the verumontanum towards the bladder neck, thereby undermining tissue and cutting chips.

Measurements

Blood loss, postvoiding residual urine (PVRU), maximum flow rate (Q_max), and the International Prostate Symptom Score (IPSS) were measured as well as prostate volume and prostate-specific antigen (PSA). The duration of the procedure, need for postoperative irrigation, duration of catheterisation, and hospital stay were recorded.

Results and limitations

The median procedure time was 60 min, postoperative irrigation was necessary in 19 out of 56 patients, and the median duration of catheterisation was 23 hr. At the day of discharge, the mean haemoglobin value decreased by 0.2 mg/dl (p = 0.13), the average Q_max improved from 8.1 to 19.3 ml/s (p < 0.001), and the PVRU decreased from 152 ml to 57 ml (p < 0.05). The blood transfusion rate was 3.6%, and two patients needed a recatheterisation postoperatively (3.6%). After a median follow-up of 9 mo, the IPSS improved from 19.8 at baseline to 8.6 (p < 0.001). Four patients had a repeat transurethral resection of the prostate (TURP) during the learning curve, but this was not necessary in any of the later patients. One patient developed a urethral stricture, and another developed a bladder neck contracture.

Conclusions

The thulium laser seems to be a suitable tool for the endoscopic treatment of BPH.     

Hypertensive crisis inducing rhabdomyolysis during laparoscopic resection of a large pheochromocytoma: a case report

Intense vasospasm during hypertensive crisis as a cause for rhabdomyolysis has been described in ambulatory patients with pheochromocytoma. We report this phenomenon as an intraoperative complication in a patient during laparoscopic pheochromocytoma resection and discuss patient and procedure related risk factors. Unexplained intraoperative hyperkalemia following a severe hypertensive episode during surgery may be a first sign of rhabdomyolysis. Anesthesiologists should be aware of such a possibility. Intra- and postoperative serial electrolyte determinations and if suspected, timely screening for myoglobiuria, may aid in early detection and treatment of intraoperative rhabdomyolysis during pheochromocytoma resections.     

High-dose Remifentanil Does Not Impair Cerebrovascular Carbon Dioxide Reactivity in Healthy Male Volunteers

Background: Cerebrovascular carbon dioxide reactivity during high-dose remifentanil infusion was investigated in volunteers by measurement of regional cerebral blood flow (rCBF) and mean CBF velocity (CBFv).

Methods: Ten healthy male volunteers with a laryngeal mask for artificial ventilation received remifentanil at an infusion rate of 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 under normocapnia, hypocapnia, and hypercapnia. Stable xenon-enhanced computed tomography and transcranial Doppler ultrasonography of the left middle cerebral artery were used to assess rCBF and mean CBFv, respectively. If required, blood pressure was maintained within baseline values with intravenous phenylephrine to avoid confounding effects of altered hemodynamics.

Results: Hemodynamic parameters were maintained constant over time. Remifentanil infusion at 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 significantly decreased rCBF and mean CBFv. Both rCBF and mean CBFv increased as the arterial carbon dioxide tension increased from hypocapnia to hypercapnia, indicating that cerebrovascular reactivity remained intact. The average slopes of rCBF reactivity were 0.56 +/- 0.27 and 0.49 +/- 0.28 ml [middle dot] 100 g-1 [middle dot] min-1 [middle dot] mmHg-1 for 2 and 4 [mu]g[middle dot]kg-1[middle dot]min-1 remifentanil, respectively (relative change in percent/mmHg: 1.9 +/- 0.8 and 1.6 +/- 0.5, respectively). The average slopes for mean CBFv reactivity were 1.61 +/- 0.95 and 1.54 +/- 0.83 cm [middle dot] s-1 [middle dot] mmHg-1 for 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil, respectively (relative change in percent/mmHg: 1.86 +/- 0.59 and 1.79 +/- 0.59, respectively). Preanesthesia and postanesthesia values of rCBF and mean CBFv did not differ.