Sexual dysfunction in multiple sclerosis

Multiple sclerosis is a chronic disease that commonly affects young adults who may be sexually active. Sexual dysfunction is a significant, but often underestimated, symptom of multiple sclerosis, affecting 50-90% of men and 40-80% of women. The types of sexual dysfunction can be categorized in terms of the normal sexual response cycle: sexual interest/desire dysfunction (reduced libido), sexual arousal dysfunction (including erectile dysfunction) and ejaculatory and orgasmic dysfunction. Sexual dysfunction may not only be due to lesions affecting the neural pathways involved in physiological function (primary dysfunction), but also result from general physical disabilities (secondary dysfunction) or psychological and emotional issues (tertiary dysfunction). Comprehensive management should address all these possible contributing problems. Specific pharmacotherapy is only currently available for erectile dysfunction. This review summarizes the available information about sexual dysfunction in men and women with multiple sclerosis.

C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE

Interleukin 17-producing T helper cells (T(H)-17 cells) are important in experimental autoimmune encephalomyelitis, but their route of entry into the central nervous system (CNS) and their contribution relative to that of other effector T cells remain to be determined. Here we found that mice lacking CCR6, a chemokine receptor characteristic of T(H)-17 cells, developed T(H)-17 responses but were highly resistant to the induction of experimental autoimmune encephalomyelitis. Disease susceptibility was reconstituted by transfer of wild-type T cells that entered into the CNS before disease onset and triggered massive CCR6-independent recruitment of effector T cells across activated parenchymal vessels. The CCR6 ligand CCL20 was constitutively expressed in epithelial cells of choroid plexus in mice and humans. Our results identify distinct molecular requirements and ports of lymphocyte entry into uninflamed versus inflamed CNS and suggest that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.

Long-term quality of life after hepatic resection: health is not simply the absence of disease

BACKGROUND: Due to advances in operative methods and perioperative care, mortality and morbidity following major hepatic resection have decreased substantially, making long-term quality of life (QoL) an increasingly prominent issue. We evaluated whether postoperative diagnosis was associated with long-term QoL and health in patients requiring hepatic surgery for benign or malignant disease. METHODS: QoL was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 and the liver-specific QLQ-LMC21 module. RESULTS: Between 2002 and 2006, 249 patients underwent hepatic surgery for malignant (76%) and benign (24%) conditions. One hundred thirty-five patients were available for QoL analysis after a mean of 26.5 months. There was no statistical difference in global QoL scores between patients with malignant and benign diseases (p = 0.367). Neither the extent of the resection (> or =2 segments vs. <2 segments; p = 0.975; OR = 0.988; 95% CI = 0.461-2.119) nor patient age had a significant influence on overall QoL (p = 0.092). CONCLUSIONS: These results indicate that long-term QoL for patients who underwent liver resection for malignant disease is quite good and that a poor clinical prognosis does not seem to correlate with a poor QoL.

Stenotrophomonas maltophilia: an emerging opportunist human pathogen

Stenotrophomonas maltophilia has emerged as an important opportunistic pathogen in the debilitated host. S maltophilia is not an inherently virulent pathogen, but its ability to colonise respiratory-tract epithelial cells and surfaces of medical devices makes it a ready coloniser of hospitalised patients. S maltophilia can cause blood-stream infections and pneumonia with considerable morbidity in immunosuppressed patients. Management of infection is hampered by high-level intrinsic resistance to many antibiotic classes and the increasing occurrence of acquired resistance to the first-line drug co-trimoxazole. Prevention of acquisition and infection depends upon the application of modern infection-control practices, with emphasis on the control of antibiotic use and environmental reservoirs.

Long-term changes in bone metabolism, bone mineral density, quantitative ultrasound parameters, and fracture incidence after spinal cord injury: a cross-sectional observational study in 100 paraplegic men

To study the time course of demineralization and fracture incidence after spinal cord injury (SCI), 100 paraplegic men with complete motor loss were investigated in a cross-sectional study 3 months to 30 years after their traumatic SCI. Fracture history was assessed and verified using patients' files and X-rays. BMD of the lumbar spine (LS), femoral neck (FN), distal forearm (ultradistal part = UDR, 1/3 distal part = 1/3R), distal tibial diaphysis (TDIA), and distal tibial epiphysis (TEPI) was measured using DXA. Stiffness of the calcaneus (QUI.CALC), speed of sound of the tibia (SOS.TIB), and amplitude-dependent SOS across the proximal phalanges (adSOS.PHAL) were measured using QUS. Z-Scores of BMD and quantitative ultrasound (QUS) were plotted against time-since-injury and compared among four groups of paraplegics stratified according to time-since-injury (<1 year, stratum I; 1-9 years, stratum II; 10-19 years, stratum III; 20-29 years, stratum IV). Biochemical markers of bone turnover (deoxypyridinoline/creatinine (D-pyr/Cr), osteocalcin, alkaline phosphatase) and the main parameters of calcium phosphate metabolism were measured. Fifteen out of 98 paraplegics had sustained a total of 39 fragility fractures within 1,010 years of observation. All recorded fractures were fractures of the lower limbs, mean time to first fracture being 8.9 +/- 1.4 years. Fracture incidence increased with time-after-SCI, from 1% in the first 12 months to 4.6%/year in paraplegics since >20 years ( p<.01). The overall fracture incidence was 2.2%/year. Compared with nonfractured paraplegics, those with a fracture history had been injured for a longer time ( p<.01). Furthermore, they had lower Z-scores at FN, TEPI, and TDIA ( p<.01 to <.0001), the largest difference being observed at TDIA, compared with the nonfractured. At the lower limbs, BMD decreased with time at all sites ( r=.49 to.78, all p<.0001). At FN and TEPI, bone loss followed a log curve which leveled off between 1 to 3 years after injury. In contrast, Z-scores of TDIA continuously decreased even beyond 10 years after injury. LS BMD Z-score increased with time-since-SCI ( p<.05). Similarly to DXA, QUS allowed differentiation of early and rapid trabecular bone loss (QUI.CALC) vs slow and continuous cortical bone loss (SOS.TIB). Biochemical markers reflected a disproportion between highly elevated bone resorption and almost normal bone formation early after injury. Turnover declined following a log curve with time-after-SCI, however, D-pyr/Cr remained elevated in 30% of paraplegics injured >10 years. In paraplegic men early (trabecular) and persistent (cortical) bone loss occurs at the lower limbs and leads to an increasing fracture incidence with time-after-SCI.

Potentiometric platform for the quantification of cellular potassium efflux

Renewed interest in the measurement of cellular K(+) effluxes has been prompted by the observation that potassium plays an active and important role in numerous key cellular events, in particular cell necrosis and apoptosis. Although necrosis and apoptosis follow different pathways, both induce intracellular potassium effluxes. Here, we report the use of potassium-selective microelectrodes located in a microfluidic platform for cell culture to monitor and quantify such effluxes in real time. Using this platform, we observed and measured the early signs of cell lysis induced by a modification of the extracellular osmolarity. Furthermore, we were able to quantify the number of dying cells by evaluating the extracellular potassium concentration. A comparison between the potentiometric measurement with a fluorescent live-dead assay performed under similar conditions revealed the delay between potassium effluxes and cell necrosis. These results suggest that such platforms may be exploited for applications, such as cytotoxicological screening assays or tumor cell proliferation assays, by using extracellular K(+) as cell death marker.

Cement-augmented anterior screw fixation of Type II odontoid fractures in elderly patients with osteoporosis

BACKGROUND CONTEXT: Closed reduction and internal fixation by an anterior approach is an established option for operative treatment of displaced Type II odontoid fractures. In elderly patients, however, inadequate screw purchase in osteoporotic bone can result in severe procedure-related complications. PURPOSE: To improve the stability of odontoid fracture screw fixation in the elderly using a new technique that includes injection of polymethylmethacrylat (PMMA) cement into the C2 body. STUDY DESIGN: Retrospective review of hospital and outpatient records as well as radiographs of elderly patients treated in a university hospital department of orthopedic surgery. PATIENT SAMPLE: Twenty-four elderly patients (8 males and 16 females; mean age, 81 years; range, 62-98 years) with Type II fractures of the dens. OUTCOME MEASURES: Complications, cement leakage (symptomatic/asymptomatic), operation time, loss of reduction, pseudarthrosis and revision surgery, patient complaints, return to normal activities, and signs of neurologic complications were all documented. METHODS: After closed reduction and anterior approach to the inferior border of C2, a guide wire is advanced to the tip of the odontoid under biplanar fluoroscopic control. Before the insertion of one cannulated, self-drilling, short thread screws, a 12 gauge Yamshidi cannula is inserted from anterior and 1 to 3 mL of high-viscosity PMMA cement is injected into the anteroinferior portion of the C2 body. During polymerization of the cement, the screws are further inserted using a lag-screw compression technique. The cervical spine then is immobilized with a soft collar for 8 weeks postoperatively. RESULTS: Anatomical reduction of the dens was achieved in all 24 patients. Mean operative time was 64 minutes (40-90 minutes). Early loss of reduction occurred in three patients, but revision surgery was indicated in only one patient 2 days after primary surgery. One patient died within the first eight postoperative weeks, one within 3 months after surgery. In five patients, asymptomatic cement leakage was observed (into the C1-C2 joint in three patients, into the fracture in two). Conventional radiologic follow-up at 2 and 6 months confirmed anatomical healing in 16 of the19 patients with complete follow-up. In two patients, the fractures healed in slight dorsal angulation; one patient developed a asymptomatic pseudarthrosis. All patients were able to resume their pretrauma level of activity. CONCLUSIONS: Cement augmentation of the screw in Type II odontoid fractures in elderly patients is technically feasible in a clinical setting with a low complication rate. This technique may improve screw purchase, especially in the osteoporotic C2 body.

DensiProbe Spine: an intraoperative measurement of bone quality in spinal instrumentation. A clinical feasibility study

BACKGROUND CONTEXT A new device, DensiProbe, has been developed to provide surgeons with intraoperative information about bone strength by measuring the peak breakaway torque. In cases of low bone quality, the treatment can be adapted to the patient's condition, for example, by improving screw-anchorage with augmentation techniques. PURPOSE The objective of this study was to investigate the feasibility of DensiProbe Spine in patients undergoing transpedicular fixation. STUDY DESIGN Prospective feasibility study on consecutive patients. PATIENT SAMPLE Fourteen women and 16 men were included in this study. OUTCOME MEASURES Local and general bone quality. METHODS These consecutive patients scheduled for transpedicular fixation were evaluated for bone mineral density (BMD), which was measured globally by dual-energy X-ray absorptiometry and locally via biopsies using quantitative microcomputed tomography. The breakaway torque force within the vertebral body was assessed intraoperatively via the transpedicular approach with the DensiProbe Spine. The results were correlated with the areal BMD at the lumbar spine and the local volumetric BMD (vBMD) and a subjective impression of bone strength. The feasibility of the method was evaluated, and the clinical and radiological performance was evaluated over a 1-year follow-up. This study was funded by an AO Spine research grant; DensiProbe was developed at the AO Research Institute Davos, Switzerland; the AO Foundation is owner of the intellectual property rights. RESULTS In 30 patients, 69 vertebral levels were examined. The breakaway torque consistently correlated with an experienced surgeon's quantified impression of resistance as well as with vBMD of the same vertebra. Beyond a marginal prolongation of surgery time, no adverse events related to the usage of the device were observed. CONCLUSIONS The intraoperative transpedicular measurement of the peak breakaway torque was technically feasible, safe, and reliably predictive of local vBMD during dorsal spinal instrumentations in a clinical setting. Larger studies are needed to define specific thresholds that indicate a need for the augmentation or instrumentation of additional levels.

Papain-induced in vitro disc degeneration model for the study of injectable nucleus pulposus therapy

BACKGROUND CONTEXT Proteolytic enzyme digestion of the intervertebral disc (IVD) offers a method to simulate a condition of disc degeneration for the study of cell-scaffold constructs in the degenerated disc. PURPOSE To characterize an in vitro disc degeneration model (DDM) of different severities of glycosaminoglycans (GAG) and water loss by using papain, and to determine the initial response of the human mesenchymal stem cells (MSCs) introduced into this DDM. STUDY DESIGN Disc degeneration model of a bovine disc explant with an end plate was induced by the injection of papain at various concentrations. Labeled MSCs were later introduced in this model. METHODS Phosphate-buffered saline (PBS control) or papain in various concentrations (3, 15, 30, 60, and 150 U/mL) were injected into the bovine caudal IVD explants. Ten days after the injection, GAG content of the discs was evaluated by dimethylmethylene blue assay and cell viability was determined by live/dead staining together with confocal microscopy. Overall matrix composition was evaluated by histology, and water content was visualized by magnetic resonance imaging. Compressive and torsional stiffness of the DDM were also recorded. In the second part, MSCs were labeled with a fluorescence cell membrane tracker and injected into the nucleus of the DDM or a PBS control. Mesenchymal stem cell viability and distribution were evaluated by confocal microscopy. RESULTS A large drop of GAG and water content of the bovine disc were obtained by injecting >30 U/mL papain. Magnetic resonance imaging showed Grade II, III, and IV disc degeneration by injecting 30, 60, and 150 U/mL papain. A cavity in the center of the disc could facilitate later injection of the nucleus pulposus tissue engineering construct while retaining an intact annulus fibrosus. The remaining disc cell viability was not affected. Mesenchymal stem cells injected into the protease-treated DDM disc showed significantly higher cell viability than when injected into the PBS-injected control disc. CONCLUSIONS By varying the concentration of papain for injection, an increasing amount of GAG and water loss could be induced to simulate the different severities of disc degeneration. MSC suspension introduced into the disc has a very low short-term survival. However, it should be clear that this bovine IVD DDM does not reflect a clinical situation but offers exciting possibilities to test novel tissue engineering protocols.

3D scaffolds co-seeded with human endothelial progenitor and mesenchymal stem cells: evidence of prevascularisation within 7 days

Blood supply is a critical issue in most tissue engineering approaches for large defect healing. As vessel ingrowth from surrounding tissues is proven to be insufficient, current strategies are focusing on the neo-vascularisation process. In the present study, we developed an in vitro pre-vascularised construct using 3D polyurethane (PU) scaffolds, based on the association of human Endothelial Progenitor Cells (EPC, CD34+ and CD133+) with human Mesenchymal Stem Cells (MSC). We showed the formation of luminal tubular structures in the co-seeded scaffolds as early as day 7 in culture. These tubular structures were proven positive for endothelial markers von Willebrand Factor and PECAM-1. Of special significance in our constructs is the presence of CD146-positive cells, as a part of the neovasculature scaffolding. These cells, coming from the mesenchymal stem cells population (MSC or EPC-depleted MSC), also expressed other markers of pericyte cells (NG2 and αSMA) that are known to play a pivotal function in the stabilisation of newly formed pre-vascular networks. In parallel, in co-cultures, osteogenic differentiation of MSCs occurred earlier when compared to MSCs monocultures, suggesting the close cooperation between the two cell populations. The presence of angiogenic factors (from autologous platelet lysates) in association with osteogenic factors seems to be crucial for both cell populations' cooperation. These results are promising for future clinical applications, as all components (cells, growth factors) can be prepared in an autologous way.

Challenges and strategies in the repair of ruptured annulus fibrosus

Lumbar discectomy is the surgical procedure most frequently performed for patients suffering from low back pain and sciatica. Disc herniation as a consequence of degenerative or traumatic processes is commonly encountered as the underlying cause for the painful condition. While discectomy provides favourable outcome in a majority of cases, there are conditions where unmet requirements exist in terms of treatment, such as large disc protrusions with minimal disc degeneration; in these cases, the high rate of recurrent disc herniation after discectomy is a prevalent problem. An effective biological annular repair could improve the surgical outcome in patients with contained disc herniations but otherwise minor degenerative changes. An attractive approach is a tissue-engineered implant that will enable/stimulate the repair of the ruptured annulus. The strategy is to develop three-dimensional scaffolds and activate them by seeding cells or by incorporating molecular signals that enable new matrix synthesis at the defect site, while the biomaterial provides immediate closure of the defect and maintains the mechanical properties of the disc. This review is structured into (1) introduction, (2) clinical problems, current treatment options and needs, (3) biomechanical demands, (4) cellular and extracellular components, (5) biomaterials for delivery, scaffolding and support, (6) pre-clinical models for evaluation of newly developed cell- and material-based therapies, and (7) conclusions. This article highlights that an interdisciplinary approach is necessary for successful development of new clinical methods for annulus fibrosus repair. This will benefit from a close collaboration between research groups with expertise in all areas addressed in this review.