Pro-fibrotic phenotype of bone marrow stromal cells in Modic type 1 changes.

Modic type 1 changes (MC1) are painful vertebral bone marrow lesions frequently found in patients suffering from chronic low-back pain. Marrow fibrosis is a hallmark of MC1. Bone marrow stromal cells (BMSCs) are key players in other fibrotic bone marrow pathologies, yet their role in MC1 is unknown. The present study aimed to characterise MC1 BMSCs and hypothesised a pro-fibrotic role of BMSCs in MC1. BMSCs were isolated from patients undergoing lumbar spinal fusion from MC1 and adjacent control vertebrae. Frequency of colony-forming unit fibroblast (CFU-F), expression of stem cell surface markers, differentiation capacity, transcriptome, matrix adhesion, cell contractility as well as expression of pro-collagen type I alpha 1, α-smooth muscle actin, integrins and focal adhesion kinase (FAK) were compared. More CFU-F and increased expression of C-X-C-motif-chemokine 12 were found in MC1 BMSCs, possibly indicating overrepresentation of a perisinusoidal BMSC population. RNA sequencing analysis showed enrichment in extracellular matrix proteins and fibrosis-related signalling genes. Increases in pro-collagen type I alpha 1 expression, cell adhesion, cell contractility and phosphorylation of FAK provided further evidence for their pro-fibrotic phenotype. Moreover, a leptin receptor high expressing (LEPRhigh) BMSC population was identified that differentiated under transforming growth factor beta 1 stimulation into myofibroblasts in MC1 but not in control BMSCs. In conclusion, pro-fibrotic changes in MC1 BMSCs and a LEPRhigh MC1 BMSC subpopulation susceptible to myofibroblast differentiation were found. Fibrosis is a hallmark of MC1 and a potential therapeutic target. A causal link between the pro-fibrotic phenotype and clinical characteristics needs to be demonstrated.

The Restless Spinal Cord in Degenerative Cervical Myelopathy.

BACKGROUND AND PURPOSE: The spinal cord is subject to a periodic, cardiac-related movement, which is increased at the level of a cervical stenosis. Increased oscillations may exert mechanical stress on spinal cord tissue causing intramedullary damage. Motion analysis thus holds promise as a biomarker related to disease progression in degenerative cervical myelopathy. Our aim was characterization of the cervical spinal cord motion in patients with degenerative cervical myelopathy. MATERIALS AND METHODS: Phase-contrast MR imaging data were analyzed in 55 patients (37 men; mean age, 56.2 [SD,12.0] years; 36 multisegmental stenoses) and 18 controls (9 men, P = .368; mean age, 62.2 [SD, 6.5] years; P = .024). Parameters of interest included the displacement and motion pattern. Motion data were pooled on the segmental level for comparison between groups. RESULTS: In patients, mean craniocaudal oscillations were increased manifold at any level of a cervical stenosis (eg, C5 displacement: controls [n = 18], 0.54 [SD, 0.16] mm; patients [n = 29], monosegmental stenosis [n = 10], 1.86 [SD, 0.92] mm; P < .001) and even in segments remote from the level of the stenosis (eg, C2 displacement: controls [n = 18], 0.36 [SD, 0.09] mm; patients [n = 52]; stenosis: C3, n = 21; C4, n = 11; C5, n = 18; C6, n = 2; 0.85 [SD, 0.46] mm; P < .001). Motion at C2 differed with the distance to the next stenotic segment and the number of stenotic segments. The motion pattern in most patients showed continuous spinal cord motion throughout the cardiac cycle. CONCLUSIONS: Patients with degenerative cervical myelopathy show altered spinal cord motion with increased and ongoing oscillations at and also beyond the focal level of stenosis. Phase-contrast MR imaging has promise as a biomarker to reveal mechanical stress to the cord and may be applicable to predict disease progression and the impact of surgical interventions.

Muscle fiber capillarization is associated with various indices of skeletal muscle mass in healthy, older men.

INTRODUCTION: Muscle fiber capillarization plays a fundamental role in the regulation of skeletal muscle mass maintenance. However, it remains unclear to what extent capillarization is related to various other skeletal muscle characteristics. In this study we determined whether muscle fiber capillarization is independently associated with measures of skeletal muscle mass, both on a whole-body and cellular level, and post-absorptive muscle protein synthesis rates in healthy older men. METHODS: Forty-six healthy older (70 ± 4 y) men participated in a trial during which basal muscle protein synthesis rates were assessed using stable isotope tracer methodology. Blood and muscle biopsy samples were collected to assess post-absorptive muscle protein synthesis rates over a 3-hour period. Immunohistochemistry was performed to determine various indices of muscle fiber capillarization, size, type distribution, and myonuclear content/domain size. Dual energy x-ray absorptiometry scans were performed to determine whole-body and appendicular lean tissue mass. RESULTS: Capillary-to-fiber ratio (C/Fi) and perimeter exchange (CFPE) index correlated with whole-body lean tissue mass (r = 0.43, P < 0.01 and r = 0.25, P < 0.10, respectively), appendicular lean tissue mass (r = 0.52, P < 0.001 and r = 0.37, P < 0.05, respectively) as well as appendicular lean tissue mass divided by body mass index (r = 0.65, P < 0.001 and r = 0.62, P < 0.001, respectively). Muscle fiber size correlated with C/Fi (r = 0.45, P < 0.01), but not with CFPE index. No associations were observed between different indices of muscle fiber capillarization and post-absorptive muscle protein synthesis rates in healthy, older men. CONCLUSION: The present study provides further evidence that muscle fiber capillarization may be a critical factor in the regulation of skeletal muscle maintenance in healthy older men.

Stimulated two-photon emission in bulk CdSe.

While two-photon emission processes are firmly established in atomic physics, their observation and use in semiconductor physics remains elusive. Here, we experimentally investigate stimulated two-photon emission in photoexcited bulk CdSe and identify requirements for the observation of stimulated two-photon emission. In particular, this process requires population inversion as well as two-photon transition energies close to the bandgap energy. In any regime investigated in the present study, net optical gain is not achieved, as the free-carrier absorption intrinsically linked to the photoexcitation completely masks the two-photon gain. The results are well in line with a recent study on nondegenerate versions of two-photon emission in GaAs and place clear limits for the practical use of two-photon emission in optically excited semiconductors.

Tunable femtosecond near-IR source by pumping an OPA directly with a 90 MHz Yb:fiber source.

Up to 400 mW of near-IR (1370-1500 nm) femtosecond pulses are generated from an optical parametric amplifier directly driven by a Yb:fiber oscillator delivering 100 fs pulses at 1036 nm. The process is seeded by a stable supercontinuum obtained from a photonic crystal fiber. We use a single pass through a 3 mm, magnesium oxide-doped, periodically poled LiNbO3 downconversion crystal to produce a near-IR pulse train with a remarkable power stability of 1.4% (RMS) during one hour. Tuning is achieved by the temperature and the poling period of the nonlinear crystal.

Pull-out strength of patient-specific template-guided vs. free-hand fluoroscopically controlled thoracolumbar pedicle screws: a biomechanical analysis of a randomized cadaveric study.

PURPOSE: To assess the pull-out strength of thoracolumbar pedicle screws implanted via either a patient-specific template-guided or conventional free-hand fluoroscopically controlled technique in a randomized cadaveric study, and to evaluate the influence of local vertebral bone density, quantified by Hounsfield units (HU), on pedicle screw pull-out strength. METHODS: Thoracolumbar pedicles of three spine cadavers were instrumented using either a free-hand fluoroscopically controlled or a patient-specific template-guided technique. Preoperative bone density was quantified by HU measured on CT. Pedicle perforation was evaluated on postoperative CT scans by an independent and blinded radiologist. After dissected vertebrae were embedded in aluminum fixation devices, pull-out testing was initiated with a preload of 50 N and a constant displacement rate of 0.5 mm/s. Subgroup analyses were performed excluding pedicle screws with a pedicle breach (n = 47). RESULTS: Pull-out strength was significantly different with 549 ± 278 and 441 ± 289 N in the template-guided (n = 50) versus fluoroscopically controlled (n = 48) subgroups (p = 0.031), respectively. Subgroup analysis limited to screws with an intrapedicular trajectory revealed a tendency toward a higher pull-out strength in the template-guided (n = 30) versus fluoroscopically controlled screws (n = 21) with 587 ± 309 and 454 ± 269 N (p = 0.118), respectively. There was a trend toward a higher pull-out strength (709 ± 418 versus 420 ± 149 N) in vertebrae with a bone density of (>171 HU) versus (<133 HU), respectively (p = 0.061). CONCLUSIONS: There was a significantly higher pull-out strength of thoracolumbar pedicle screws when inserted via a patient-specific template-guided versus conventional free-hand fluoroscopically controlled technique, potentially associated with screw trajectory.

Brown adipose tissue and its therapeutic potential.

Obesity and related diseases are a major cause of human morbidity and mortality and constitute a substantial economic burden for society. Effective treatment regimens are scarce, and new therapeutic targets are needed. Brown adipose tissue, an energy-expending tissue that produces heat, represents a potential therapeutic target. Its presence is associated with low body mass index, low total adipose tissue content and a lower risk of type 2 diabetes mellitus. Knowledge about the development and function of thermogenic adipocytes in brown adipose tissue has increased substantially in the last decade. Important transcriptional regulators have been identified, and hormones able to modulate the thermogenic capacity of the tissue have been recognized. Intriguingly, it is now clear that humans, like rodents, possess two types of thermogenic adipocytes: the classical brown adipocytes found in the interscapular brown adipose organ and the so-called beige adipocytes primarily found in subcutaneous white adipose tissue after adrenergic stimulation. The presence of two distinct types of energy-expending adipocytes in humans is conceptually important because these cells might be stimulated and recruited by different signals, raising the possibility that they might be separate potential targets for therapeutic intervention. In this review, we will discuss important features of the energy-expending brown adipose tissue and highlight those that may serve as potential targets for pharmacological intervention aimed at expanding the tissue and/or enhancing its function to counteract obesity.

Review of current best practice and priorities for research in radiation oncology for elderly patients with cancer: the International Society of Geriatric Oncology (SIOG) task force.

Radiotherapy (RT) is a key component of the management of older cancer patients. Level I evidence in older patients is limited. The International Society of Geriatric Oncology (SIOG) established a task force to make recommendations for curative RT in older patients and to identify future research priorities. Evidence-based guidelines are provided for breast, lung, endometrial, prostate, rectal, pancreatic, oesophageal, head and neck, central nervous system malignancies and lymphomas. Patient selection should include comorbidity and geriatric evaluation. Advances in radiation planning and delivery improve target coverage, reduce toxicity and widen eligibility for treatment. Shorter courses of hypofractionated whole breast RT are safe and effective. Conformal RT and involved-field techniques without elective nodal irradiation have improved outcomes in non-small-cell lung cancer (NSCLC) without increasing toxicity. Where comorbidities preclude surgery, stereotactic body radiotherapy (SBRT) is an option for early-stage NSCLC and pancreatic cancer. Modern involved-field RT for lymphoma based on pre-treatment positron emission tomography data has reduced toxicity. Significant comorbidity is a relative contraindication to aggressive treatment in low-risk prostate cancer (PC). For intermediate-risk disease, 4-6 months of hormones are combined with external beam radiotherapy (EBRT). For high-risk PC, combined modality therapy (CMT) is advised. For high-intermediate risk, endometrial cancer vaginal brachytherapy is recommended. Short-course EBRT is an alternative to CMT in older patients with rectal cancer without significant comorbidities. Endorectal RT may be an option for early disease. For primary brain tumours, shorter courses of postoperative RT following maximal debulking provide equivalent survival to longer schedules. MGMT methylation status may help select older patients for temozolomide alone. Stereotactic RT provides an alternative to whole-brain RT in patients with limited brain metastases. Intensity-modulated radiation therapy provides an excellent technique to reduce dose to the carotids in head and neck cancer and improves locoregional control in oesophageal cancer. Best practice and research priorities are summarised.

The expression of glycophorin A and osteoprotegerin is locally increased in carotid atherosclerotic lesions of symptomatic compared to asymptomatic patients.

The aim of this study was to evaluate in detail the histopathological characteristics of endarterectomized carotid atherosclerotic lesions in symptomatic versus asymptomatic patients. Twenty carotid lesions, 10 from asymptomatic and 10 from symptomatic patients who underwent carotid endarterectomy were classified according to histomorphological features. Samples were analyzed for intraplaque localization and for the expression of proteins associated with inflammation, such as CD68, interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), pentraxin-3 (PTX-3), nuclear factor-κB (NF-κB), C-reactive protein (CRP) and transforming growth factor-ß (TGF-ß), as well as for proteins associated with vascular remodelling, such as matrix-metalloproteinase-9 (MMP-9), glycophorin A (GYPA), osteoprotegerin (OPG), vascular cell adhesion molecule-1 (VCAM-1), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF) and vascular smooth muscle cell actin (VSMA). Corresponding expression scores were compared between the symptomatic and asymptomatic patients and evaluated statistically. The expression of all 14 evaluated markers was significantly elevated in the border zone adjacent to the mixed plaque compared with the unaffected control area of the same sample (p<0,016). The expression scores of GYPA and OPG were significantly higher in the border zones around the calcified (GYPA, p=0.035; OPG, p=0.043) and mixed (GYPA, p<0.001; OPG, p=0.007) plaque zones of symptomatic patients compared to asymptomatic patients. No difference in expression scores was observed for any of the analyzed inflammatory marker proteins between the border zones of symptomatic and asymptomatic patients. In conclusion, the increased expression of GYPA, indicating intraplaque hemorrhage, and OPG, indicating the transdifferentiation of vascular cells, in carotid atherosclerotic lesions may be associated with an increased risk of plaque instability.

Electrical control of interdot electron tunneling in a double InGaAs quantum-dot nanostructure.

We employ ultrafast pump-probe spectroscopy to directly monitor electron tunneling between discrete orbital states in a pair of spatially separated quantum dots. Immediately after excitation, several peaks are observed in the pump-probe spectrum due to Coulomb interactions between the photogenerated charge carriers. By tuning the relative energy of the orbital states in the two dots and monitoring the temporal evolution of the pump-probe spectra the electron and hole tunneling times are separately measured and resonant tunneling between the two dots is shown to be mediated both by elastic and inelastic processes. Ultrafast (<5 ps) interdot tunneling is shown to occur over a surprisingly wide bandwidth, up to ∼8 meV, reflecting the spectrum of exciton-acoustic phonon coupling in the system.

Impact of intensity-modulated and image-guided radiotherapy on elderly patients undergoing chemoradiation for locally advanced head and neck cancer.

PURPOSE: In this work, the treatment tolerance of elderly patients (≥70 years) undergoing intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) and chemotherapy for locally advanced head and neck cancer was assessed. PATIENTS AND METHODS: A retrospective review of 112 patients undergoing concurrent chemoradiation for locally advanced head and neck cancer was performed. Treatment toxicity, protocol violations, long-term complications, and survival were compared between 85 younger patients (< 70 years) and 27 older patients (≥ 70 years). RESULTS: Grade 3-4 treatment toxicity was observed in 88.2% and 88.8% for younger and older patients, respectively. Mean weight loss and treatment break were 5.9 and 3.9 kg (p = 0.03) and 7.3 and 7.8 days (p = 0.8) for younger and older patients, respectively. Seven patients (8.2%) did not complete treatment in the younger group compared to 1 patient (3.7%) in the older group (p = 0.6). No significant differences in protocol violations and survival were found between the two groups. CONCLUSION: Compared to younger patients, elderly patients with locally advanced head and neck cancer tolerated chemoradiation with IMRT and IGRT well, and should not be denied curative treatment based solely on age.

Mc2 receptor knockdown modulates differentiation and lipid composition in adipocytes.

The melanocortin system is involved in central and peripheral regulation of energy homeostasis. In adipocytes, the melanocortin 2 receptor (MC2R) transmits ACTH-dependent signaling and its expression rises substantially during adipocyte differentiation. An in vitro system of retrovirally expressed shRNA directed against Mc2r mRNA in 3T3-L1 cells was established and effects of Mc2r knockdown (kd) in comparison to cells expressing non-targeting shRNA (control) were explored in differentiated adipocytes. Morphology, gene expression, lipolysis and fatty acid composition were analyzed. While gross morphology was unchanged extractable amount of lipids was reduced to 70-80% in kd cell lines (p<0.01). Moreover, expression changes of Pparγ2, aP2, and Pref1 indicated reduced differentiation in Mc2r kd cells. Intriguingly, not only ACTH, but also norepinephrine stimulated lipolysis were substantially reduced demonstrating functional significance of MC2R for general lipolysis pathway. Analysis of fatty acid composition in triglyceride and phospholipid fractions showed a lowered ratio of C16:1/C16:0 and C18:1/C18:0, but increased concentrations of arachidonic acid upon Mc2r knockdown. Reduction of mono-unsaturated fatty acids (MUFAs) was associated with lower expression of stearoyl-Coenzyme A desaturase 1 and 2 in kd cells (21 ± 8% vs. 100 ± 13%, p=0.01 and 32 ± 3% vs. 100 ± 15%, p=0.046). Conversely, high doses of ACTH resulted in gene expression changes, mirroring Mc2r knockdown (higher Pparγ2, Scd1, Hsl expression). MC2R plays an important role for regular lipolytic function and lipid composition in 3T3-L1 adipocytes. Of interest, desaturase expression was reduced and MUFA content accordingly altered in kd cells.

Identifying patients at risk for late radiation-induced toxicity.

The impact of curative radiotherapy depends mainly on the total dose delivered in the targeted volume. Nevertheless, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many treatments. Two different side effects (acute and late) can occur during and after radiotherapy. Of particular interest are the radiation-induced late complications (LC) due to their irreversibility and the potential impact on quality of life. In one population treated with the same technique, it appears that individual radiosensitivity clearly exists. In the hypothesis that genetic is involved in this area of research, low CD4 and CD8 lymphocyte apoptosis were shown to be correlated with high grade of LC. In addition, recent data suggest that patients with severe radiation-induced LC possess 4 or more single nucleotide polymorphisms (SNPs) in candidate genes and low radiation-induced CD8 lymphocyte apoptosis in vitro. On-going studies are being analyzing the entire genome using a genome-wide association study (GWAS).

[Management of anal canal carcinoma]. / Prise en charge du carcinome du canal anal.

Although anal canal squamous cell carcinoma is rare, the general practitioner should consider this diagnosis in a patient with persistent lower abdominal symptoms. While classically observed in older women, an increased incidence is also seen in HIV-positive patients or patients with a history of human papillomavirus infection. Initial diagnosis and local work-up require assessment by a proctologist. Standard curative treatment combines radiotherapy with 5-FU- and MMC-based chemotherapy. Salvage surgery should be discussed in case of local relapse. The general practitioner, the proctologist and the radiation oncologist, all participate in post-treatment surveillance.

[Oesophageal cancer: multidisciplinary approach]. / Cancer de l'oesophage: traitement multidisciplinaire.

Despite recent progresses, the prognosis of oesophageal cancer is still bad, mostly because of frequent late diagnosis. In early cases, radical surgery alone is able to cure 60-70% of the patients. In locally-advanced cases, on the other hand, surgical results are considerably worse and combined therapies are contemplated. In these cases, neoadjuvant therapy (induction chemotherapy followed by radiotherapy and surgical resection) is often proposed, but without formal proof of superiority. These combined therapies are heavy for the patient and complex for the team. They can only be decided and managed in the frame of intensive multidisciplinary collaboration. Future progresses will come at the same time from larger studies and from the efforts of the medical community towards earlier diagnosis of this disease.

Effects of cerebral hypoperfusion on bispectral index: a randomised, controlled animal experiment during haemorrhagic shock.

BACKGROUND: The aim of this porcine haemorrhagic shock model was to investigate the changes of bispectral index (BIS) after slow and fast recovery of cerebral perfusion, and its correlation with plasma propofol concentrations. METHODS: After Animal Investigational Committee approval, 16 pigs during propofol anaesthesia underwent a liver trauma with severe hypotension, and were randomly assigned to receive therapy for either slow recovery (fluid resuscitation; slow group; n=8) or fast recovery of cerebral perfusion (vasopressor combined with hypertonic-saline-starch; fast group; n=8), respectively. Cerebral perfusion pressure (CPP=MAP-ICP), cerebral tissue oxygenation index (TOI), BIS, and plasma concentrations of propofol and haemoglobin were measured at baseline (Pre-shock), haemodynamic decompensation (Shock), and 5 (Therapy) and 30 min (End) after therapy, respectively. RESULTS: CPP, TOI, and BIS decreased significantly during shock (pre-shock vs. shock, fast: CPP: 65+/-14 vs. 15+/-4 mmHg; TOI: 64+/-6 vs. 47+/-7%; BIS 60+/-5 vs. 9+/-10; slow: CPP: 60+/-12 vs. 13+/-7 mmHg; TOI: 68+/-7 vs. 49+/-7%; BIS 63+/-5 vs. 13+/-12; P<0.05). In the fast group, CPP, TOI, and BIS increased after therapy compared to the slow group (Therapy, fast: CPP: 47+/-15 mmHg, TOI: 61+/-7%, BIS: 47+/-21; slow: CPP: 18+/-9 mmHg, TOI: 51+/-5%, BIS: 21+/-19; P<0.05). Propofol and haemoglobin concentrations were comparable between groups throughout the resuscitation phase. CONCLUSIONS: In a haemorrhagic shock scenario, therapies with different impact on cerebral perfusion resulted in differing changes of BIS values, while plasma propofol and haemoglobin concentrations were comparable during the resuscitation phase; this suggests that BIS may also have reflected changes of cerebral perfusion.

Sepsis and cardiomyopathy as rare clinical manifestations of pheochromocytoma--two case report studies.

The clinical manifestation of pheochromocytomas is highly variable and can closely resemble numerous clinical conditions. Here, we report on two cases of patients with pheochromocytoma, which manifested as sepsis or cardiomyopathy. The first patient initially presented with bacterial urosepsis due to klebsiella oxytoca. Despite effective antibiotic therapy, the patient developed recurring fever accompanied by hypertension. The inconsistency between therapy-refractory hypertension and fever indicated the possibility of excessive catecholamine production. In the second case, the patient presented with a suspected ST-segment elevation myocardial infarction accompanied by E. coli sepsis and a previously undiagnosed unilateral tumor mass of the adrenal gland. Severely impaired myocardial contraction of the apical anterior and inferior regions without significant coronary artery disease was consistent with the Takotsubo cardiomyopathy, a known transient functional myocardial complication associated with pheochromocytoma. Both patients were diagnosed with unilateral pheochromocytoma. Following pre-operative antihypertensive therapy, both patients were cured by surgery and still remain free of disease after two years of follow-up.