Hymovis MO.RE. in the treatment of knee and ankle chondropathy in elite athletes: preliminary results of the CHAMPS (Cohort study about HYADD4-G Administration for Pain relief on Soccer players) prospective clinical study.

OBJECTIVE: This study evaluated single intra-articular injections of Hymovis MO.RE., a hyaluronic acid hexadecyl derivative (HYADD4-G), to manage post-traumatic or degenerative knee or ankle chondropathy in professional soccer players. PATIENTS AND METHODS: Twenty-five players affected by knee (n = 12) or ankle (n = 13) chondropathy were prospectively enrolled and treated by two single Hymovis MO.RE. (32 mg/4 ml) injections at the beginning of the football season (V0, baseline) and at mid-season (V1, 19-20 weeks thereafter), and were followed-up until the end of the season (V2, after further 19-20 weeks). Knee cases were evaluated using the 2000 IKDC knee subjective examination form and the modified Lysholm scoring system. Ankle cases were evaluated using the American Orthopaedic Foot Ankle Society (AOFAS) ankle-hindfoot score. Patients were also evaluated using a VAS Likert scale and a four-category scale recording both the patient's and the doctor's assessment on joint mobility in degrees and overall treatment efficacy. Adverse events, patient withdrawals and local reaction to injections were also assessed. RESULTS: In knee patients, the 2000 IKDC subjective score improved from 46.8 ± 11.4 at V0 to 83.1 ± 12.5 at V2. Their modified Lysholm score improved from 58.8 ± 8.9 at V0 to 90.6 ± 8.3 at V2. In the ankle patients, the AOFAS score improved from 52.2 ± 5.6 at V0 to 96.4 ± 4.5 at V2. VAS Likert values and subjective evaluations improved at V1 and were maintained at V2. No side effects were recorded. CONCLUSIONS: A single Hymovis MO.RE. (32 mg/4 ml) intra-articular injection, repeated after 19-20 weeks, may be a viable option to improve symptoms and function in professional soccer players suffering from knee and ankle chondropathy.

Sensor Noise in LISA Pathfinder: In-Flight Performance of the Optical Test Mass Readout.

We report on the first subpicometer interferometer flown in space. It was part of ESA's Laser Interferometer Space Antenna (LISA) Pathfinder mission and performed the fundamental measurement of the positional and angular motion of two free-falling test masses. The interferometer worked immediately, stably, and reliably from switch on until the end of the mission with exceptionally low residual noise of 32.0_{-1.7}^{+2.4} fm/sqrt[Hz], significantly better than required. We present an upper limit for the sensor performance at millihertz frequencies and a model for the measured sensitivity above 200 mHz.

Analysis of the accuracy of actuation electronics in the laser interferometer space antenna pathfinder.

The Laser Interferometer Space Antenna Pathfinder (LPF) main observable, labeled Δg, is the differential force per unit mass acting on the two test masses under free fall conditions after the contribution of all non-gravitational forces has been compensated. At low frequencies, the differential force is compensated by an applied electrostatic actuation force, which then must be subtracted from the measured acceleration to obtain Δg. Any inaccuracy in the actuation force contaminates the residual acceleration. This study investigates the accuracy of the electrostatic actuation system and its impact on the LPF main observable. It is shown that the inaccuracy is mainly caused by the rounding errors in the waveform processing and also by the random error caused by the analog to digital converter random noise in the control loop. Both errors are one order of magnitude smaller than the resolution of the commanded voltages. We developed a simulator based on the LPF design to compute the close-to-reality actuation voltages and, consequently, the resulting actuation forces. The simulator is applied during post-processing the LPF data.

LISA Pathfinder Performance Confirmed in an Open-Loop Configuration: Results from the Free-Fall Actuation Mode.

We report on the results of the LISA Pathfinder (LPF) free-fall mode experiment, in which the control force needed to compensate the quasistatic differential force acting on two test masses is applied intermittently as a series of "impulse" forces lasting a few seconds and separated by roughly 350 s periods of true free fall. This represents an alternative to the normal LPF mode of operation in which this balancing force is applied continuously, with the advantage that the acceleration noise during free fall is measured in the absence of the actuation force, thus eliminating associated noise and force calibration errors. The differential acceleration noise measurement presented here with the free-fall mode agrees with noise measured with the continuous actuation scheme, representing an important and independent confirmation of the LPF result. An additional measurement with larger actuation forces also shows that the technique can be used to eliminate actuation noise when this is a dominant factor.

MpMRI of the prostate: is there a role for semi-quantitative analysis of DCE-MRI and late gadolinium enhancement in the characterisation of prostate cancer?

AIM: To assess whether there is a significant difference in perfusion parameters between benign and malignant prostatic lesions, focusing on semi-quantitative analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and presence of late gadolinium enhancement (LGE). MATERIAL AND METHODS: Three hundred and thirteen patients who underwent multiparametric MRI (mpMRI) of the prostate and with available corresponding histology (prostatectomy or biopsy) were selected retrospectively for this study. The MRI protocol consisted of multiplanar T2-and diffusion-weighted imaging, DCE and delayed axial T1 images. Images were reviewed independently by two radiologists for LGE assessment and Prostate Imaging - Reporting and Data System (PI-RADS) scoring. For each lesion, semi-quantitative analysis of DCE-MRI was performed and the following data were evaluated: time to peak, wash-in rate, wash-out rate, brevity of enhancement, and area under the curve. The presence or absence of LGE in delayed axial T1 images was assessed qualitatively. MRI results were compared to histology. The presence of significant prostate cancer was based both on Epstein criteria (SPC) and Gleason score (GS ≥7). RESULTS: SPC and Gleason score ≥7 tumours showed significant lower time to peak and brevity of enhancement (p<0.001) with higher wash-in rate (p=0.001). LGE was observed in 152/313 (49%) cases; among them 103/152 (68%) did not show SPC whereas 49/152 (32%) had SPC (p<0.001). The presence of LGE determined a risk reduction of SPC resulting as an independent predictor at multivariate analysis (logOR=-0.78, SE 0.33, p=0.02). CONCLUSION: Semi-quantitative perfusion analysis and LGE may help to predict the presence/absence of a significant prostate tumour and represent a promising tool to improve mpMRI diagnostic performance.

Beyond the Required LISA Free-Fall Performance: New LISA Pathfinder Results down to 20 µHz.

In the months since the publication of the first results, the noise performance of LISA Pathfinder has improved because of reduced Brownian noise due to the continued decrease in pressure around the test masses, from a better correction of noninertial effects, and from a better calibration of the electrostatic force actuation. In addition, the availability of numerous long noise measurement runs, during which no perturbation is purposely applied to the test masses, has allowed the measurement of noise with good statistics down to 20 µHz. The Letter presents the measured differential acceleration noise figure, which is at (1.74±0.05) fm s^{-2}/sqrt[Hz] above 2 mHz and (6±1)×10 fm s^{-2}/sqrt[Hz] at 20 µHz, and discusses the physical sources for the measured noise. This performance provides an experimental benchmark demonstrating the ability to realize the low-frequency science potential of the LISA mission, recently selected by the European Space Agency.

Charge-Induced Force Noise on Free-Falling Test Masses: Results from LISA Pathfinder.

We report on electrostatic measurements made on board the European Space Agency mission LISA Pathfinder. Detailed measurements of the charge-induced electrostatic forces exerted on free-falling test masses (TMs) inside the capacitive gravitational reference sensor are the first made in a relevant environment for a space-based gravitational wave detector. Employing a combination of charge control and electric-field compensation, we show that the level of charge-induced acceleration noise on a single TM can be maintained at a level close to 1.0 fm s^{-2} Hz^{-1/2} across the 0.1-100 mHz frequency band that is crucial to an observatory such as the Laser Interferometer Space Antenna (LISA). Using dedicated measurements that detect these effects in the differential acceleration between the two test masses, we resolve the stochastic nature of the TM charge buildup due to interplanetary cosmic rays and the TM charge-to-force coupling through stray electric fields in the sensor. All our measurements are in good agreement with predictions based on a relatively simple electrostatic model of the LISA Pathfinder instrument.

Sub-Femto-g Free Fall for Space-Based Gravitational Wave Observatories: LISA Pathfinder Results.

We report the first results of the LISA Pathfinder in-flight experiment. The results demonstrate that two free-falling reference test masses, such as those needed for a space-based gravitational wave observatory like LISA, can be put in free fall with a relative acceleration noise with a square root of the power spectral density of 5.2±0.1 fm s^{-2}/sqrt[Hz], or (0.54±0.01)×10^{-15} g/sqrt[Hz], with g the standard gravity, for frequencies between 0.7 and 20 mHz. This value is lower than the LISA Pathfinder requirement by more than a factor 5 and within a factor 1.25 of the requirement for the LISA mission, and is compatible with Brownian noise from viscous damping due to the residual gas surrounding the test masses. Above 60 mHz the acceleration noise is dominated by interferometer displacement readout noise at a level of (34.8±0.3) fm/sqrt[Hz], about 2 orders of magnitude better than requirements. At f≤0.5 mHz we observe a low-frequency tail that stays below 12 fm s^{-2}/sqrt[Hz] down to 0.1 mHz. This performance would allow for a space-based gravitational wave observatory with a sensitivity close to what was originally foreseen for LISA.

Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer.

Overwhelming evidence indicates that cancer is a genetic disease caused by the accumulation of mutations in oncogenes and tumor suppressor genes. It is also increasingly apparent, however, that cancer depends not only on mutations in these coding genes but also on alterations in the large class of non-coding RNAs. Here, we report that one such long non-coding RNA, TRPM2-AS, an antisense transcript of TRPM2, which encodes an oxidative stress-activated ion channel, is overexpressed in prostate cancer (PCa). The high expression of TRPM2-AS and its related gene signature were found to be linked to poor clinical outcome, with the related gene signature working also independently of the patient's Gleason score. Mechanistically, TRPM2-AS knockdown led to PCa cell apoptosis, with a transcriptional profile that indicated an unbearable increase in cellular stress in the dying cells, which was coupled to cell cycle arrest, an increase in intracellular hydrogen peroxide and activation of the sense TRPM2 gene. Moreover, targets of existing drugs and treatments were found to be consistently associated with high TRPM2-AS levels in both targeted cells and patients, ultimately suggesting that the measurement of the expression levels of TRPM2-AS allows not only for the early identification of aggressive PCa tumors, but also identifies a subset of at-risk patients who would benefit from currently available, but mostly differently purposed, therapeutic agents.

GastroPanel® test for non-invasive diagnosis of atrophic gastritis in patients with dyspepsia.

AIM: Atrophic gastritis (AG), first step in the cascade leading to gastric adenocarcinoma, is related to Helicobacter pylori (H. pylori) infection. Currently, the gold standard for the diagnosis of AG is esophagogastroduodenoscopy (EGD) with histological examination of the biopsy specimens. However, since the latter are taken in random order and the distribution of AG is often patchy, histology is only representative of mucosal status. Considering this limitation, a test named GastroPanel®, that measures the blood concentrations of pepsinogen I and II, gastrin-17 and H. pylori antibodies, has been developed as a potential non-invasive biopsy. Aim of this study has been to assess the accuracy of GastroPanel® in patients with AG. METHODS: Forty-seven dyspeptic patients (24 males, mean age 52.2±9.3 years), in follow-up for antral or diffuse AG, were enrolled. All underwent at least two EGDs with random biopsies and blood collection for GastroPanel® parameters examination. RESULTS: Of the 47 patients, 16 (34.1%) had histological diagnosis of antral and 31 (65.9%) multifocal AG; 17 (36.2%) patients had mild and 30 (63.8%) had moderate-severe AG. H. pylori was detected in 39 (82.9%) and intestinal metaplasia was found in all patients. GastroPanel® showed 82.9% sensitivity for the diagnosis of AG and 53.8% for the diagnosis of H. pylori infection. The prediction of advanced atrophy was not sufficiently accurate, neither in patients with antral nor in those with multifocal AG. CONCLUSION: GastroPanel® can be useful for detecting patients with AG. However, it does not reflect the severity of atrophy.

Attentional networks efficiency in preterm children.

Recent studies have reported specific executive and attentional deficits in preterm children. However, the majority of this research has used multidetermined tasks to assess these abilities, and the interpretation of the results lacks an explicit theoretical backdrop to better understand the origin of the difficulties observed. In the present study, we used the Child Attention Network Task (Child ANT; Rueda et al. 2004) to assess the efficiency of the alerting, orienting and executive control networks. We compared the performance of 25 preterm children (gestational age < or = 32 weeks) to 25 full-term children, all between 5(1/2) and 6(1/2) years of age. Results showed that, as compared to full-term children, preterm children were slower on all conditions of the Child ANT and had a specific deficit in executive control abilities. We also observed a significantly higher correlation between the orienting and executive control networks in the preterm group, suggesting less differentiation of these two networks in this population.

Soluble transferrin receptor values in top level soccer players and skiers: comparison with sedentary people and pitfalls of laboratory methods.

AIM: Hematological assessment is crucial in athletes: the risk of sports' anemia should be monitored with hematological parameters and iron metabolism tests. The aim of this study was to evaluate soluble transferrin receptor (sTfR) efficacy, as it is highly sensitive and specific and usually utilized in sport medicine for monitoring iron metabolism. METHODS: sTfR was studied using two immunological methods (IDeA Orion, and Biokit) on a group of professional athletes, together with hematological and iron metabolism parameters. Values have been compared with those of sedentary people, before and during competitive season. Athletes were 76 professional male soccer players plus 20 males and 14 females of the alpine ski Italian National Teams. RESULTS: The sTfR values in athletes are similar to those found in sedentary people. Different results have been observed between the two different methods: a bias of 0.37 mg/L was found comparing them. A significant correlation between sTfR and iron, transferrin saturation, and reticulocytes was found in skiers; there was no correlation with hemoglobin, erythrocytes, ferritin. In soccer players significant differences have been retrieved among different teams' distribution of data. CONCLUSIONS: The principal limit for using sTfR in sports medicine, but also in the general population, is the lack of standardization among methods. The quantitative differences in athletes between the two methods are high, although the behavior of the parameter is similar from the quality point of view. The differences between measured concentrations could influence the thresholds used in antidoping context.

The prevalence and clinical implications of c-kit expression in plasma cell myeloma.

AIM: To evaluate the clinical implications of c-kit (CD117) expression in plasma cell myeloma (PCM). METHODS AND RESULTS: We first evaluated the reliability of immunohistochemistry in assessing c-kit expression by comparing the results with those obtained by flow cytometry and gene expression arrays in 22 PCM and in 10 PCM cell lines. Immunohistochemical results showed a perfect concordance with those of flow cytometry; likewise, immunohistochemical and gene expression data were also concordant in all but one PCM and cell lines analysed. Then, we investigated the clinical implications of c-kit immunoreactivity in bone marrow biopsies of 85 PCM patients with a mean follow-up of 41 months. C-kit immunoreactivity was detected in 24 (28.2%) of the 85 cases and it was significantly associated with a high microvessel density, but not with traditional clinicopathological characteristics or with survival. CONCLUSIONS: Our findings suggest that immunohistochemistry is a reliable indicator of c-kit gene expression and reinforce the notion that approximately one-third of PCM express high levels of c-kit. The lack of association with traditional clinicopathological parameters and patient survival suggests that c-kit expression may not be an adjunct in predicting the clinical course of the disease.

Bilateral renal mass suggestive of cancer.

We present the case of a 44-year old man, presenting with acute left flank pain and gross haematuria, affected by bilateral renal mass and massive para-aortic and mediastinic lymphadenopathy, highly suspicious for metastatic renal cancer.

Islet isolation for allotransplantation: variables associated with successful islet yield and graft function.

AIMS/HYPOTHESIS: Efficient islet isolation is an important prerequisite for successful clinical islet transplantation. Although progressively improved, islet yield and quality are, however, unpredictable and variable and require standardisation. METHODS: Since 1989 we have processed 437 pancreases using the automated method. The donor characteristics, pancreas procurement, and digestion and purification procedures including a wide enzyme characterisation of these pancreases were analysed and correlated with islet yield and transplant outcome. RESULTS: By univariate analysis, islet yield was significantly associated with donor age (r=0.16; p=0.0009), BMI (r=0.19; p=0.0004), good pancreas condition (p=0.0031) and weight (r=0.15; p=0.0056), total collagenase activity (r=0.22; p=0.0001), adjusted collagenase activity/mg (r=0.18; p=0.0002), collagenase activity/solution volume (r=0.18; p=0.0002) and neutral protease activity/solution volume (r=0.14; p=0.0029). A statistically significant contribution to the variability of islet yield in a multivariate analysis performed on donor variables was found for donor BMI (p=0.0008). In a multivariate analysis performed on pancreas variables a contribution was found for pancreas weight (p=0.0064), and for a multivariate analysis performed on digestion variables we found a contribution for digestion time (p=0.0048) and total collagenase activity (p=0.0001). Twenty-four patients with type 1 diabetes received single islet preparations from single donors. In these patients, multivariate analyses showed that the reduction in insulin requirement was significantly associated with morphological aspects of islets (p=0.0010) and that 1-month C-peptide values were associated with islet purity (p=0.0071). CONCLUSIONS/INTERPRETATION: These data provide baseline donor, digestion and purification selection criteria for islet isolation using the automated method and indicate that the morphological aspect may be a clinically relevant measure of islets on which the decision for transplant can be based.

Combination of intravesical chemotherapy and hyperthermia for the treatment of superficial bladder cancer: preliminary clinical experience.

The prevalence of superficial transitional cell carcinoma of the bladder (STCCB) is still increasing in spite of improved adjuvant chemotherapeutic and/or immunoprophylaxis approaches. Thus, there is certainly an urgent need to improve our ability to control this disease. Local hyperthermia has a therapeutical potential for the treatment of many solid tumors, especially when used in combination with other treatments, such as radiation and chemotherapy. In particular, a synergistic or, at least, supra-additive anti-tumor cell killing effect was documented when local hyperthermia was administered in combination with selected cytostatic drugs. Recently, advances in miniaturized technology have allowed the development of a system specifically designed for delivering an endovesical thermo-chemotherapy regimen in humans. In preliminary clinical experiences, insofar mainly carried out as mono-institutional investigations, the combined treatment using this system was demonstrated to be feasible, minimally invasive and safe when performed on out-patient basis. Moreover, the anti-tumoral efficacy seemed to be significantly enhanced when compared with that obtained using intravesical chemotherapy alone for both adjuvant (prophylaxis) and neo-adjuvant (ablative) approaches to superficial bladder cancer.