Interleukin-2 promoter activation in T-cells expressing activated Ha-ras.

Antigen triggering of the T-cell receptor results in an accumulation of activated GTP-bound p21ras protein. To assess the role of ras protein in T-cell activation we have cotransfected the murine thymoma line EL4 with a construct capable of expressing a constitutively active, oncogenic form of Ha-ras and a reporter construct containing the human interleukin-2 promoter fused upstream of the bacterial gene for chloramphenicol acetyltransferase. We show that the ras oncoprotein contributes to interleukin-2 promoter activation. Its pattern of synergism with a calcium ionophore or the lymphokine interleukin-1 indicates that it replaces a signal mediated by protein kinase C. Interleukin-2 promoter activity in the presence of ras oncoprotein was inhibited by H7, a potent inhibitor of protein kinase C, but not by HA1004, an inhibitor of cyclic nucleotide-dependent kinase, suggesting that protein kinase C mediates the ras effect. In addition, we show that in these cells, expression of activated ras results in activation of a synthetic promoter containing several copies of an NF kappa B binding site

RSA, CMJ, Leger, 10m sprint responses to Pre-season training in semi-Professional Soccer Players

Aim: The aim of this study was to analyze RSA, CMJ, Leger, 10m sprint responses to Pre-season Training in Semi-Professional Soccer Players (SPSP). Considering that numerous studies1,2 highlighted the combination of high levels of physical, technical and tactical skills during a soccer match, the cure of physical training pose a particular attention on training load that generally increases up to 2.4 times during the pre-season period compared with the in-season3. Methods: Six SPSP (age: 23±7yr; BMI: 23.3±1.8) were requested to perform aerobic training over an 8-week period on alternate days with the functional strength training sessions and sprint training drills as prescribed by the coaches and strength and conditioning staff. Repeated Sprint Ability (RSA, Total Time –TT- and percentage of fatigue index -%FI), Leger, 10m sprint and Counter Mouvement Jump (CMJ) tests, were performed before and after pre-season soccer training. ANOVA for repeated measures was conducted to assess differences (p<0.05) with respect to pre seasonal training. Correlation was calculated between the percentage of variation (Δ) of each test. Results: Compared to the values recorded before the pre-season, improvement of Leger (3%) and %FI (17.6%) and a deterioration of TT (10%), 10m sprint (0.2%) and CMJ (2.4%) were found. In addition, we have found a main effect between before and after pre-seasonal training in TT (F(1,4)=60.2; p=0.001) and Leger (F(1,5)=25; p<0.005). ΔCMJ showed very large correlation with ΔLeger (r=-0.88) and nearly perfect with Δ%FI (r=0.93); while ΔLeger was largely correlated with Δ%FI (r=-0.69). Conclusions: Given that the cure of the physical preparation is considered as an important element in order to influence the final soccer game result, this study want to be useful information for the coach in order to maximize the best physical condition of the whole team relative to the beginning of the regular season

Cyclosporin A blocks calcium-dependent pathways of gene activation

We have used an interleukin-2 (IL-2) promoter-CAT fusion gene to study activation of IL-2 gene expression by IL-1, phytohemagglutinin (PHA), phorbol myristate acetate (PMA), and calcium ionophore in the murine thymoma line EL4 and the human lymphoma line Jurkat. The two cell lines respond differently to combinations of these stimuli. IL-1 in combination with suboptimal concentration of PMA induced chloramphenicol acetyltransferase (CAT) activity in EL4. In Jurkat cells, IL-1 failed to synergize with PMA or PHA. Cotransfection with the IL-2/CAT gene and a construct capable of expressing murine T-cell type IL-1 receptors converted Jurkat cells to IL-1 responsiveness. IL-1 in combination with PHA but not with PMA resulted in induction of CAT activity in these cells. Induction of IL-2/CAT activity by all stimuli in both cell lines was blocked by the presence of EGTA in the culture medium. EGTA did not inhibit IL-1/PMA activation of an SV40 early promoter-CAT fusion gene in either EL4 or Jurkat cells; therefore, calcium was not required for IL-1 or PMA signal transduction. Jurkat cells were shown to differ from EL4 in their requirement for calcium mobilization. Two different calcium-dependent pathways of gene activation were distinguished, both of which were blocked by the immunosuppressive drug cyclosporin A

Effects of open (Racket) and closed (running) skill sports practice on children’s attentional performance

Aims: The first aim of the study was to examine the attentional performance of children (8–13 years of age) who practiced two different sport disciplines: Open skill sport – racket and closed skill sport – running and also to investigate the acute effects of these two specific training sessions on children’s immediate and delayed attentional performance. The second aim of the present study was to verify gender differences in attentional performance. Eighteen children+ (8 girls and 10 boys; age = 10.6 ± 1.5 yrs; height = 144.3 ± 12.2 cm; weight = 44.2 ± 12.5 kg; BMI = 20.8 ± 2.7 kg/m2) engaged in a racket sports and eighteen children (9 girls and 9 boys; age = 9.9 ± 1.2 yrs; height = 142.4 ± 9.5 cm; weight = 40.0 ± 8.6 kg; BMI = 19.6 ± 2.4 kg/m2) engaged in running were enrolled. Methods: Children’s training and experience with these activities averaged 2.3 (± 1.0) years. Children’s attentional capacity was measured before, immediately after and 50 minutes after each specific training session by the d2 test of attention. This paper-and-pencil letter cancellation test evaluated concentration and sustained attention under stress induced by a fixed executing time. A 2 (Sport: open vs closed skill) x 2 (Gender: boys vs girls) x 3 (Time: pre vs 0’ post vs 50’ post) repeated measures ANOVA for time was used to compare the effect of an open skill session and a closed skill session on the individual attentional variables. Results: Children of open skill sport showed higher attentional scores (higher processing speed-TN, higher concentration performance-CP and lower percentage of errors-E%; p &lt; 0.01), improved CP from pre to 0’ post intervention (p = 0.01) and maintained this improved performance at 50’ post intervention (50’ post vs pre; p &lt; 0.01), and decreased E% from pre to 0’ post intervention (p = 0.01) and maintained this improvement at 50’ post intervention (50’ post vs pre; p &lt; 0.001). Children of closed skill sport significantly decreased their CP from pre to 50’ post intervention (50’ post vs pre; p = 0.001 and 50’ post vs 0’ post; p &lt; 0.0001) and worsened their E% across the time (50’ post vs pre; p = 0.001 and 50’ post vs 0’ post; p &lt; 0.0001). Boys showed significantly higher TN values than girls only in closed skill sport (p = 0.023). Finally, all girls of both open and closed skill sports significantly improved their CP from pre to 0’ post intervention (p = 0.04). Conclusion: Results of the study showed that open skill sport practice and training session positively affects children’s attentional performance

[177Lu]Lu-DOTA-TATE versus standard of care in adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs): a cost-consequence analysis from an Italian hospital perspective

Purpose: To assess and compare clinical outcomes and costs, to the Italian healthcare system, of three therapeutic options approved in the management of adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs). Methods: We compared the efficacy, safety, and costs of [177Lu]Lu-DOTA-TATE, everolimus (both originator and generic products), and sunitinib in patients with advanced GEP-NETs (NET G1 and G2) that had progressed following treatment with somatostatin analogs (SSAs). A cost-consequence model was developed and validated by a panel of clinical experts from three NET reference centres in Italy. The clinical outcomes included in the model were median progression-free survival and the incidence of grade 3 or 4 adverse events (AEs), as reported in pivotal clinical trials. The costs for acquisition and administration of each treatment, and of managing AEs, were calculated from the perspective of the Italian national health service. Treatment costs per progression-free month were calculated separately for patients with NETs of pancreatic (PanNETs; all three treatments) and gastrointestinal (GI-NETs; [177Lu]Lu-DOTA-TATE and everolimus only) origin. Results: In patients with PanNETs, total costs per progression-free month were €2989 for [177Lu]Lu-DOTA-TATE, €4975 for originator everolimus, €3472 for generic everolimus, and €5337 for sunitinib. In patients with GI-NETs, total costs per progression-free month were €3189 for [177Lu]Lu-DOTA-TATE, €4990 for originator everolimus, and €3483 for generic everolimus. Conclusions: [177Lu]Lu-DOTA-TATE was associated with lower costs per progression-free month versus relevant treatment options in patients with GI-NETs or PanNETs (NET G1–G2; progressed following SSA treatment), although acquisition and administration costs are higher. These findings provide further economic arguments in the overall context of treatment decision-making

Immunohistochemical localization and functional characterization of somatostatin receptor subtypes in a corticotropin releasing hormone-secreting adrenal phaeochromocytoma: review of the literature and report of a case

Somastostatin receptors are frequently expressed in phaeochromocytoma but data on somatostatin receptor subtyping are scanty and the functional response to the somatostatin analogue octretide is still debated.We report an unusual case of pheochromocytoma, causing ectopic Cushing’s syndrome due to CRH production by the tumour cells, in a 50-yr-old woman. Abdominal computed tomography revealed an inhomogeneous, 9-cm mass in the right adrenal gland, and [111In-DTPA0] octreotide scintigraphy showed an abnormal uptake of the radiotracer in the right perirenal region, corresponding to the adrenal mass. The patient underwent laparoscopic surgery and formalin-fixed and paraffin-embedded samples were studied. The tumour was extensively characterized by immunohistochemistry and somatostatin receptor (SSTRs) subtypes expression was analyzed. Histological and immunohistochemical examination of the surgical specimens displayed a typical pheochromocytoma, which was found to be immunoreative to S-100, chromogranin A and neurofilaments. Immunostaining for SSTR subtypes showed a positive reaction for SSTR1, SSTR2A, SSTR2B, antisera on tumour cells. The intense and diffuse immunostaining for corticotropin releasing hormone (CRH) antiserum indicated that Cushing’s disease was dependent on CRH overproduction by the pheochromocytoma, in which no immunostaining for adrenocorticotropic hormone was found. Our report confirms the heterogeneity of the pattern of SSTR expression in pheochromocytomas, and provide further evidence for functional SSTR subtype SSTR2a in a subgroup of pheochromocytomas, suggesting that these tumours may represent potential target for octreotide treatment

Neutropenic enterocolitis and sepsis: Towards the definition of a pathologic profile

Background: Neutropenic enterocolitis (NE), which in the past was also known as typhlitis or ileocecal syndrome for the segment of the gastrointestinal tract most affected, is a nosological entity that is difficult to diagnose and whose pathogenesis is not fully known to date. Initially described in pediatric patients with leukemic diseases, it has been gradually reported in adults with hematological malignancies and non-hematological conditions, such as leukemia, lymphoma, multiple myeloma, aplastic anemia, and also myelodysplastic syndromes, as well as being associated with other immunosuppressive causes such as AIDS treatment, therapy for solid tumors, and organ transplantation. Therefore, it is associated with high mortality due to the rapid evolution in worse clinical pictures: Rapid progression to ischemia, necrosis, hemorrhage, perforation, multisystem organ failure, and sepsis. Case report: A case report is included to exemplify the clinical profile of patients with NE who develop sepsis. Literature Review: To identify a specific profile of subjects affected by neutropenic enterocolitis and the entity of the clinical condition most frequently associated with septic evolution, a systematic review of the literature was conducted. The inclusion criteria were as follows: English language, full-text availability, human subjects, and adult subjects. Finally, the papers were selected after the evaluation of the title and abstract to evaluate their congruity with the subject of this manuscript. Following these procedures, 19 eligible empirical studies were included in the present review. Conclusions: Despite the recent interest and the growing number of publications targeting sepsis and intending to identify biomarkers useful for its diagnosis, prognosis, and for the understanding of its pathogenesis, and especially for multi-organ dysfunction, and despite the extensive research period of the literature review, the number of publications on the topic “neutropenic enterocolitis and sepsis” appears to be very small. In any case, the extrapolated data allowed us to conclude that the integration of medical history, clinical and laboratory data, radiological imaging, and macroscopic and histological investigations can allow us to identify a specific pathological profile

The efficacy of trabecular titanium cages to Induce reparative bone activity after lumbar arthrodesis studied through the 18f-Naf PET/CT scan: observational clinical in-vivo study

Background: Titanium trabecular cages (TTCs) are emerging implants designed to achieve immediate and long-term spinal fixation with early osseointegration. However, a clear radiological and clinical demonstration of their efficacy has not yet been obtained. The purpose of this study was to evaluate the reactive bone activity of adjacent plates after insertion of custom-made titanium trabecular cages for the lumbar interbody with positron emission tomography (PET)/computed tomography (CT) 18F sodium fluoride (18F-NaF). Methods: This was an observational clinical study that included patients who underwent surgery for degenerative disease with lumbar interbody fusion performed with custom-made TTCs. Data related to the metabolic-reparative reaction following the surgery and its relationship with clinical follow-up from PET/CT performed at different weeks were evaluated. PET/CTs provided reliable data, such as areas showing abnormally high increases in uptake using a volumetric region of interest (VOI) comprising the upper (UP) and lower (DOWN) limits of the cage. Results: A total of 15 patients was selected for PET examination. Timing of PET/CTs ranged from one week to a maximum of 100 weeks after surgery. The analysis showed a negative correlation between the variables SUVmaxDOWN/time (r = −0.48, p = 0.04), ratio-DOWN/time (r = −0.53, p = 0.02), and ratio-MEAN/time (r = −0.5, p = 0.03). Shapiro−Wilk normality tests showed significant results for the variables ratio-DOWN (p = 0.002), ratio-UP (0.013), and ratio-MEAN (0.002). Conclusions: 18F-NaF PET/CT has proven to be a reliable tool for investigating the metabolic-reparative reaction following implantation of TTCs, demonstrating radiologically how this type of cage can induce reparative osteoblastic activity at the level of the vertebral endplate surface. This study further confirms how electron-beam melting (EBM)-molded titanium trabecular cages represent a promising material for reducing hardware complication rates and promoting fusion

Recurrence quantification analysis of heart rate variability to detect both ventilatory thresholds

Aims of this study were: To verify if Recurrence Quantification Analysis (RQA) of Heart Rate Variability (HRV) time series could determine both ventilatory thresholds in individuals with different fitness levels, and to assess the validity of RQA method compared to gasexchange method (GE). The two thresholds were estimated in thirty young individuals during incremental exercise on cycle-ergometer: Heart rate (HR), Oxygen consumption (VO2) and Workload were measured by the two methods (RQA and GE). Repeated measures ANOVA was used to assess main effects of methods and methods-by-groups interaction effects for HR, VO2 and Workload at aerobic (AerT) and anaerobic (AnT) thresholds. Validity of RQA at both thresholds was assessed for HR, VO2 and Workload by Ordinary Least Products (OLP) regression, Typical Percentage Error (TE), Intraclass Correlation Coefficients (ICC) and the Bland Altman plots. No methods-by-groups interaction effects were detected for HR, VO2 and Workload at AerT and AnT. The OLP analysis showed that at both thresholds RQA and GE methods had very strong correlations (r &gt;0.8) in all variables (HR, VO2 and Workload). Slope and intercept values always included the 1 and the 0, respectively. At AerT the TE ranged from 4.02% (5.48 bpm) to 10.47% (8.53 Watts) (HR and Workload, respectively) and in all variables ICC values were excellent (≥0.85). At AnT the TE ranged from 2.53% (3.98 bpm) to 6.64% (7.81 Watts) (HR and Workload, respectively) and in all variables ICC values were excellent (≥0.90). Therefore, RQA of HRV time series is a new valid approach to determine both ventilatory thresholds in individuals with different physical fitness levels, it can be used when gas analysis is not possible or not convenient

Which physical activity in patients affected by hypoparathyroidism? A review of the literature and practical recommendations

Background Hypoparathyroidism (HypoP) is a rare endocrine condition characterized by hypocalcaemia and hyperphos- phatemia, as a consequence of absent or improperly low parathyroid hormone (PTH) levels. Patients affected by HypoP have a clinical condition often characterized by paresthesias and muscle spasms, as well as long-term consequences as nephro- lithiasis, extraskeletal calcification, and fractures. In the literature, likely due to these symptoms, few data exist regarding the appropriate physical activity (PA) in subjects suffering from HypoP. Purpose This review evaluates the literature on exercise-based approaches to the management of individuals affected by HypoP and evaluates: (1) the effects of physical exercise on muscle cramps and other clinical symptoms; (2) the effects of exercise on PTH and calcium level; (3) the most suitable clinical exercise testing; and (4) the most suitable exercise combination. Methods and results A systematic search was conducted using the databases MEDLINE, Google Scholar using “hypopar- athyroidism AND Physical Activity”, “Training AND hypoparathyroidism”, “Exercise AND muscle cramps”, “Exercise AND Fatigue” as keywords. In addition, references list from the included articles were searched and cross-checked to identify any further potentially eligible studies. A total of 50 manuscripts were found among which 39 manuscripts were selected. A few clinical studies have been performed in HypoP patients to evaluate PA training protocols. Conclusion Although further research is needed to draw solid conclusions regarding best PA protocols in subjects affected by HypoP, a PA protocol has been proposed within the manuscript to encourage patients to attempt exercise to improve their clinical conditions and their quality of life