ras protein activity is essential for T-cell antigen receptor signal transduction.

In a Jurkat cell model of T-cell activation an interleukin-2 promoter/reporter gene construct was activated by antigen receptor agonism in combination with the lymphokine interleukin-1. Antigen receptor signals could be mimicked by suboptimal activation of protein kinase C (PKC) with phorbol esters in combination with calcium mobilization by an ionophore. In cotransfection experiments, oncogenic rats obviated the need for PKC stimulation but did not replace either the calcium signal or interleukin-1. Activated ras expression also replaced the requirement for PKC stimulation in activation of the T-cell transcription factor NF-AT. A dominant inhibitory ras mutant specifically blocked antigen receptor agonism, indicating that ras activity is required for antigen receptor signaling. In addition, an inhibitor of PKC blocked both activated ras and phorbol ester stimulation, suggesting a role for ras upstream of PKC

Calcium-dependent cyclosporin A-sensitive activation of the interleukin-2 promoter by p56lck.

T-cell antigen receptor engagement results in suboptimal activation of protein kinase C and a prolonged increase in intracellular free calcium concentration. These signals, in combination with stimulation via accessory molecules usually supplied by the antigen presenting cell, activate expression of interleukin-2 (IL-2) and initiate autocrine growth. The lymphocyte-specific tyrosine kinase p56lck is physically associated with CD4 and is brought into close proximity of the intracellular domain of the antigen receptor by CD4 recognition of the major histocompatibility complex during antigen presentation. p56lck activation enhances and may be essential for antigen receptor signaling. We report that a constitutively active form of p56lck delivers a signal which contributes to IL-2 promoter activation. The signal substituted for a calcium-mobilizing signal in a Jurkat cell model of T-cell activation. The activation was sensitive to EGTA and cyclosporin A, indicating that p56lck functions at an early stage of the calcium-mediated pathway. The transcription factor NF-AT mediated, at least in part, the p56lck activation of IL-2 expression. In addition, activated p56lck synergized with constitutively active p21Ha-ras, which can replace protein kinase C activation, resulting in activation of NF-AT in the absence of external signals

Laparoscopic Cholecystectomy in the Cirrhotic: Review of Literature on Indications and Technique

Cholelithiasis is twice more common in patients suffering from liver cirrhosis compared to overall population and in those patients, acute cholecystitis occurs significantly more often. Our goal was to review the literature and to overview the indications, contra-indications, and alternatives in the cirrhotic with biliary stones. We conducted a systematic review of the literature using the key words "Cirrhosis", "cholecystectomy", "laparoscopy"and "indications". Selected articles were reviewed for information specific to indications, contra-indications, and alternatives to laparoscopic cholecystectomy in cirrhotics. Results showed that laparoscopic cholecystectomy might offer several advantages in cirrhotic population, however cholecystectomy can be challenging: specific indications and alternatives to surgery must be discussed case by case. Laparoscopic cholecystectomy can be performed safely in selected patients with cirrhosis; special precautions are warranted regarding pneumoperitoneum pressure, trocar placement and increased safety with Indocyanine-green (ICG) fluorescence cholangiography. Nevertheless, in high-risk cirrhotic patients (Child C) and/or in common bile duct lithiasis endoscopic and non-surgical conservative treatments are preferable

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

Prediction of 2 years-survival in patients with stage I and II non-small cell lung cancer utilizing (18)F-FDG PET/CT SUV quantification.

BACKGROUND: The purpose of the study was to evaluate the correlation between the maximum standardized uptake value (SUVmax), size of primary lung lesion, disease-free survival (DFS) and overall survival (OS) in patients with stage I and II non-small cell lung cancer (NSCLC) in 2 years follow-up. PATIENTS AND METHODS. Forty-nine patients with stage I–II NSCLC were included in this study. Pre-surgical 2-deoxy-2-[18F]fluoro-D-glucose positron-emission tomography ((18)F-FDG PET/CT) study was performed for all patients. The relationship between SUVmax, tumour size and clinical outcome was measured. The cut-off value for SUVmax and tumour size with the best prognostic significance, probability of DFS and the correlation between SUVmax and the response to therapy were calculated. RESULTS: There was a statistically significant correlation between SUVmax and DFS (p = 0.029). The optimal cut-offs were 9.00 for SUVmax (p = 0.0013) and 30mm for tumour size (p = 0.0028). Patients with SUVmax > 9 and primary lesion size > 30 mm had an expected 2years-DFS of 37.5%, while this rose to 90% if the tumour was <30 mm and/or SUVmax was <9. CONCLUSIONS: In stage I-II, SUVmax and tumour size might be helpful to identify the subgroup of patients with high chance for recurrence

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

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

Constrangimento mecânico provocado pela válvula aquatrainer® associada ao sistema de oximetria directa (K4 B2) na cinemática de bruços

estudo teve como objectivo determinar o constrangimento cinemático provocado pela válvula de treino Aquatrainer® (Cosmed, Roma, Itália), integrada com o sistema portátil analisador de gases K4 b2 (Cosmed, Roma, Itália), durante um esforço máximo na técnica de Bruços. O protocolo consistiu na realização de dois percursos à intensidade máxima de 100 m bruços, em piscina de 50 metros: um percurso com o sistema de oximetria acoplado e outro em nado livre (sem o sistema) e um intervalo mínimo de 48 horas por sete bruçistas. Duas câmaras registaram respectivamente imagens aéreas e subaquáticas no plano sagital. Foi efectuada a análise cinemática (Ariel Performance Analysis System, Ariel Dynamics Inc., Califórnia, EUA) de um ciclo gestual completo, através de um leitor de vídeo a 50 Hz (Panasonic, AG 7355, Japão). A duração do teste foi significativamente superior quando acoplados à válvula do que em nado livre (P = 0,02). Sem a válvula os bruçistas cumpriram os 100 metros em 109.09 ± 2.23 % do seu recorde pessoal e com a válvula a 115.94 ± 3.31 %. As restantes variáveis não apresentaram diferenças significativas entre as duas condições de exercitação. Contudo, verifica-se uma tendência para a frequência gestual (3.56 %) ser superior com a utilização da válvula; a distância de ciclo (-8.47 %), a velocidade de nado (-5.98 %), o índice de nado (-13.94 %), a flutuação da velocidade do centro de massa (-0.16 %) e periodo do ciclo (-3.24 %) serem inferiores com a utilização da válvula. Em síntese, a válvula Aquatrainer® induz constrangimentos significativos na performance durante uma prova máxima em Bruço

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