One side effect of the immunomodulatory effect of interferon is the possible triggering or exacerbation of systemic or cutaneous sarcoidosis. We report two new cases and offer an exhaustive review of ...the literature. A 39-year-old man with type C chronic active hepatitis developed new respiratory symptoms and pulmonary infiltrates with hilar and mediastinal adenopathy after 7 months of treatment with pegylated interferon. The evolution was favourable after stopping treatment. The second patient developed cutaneous lesions after 6 months of treatment. Resolution occurred after the discontinuation of the treatment. In these two cases ribavirin was stopped before the first signs of sarcoidosis.
Le mécanisme de formation du granulome sarcoïdosique est peu clair. L’activation des lymphocytes CD4+ et l’interféron gamma semblent jouer un rôle important. L’interféron par ses effets ...immunomodulateurs pourrait induire ou aggraver une sarcoïdose. Nous rapportons deux cas de sarcoïdose sous interféron retard. Le premier malade âgé de 39 ans développait une sarcoïdose pulmonaire (syndrome interstitiel et adénopathies médiastinales) après sept mois de traitement. L’évolution était favorable après arrêt de l’interféron. Le deuxième malade présentait une forme cutanée après six mois et demi de traitement. L’évolution était favorable à l’arrêt du traitement et sans corticothérapie.
One side effect of the immunomodulatory effect of interferon is the possible triggering or exacerbation of systemic or cutaneous sarcoidosis. We report two new cases and offer an exhaustive review of the literature. A 39-year-old man with type C chronic active hepatitis developed new respiratory symptoms and pulmonary infiltrates with hilar and mediastinal adenopathy after 7 months of treatment with pegylated interferon. The evolution was favourable after stopping treatment. The second patient developed cutaneous lesions after 6 months of treatment. Resolution occurred after the discontinuation of the treatment. In these two cases ribavirin was stopped before the first signs of sarcoidosis.
Cell fate assignment in the nervous system of vertebrates and invertebrates often hinges on the unequal distribution of molecules during progenitor cell division. We address asymmetric fate ...determinant localization in the developing
nervous system, specifically the control of the polarized distribution of the cell fate adapter protein Miranda. We reveal a step-wise polarization of Miranda in larval neuroblasts and find that Miranda's dynamics and cortical association are differently regulated between interphase and mitosis. In interphase, Miranda binds to the plasma membrane. Then, before nuclear envelope breakdown, Miranda is phosphorylated by aPKC and displaced into the cytoplasm. This clearance is necessary for the subsequent establishment of asymmetric Miranda localization. After nuclear envelope breakdown, actomyosin activity is required to maintain Miranda asymmetry. Therefore, phosphorylation by aPKC and differential binding to the actomyosin network are required at distinct phases of the cell cycle to polarize fate determinant localization in neuroblasts.
The Nod-like receptor family protein 3 (NLRP3)-inflammasome pathway is known to be activated by danger signals such as monosodium urate (MSU). We investigated the role of P2 purinergic receptors in ...the activation of NLRP3-inflammasome pathway after MSU treatment of primary human monocyte-derived macrophages (MDMs). After initial stimulation with a low concentration of LPS (0.1 µg/ml), a 6 h treatment with MSU crystals (250, 500, and 1000 µg/ml) induced the MDMs to release IL-1β, IL-1α, and IL-6 in a dose-dependent manner. Moreover, the caspase 1 inhibitor Z-YVAD-FMK and the cathepsin B inhibitor CA-074Me reduced production of IL-1β in a dose-dependent manner after LPS + MSU treatment. We used real-time reverse transcription-quantitative PCR to show that treatment with LPS and MSU (500 µg/ml) induced significantly greater expression of NLRP3 and IL-1β than after treatment with LPS. We also found that MSU treatment induced P2X purinergic receptor 7 (P2X7R) mRNA and protein expression. Furthermore, addition of the P2X7 purinergic receptor antagonist A-740003 significantly impeded IL-1β production and pro-IL-1β cleavage after treatment with LPS + MSU. Remarkably, RNA silencing of P2X7R (but not P2X4R) inhibited the release of IL-1β and other M1 macrophage cytokines (such as IL-1α, IL-6, and TNF-α) from MDMs stimulated with LPS + MSU. Taken as a whole, our results show that P2 purinergic receptors and the NLRP3 inflammasome pathway are involved in the secretion of IL-1β from MSU-stimulated human macrophages. This pathway may constitute a novel therapeutic target for controlling the inflammatory process in several associated pathologies.
Background Children with body weight less than 2.5 kg who undergo the arterial switch operation (ASO) represent a challenging group. We sought to determine outcomes of patients with weight less than ...2.5 kg at ASO at a single institution. Methods All patients who underwent an ASO with biventricular repair and weighed less than 2.5 kg at time of surgery were identified from the hospital database and reviewed retrospectively. Results From 1983 to 2014, 870 patients underwent an ASO with biventricular repair at our institution. At the time of ASO, 31 patients (3.6%, 31 of 870) weighed less than 2.5 kg (mean 2.1; median 2.1; range, 1.1 to 2.4). Twenty-nine patients underwent an ASO for d-transposition of the great arteries, and 2 patients had an ASO for Taussig-Bing anomaly. Mean age at operation was 16 days (median 11; range, 3 to 66). There were 6 hospital deaths (19%, 6 of 31) among patients weighing less than 2.5 kg compared with a hospital mortality of 1.9% (16 of 839) among patients weighing more than 2.5 kg ( p < 0.0001). Mortality for children weighing 2.0 kg or less was 50% (5 of 10) compared with a mortality of 2.8% (1 of 21) for children weighing more than 2.0 kg but less than 2.5 kg. Four patients (13%, 4 of 31) required reoperation during hospital admission. Follow-up was available for 24 survivors (96%, 24 of 25). Mean follow-up was 13.2 years (median 11.9; range, 6 months to 25 years). There were no late deaths. Two patients (8%, 2 of 24) required late reoperation. No patient had more than mild neoaortic valve regurgitation, and all survivors were in New York Heart Association class I at last follow-up. Conclusions Early mortality for children weighing less than 2.5 kg undergoing the ASO remains high; however, most of the mortality occurred in children weighing 2.0 kg or less. Long-term outcomes for survivors are excellent.
Radiofrequency ablation (RFA) has become a common treatment of patients with unresectable primary and secondary hepatic malignancies. We performed this prospective analysis to determine early (within ...30 days) and late (more than 30 days after) complication rates associated with hepatic tumor RFA.
All patients treated between January 1, 1996 and June 30, 2002 with RFA for hepatic malignancies were entered into a prospective database. Patients were evaluated during RFA treatment, throughout the immediate post RFA course, and then every 3 months after RFA to assess for the development of treatment-related complications.
A total of 608 patients, 345 men (56.7%) and 263 women (43.3%), with a median age of 58 years (range 18-85 years) underwent RFA of 1225 malignant liver tumors. Open intraoperative RFA was performed in 382 patients (62.8%), while percutaneous RFA was performed in 226 (37.2%). The treatment-related mortality rate was 0.5%. Early complications developed in 43 patients (7.1%). Early complications were more likely to occur in patients treated with open RFA (33 8.6% of 382 patients) compared with percutaneous RFA (10 4.4% 226 patients, P < 0.01), and in patients with cirrhosis (25 12.9% complications in 194 patients) compared with noncirrhotic patients (31 7.5% complications in 414 patients, P < 0.05). Late complications arose in 15 patients (2.4%) with no difference in incidence between open and percutaneous RFA treatment. The combined overall early and late complication rate was 9.5%.
Hepatic tumor RFA can be performed with low mortality and morbidity rates. Though relatively rare, late complications can develop and physicians performing hepatic RFA must be cognizant of these delayed treatment-related problems.
Characterizing myocardial activation is of major interest for understanding the underlying mechanism of cardiac arrhythmias. Electromechanical wave imaging (EWI) is an ultrafast ultrasound-based ...method used to map the propagation of the local contraction triggered by electrical activation of the heart. This study introduces a novel way to characterize cardiac activation based on the time evolution of the instantaneous frequency content of the cardiac tissue displacement curves. The first validation of this method was performed on an ex vivo dataset of 36 acquisitions acquired from two working heart models in paced rhythms. It was shown that the activation mapping described by spectral analysis of interframe displacement is similar to the standard EWI method based on zero-crossing of interframe strain. An average median error of 3.3 ms was found in the ex vivo dataset between the activation maps obtained with the two methods. The feasibility of mapping cardiac activation by EWI was then investigated on two open-chest pigs during sinus and paced rhythms in a pilot trial of cardiac mapping with an intracardiac probe. Seventy-five acquisitions were performed with reasonable stability and analyzed with the novel algorithm to map cardiac contraction propagation in the left ventricle (LV). Sixty-one qualitatively continuous isochrones were successfully computed based on this method. The region of contraction onset was coherently described while pacing in the imaging plane. These findings highlight the potential of implementing EWI acquisition on intracardiac probes and emphasize the benefit of performing short time-frequency analysis of displacement data to characterize cardiac activation in vivo .
Purpose: The purpose is to evaluate the feasibility and safety of aerosol administration of the topoisomerase I inhibitor, 9-nitrocamptothecin,
in a liposome formulation, and to recommend a dosage ...for a Phase II trial for an 8-week daily treatment schedule.
Experimental Design: Patients with primary or metastatic lung cancer received aerosolized liposomal 9-nitrocamptothecin for 5 consecutive days/week
for 1, 2, 4, or 6 weeks followed by 2 weeks of rest to determine feasibility. For the Phase I part, the dose was increased
stepwise from 6.7 up to 26.6 μg/kg/day Monday to Friday for 8 weeks followed by 2 weeks of rest.
Results: Twenty-five patients received treatment. The mean baseline forced expiratory volume in 1 second for all patients was 85%
of predicted. A dose-limiting toxicity was chemical pharyngitis seen after 1 week in 2 of 2 patients at 26.6 μg/kg/day. At
20.0 μg/kg/day, grade 2 and 3 fatigue prompting a dose reduction was seen after 4 weeks in 2 of 4 patients. Grade 2 toxic
effects included nausea/vomiting (9 patients), cough and bronchial irritation (6 patients), fatigue (5 patients), anemia (4
patients), neutropenia (2 patients), anorexia (1 patient), and skin rash around the face mask (1 patient). 9-Nitro-20(S)-camptothecin
(9NC) was absorbed systemically. Partial remissions were observed in 2 patients with uterine cancer, and stabilization occurred
in 3 patients with primary lung cancer.
Conclusions: Aerosol administration of liposomal 9NC was found to be feasible and safe. 9NC delivered as an aerosol was detected in patient’s
plasma shortly after the start of treatment. The recommended dose for Phase II studies is 13.3 μg/kg/day (equivalent to 0.5
mg/m 2 /day), which constitutes two consecutive 30-min nebulizations/day from a nebulizer reservoir with 4 mg of 9NC in 10 ml of
sterile water, Monday to Friday for 8 weeks every 10 weeks.
Gastrointestinal stromal tumors (GISTs), which arise from the interstitial cells of Cajal, are the most common nonepithelial tumors of the gastrointestinal tract. It is now well known that imatinib, ...a new molecularly targeted tyrosine kinase receptor blocker, results in a dramatic response and markedly improved long-term survival in patients with GISTs. The increasing recognition of GISTs and the prolonged survival have made imaging increasingly important not only for diagnosis but also for monitoring the effects of treatment and detecting tumor progression. Computed tomography (CT) is the imaging modality of choice for these purposes. The imaging findings at initial presentation, during treatment, and at tumor progression were studied in 113 patients with primary and advanced GISTs before and up to 37 months after imatinib treatment. GISTs occur anywhere along the gastrointestinal tract, most commonly in the stomach and small bowel. At contrast material-enhanced CT, localized primary GISTs are typically exophytic, large, hypervascular masses. When the tumors respond to treatment, the changes in tumor size may initially vary; however, GISTs typically become homogeneous and hypoattenuating, with disappearance of enhancing tumor nodules and tumor vessels in the early posttreatment period. Development of a nodule within the treated tumor is unique to GISTs and indicates recurrence regardless of changes in tumor size.
The production of mRNAs in all living organisms is an extremely complex process that includes multiple catalytic activities such as transcription, capping, splicing, polyadenylation, cleavage and ...export. All of these processes are controlled by a large group of proteins which form very dynamic complexes interacting with DNA and pre-mRNAs to coordinate these activities. Phosphorylations play a central role in regulating formation, activation and inactivation of these complexes. A growing number of protein kinases have been identified that are capable of phosphorylating proteins involved in mRNA production. Among them, Cyclin-dependent Kinases (CDKs) represent a family of serine/threonine protein kinases that become active upon binding to a cyclin regulatory partner. CDK/cyclin complexes were first identified as crucial regulators of cell cycle progression. More recently, CDK/cyclin complexes have also been implicated in transcription and mRNA processing leading to the concept of an intricate network of CDK/cyclin complexes regulating cell cycle, transcription and mRNA processing via cross-talk between multiple CDKs. In this review, we discuss the role of CDK/cyclin-dependent phosphorylation in the regulation of transcription and RNA splicing and highlight recent findings that indicate the involvement of CDK/cyclin complexes in connecting transcription and RNA splicing.
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