Sweet syndrome presenting late after non Hodgkin’s lymphoma and dermatomyositis

Abstract Sweet syndrome is a rare neutrophilic dermatosis consisting in the onset of high fever, neutrophilia, and typical painful skin lesions including erythematous papules, nodules, and plaques on the face, trunk, and extremities, with a bilateral and asymmetrical pattern. Sweet syndrome is classiied as idiopathic, predominating in women; malignancy-associated, mainly with hematological cancer, and drug-induced. The diagnosis is based on clinical history and skin manifestations, being conirmed by a complete blood count showing neutrophilic leukocytosis, and speciic indings in the skin biopsy. We report the case of a 68 year-old man with a 10-year evolution of dermatomyositis complicated by lung ibrosis, followed 8 years later by non-Hodgkin lymphoma (NHL) accompanied by worsening of his ibrosis. Two years after the successful treatment of NHL the patient developed an acute episode of severe dyspnea, multiple skin lesions, and 95% neutrophilia. At that time the patient had a severe lung function impairment complicated by nosocomial pneumonia that led to his death, a few days after the diagnosis of Sweet syndrome was established by histopathology examination. Sweet syndrome is a rare dermatologic entity that can appear several years after diseases characterized by immune dysfunction such as dermatomyositis and NHL.

Awake examination versus DISE for surgical decision making in patients with OSA: A systematic review

OBJECTIVE: Traditionally, upper airway examination is performed while the patient is awake. However, in the past two decades, drug-induced sleep endoscopy (DISE) has been used as a method of tridimensional evaluation of the upper airway during pharmacologically induced sleep. This study aimed to systematically review the evidence regarding the usefulness of DISE compared with that of traditional awake examination for surgical decision making in patients with obstructive sleep apnea (OSA). DATA SOURCES: Scopus, PubMed, and Cochrane Library databases were searched. REVIEW METHODS: Only studies with a primary objective of evaluating the usefulness of DISE for surgical decision making in patients with OSA were selected. The included studies directly compared awake examination data with DISE outcome data in terms of possible influences on surgical decision making and operation success. RESULTS: A total of eight studies with 535 patients were included in this review. Overall, the surgical treatment changed after DISE in 50.24% (standard deviation 8.4) cases. These changes were more frequently associated with structures contributing to hypopharyngeal or laryngeal obstruction. However, these differences do not automatically indicate a higher success rate. CONCLUSION: This review emphasized the direct impact of DISE compared with that of awake examination on surgical decision making in OSA patients. However, it is also clear that the available published studies lack evidence on the association between this impact and surgical outcomes

Glutamatergic Modulation of Cue-Induced Drug-Seeking Behavior in the Rat

The characteristics of drug addiction include compulsive drug use despite negative consequences and re-occurring relapses, returns to drug use after a period of abstinence. Therefore, relapse prevention is one of the major challenges for the treatment of drug addiction. There are three main factors capable of inducing craving for drugs and triggering relapse long after cessation of drug use and dissipation of physical withdrawal signs: stress, re-exposure to the drug, and environmental stimuli (cues) that have been previously associated with drug use. The neurotransmitters dopamine and glutamate have been implicated in the modulation of drug-seeking behavior. The aim of this project was to examine the role of glutamatergic neurotransmission in relapse triggered by conditioned drug-associated stimuli. The focus was on clarifying whether relapse to drug seeking can be attenuated by blockade of glutamate receptors. In addition, as the nucleus accumbens has been proposed to participate in the modulation of drug-seeking behavior, the effects of glutamate receptor blockade in this brain structure on cue-induced relapse were investigated. The studies employed animals models in which rats were trained to press a lever in a test cage to obtain alcohol or intravenous cocaine. Drug availability was paired with distinct olfactory, auditory, or visual stimuli. This phase was followed by extinction training, during which lever presses did not result in the presentation of the drug or the drug-associated stimuli. Extinction training led to a gradual decrease in the number of lever presses during test sessions. Relapse was triggered by presenting the rats with the drug-associated stimuli in the absence of alcohol or cocaine. The drug-associated stimuli were alone capable of inducing resumption of lever pressing and maintaining this behavior during repeated testing. The number of lever presses during a session represented the intensity of drug-seeking and relapse behavior. The results suggest that glutamatergic neurotransmission is involved in the modulation of drug-seeking behavior. Both alcohol and cocaine relapse were attenuated by systemic pretreatment with glutamate receptor antagonists. However, differences were found in the ability of ionotropic AMPA/kainate and NMDA receptor antagonists to regulate drug-seeking behavior. The AMPA/kainate antagonists CNQX and NBQX, and L-701,324, an antagonist with affinity for the glycine site of the NMDA receptor, attenuated cue-induced drug seeking, whereas the competitive NMDA antagonist CGP39551 and the NMDA channel blocker MK-801 were without effect. MPEP, an antagonist at metabotropic mGlu5 glutamate receptors, also decreased drug seeking, but its administration was found to lead to conditioned suppression of behavior during subsequent treatment sessions, suggesting that MPEP may have undesirable side effects. The mGluR2/3 agonist LY379268 and the mGluR8 agonist (S)-3,4-DCPG decreased both cue-induced relapse to alcohol drinking and alcohol consumption. Control experiments showed however that administration of the agonists was accompanied by motor suppression limiting their usefulness. Administration of the AMPA/kainate antagonist CNQX, the NMDA antagonist D-AP5, and the mGluR5 antagonist MPEP into the nucleus accumbens resulted also in a decrease in drug-seeking behavior, suggesting that the nucleus accumbens is at least one of the anatomical sites regulating drug seeking and mediating the effects of glutamate receptor antagonists on this behavior.

The Role of the Subthalamic Nucleus in L-DOPA Induced Dyskinesia in 6-Hydroxydopamine Lesioned Rats

14 p.

The locus coeruleus Is Directly Implicated in L-DOPA-Induced Dyskinesia in Parkinsonian Rats: An Electrophysiological and Behavioural Study

Despite being the most effective treatment for Parkinson's disease, L-DOPA causes a development of dyskinetic movements in the majority of treated patients. L-DOPA-induced dyskinesia is attributed to a dysregulated dopamine transmission within the basal ganglia, but serotonergic and noradrenergic systems are believed to play an important modulatory role. In this study, we have addressed the role of the locus coeruleus nucleus (LC) in a rat model of L-DOPA-induced dyskinesia. Single-unit extracellular recordings in vivo and behavioural and immunohistochemical approaches were applied in rats rendered dyskinetic by the destruction of the nigrostriatal dopamine neurons followed by chronic treatment with L-DOPA. The results showed that L-DOPA treatment reversed the change induced by 6-hydroxydopamine lesions on LC neuronal activity. The severity of the abnormal involuntary movements induced by L-DOPA correlated with the basal firing parameters of LC neuronal activity. Systemic administration of the LC-selective noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine did not modify axial, limb, and orolingual dyskinesia, whereas chemical destruction of the LC with ibotenic acid significantly increased the abnormal involuntary movement scores. These results are the first to demonstrate altered LC neuronal activity in 6-OHDA lesioned rats treated with L-DOPA, and indicate that an intact noradrenergic system may limit the severity of this movement disorder.

Chemotherapy-Induced Activation of ADAM-17: A Novel Mechanism of Drug Resistance in Colorectal Cancer

Purpose: We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a disintegrin and metalloproteinases) and soluble growth factors in this acute drug resistance mechanism.

Experimental Design: In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting.

Results: Chemotherapy (5-fluorouracil) treatment resulted in acute increases in transforming growth factor-a, amphiregulin, and heregulin ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. Small interfering RNA–mediated silencing and pharmacologic inhibition confirmed that ADAM-17 was the principal ADAM involved in this prosurvival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumor growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of human epidermal receptors but also increased the activity of a number of other growth factor receptors, such as insulin-like growth factor-I receptor and vascular endothelial growth factor receptor.

Conclusions: Chemotherapy acutely activates ADAM-17, which results in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. Thus, pharmacologic inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC.

Solvent induced phase inversion-based in situ forming controlled release drug delivery implants

In situ forming (ISF) drug delivery implants have gained tremendous levels of interest over the last few decades. This is due to their wide range of biomedical applications such as in tissue engineering, cell encapsulation, microfluidics, bioengineering and drug delivery. Drug delivery implants forming upon injection has shown a range of advantages which include localized drug delivery, easy and less invasive application, sustained drug action, ability to tailor drug delivery, reduction in side effects associated with systemic delivery and also improved patient compliance and comfort. Different factors such as temperature, pH, ions, and exchange of solvents are involved in in situ implant formation. This review especially focuses on ISF implants that are formed through solvent induced phase inversion (SPI) technique. The article critically reviews and compares a wide range of polymers, solvents, and co-solvents that have been used in SPI implant preparation for control release of a range of drug molecules. Major drawback of SPI systems has been their high burst release. In this regard, the article exhaustively discusses factors that affect the burst release and different modification strategies that has been utilised to reduce the burst effect from these implants. Performance and controversial issues associated with the use of different biocompatible solvents in SPI systems is also discussed. Biodegradation, formulation stability, methods of characterisation and sterilisation techniques of SPI systems is comprehensively reviewed. Furthermore, the review also examines current SPI-based marketed products, their therapeutic application and associated clinical data. It also exemplifies the interest of multi-billion dollar pharma companies worldwide for further developments of SPI systems to a range of therapeutic applications. The authors believe that this will be the first review article that extensively investigate and discusses studies done to date on SPI systems. In so doing, this article will undoubtedly serve as an enlightening tool for the scientists working in the concerned area.

Anti-Tumor Necrosis Factor Alpha-Induced Drug Eruptions: One Patient, More Than a Pattern

Background: Tumor necrosis factor alpha (TNFα) antagonists are effective in treating several immune-inflammatory diseases, including psoriasis and inflammatory bowel disease. The paradoxical and unpredictable induction of psoriasis and psoriasiform skin lesions is a recognized adverse event, although of unclear aetiology. However, histological analysis of these eruptions remains insufficient, yet suggesting that some might constitute a new pattern of adverse drug reaction, rather than true psoriasis. Case report: The authors report the case of a 43-year-old woman with severe recalcitrant Crohn disease who started treatment with infliximab. There was also a personal history of mild plaque psoriasis without clinical expression for the past eight years. She developed a heterogeneous cutaneous eruption of psoriasiform morphology with pustules and crusts after the third infliximab infusion. The histopathological diagnosis was of a Sweet-like dermatosis. The patient was successfully treated with cyclosporine in association with both topical corticosteroid and vitamin D3 analogue. Three weeks after switching to adalimumab a new psoriasiform eruption was observed, histologically compatible with a psoriasiform drug eruption. Despite this, and considering the beneficial effect on the inflammatory bowel disease, it was decided to maintain treatment with adalimumab and to treat through with topicals, with progressive control of skin disease. Discussion: Not much is known about the pathogenesis of psoriasiform eruptions induced by biological therapies, but genetic predisposition and Koebner phenomenon may contribute to it. Histopathology can add new facets to the comprehension of psoriasiform reactions. In fact, histopathologic patterns of such skin lesions appear to be varied, in a clear asymmetry with clinical findings. Conclusion: The sequential identification in the same patient of two clinical and histopathologic patterns of drug reaction to TNFα antagonists is rare. Additionally, to the authors’ knowledge, there is only one other description in literature of a TNFα antagonist-induced Sweet-like dermatosis, emphasizing the singularity of this case report.

Efficacy of a combined drug therapy for ameliorating noise-induced hearing loss

Experiments investigated the median effective dose of antiepileptic drugs and synthetic glucocorticoids for the prevention and treatment of noise-induced hearing loss for C57BL/6J mice. We also tested the possible synergistic effects of combining drugs from the two drug families.

THE BEHAVIORAL SENSITIZATION INDUCED BY FENCAMFAMINE IS NOT RELATED TO PLASMA DRUG LEVELS

Fencamfamine (FCF) is a CNS stimulant that facilitates central dopaminergic transmission primarily through blockade of dopamine uptake. In the present study we evaluated the relationship between plasma FCF concentration and behavioral sensitization effect. Adult male Wistar rats (250-300 g) received FCF (10 mg/kg, kg, ip) or saline once or daily for 10 consecutive days (N = 10 for each group). Blood samples were collected 30 min after injections and plasma FCF was measured by gas chromatography using an electron capture detector. FCF treatment enhanced sniffing duration (16.8 +/- 0.8 vs 26.6 +/- 0.9 s) and decreased rearing behavior (8.2 +/- 0.8 vs 3.7 +/- 0.6 s) when days 1 and 10 of drug administration were compared. Comparison of pair of means by the Student t-test did not show significant differences in plasma FCF concentration (390 +/- 40 vs 420 +/- 11 ng/ml) when blood samples were collected 30 min after acute FCF administration or after daily administration of 10 mg/kg for 10 days. In conclusion, the behavioral sensitization to FCF could not be correlated with plasma drug levels, and changes in the activity of dopaminergic systems should be considered to explain the sensitization to the effect of FCF.

Resting tremor in Parkinson disease: a negative predictor of levodopa-induced dyskinesia

It is unclear whether patients with different clinical subtypes of Parkinson disease (PD) differ in their risk of developing levodopa-induced dyskinesia (LID) and whether resting tremor is negatively correlated with this risk.