Acute hypersensitivity pneumonitis in a paint quality controller : a case report

Introduction: Isocyanates are sensitizing chemicals used in various industries such as polyurethane foam production or paint-related purposes. Acting as haptens recognized by T-lymphocytes, they can cause allergic asthma and rarely hypersensitivity pneumonitis (HP). We aim to present a case report of acute HP due to hexamethylene diisocyanate (HDI) in a paint quality controller, a profession not generally considered at a high risk for work-related Isocyanates exposure. Case report: A 30-yr-old otherwise healthy female, light smoker working as a paint quality controller developed shortness of breath, malaise, sweating and chills at workplace six hours after handling a HDI-based hardener. Upon admission to emergency department, symptoms had progressed to severe respiratory failure. HR computer tomography (HRCT) showed bilateral ground-glass attenuation without pleural effusion. Rapid clinical and radiological improvement occurred under facial oxygen supply and systemic steroid therapy. Occupational medicine investigations revealed regular handling of HDI using latex gloves without respiratory protection. Assessment at workplace showed insufficient air renewal (1.5 times per hour), inadequate local aspiration and HDI exposure at levels of 1-4.25 ppb/m3 (Swiss Occupation Exposure Limit 5 ppb/m3). Biological monitoring after identical work procedure executed by a co-worker showed HDI exposure (5.1 micrograms hexamethylene diamine/g creatinine). Resumption of work was disadvised because of the life-threatening event. Discussion: The diagnosis of occupational HP is highly supported by classical findings on imagery and typical symptoms occurring within approved latency interval, associated with rapid clinical improvement. Although neither broncho-alveolar lavage nor specific IgG diagnosis (en route) were performed during the acute episode, various blood tests managed to rule out evidence of an infection or autoimmune disease. Other causes of HP seem unlikely as the patient did not have any recurrence of symptoms since absence from work. Workplace evaluation provided significant information on HDI exposure and allowed substantial recommendations to diminish Isocyanate exposure for the 20 still healthy laboratory co-workers. Although the entryways (air or skin) and precise mechanism of toxicity remain unclear, the present case clearly shows that Isocyanates may trigger acute HP in susceptible workers in a profession not generally considered at a high risk.

The joint influence of gender and amount of smoking on weight gain one year after smoking cessation.

Weight gain is often associated with smoking cessation and may discourage smokers from quitting. This study estimated the weight gained one year after smoking cessation and examined the risk factors associated with weight gain in order to identify socio-demographic groups at higher risk of increased weight after quitting. We analyzed data from 750 adults in two randomized controlled studies that included smokers motivated to quit and found a gradient in weight gain according to the actual duration of abstinence during follow-up. Subjects who were abstinent for at least 40 weeks gained 4.6 kg (SD = 3.8) on average, compared to 1.2 kg (SD = 2.6) for those who were abstinent less than 20 weeks during the 1-year follow-up. Considering the duration of abstinence as an exposure variable, we found an age effect and a significant interaction between sex and the amount of smoking before quitting: younger subjects gained more weight than older subjects; among light smokers, men gained more weight on average than women one year after quitting, while the opposite was observed among heavy smokers. Young women smoking heavily at baseline had the highest risk of weight gain after quitting.

PFO closure vs. medical therapy in cryptogenic stroke or transient ischemic attack: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: This study aims to assess whether patent foramen ovale (PFO) closure is superior to medical therapy in preventing recurrence of cryptogenic ischemic stroke or transient ischemic attack (TIA). METHODS: We searched PubMed for randomized trials which compared PFO closure with medical therapy in cryptogenic stroke/TIA using the items: "stroke or cerebrovascular accident or TIA" and "patent foramen ovale or paradoxical embolism" and "trial or study". RESULTS: Among 650 potentially eligible articles, 3 were included including 2303 patients. There was no statistically significant difference between PFO-closure and medical therapy in ischemic stroke recurrence (1.91% vs. 2.94% respectively, OR: 0.64, 95%CI: 0.37-1.10), TIA (2.08% vs. 2.42% respectively, OR: 0.87, 95%CI: 0.50-1.51) and death (0.60% vs. 0.86% respectively, OR: 0.71, 95%CI: 0.28-1.82). In subgroup analysis, there was significant reduction of ischemic strokes in the AMPLATZER PFO Occluder arm vs. medical therapy (1.4% vs. 3.04% respectively, OR: 0.46, 95%CI: 0.21-0.98, relative-risk-reduction: 53.2%, absolute-risk-reduction: 1.6%, number-needed-to-treat: 61.8) but not in the STARFlex device (2.7% vs. 2.8% with medical therapy, OR: 0.93, 95%CI: 0.45-2.11). Compared to medical therapy, the number of patients with new-onset atrial fibrillation (AF) was similar in the AMPLATZER PFO Occluder arm (0.72% vs. 1.28% respectively, OR: 1.81, 95%CI: 0.60-5.42) but higher in the STARFlex device (0.64% vs. 5.14% respectively, OR: 8.30, 95%CI: 2.47-27.84). CONCLUSIONS: This meta-analysis does not support PFO closure for secondary prevention with unselected devices in cryptogenic stroke/TIA. In subgroup analysis, selected closure devices may be superior to medical therapy without increasing the risk of new-onset AF, however. This observation should be confirmed in further trials using inclusion criteria for patients with high likelihood of PFO-related stroke recurrence.

A peptide inhibitor of C-jun N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation

Hemorrhage and resuscitation (H/R) leads to phosphorylation of mitogen-activated stress kinases, an event that is associated with organ damage. Recently, a specific, cell-penetrating, protease-resistant inhibitory peptide of the mitogen-activated protein kinase c-JUN N-terminal kinase (JNK) was developed (D-JNKI-1). Here, using this peptide, we tested if inhibition of JNK protects against organ damage after H/R. Male Sprague-Dawley rats were treated with D-JNKI-1 (11 mg/kg, i.p.) or vehicle. Thirty minutes later, rats were hemorrhaged for 1 h to a MAP of 30 to 35 mmHg and then resuscitated with 60% of the shed blood and twice the shed blood volume as Ringer lactate. Tissues were harvested 2 h later. ANOVA with Tukey post hoc analysis or Kruskal-Wallis ANOVA on ranks, P < 0.05, was considered significant. c-JUN N-terminal kinase inhibition decreased serum alanine aminotransferase activity as a marker of liver injury by 70%, serum creatine kinase activity by 67%, and serum lactate dehydrogenase activity by 60% as compared with vehicle treatment. The histological tissue damage observed was blunted after D-JNKI-1 pretreatment both for necrotic and apoptotic cell death. Hepatic leukocyte infiltration and serum IL-6 levels were largely diminished after D-JNKI-1 pretreatment. The extent of oxidative stress as evaluated by immunohistochemical detection of 4-hydroxynonenal was largely abrogated after JNK inhibition. After JNK inhibition, activation of cJUN after H/R was also reduced. Hemorrhage and resuscitation induces a systemic inflammatory response and leads to end-organ damage. These changes are mediated, at least in part, by JNK. Therefore, JNK inhibition deserves further evaluation as a potential treatment option in patients after resuscitated blood loss.

Options chirurgicates pour l'insuffisance cardiaque terminale [Surgical options for terminal heart failure]

Terminal heart failure can be the cause or the result of major dysfunctions of the organisms. Although, the outcome of the natural history is the same in both situations, it is of prime importance to differentiate the two, as only heart failure as the primary cause allows for successful mechanical circulatory support as bridge to transplantation or towards recovery. Various objective parameters allow for the establishment of the diagnosis of terminal heart failure despite optimal medical treatment. A cardiac index <2.0 l/min, and a mixed venous oxygen saturation <60%, in combination with progressive renal failure, should trigger a diagnostic work-up in order to identify cardiac defects that can be corrected or to list the patient for transplantation with/without mechanical circulatory support.

Association of the Epstein-Barr virus latent membrane protein 1 with lipid rafts is mediated through its N-terminal region.

The latent membrane protein 1 (LMP1) encoded by the Epstein-Barr virus acts like a constitutively activated receptor of the tumor necrosis factor receptor (TNFR) family and is enriched in lipid rafts. We showed that LMP1 is targeted to lipid rafts in transfected HEK 293 cells, and that the endogenous TNFR-associated factor 3 binds LMP1 and is recruited to lipid rafts upon LMP1 expression. An LMP1 mutant lacking the C-terminal 55 amino acids (Cdelta55) behaves like the wild-type (WT) LMP1 with respect to membrane localization. In contrast, a mutant with a deletion of the 25 N-terminal residues (Ndelta25) does not concentrate in lipid rafts but still binds TRAF3, demonstrating that cell localization of LMP1 was not crucial for TRAF3 localization. Moreover, Ndelta25 inhibited WT LMP1-mediated induction of the transcription factors NF-kappaB and AP-1. Morphological data indicate that Ndelta25 hampers WT LMP1 plasma membrane localization, thus blocking LMP1 function.

Importance of sequences adjacent to the terminal tripeptide in the import of a peroxisomal Candida tropicalis protein in plant peroxisomes.

The peroxisome targeting signal (PTS) required for import of the rat acyl-CoA oxidase (AOX; EC 1.3.3.6) and the Candida tropicalis multifunctional protein (MFP) in plant peroxisomes was assessed in transgenic Arabidopsis thaliana (L.) Heynh. The native rat AOX accumulated in peroxisomes in A. thaliana cotyledons and targeting was dependent on the presence of the C-terminal tripeptide S-K-L. In contrast, the native C. tropicalis MFP, containing the consensus PTS sequence A-K-I was not targeted to plant peroxisomes. Modification of the carboxy terminus to the S-K-L tripeptide also failed to deliver the MFP to peroxisomes while addition of the last 34 amino acids of the Brassica napus isocitrate lyase, containing the terminal tripeptide S-R-M, enabled import of the fusion protein into peroxisomes. These results underline the influence of the amino acids adjacent to the terminal tripeptide of the C. tropicalis MFP on peroxisomal targeting, even in the context of a protein having a consensus PTS sequence S-K-L.

Role of the c-Jun N-terminal Kinase signaling in pancreatic β-cells

L'insuline est une hormone qui diminue la concentration de sucre dans le sang et qui est produite par la cellule β du pancréas. Un défaut de production de cette hormone est une des causes principales du diabète. Cette perte de production d'insuline est la conséquence à la fois, de la réduction du nombre de cellules β et du mauvais fonctionnement des cellules β restantes. L'inflammation, en activant la voie de signalisation «c-Jun N-terminal Kinase» (JNK) contribue au déclin de ces cellules. Cette voie de signalisation est activée par des protéines telles que des kinases qui reçoivent le signal de stress. Dans ce travail de thèse nous nous sommes intéressés à étudier le rôle de «Dual leucine zipper bearing kinase» (DLK) comme protéine capable de relayer le stress inflammatoire vers l'activation de la voie JNK dans les cellules β-pancréatiques. Nous montrons que DLK est présente dans les cellules β-pancréatiques et qu'elle agit effectivement comme un activateur de la voie de signalisation de JNK. En outre, DLK joue un rôle clé dans le contrôle de l'expression de l'insuline, de la sécrétion de l'insuline en réponse au glucose et au maintien de la survie des cellules β. Si l'expression de cette protéine diminue, la cellule produit moins d'insuline et sera plus sensible à la mort en réponse au stress inflammatoire. A l'inverse si l'expression de DLK est augmentée, la cellule β produit et secrète plus d'insuline. Des variations de l'expression de DLK sont par ailleurs, associées à l'état de santé de la cellule β. Chez la ratte en gestation ou la souris obèse, dans lesquelles la cellule β produit plus d'insuline, l'expression de DLK est augmentée. En revanche dans les cellules β des patients diabétiques, l'expression de DLK est diminuée par rapport aux cellules non malades. En résumé, DLK est nécessaire pour le bon fonctionnement de la cellule β-pancréatique et son expression corrèle avec le degré de santé des cellules, faisant que cette protéine pourrait être une cible thérapeutique potentiel. Les cellules β-pancréatiques ont la capacité de réguler la sécrétion d'insuline en s'adaptant précisément au stimulus et à la glycémie. La fonction de la cellule β est cruciale dans l'homéostasie du glucose puisque sa dysfonction et sa mort mènent au développement des diabètes de type 1 et 2. De nombreuses études suggèrent que l'inflammation pourrait avoir un rôle dans la dysfonction et la destruction de ces cellules dans le diabète de type 2. L'excès chronique de cytokines proinflammatoires accélère le dysfonctionnement de la cellule β pancréatique par un mécanisme qui implique la voie de signalisation «c-Jun N-terminal Kinase» (JNK). L'activation de cette voie est organisée par des protéines d'échafaudages. Elle se fait par trois étapes successives de phosphorylation impliquant une «Mitogen Activated Protein Kinase Kinase Kinase» (MAP3K), une MAP2K et JNK. Dans ce travail de thèse nous montrons l'expression abondante et spécifique de la MAP3K «Dual Leucine Zipper Bearing Kinase» (DLK) dans les cellules β pancréatiques. Cela est la conséquence de l'absence du répresseur transcriptionnel «Repressor Element 1 Silencing Transcription». Nous montrons également que DLK régule l'activation de JNK et qu'il s'avère nécessaire pour la fonction et la survie de la cellule β pancréatique par un mécanisme impliquant le facteur de transcription PDX-1. L'invalidation de l'expression de DLK diminue l'expression de l'insuline et potentialise l'apoptose induite par des cytokines proinflammatoires. A l'inverse, la surexpression de DLK augmente l'expression et la sécrétion d'insuline induites par le glucose. Par conséquent des niveaux d'expression appropriés de DLK sont déterminants pour la fonction et la survie de la cellule β pancréatique. L'obésité et la grossesse sont caractérisées par une hyperinsulinémie qui résulte d'une augmentation de la production et de la sécrétion de l'insuline. L'expression de DLK est augmentée dans des îlots de rattes gestantes et des souris obèses comparés à leurs contrôles respectifs. A l'inverse, dans des sujets diabétiques, l'expression de DLK est diminuée. Ensemble ces résultats montrent l'importance de DLK dans l'adaptation des îlots par un mécanisme qui pourrait impliquer la voie de signalisation de JNK. Des défauts dans cette voie régulée par DLK pourraient contribuer au dysfonctionnement et la mort de la cellule β pancréatique et par conséquent au développement du diabète. L'étude détaillée du mécanisme par lequel DLK active la voie de signalisation JNK et régule la fonction de la cellule β pancréatique pourrait ouvrir la voie des nouvelles thérapies ciblant l'amélioration de la fonction de la cellule β dans le diabète. - Pancreatic β-cells are evidently plastic in their ability to regulate insulin secretion. The quantity of insulin released by these cells varies according to the stimulus, and the prevailing glucose concentration, β-cell function is pivotal in glucose homeostasis, as their dysfunction, and death can lead to development of type 1 and type 2 diabetes. There are numerous reports so far underlying the role of inflammation in dysfunction, and destruction of β-cells, in both type 1 and type 2 diabetes. Chronic excess of pro¬inflammatory cytokines promotes a β-cell decline, via induction of the c-Jun N-terminal Kinase (JNK) pathway. The activation of the JNK pathway is organized by a scaffold protein-mediated module in which, a three-step phosphorylation cascade occurs. The latter includes, Mitogen activated protein kinase kinase kinase (MAP3K), MAP2K and JNK. In this thesis, we unveil that the MAP3K Dual Leucine Zipper Bearing Kinase (DLK) is selectively, and highly expressed in pancreatic β-cells, as the result from the absence of the transcriptional repressor named, Repressor Element 1 Silencing Transcription (REST). We show that DLK regulates activation of JNK, and is required for β-cell function and survival by modulating the PDX-1 transcription factor. Silencing of DLK expression diminishes insulin expression, and potentiated cytokine-mediated apoptosis. Conversely, overexpression of DLK increased insulin expression, and glucose-induced insulin secretion. Therefore, an appropriate level of DLK is critical for β-cell function and survival. Obesity and pregnancy are characterized by hyperinsulinemia resulting from an increased production and secretion of insulin. In isolated islets of pregnant rats, and obese mice, the expression of DLK was elevated when compared to their respective controls. However, decreased expression of DLK was observed in islets of individuals with diabetes. Taken together, we highlight the importance of DLK in islet adaptation, and describe a mechanism that may involve the JNK signaling. Deficiency in the JNK pathway regulated by DLK may contribute to β-cell failure and death, and thereby development of diabetes. Unraveling the mechanism whereby DLK activates the JNK pathway, and β-cell function, may pave the way for the design of novel therapies, aiming to improve β-cell function and survival in diabetes in general.

Chondrodysplasia and Abnormal Joint Development Associated with Mutations in IMPAD1, Encoding the Golgi-Resident Nucleotide Phosphatase, gPAPP.

We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints.

Methicillin-susceptible Staphylococcus aureus clonal complex 398: high prevalence and geographical heterogeneity in bone and joint infection and nasal carriage.

The prevalence of clonal complex (CC) 398 methicillin-susceptible Staphylococcus aureus (MSSA) was unexpectedly high among bone and joint infections (BJIs) and nasal-colonizing isolates in France, with surprising geographical heterogeneity. With none of the major, most-known staphylococcal virulence genes, MSSA CC398 BJI was associated with lower biological inflammatory syndrome and lower treatment failure rates.

Stent graft exclusion of a ruptured mycotic popliteal pseudoaneurysm complicating sternoclavicular joint infection.

A mycotic pseudoaneurysm of the popliteal artery is usually a consequence of septic embolization and often a result of bacterial endocarditis. Conventional treatment is surgical and avoids the placement of foreign material in infected sites. Here we report our treatment of a 59-year-old man who presented with a rupture of a mycotic pseudoaneurysm of the popliteal artery due to septic embolism from sternoclavicular infectious arthritis. Radiological investigations are included. This is the first documented case of septic arthritis complicated by a rupture of a mycotic popliteal false aneurysm and treated using an endovascular procedure. Combining endovascular stent grafts with evacuation of the joint abscess and antibiotic therapy can offer a safe alternative for frail and unstable patients.

c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo.

Altered synaptic function is considered one of the first features of Alzheimer disease (AD). Currently, no treatment is available to prevent the dysfunction of excitatory synapses in AD. Identification of the key modulators of synaptopathy is of particular significance in the treatment of AD. We here characterized the pathways leading to synaptopathy in TgCRND8 mice and showed that c-Jun N-terminal kinase (JNK) is activated at the spine prior to the onset of cognitive impairment. The specific inhibition of JNK, with its specific inhibiting peptide D-JNKI1, prevented synaptic dysfunction in TgCRND8 mice. D-JNKI1 avoided both the loss of postsynaptic proteins and glutamate receptors from the postsynaptic density and the reduction in size of excitatory synapses, reverting their dysfunction. This set of data reveals that JNK is a key signaling pathway in AD synaptic injury and that its specific inhibition offers an innovative therapeutic strategy to prevent spine degeneration in AD.