Hypersensitivity pneumonitis secondary to lovebirds: a new cause of bird fancier's disease.

Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease due to the repetitive inhalation of antigens. Most new cases arise from residential exposures, notably to birds, and are thus more difficult to recognise. The present authors report a 59-yr-old male who complained of dyspnoea and cough while being treated with amiodarone. Pulmonary function tests revealed restriction and obstruction with low diffusing lung capacity for carbon monoxide and partial pressure of oxygen. A high-resolution computed tomography chest scan and bronchoalveolar lavage showed diffuse bilateral ground-glass attenuation and lymphocytic alveolitis, respectively. Initial diagnosis was amiodarone pulmonary toxicity, but because of a rapidly favourable evolution, this diagnosis was questioned. A careful environmental history revealed a close contact with lovebirds shortly before the onset of symptoms. Precipitins were strongly positive against lovebird droppings, but were negative against other avian antigens. The patient was diagnosed with hypersensitivity pneumonitis to lovebirds. Avoidance of lovebirds and steroid treatment led to rapid improvement. The present observation identifies a new causative agent for hypersensitivity pneumonitis and highlights the importance of a thorough environmental history and of searching for precipitins against antigens directly extracted from the patient's environment. These two procedures should allow a more precise classification of some cases of pneumonitis, and thus might avoid progression of active undiagnosed hypersensitivity pneumonitis to irreversible fibrosis or emphysema.

Inferring ultraviolet anatomical exposure patterns while distinguishing the relative contribution of radiation components

Exposure to solar ultraviolet (UV) radiation is the main causative factor for skin cancer. UV exposure depends on environmental and individual factors, but individual exposure data remain scarce. While ground UV irradiance is monitored via different techniques, it is difficult to translate such observations into human UV exposure or dose because of confounding factors. A multi-disciplinary collaboration developed a model predicting the dose and distribution of UV exposure on the basis of ground irradiation and morphological data. Standard 3D computer graphics techniques were adapted to develop a simulation tool that estimates solar exposure of a virtual manikin depicted as a triangle mesh surface. The amount of solar energy received by various body locations is computed for direct, diffuse and reflected radiation separately. Dosimetric measurements obtained in field conditions were used to assess the model performance. The model predicted exposure to solar UV adequately with a symmetric mean absolute percentage error of 13% and half of the predictions within 17% range of the measurements. Using this tool, solar UV exposure patterns were investigated with respect to the relative contribution of the direct, diffuse and reflected radiation. Exposure doses for various body parts and exposure scenarios of a standing individual were assessed using erythemally-weighted UV ground irradiance data measured in 2009 at Payerne, Switzerland as input. For most anatomical sites, mean daily doses were high (typically 6.2-14.6 Standard Erythemal Dose, SED) and exceeded recommended exposure values. Direct exposure was important during specific periods (e. g. midday during summer), but contributed moderately to the annual dose, ranging from 15 to 24% for vertical and horizontal body parts, respectively. Diffuse irradiation explained about 80% of the cumulative annual exposure dose.

Angiogenesehemmung in der Neuroonkologie. Eine vielversprechende Therapiestrategie gegen maligne Gliome [Angiogenesis inhibition in neurooncology. A very promising therapy strategy for malignant glioma]

The application of angiogenesis inhibitors in neurooncology is increasing. Initially, these drugs seemed to be very promising because of the surprisingly high neuroradiological response rates that were observed in first clinical trials. Meanwhile, this enthusiasm is waning, as the high response rates did not translate into substantial improvements in progression-free and overall survival. Tumor progression during or after antiangiogenic therapy is often associated with rapid clinical neurological deterioration and sometimes even with diffuse infiltrative gliomatosis-like neuroradiological phenotypes. Thus, the characterization and understanding of escape mechanisms are needed. The identification of criteria for defining the personalized use of angiogenesis inhibitors remains a challenge.

Nemaline myopathy revealed by respiratory failure in adults

Most forms of myopathy may involve the respiratory muscles and progress to respiratory failure. However, the diagnosis of myopathy is seldom considered in an adult patient with no history of muscle disease and presenting with respiratory failure. Nemaline myopathy (NM) is a rare disorder characterized by symmetrical diffuse muscle weakness and rod-like nemaline bodies in muscle fibers. Respiratory muscle involvement is a major determinant of mortality in congenital NM, but is rare in late onset NM. Here, we report that acute or chronic respiratory failure may be caused by NM in subjects with no known history of muscle disease. Adult-onset NM was diagnosed in a 67-year-old woman with chronic respiratory insufficiency. Late onset childhood NM was revealed by respiratory failure in twin sisters aged 31. The diagnosis was established by muscle biopsy and electron microscopy (and mutations in the nebulin gene in the two sisters). Long-term clinical improvement was obtained with non-invasive ventilation (NIV) in the three patients. In conclusion, respiratory failure in an adult patient with no known history may correspond to NM with diaphragm involvement. Long-term outcome may be favorable with NIV.

Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines.

The protease activity of the paracaspase Malt1 contributes to antigen receptor-mediated lymphocyte activation and lymphomagenesis. Malt1 activity is required for optimal NF-κB activation, but little is known about the responsible substrate(s). Here we report that Malt1 cleaved the NF-κB family member RelB after Arg-85. RelB cleavage induced its proteasomal degradation and specifically controlled DNA binding of RelA- or c-Rel-containing NF-κB complexes. Overexpression of RelB inhibited expression of canonical NF-κB target genes and led to impaired survival of diffuse large B-cell lymphoma cell lines characterized by constitutive Malt1 activity. These findings identify a central role for Malt1-dependent RelB cleavage in canonical NF-κB activation and thereby provide a rationale for the targeting of Malt1 in immunomodulation and cancer treatment.

Early pattern recognition in severe perinatal asphyxia: a prospective MRI study.

On the basis of MRI examinations in 88 neonates and infants with perinatal asphyxia, we defined 6 different patterns on T2-weighted images: pattern A--scattered hyperintensity of both hemispheres of the telencephalon with blurred border zones between cortex and white matter, indicating diffuse brain injury; pattern B--parasagittal hyperintensity extending into the corona radiata, corresponding to the watershed zones; pattern C--hyper- and hypointense lesions in thalamus and basal ganglia, which relate to haemorrhagic necrosis or iron deposition in these areas; pattern D--periventricular hyperintensity, mainly along the lateral ventricles, i.e. periventricular leukomalacia (PVL), originating from the matrix zone; pattern E--small multifocal lesions varying from hyper--to hypointense, interpreted as necrosis and haemorrhage; pattern F--periventricular centrifugal hypointense stripes in the centrum semiovale and deep white matter of the frontal and occipital lobes. Contrast was effectively inverted on T1-weighted images. Patterns A, B and C were found in 17%, 25% and 37% of patients, and patterns D, E and F in 19%, 17% and 35%, respectively. In 49 patients a combination of patterns was observed, but 30% of the initial images were normal. At follow-up, persistent abnormalities were seen in all children with patterns A and D, but in only 52% of those with pattern C. Myelination was retarded most often in patients with diffuse brain injury and PVL (patterns A and D).

An unusual uterine tumor with signet ring cell features.

In 2004, a 56-year-old woman was diagnosed with Stage IA follicular lymphoma in a cervical lymph node biopsy. The patient experienced total remission after local radiation therapy. In 2009, a control computed tomography scan evidenced a pelvic mass, prompting total hysterectomy. The latter harbored a 4.8-cm intramural uterine tumor corresponding to a mostly diffuse and focally nodular proliferation of medium to large cells, with extensive, periodic acid-Schiff negative, signet ring cell changes, and a pan-keratin negative, CD20+, CD10+, Bcl2+, Bcl6+ immunophenotype. Molecular genetic studies showed the same clonal IGH gene rearrangement in the lymph node and the uterus, establishing the uterine tumor as a relapse of the preceding follicular lymphoma, although no signet ring cells were evidenced at presentation. Uterine localization of lymphomas is rare, and lymphomas with signet ring cell features are uncommon. This exceptional case exemplifies a diagnostically challenging situation and expands the differential diagnosis of uterine neoplasms displaying signet ring cell morphology.

Modelling short-term ultraviolet exposure as an alternative to individual dosimetry

Background: Excessive exposure to solar Ultra-Violet (UV) light is the main cause of most skin cancers in humans. Factors such as the increase of solar irradiation at ground level (anthropic pollution), the rise in standard of living (vacation in sunny areas), and (mostly) the development of outdoor activities have contributed to increase exposure. Thus, unsurprisingly, incidence of skin cancers has increased over the last decades more than that of any other cancer. Melanoma is the most lethal cutaneous cancer, while cutaneous carcinomas are the most common cancer type worldwide. UV exposure depends on environmental as well as individual factors related to activity. The influence of individual factors on exposure among building workers was investigated in a previous study. Posture and orientation were found to account for at least 38% of the total variance of relative individual exposure. A high variance of short-term exposure was observed between different body locations, indicating the occurrence of intense, subacute exposures. It was also found that effective short-term exposure ranged between 0 and 200% of ambient irradiation, suggesting that ambient irradiation is a poor predictor of effective exposure. Various dosimetric techniques enable to assess individual effective exposure, but dosimetric measurements remain tedious and tend to be situation-specific. As a matter of facts, individual factors (exposure time, body posture and orientation in the sun) often limit the extrapolation of exposure results to similar activities conducted in other conditions. Objective: The research presented in this paper aims at developing and validating a predictive tool of effective individual exposure to solar UV. Methods: Existing computer graphic techniques (3D rendering) were adapted to reflect solar exposure conditions and calculate short-term anatomical doses. A numerical model, represented as a 3D triangular mesh, is used to represent the exposed body. The amount of solar energy received by each "triangle is calculated, taking into account irradiation intensity, incidence angle and possible shadowing from other body parts. The model take into account the three components of the solar irradiation (direct, diffuse and albedo) as well as the orientation and posture of the body. Field measurements were carried out using a forensic mannequin at the Payerne MeteoSwiss station. Short-term dosimetric measurements were performed in 7 anatomical locations for 5 body postures. Field results were compared to the model prediction obtained from the numerical model. Results: The best match between prediction and measurements was obtained for upper body parts such as shoulders (Ratio Modelled/Measured; Mean = 1.21, SD = 0.34) and neck (Mean = 0.81, SD = 0.32). Small curved body parts such as forehead (Mean = 6.48, SD = 9.61) exhibited a lower matching. The prediction is less accurate for complex postures such as kneeling (Mean = 4.13, SD = 8.38) compared to standing up (Mean = 0.85, SD = 0.48). The values obtained from the dosimeters and the ones computed from the model are globally consistent. Conclusion: Although further development and validation are required, these results suggest that effective exposure could be predicted for a given activity (work or leisure) in various ambient irradiation conditions. Using a generic modelling approach is of high interest in terms of implementation costs as well as predictive and retrospective capabilities.

Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study.

PURPOSE Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22(+) B-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m(2). Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival. Results Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m(2). Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively. CONCLUSION Inotuzumab ozogamicin has demonstrated efficacy against CD22(+) B-cell NHL, with reversible thrombocytopenia as the main toxicity.

Ecology and evolution of soil nematode chemotaxis.

Plants influence the behavior of and modify community composition of soil-dwelling organisms through the exudation of organic molecules. Given the chemical complexity of the soil matrix, soil-dwelling organisms have evolved the ability to detect and respond to these cues for successful foraging. A key question is how specific these responses are and how they may evolve. Here, we review and discuss the ecology and evolution of chemotaxis of soil nematodes. Soil nematodes are a group of diverse functional and taxonomic types, which may reveal a variety of responses. We predicted that nematodes of different feeding guilds use host-specific cues for chemotaxis. However, the examination of a comprehensive nematode phylogeny revealed that distantly related nematodes, and nematodes from different feeding guilds, can exploit the same signals for positive orientation. Carbon dioxide (CO(2)), which is ubiquitous in soil and indicates biological activity, is widely used as such a cue. The use of the same signals by a variety of species and species groups suggests that parts of the chemo-sensory machinery have remained highly conserved during the radiation of nematodes. However, besides CO(2), many other chemical compounds, belonging to different chemical classes, have been shown to induce chemotaxis in nematodes. Plants surrounded by a complex nematode community, including beneficial entomopathogenic nematodes, plant-parasitic nematodes, as well as microbial feeders, are thus under diffuse selection for producing specific molecules in the rhizosphere that maximize their fitness. However, it is largely unknown how selection may operate and how belowground signaling may evolve. Given the paucity of data for certain groups of nematodes, future work is needed to better understand the evolutionary mechanisms of communication between plant roots and soil biota.

Idiopathic desquamative interstitial pneumonia in a child: a case report.

BACKGROUND: Desquamative interstitial pneumonia is a rare form of interstitial lung disease in children. Respiratory symptoms appear progressively, are often subtle, and diagnosis is often delayed by a mean of 6 months after onset. High resolution chest computed tomography is the most sensitive imaging technique for demonstrating and identifying interstitial pneumonia. The typical histologic pattern of desquamative interstitial pneumonia, with prominent clustered alveolar macrophages, diffuse reactive alveolar epithelial hyperplasia and globular proteinaceous material, is diagnostic. Desquamative interstitial pneumonia in children can be idiopathic, though it is mostly related to an inborn error of surfactant metabolism. CASE PRESENTATION: We present the complex clinical course and pathologic findings of a 30-months-old Mauritian and Senegalese girl with idiopathic desquamative interstitial pneumonia and multiple extrapulmonary manifestations. To our knowledge, this is the first case report of desquamative interstitial pneumonia to occur as part of a syndrome with multiple organ involvement. CONCLUSION: We believe that desquamative interstitial pneumonia is not always associated with mutations of the surfactant proteins, and can still be idiopathic, especially when occurring as part of a syndrome with multiple organ involvement, as described in other interstitial lung diseases.

Several neuronal and axonal types form long intrinsic connections in the cat primary auditory cortical field (AI).

Intrinsic connections in the cat primary auditory field (AI) as revealed by injections of Phaseolus vulgaris leucoagglutinin (PHA-L) or biocytin, had an anisotropic and patchy distribution. Neurons, labelled retrogradely with PHA-L were concentrated along a dorsoventral stripe through the injection site and rostral to it; the spread of rostrally located neurons was greater after injections into regions of low rather than high characteristic frequencies. The intensity of retrograde labelling varied from weak and granular to very strong and Golgi-like. Out of 313 Golgi like retrogradely labelled neurons 79.6% were pyramidal, 17.2% multipolar, 2.6% bipolar, and 0.6% bitufted; 13.4% were putatively inhibitory, i.e. aspiny or sparsely spiny multipolar, or bitufted. Individual anterogradely labelled intrinsic axons were reconstructed for distances of 2 to 7 mm. Five main types were distinguished on the basis of the branching pattern and the location of synaptic specialisations. Type 1 axons travelled horizontally within layers II to VI and sent collaterals at regular intervals; boutons were only present in the terminal arborizations of these collaterals. Type 2 axons also travelled horizontally within layers II to VI and had rather short and thin collateral branches; boutons or spine-like protrusions occurred in most parts of the axon. Type 3 axons travelled obliquely through the cortex and formed a single terminal arborization, the only site where boutons were found. Type 4 axons travelled for some distance in layer I; they formed a heterogeneous group as to their collaterals and synaptic specializations. Type 5 axons travelled at the interface between layer VI and the white matter; boutons en passant, spine-like protrusions, and thin short branches with boutons en passant were frequent all along their trajectory. Thus, only some axonal types sustain the patchy pattern of intrinsic connectivity, whereas others are involved in a more diffuse connectivity.

Effectiveness of cladribine therapy in patients with pulmonary Langerhans cell histiocytosis.

BackgroundPulmonary Langerhans cell histiocytosis (PLCH) is a rare disorder characterised by granulomatous proliferation of CD1a-positive histiocytes forming granulomas within lung parenchyma, in strong association with tobacco smoking, and which may result in chronic respiratory failure. Smoking cessation is considered to be critical in management, but has variable effects on outcome. No drug therapy has been validated. Cladribine (chlorodeoxyadenosine, 2-CDA) down-regulates histiocyte proliferation and has been successful in curbing multi-system Langerhans cell histiocytosis and isolated PLCH.Methods and patientsWe retrospectively studied 5 patients (aged 37¿55 years, 3 females) with PLCH who received 3 to 4 courses of cladribine therapy as a single agent (0.1 mg/kg per day for 5 consecutive days at monthly intervals). One patient was treated twice because of relapse at 1 year. Progressive pulmonary disease with obstructive ventilatory pattern despite smoking cessation and/or corticosteroid therapy were indications for treatment. Patients were administered oral trimethoprim/sulfamethoxazole and valaciclovir to prevent opportunistic infections. They gave written consent to receive off-label cladribine in the absence of validated treatment.ResultsFunctional class dyspnea improved with cladribine therapy in 4 out of 5 cases, and forced expiratory volume in 1 second (FEV1) increased in all cases by a mean of 387 ml (100¿920 ml), contrasting with a steady decline prior to treatment. Chest high-resolution computed tomography (HRCT) features improved with cladribine therapy in 4 patients. Hemodynamic improvement was observed in 1 patient with pre-capillary pulmonary hypertension. The results suggested a greater treatment effect in subjects with nodular lung lesions and/or thick-walled cysts on chest HRCT, with diffuse hypermetabolism of lung lesions on positron emission tomography (PET)-scan, and with progressive disease despite smoking cessation. Infectious pneumonia developed in 1 patient, with later grade 4 neutrocytopenia but without infection.DiscussionData interpretation was limited by the retrospective, uncontrolled study design and small sample size.ConclusionCladribine as a single agent may be effective therapy in patients with progressive PLCH.

Monoubiquitination and Activity of the Paracaspase MALT1 Requires Glutamate 549 in the Dimerization Interface.

The mucosa-associated lymphoid tissue protein-1 (MALT1, also known as paracaspase) is a protease whose activity is essential for the activation of lymphocytes and the growth of cells derived from human diffuse large B-cell lymphomas of the activated B-cell subtype (ABC DLBCL). Crystallographic approaches have shown that MALT1 can form dimers via its protease domain, but why dimerization is relevant for the biological activity of MALT1 remains largely unknown. Using a molecular modeling approach, we predicted Glu 549 (E549) to be localized within the MALT1 dimer interface and thus potentially relevant. Experimental mutation of this residue into alanine (E549A) led to a complete impairment of MALT1 proteolytic activity. This correlated with an impaired capacity of the mutant to form dimers of the protease domain in vitro, and a reduced capacity to promote NF-κB activation and transcription of the growth-promoting cytokine interleukin-2 in antigen receptor-stimulated lymphocytes. Moreover, this mutant could not rescue the growth of ABC DLBCL cell lines upon MALT1 silencing. Interestingly, the MALT1 mutant E549A was unable to undergo monoubiquitination, which we identified previously as a critical step in MALT1 activation. Collectively, these findings suggest a model in which E549 at the dimerization interface is required for the formation of the enzymatically active, monoubiquitinated form of MALT1.

Melastatin Expression in Ocular Melanocytic Proliferations

Purpose: Melastatin (MLSN-1) belongs to the transient receptor potential (TRP) superfamilly of calcium-permeable channels, and has been reported to be a melanocyte-specific gene. In human cutaneous melanoma, MLSN-1 mRNA expression displays a pattern of inverse correlation to disease free survival. We describe the patterns of MLSN-1 mRNA expression in conjunctival nevi, conjunctival melanoma, and uveal melanoma. Methods: In situ hybridization using two S35-labelled riboprobes for MLSN-1 was performed on formalin-fixed, paraffin-embedded tissues. A control probe for H4 histone was used to confirm mRNA integrity in these archival tissues. The 21 ocular melanocytic lesions studied included 5 conjunctival nevi, 6 conjunctival melanomas, and 10 enucleated eyes with uveal melanoma. The minimal requirement for interpretation of MLSN-1 mRNA loss was the presence of only background signal in a focus of at least 5 adjacent melanocytic cells. Results: Ubiquitous expression of MLSN-1 mRNA was found in conjunctival melanocytes in the non-lesional epithelium adjacent to the conjunctival melanocytic proliferations and in all 5 conjunctival nevi studied. Four different patterns of MLSN-1 mRNA expression were observed in conjunctival melanomas: one case showed complete preservation of MLSN-1 mRNA, two cases showed diffuse scattered loss of MLSN-1 mRNA, two cases showed focal clonal loss of MLSN-1 mRNA expression, and one case had no detected MLSN-1 mRNA. In uveal melanomas, MLSN-1 mRNA expression was partially preserved in two cases, lost by a clearly delimited subset of tumor cells (focal clonal loss) in four cases, and was not detectable in the entire tumor in four cases. MLSN-1 mRNA expression was also found in the normal iris, ciliary and choroidal melanocytes as well as in the retinal pigmented epithelium and in the inner nuclear layer of the retina. Conclusions: The patterns of MLSN-1 mRNA expression in the ocular melanocytic proliferations are similar to those reported in cutaneous melanocytic proliferations. In the conjunctiva, MLSN-1 mRNA expression appeared to correlate with tumor progression; all the benign conjunctival nevi had preserved expression of MLSN-1 mRNA and most of the conjunctival melanomas partial or complete loss of expression. In uveal melanoma, patterns of melastatin expression ranging from partial preservation to complete loss were found. Additional studies of a large number of ocular melanocytic proliferations may show a correlation with tumor progression and prognosis similar to that observed in cutaneous melanoma.