Enhancement of the Nonresonant Streaming Instability by Particle Collisions.

Streaming cosmic rays can power the exponential growth of a seed magnetic field by exciting a nonresonant instability that feeds on their bulk kinetic energy. By generating the necessary turbulent magnetic field, it is thought to play a key role in the confinement and acceleration of cosmic rays at shocks. In this Letter we present hybrid-particle-in-cell simulations of the nonresonant mode including Monte Carlo collisions, and investigate the interplay between the pressure anisotropies produced by the instability and particle collisions in the background plasma. Simulations of poorly ionized plasmas confirm the rapid damping of the instability by proton-neutral collisions predicted by linear fluid theory calculations. In contrast we find that Coulomb collisions in fully ionized plasmas do not oppose the growth of the magnetic field, but under certain conditions suppress the pressure anisotropies and actually enhance the magnetic field amplification.

Targeted next-generation sequencing using a multigene panel in myeloid neoplasms: Implementation in clinical diagnostics.

INTRODUCTION: Detection of mutations in patients with myeloid neoplasms (MNs) has shown great potential for diagnostic and prognostic purposes. Next-generation sequencing (NGS) is currently implemented for the diagnostic profiling of the four major MN subgroups. METHODS: First, we validated the targeted NGS approach using the TruSight Myeloid panel. Next, we screened 287 patients with a clinical suspicion of MN and 61 follow-up patients with documented MN. RESULTS: Validation of the NGS workflow resulted in maximal precision, accuracy, sensitivity, and specificity for gene variants with an allele frequency of at least 5% and a minimal read depth of 300. In our diagnostic screen, we identified at least one somatic mutation in 89% of patients with proven MN. Of the 155 newly diagnosed MN cases, 126 (81%) showed at least one mutation, confirming clonality. Moreover, the co-occurrence of mutated genes in the different MN subentities facilitates their classification and justifies the diagnostic use of a pan-myeloid panel. Furthermore, several of these mutations provide additional prognostic information independently of traditional prognostic scoring systems. CONCLUSION: Pan-myeloid targeted NGS fits elegantly in the routine diagnostic approach of MNs allowing for an improved diagnosis, subclassification, and prognosis.

Retinal layer location of increased retinal thickness in eyes with subclinical and clinical macular edema in diabetes type 2.

PURPOSE: To identify the retinal layer predominantly affected in eyes with subclinical and clinical macular edema in diabetes type 2. METHODS: A cohort of 194 type 2 diabetic eyes/patients with mild nonproliferative diabetic retinopathy (ETDRS levels 20/35) were examined with Cirrus spectral-domain optical coherence tomography (OCT) at the baseline visit (ClinicalTrials.gov identifier: NCT01145599). Automated segmentation of the retinal layers of the eyes with subclinical and clinical macular edema was compared with a sample of 31 eyes from diabetic patients with normal OCT and an age-matched control group of 58 healthy eyes. RESULTS: From the 194 eyes in the study, 62 had subclinical macular edema and 12 had clinical macular edema. The highest increases in retinal thickness (RT) were found in the inner nuclear layer (INL; 33.6% in subclinical macular edema and 81.8% in clinical macular edema). Increases were also found in the neighboring layers. Thinning of the retina was registered in the retinal nerve fiber, ganglion cells and inner plexiform layers in the diabetic eyes without macular edema. CONCLUSIONS: The increase in RT occurring in diabetic eyes with macular edema is predominantly located in the INL but extends to neighboring retinal layers indicating that it may be due to extracellular fluid accumulation.

Effect of soil temperature on optical frequency transfer through unidirectional dense-wavelength-division-multiplexing fiber-optic links.

Results of optical frequency transfer over a carrier-grade dense-wavelength-division-multiplexing (DWDM) optical fiber network are presented. The relation between soil temperature changes on a buried optical fiber and frequency changes of an optical carrier through the fiber is modeled. Soil temperatures, measured at various depths by the Royal Netherlands Meteorology Institute (KNMI) are compared with observed frequency variations through this model. A comparison of a nine-day record of optical frequency measurements through the 2×298 km fiber link with soil temperature data shows qualitative agreement. A soil temperature model is used to predict the link stability over longer periods (days-months-years). We show that optical frequency dissemination is sufficiently stable to distribute and compare, e.g., rubidium frequency standards over standard DWDM optical fiber networks using unidirectional fibers.

p38 inhibition and not MK2 inhibition enhances the secretion of chemokines from TNF-α activated rheumatoid arthritis fibroblast-like synoviocytes.

OBJECTIVES: For many years the p38 MAP kinase (MAPK) has been a major anti-inflammatory target for the development of an oral therapy for rheumatoid arthritis (RA). However, disappointing results from Phase II clinical studies suggest that adaptations may occur, which allow escape from blockade of the p38 pathway. In this study we investigated whether p38 inhibition mediated JNK activation represents such an escape mechanism. METHODS: Interaction between the JNK and p38 pathways was studied in TNF-α stimulated THP-1 monocytes, primary macrophages and fibroblast-like synoviocytes from OA and RA patients using pharmacological inhibitors and siRNAs. RESULTS: TNF-α induced phosphorylation of JNK and c-Jun was sustained by p38 inhibitors in monocytes, primary macrophages and FLS. Upregulation of Mip1α, Mip1ß and IL-8 mRNAs and protein were observed upon p38 inhibition. More importantly, inhibition of MK2, the substrate of p38 did not sustain JNK activation upon TNF-α activation and did not elevate Mip1α, Mip1ß and IL-8 chemokines as compared to TNF-α alone. In this study, TNF-α or IL-1ß induced JNK activation is sustained by p38 inhibition, resulting in enhanced chemokine secretion. CONCLUSIONS: Based on the suggested role of these chemokines in RA pathogenesis, the upregulation of these chemokines may provide an explanation for the lack of efficacy of p38 inhibitors in Phase II. The absence of any effect of MK2 inhibition in our models on this mechanism, while coming with similar efficacy on blocking p38, provides support for further investigations to reveal the potential of MK2 inhibition as a novel treatment of RA.

Stickler syndrome: an underdiagnosed disease. Report of a family.

PURPOSE: To report a family diagnosed with Stickler syndrome. To emphasize that early recognition of patients with Stickler syndrome could improve the visual outcome. METHODS: Case report. RESULTS: A 14 year old girl of Mahgrebian origin presented with a longstanding subtotal RRD in the right eye. Subsequently 6 family members in 3 generations have been identified with the same COL2A1 mutation. 4 eyes lost perception of light and 1 eye was enucleated. Stickler syndrome is the commonest inherited cause of rhegmatogenous retinal detachment (RRD). These tend to be complex and to occur at young age, frequently affecting both eyes. Other ocular features consist of high myopia, optically empty vitreous cavity, posterior radial paravascular lattice-type degeneration, cataract and glaucoma. Non-ocular findings include midface hypoplasia, musculoskeletal changes and hearing loss. In severe cases the disorder will readily be suspected. In mildly affected patients, clinical diagnosis can be quite difficult. Therefore, all family members of a Stickler patient should be offered molecular genetic testing. Stickler patients benefit from a multidisciplinary approach, including audiologic examination. They should be informed about the symptoms associated with retinal tears and retinal detachment and have priviliged access to the ophthalmic care unit. In case of RRD, vitrectomy is the preferred surgery. Prophylaxis of RRD in Stickler syndrome patients consisting of a 360 degrees peripheral cryotherapy or photocoagulation has been proposed. Practical guidelines for follow up or thresholds for initiating treatment have not been formulated. CONCLUSIONS: Stickler syndrome remains under-diagnosed. Hightened awareness of Stickler syndrome could improve visual outcome in affected individuals and makes genetic counseling possible

A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene.

Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory manifestations. It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan origin that consists of four children with Stickler syndrome, six unaffected children, and two unaffected parents who are distant relatives (fifth degree). All family members were clinically investigated for ear, nose, and throat; ophthalmologic; and radiological abnormalities. Four children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located on chromosome 6q13, to be a candidate gene on the basis of the structural association with collagen types II and XI and because of the high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous R295X mutation in the four affected children. The parents and four unaffected children were heterozygous carriers of the R295X mutation. Two unaffected children were homozygous for the wild-type allele. None of the family members except the homozygous R295X carriers had any signs of Stickler syndrome. Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In contrast to the three previously reported Stickler syndrome-causing genes, this gene causes a form of Stickler syndrome with an autosomal recessive inheritance pattern. This finding will have a major impact on the genetic counseling of patients with Stickler syndrome and on the understanding of the pathophysiology of collagens. Mutation analysis of this gene is recommended in patients with Stickler syndrome with possible autosomal recessive inheritance.

Bilateral blindness after starting highly active antiretroviral treatment in a patient with HIV infection and cryptococcal meningitis.

A 26-year-old HIV-seropositive Caucasian man with cryptococcal meningitis developed permanent bilateral blindness shortly after starting highly active antiretroviral treatment. The blindness may have been a consequence of an immune reactivation inflammatory syndrome caused by this treatment.

Clinical and genetic significance of unilateral Lisch nodules.

PURPOSE: Bilateral Lisch nodules are highly characteristic for neurofibromatosis type 1 (NF1). We wished to study the clinical and genetic implications of unilateral Lisch nodules. METHODS: Retrospective study of the clinical data of 59 patients who received genetic counselling for neurofibromatosis type 1 (NF1) or type 2 (NF2) and were examined at the department of ophthalmology. RESULTS: Unilateral Lisch nodules were observed in 4 cases: one child with NF1 initially presented unilateral Lisch nodules but developed bilateral Lisch nodules by the age of 9. In 2 cases segmental NF1 was the most probable diagnosis and in one case isolated Lisch nodules were observed. Of the 35 NF1 patients 28 ultimately developed bilateral Lisch nodules. Seven NF1 patients did not demonstrate the nodules. At follow-up no Lisch nodules were detected in 2 neurofibromatosis type 2 patients, in 4 patients in whom the diagnosis of NF1 remained doubtful and in 15 patients without NF1. CONCLUSION: Because isolated Lisch nodules are very rare, their presence warrants a thorough patient history and clinical examination to either confirm or exclude generalised or segmental neurofibromatosis type 1.

Glucocorticoid receptor antagonists: new tools to investigate disorders characterized by cortisol hypersecretion.

Increased cortisol levels have been observed in patients suffering from a number of metabolic and psychiatric disorders. In some of these disorders a causal relationship has been suggested between the increased cortisol secretion and the observed clinical phenomena. Glucocorticoid receptor antagonists which block cortisol effects might have a benefit in both the diagnosis and treatment of these disorders. Selective glucocorticoid receptor antagonists with in vivo potency have not been described thus far, partly due to the similarity between the glucocorticoid and progesterone receptors. In the present studies, we report on three different chemical classes derived from the glucocorticoid/progestagen antagonist RU486. Selected compounds from the classes 11-monoaryl steroids, 11,21-bisaryl steroids and 11-aryl, 16-hydroxy steroids proved to be selective glucocorticoid receptor binders with in vivo antagonistic activity. Most compounds were able to pass the blood-brain barrier. These compounds offer the opportunity to investigate and possibly treat patients with a disturbed hypothalamus-pituitary-adrenal axis without side effects caused by an antiprogestagenic action.

Hereditary otovestibular dysfunction and Ménière's disease in a large Belgian family is caused by a missense mutation in the COCH gene.

OBJECTIVE: To report the clinical, auditory, and vestibular characteristics of a nonsyndromic otovestibular dysfunction in a large Belgian family caused by a missense mutation of the DFNA9 gene: COCH. STUDY DESIGN: Retrospective study of the clinical, audiologic, and vestibular data of 60 genetically affected cases. SETTING: Tertiary referral center. PATIENTS: All members of a Belgian kindred who carry the genetic (P51S) defect linked to the inherited hearing and vestibular impairment. INTERVENTIONS: Diagnostic otologic, audiometric, and vestibular analysis and imaging. MAIN OUTCOME MEASURES: Pure tone audiometry, supraliminary audiometry. and vestibular investigation. RESULTS: The autosomal dominant inherited impairment was characterized by peripheral degeneration of the inner ear, leading to total deafness and bilateral vestibular areflexia. CONCLUSIONS: The genetically affected persons of a Belgian family shared a progressive sensorineural hearing loss starting between the third and sixth decade. Vestibular symptoms started at about the same age as the hearing loss. The vestibular symptoms consisted of instability in darkness, a tendency to fall sideways, light-headiness, a drunken feeling, and attacks of vertigo. Most of the patients reported tinnitus, and half of them reported pressure in the ears. Clinically, 9 of the 60 patients met the criteria for definite Ménière's disease, and another 13 and 17 patients met the criteria for probable or possible Ménière's disease, respectively. All 9 were older than the age of 35, but only 1 was older than 55 years, so more than 30% of the patients were between 35 and 55 years old. A specific pattern could be recognized in the evolution of the otovestibular impairment. Under the age of 35 years, almost all the affected family members had normal hearing, whereas above the age of 55 years, the hearing loss was at least moderate, and vestibular hypofunction occurred. In between, there was a transition period of two to three decades, when deterioration of the cochleovestibular function occurred, with a temporary audiometric and vestibular asymmetry.

Apical dominance in Pssu-ipt-transformed tobacco.

In Pssu-ipt-transformed tobacco, apical dominance was released by defoliation of the upper nodes, while the apex remained intact. After defoliation, the concentration of cytokinins (CKs) increased whereas IAA remained constant, evoking an increase in the CK/IAA ratio in the buds. Moreover, defoliation resulted in a tremendous increase in the concentrations of aromatic amines (AAs): tyramine (TYR), phenethylamine (PEA) and an as yet unidentified compound. Although the total aliphatic monoamine and polyamine (PA) concentration remained constant, putrescine (PUT) and spermidine (SPD) concentrations in the axillary buds decreased, whereas the concentration of spermine (SPM) increased. Similar changes in PAs and AAs could be observed in the buds of untransformed SR1 plants after decapitation, whereas defoliation without removal of the apex had no effect. This is the first report on the possible involvement of PAs and AAs in apical dominance.

Arabidopsis mutants with increased organ regeneration in tissue culture are more competent to respond to hormonal signals.

Shoots and roots can be regenerated through organogenesis in tissue culture by subjecting plant explants to the appropriate regime of hormone treatments. In an effort to understand the control of shoot organogenesis, we screened for mutants in Arabidopsis thaliana (L.) Heynh. Columbia ecotype for enhanced shoot development at sub-optimal concentrations of cytokinin. Mutants in four different complementation groups were identified, one of which represents a new locus named increased organ regeneration1 (ire1) and another that is allelic to the previously identified pom1/erh2 mutant. Although the mutants were selected for their response to cytokinin, they were neither hypersensitive to, nor were they over-producers of cytokinins. The mutations identified in this study not only promote more robust shoot production in tissue culture, but also enhance green-callus and root formation. We interpret this to mean that, in tissue culture, IRE genes act before organ specification during the time when root explants acquire the competency to respond to organ formation signals. In normal plant development, IRE genes may down-regulate the competency of vegetative tissue to respond to hormonal signals involved in shoot and root organogenesis.

A low content in zeatin type cytokinins is not restrictive for the occurrence of G1/S transition in tobacco BY-2 cells.

Theories on the importance of cytokinins in G1/S transition control are manifold and contradictory. By establishing a double A(phi-PZ block, maximal synchronization of a BY-2 suspension culture was obtained to investigate the effect of cytokinin depletion on G1/S transition. Lovastatin was used as a specific inhibitor of cytokinin biosynthesis. Flow cytometry showed that the G1/S transition occurred regardless of the cytokinin drop. This observation indicates an extremely low dose requiry for that stage of the cell cycle. It is very likely that precisely the downregulation of zeatin type cytokinins matters for the G1/S transition to occur, since cytokinin addition at early G1 blocked the cycle at G1/S.

Unusual combination of night blindness and optic neuropathy after biliopancreatic bypass.

Night blindness and optic neuropathy were the presenting symptoms of an iatrogenic malabsorption syndrome in a 64-year old female. This case illustrates the necessity of lifelong vitamin supplementation after biliopancreatic bypass for morbid obesity.

Secondary closure of posterior continuous curvilinear capsulorhexis.

PURPOSE: To examine the hypothesis that removing the center of the posterior capsule would prevent posterior capsular opacification (PCO). SETTING: Department of Ophthalmology, University Hospital Antwerp, Belgium. METHODS: A posterior continuous curvilinear capsulorhexis (CCC) was done before intraocular lens (IOL) implantation in eyes at risk for PCO (uveitic, young adult), retinal detachment after neodymium:YAG (Nd:YAG) laser capsulotomy (highly myopic) or for cystoid macular edema (uveitic, diabetic) and in eyes in which the posterior capsule was opaque intraoperatively. The 51 eyes of 40 patients had a follow-up ranging from 6 months to 2 years. RESULTS: Four eyes (8%) developed partial closure of the posterior CCC without vision impairment; 6 eyes (12%) had total closure, of which 2 (4%) had a loss of two or more Snellen lines necessitating an Nd:YAG laser capsulotomy. CONCLUSION: Young adult eyes and eyes with underlying diabetic retinopathy or uveitis are at risk for total closure of the posterior CCC. Only young adult eyes required Nd:YAG laser capsulotomy after the posterior CCC.

Secondary closure of posterior continuous circular capsulorhexis.

We examined the hypothesis that removing the center of the posterior capsule would reduce the risk for posterior opacification (PCO). We considered the prevalence of post-operative complications after PCCC like retinal detachment and cystoid macular edema, as found after Nd-YAG laser capsulotomy.