Beyond nephronophthisis: Retinal dystrophy in the absence of kidney dysfunction in childhood expands the clinical spectrum of CEP83 deficiency

The CEP83 protein is an essential part in the first steps of ciliogenesis, causing a ciliopathy if deficient. As a core component of the distal appendages of the centriole, CEP83 is located in almost all cell types and is involved in the primary cilium assembly. Previously reported CEP83 deficient patients all presented with nephronophthisis and kidney dysfunction. Despite retinal degeneration being a common feature in ciliopathies, only one patient also had retinitis. Here, we present two unrelated patients, who both presented with retinitis pigmentosa, without nephronophthisis or any form of kidney dysfunction. Both patients harbor bi-allelic variants in CEP83. This report expands the current clinical spectrum of CEP83 deficiency. For timely diagnosis of CEP83 deficiency, we advocate that CEP83 should be included in gene panels for inherited retinal diseases

Particles-vortex interactions and flow visualization in He4

Recent experiments have demonstrated a remarkable progress in implementing and use of the Particle Image Velocimetry (PIV) and particle tracking techniques for the study of turbulence in He4. However, an interpretation of the experimental data in the superfluid phase requires understanding how the motion of tracer particles is affected by the two components, the viscous normal fluid and the inviscid superfluid. Of a particular importance is the problem of particle interactions with quantized vortex lines which may not only strongly affect the particle motion, but, under certain conditions, may even trap particles on quantized vortex cores. The article reviews recent theoretical, numerical, and experimental results in this rapidly developing area of research, putting critically together recent results, and solving apparent inconsistencies. Also discussed is a closely related technique of detection of quantized vortices negative ion bubbles in He4.Comment: To appear in the J Low Temperature Physic

The Influence of Dormitory Architecture On Resident Behavior

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66943/2/10.1177_001391657300500402.pd

Pre-exposure to sulfur dioxide attenuates most allergic reactions upon trimellitic anhydride challenge in sensitized Brown Norway rats

Irritant-induced inflammation of the airways may aggravate respiratory allergy induced by chemical respiratory allergens. Therefore, it was studied whether airway irritation by sulfur dioxide (SO2) would enhance respiratory allergic reactions to trimellitic anhydride (TMA), using a rat model. Brown Norway (BN) rats were topically sensitized, subsequently exposed for a single time or repeatedly to 300ppm SO2, and challenged by inhalation to a distinctly irritating or minimally irritating concentration of TMA after the (last) SO2 exposure. Repeated exposure to SO 2 alone reduced breathing frequency during exposure, and caused epithelial alterations including hyperplasia and squamous metaplasia, and infiltration of polymorphonuclear inflammatory cells into nasal tissues, larynx, trachea, and bronchi/bronchioli. Histopathological changes were less prominent after 1 day of SO2 exposure. Repeated pre-exposure to SO2 reduced the number of TMA-induced apnoeas, in an SO2 exposure duration-dependent manner. This effect of SO2 on TMA-induced functional allergic reactions (apnoeas) was distinct only when the TMA challenge concentration was not too irritating itself. Repeated pre-exposure to SO 2 reduced TMA-induced laryngeal ulceration, goblet-cell hyperplasia, and inflammation in the lungs in most animals, regardless of the TMA challenge concentration. The SO2-induced replacement of normal respiratory epithelium by less sensitive, squamous epithelium may offer an explanation for the, unexpected, reduced allergic manifestation. However in a few animals, SO2 appeared to facilitate TMA-induced irritation, probably due to incomplete protection. Overall, SO2 exposure of TMA-sensitized rats reduced TMA-related allergic respiratory responses in most animals

Toxicity to nasal-associated lymphoid tissue

The mucosal membranes form a weak mechanical barrier, but they are provided with an extensive specific and non-specific defence system. Antigenic stimulation of the mucosal immune system of the oronasal passages induces specific, local immune responses, and activates immune components of mucosae elsewhere as well as the systemic immune system. Nasal lymphocytes are disseminated diffusely in the mucosa or are organised in structures at the entrance of the nasopharynx (nasal-associated lymphoid tissues, NALT). Nasal lymphatics, and possibly NALT, play an important role in drainage of brain fluid, especially in small animals. Little is known about toxicity to the NALT, despite its central role in mucosal immunity. Its strategic position in the nasal passages suggests that it comes easily into contact with inhaled nasal toxicants. Therefore, we recommend to include histopathological examination of NALT in standard guideline-driven inhalation toxicity studies. © 2003 Elsevier Science Ireland Ltd. All rights reserved

Chronic tissue changes and carcinogenesis in the upper airway,

Inhalation toxicity testing is becoming increasingly important, among other things because of the increasing number of drugs that are administered through the intranasal route to avoid enzymatic and acid breakdown and first pass metabolism in the gastrointestinal mucosa and the liver. The nature and site of damage to the nasal mucosa are influenced by a series of factors related to the airborne substance (dose, exposure concentration, solubility, polarity, diffusion rate, particle size, shape, and density), the exposure pattern (continuous, interrupted, peak loads), the subject (genetic constitution, anatomy of the respiratory tract, respiration rate, detoxification systems), and coexposures (lifestyle, occupation). A great number of chemicals are capable of inducing upper respiratory tract tumors in rodents. Nasal tumors are encountered most frequently, whereas laryngeal tumors are relatively rare (1,2,3,4,5). A large number of nitrosamines are capable of inducing nasal tumors in rats and hamsters (6,7,8,9). Furthermore, tumors of the nose develop in experimental animals after exposure to a variety of industrial chemicals such as ethylene dibromide (10), dimethyl sulfate (11), formaldehyde (12), acetaldehyde (13), bis(chloromethyl) ether (14), hexamethylphosphoramide (15), propylene oxide (16,17), phenylglycidyl ether (18), dimethylcarbamoyl chloride (19), epichlorohydrin (20), and vinyl chloride (21). Read More: http://informahealthcare.com/doi/abs/10.3109/9781420081886.01

Disposition, accumulation and toxicity of iron fed as iron (II) sulfate or as sodium iron EDTA in rats

A study was performed to provide data on the disposition, accumulation and toxicity of sodium iron EDTA in comparison with iron (II) sulfate in rats on administration via the diet for 31 and 61 days. Clinical signs, body weights, food consumption, food conversion efficiency, hematology, clinical chemistry and pathology of selected organs were used as criteria for disclosing possible harmful effects. Determination of iron and total iron binding capacity in blood plasma and non-heme iron analysis in liver, spleen and kidneys were used to assess the disposition and accumulation of iron originating from sodium iron EDTA or iron (II) sulfate. It was concluded that, under the conditions of the present study, iron is accumulated from the diet in liver, spleen and kidneys in a dose-dependent manner, and iron derived from FeEDTA is taken up and/or accumulated less efficiently in liver and spleen than iron from FeSO4. Moreover, feeding iron up to 11.5 and 11.2 mg/kg body weight/day, derived from FeSO4 and FeEDTA, respectively, did not result in tissue iron excess nor in any other toxicologically significant effects. © 2001 Elsevier Science Ltd. Chemicals/CAS: Coloring Agents; Edetic Acid, 60-00-4; Fe(III)-EDTA, 15275-07-7; Ferric Compounds; ferric sulfate, 10028-22-5; Iron, 7439-89-6; Nonheme Iron Protein

Preexposure to amorphous silica particles attenuates but also enhances allergic reactions in trimellitic anhydride-sensitized brown Norway rats

Irritant-induced inflammation of the airways may aggravate respiratory allergy induced by chemical respiratory allergens. Therefore, the effect of airway irritation by synthetic amorphous silica (SAS) on respiratory allergy to trimellitic anhydride (TMA) was studied. Brown Norway (BN) rats were topically sensitized on day 0 and on day 7, subsequently exposed for 6 h/day for 6 days to 27 mg/m3 SAS, and challenged by inhalation to a minimally irritating concentration of 12 mg/m3 TMA, 24 h after the last SAS exposure. An additional group was exposed to SAS before a second challenge to TMA. Control groups were treated with vehicle, and/or did not receive SAS exposure. Breathing parameters, cellular and biochemical changes in bronchoalveolar lavage (BAL) fluid, and histopathological airway changes 24 h after challenge were the main parameters studied. Exposure to SAS alone resulted in transient changes in breathing parameters during exposure, and in nasal and alveolar inflammation with neutrophils and macrophages. Exposure to SAS before a single TMA challenge resulted in a slightly irregular breathing pattern during TMA challenge. SAS also diminished the effect of TMA on tidal volume, laryngeal ulceration, laryngeal inflammation, and the number of BAL (lung) eosinophils in most animals, but aggravated laryngeal squamous metaplasia and inflammation in a single animal. The pulmonary eosinophilic infiltrate and edema induced by a second TMA challenge was diminished by the preceding SAS exposure, but the number of lymphocytes in BAL was increased. Thus, a respiratory particulate irritant like SAS can reduce as well as aggravate certain aspects of TMA-induced respiratory allergy. Copyright © Informa UK Ltd

Lymphoid Tissue and Pathological Influences of Toxicants

Toxicologic pathology plays a crucial role in the identification and interpretation of substance-induced health effects. Histology of lymphoid organs is quite sensitive, although it does not flag every model immunotoxic substance. Subtle interferences of toxic compounds, like transmembrane signaling and cell activation, are often not detectable by conventional histology. The immune system by its very dynamic nature manifests a bandwidth in its morphological picture, hence the 'normal' state can be quite variable. Interspecies- and interstrain-dependent differences in the histophysiology of lymphoid organs should be taken into account, as well as the functional and morphological changes in lymphoid organs during life. Increased susceptibility to immunotoxicants may occur during periods of marked histophysiological changes in lymphoid organs. The high sensitivity at perinatal age for a number of immunotoxicants has received specific attention in immunotoxicity testing. In the interpretation of effects, it should be noted that particular components of lymphoid organs may be decreased in number (suppressed-involuted) or increased (stimulated-expanded), but that does not necessarily reflect the overall effects on the immune system.The chapter addresses the histology of lymphoid organs, including tertiary lymphoid structures. Toxicant-induced pathologies are presented and associated mechanisms of toxicity are discussed

Airway morphology and function of rats following dermal sensitization and respiratory challenge with low molecular weight chemicals

Local lymph node activation and increased total serum IgE levels are suggested to be predictive parameters of airway hypersensitivity caused by low molecular weight (LMW) chemicals. Whether increases of total serum IgE are indicative of actual induction of specific airway reactions (morphological and functional) after inhalation challenge was examined in the present study. In Brown Norway (BN) and Wistar rats, serum IgE concentrations were examined following topical exposure of chemicals with known diverse sensitization potential in humans: trimellitic anhydride (TMA), a dermal and respiratory sensitizer; dinitrochlorobenzene (DNCB), a dermal sensitizer with no known potential to cause respiratory allergy; and methyl salicylate, a skin irritant devoid of sensitizing properties. Functional and histopathological changes in the respiratory tract were examined after subsequent inhalatory challenge with these chemicals. Of the three tested chemicals, only topical exposure to TMA resulted in a significant increase in total serum IgE concentrations in the high-IgE-responding BN rat. Upon subsequent inhalatory challenge of these rats, TMA induced specific airway reactions which included a sharp decrease in respiratory rate during challenge, followed by an increase in breathing rate with a concomitant decrease in tidal volume 24 and 48 h after inhalatory challenge, and histopathological changes in the larynx and lungs of animals necropsied 48 h after challenge. Interestingly, despite low IgE levels, TMA induced histopathological changes in the larynx and lungs of Wistar rats too. Laryngeal changes were also observed in Wistar rats upon sensitization and challenge with DNCB. These data suggest that increased total serum IgE after topical sensitization is associated with immediate-type specific airway reactivity after inhalation challenge in BN rats and thus may be a valuable parameter in testing for respiratory sensitization potential of LMW compounds. Histopathological examination upon subsequent inhalation challenge of sensitized low-IgE-responders may provide information on other allergic inflammatory airway reactions