Uptake and dissolution of particulate iodipamide ethyl ester in the spleen. A morphologic study

Iodipamide ethyl ester (IDE) is an experimental particulate contrast agent being developed for CT image enhancement of the liver and spleen. IDE particles are phagocytized by the reticuloendothelial cells after an intravenous injection. The uptake and dissolution of IDE particles were studied in the spleen with light and electron microscopy. Two minutes after injection, intra- and extracellular IDE particles were found in the red pulp of the spleen. Highest concentration of IDE was seen in the marginal zone surrounding the white pulp. Particles also were seen elsewhere in the red pulp but only occasionally between the outermost cells of the white pulp. The extracellular particles disappeared within 4 hours postinjection. At one day postinjection, the amount of intracellular IDE particles had begun to decrease. Electron micrographs showed that the intracellular particles dissolved gradually in the phagocytes and caused transient degenerative morphologic changes. At three days postinjection, practically all IDE particles had disappeared from the spleen. Polystyrene latex particles were used as controls. They were phagocytized like the IDE particles, but they did not disappear from the phagocytes. IDE particles caused no morphologic injuries in nonphagocytic cells of the spleen.     

Synthesis of poly[isobutyl (2S,3R)-3-benzyloxyaspartate]

A chiral poly(3-substituted isobutyl D -aspartate) 12 was synthesized by polymerization of the chiral β-lactam 11 derived from D -glyceraldehyde. The new polyamide was characterized by elemental analyses, and infrared, ¹H- and ¹³C nuclear magnetic resonance spectroscopies. The molecular weight was estimated as 543 000 and 230 000 on the basis of viscosimetric measurements and gel-permeation chromatography, respectively. Polyamide 12 is soluble in a variety of organic solvents including chloroform.     

Micronuclei frequencies in hospital workers occupationally exposed to low levels of ionizing radiation: influence of smoking status and other factors

In the context of a medical surveillance program aimed at preventing cancer risk from exposure to ionizing radiation, we investigated chromosomal damage in peripheral lymphocytes from 37 hospital workers exposed to low levels of ionizing radiation and 37 controls. The micronuleus (MN) assay was used as a biomarker of genetic damage. The influence of confounding factors like smoking status, age and gender was investigated by multiple regression analysis. The results indicated that, overall, MN frequency was higher in exposed workers than in controls, although the difference was not statistically significant. Interestingly, smoking status significantly raised MN frequency among the exposed workers but not among controls. This suggests that smoking can influence chromosomal damage induced in humans by ionizing radiation. Among both exposed workers and controls, MN frequency was found to increase with age. Female gender influenced the increase in MN frequency in the exposed group. Our results suggest that the effect of cigarette smoking should be carefully factored into genetic monitoring studies assessing the risks associated with low level radiation exposure.     

Protein binding of brequinar in the plasma of healthy donors and cancer patients and analysis of the relationship between protein binding and pharmacokinetics in cancer patients

The protein binding of weakly acidic and basic drugs has been shown to be altered in cancer patients. Brequinar is a weakly acidic, low-clearance, and highly protein-bound (>98% bound) antitumor agent. The pharmacokinetic parameters of brequinar are subject to large interpatient variability. This large interpatient variability may be related to brequinar's plasma protein-binding capacity (assuming no change in the intrinsic clearance of the unbound drug). The objectives of this study, therefore, were (a) to characterize brequinar's protein binding in the plasma of healthy donors and cancer patients and (b) to examine the relationships between brequinar's plasma protein binding and its pharmacokinetics in patients. Brequinar protein binding was determined in human serum albumin (HSA) solution, drug-free donor plasma, and brequinar-free, predose plasma samples obtained from a phase I cancer trial. Pharmacokinetic results from this study were used to examine relationships between plasma protein binding and drug disposition. In HSA solution and healthy donor plasma, brequinar's protein binding as determined using spiked samples was concentration-dependent. The unbound brequinar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4% HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor plasma as the brequinar concentrations increased from 0.1 to 2.3 mM in the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysis of brequinar binding characteristics using the binding ratio and Rosenthal binding plots showed that albumin was the primary protein for brequinar binding in human plasma. The addition of various concentrations of ₁-acid glycoprotein to 4% HSA solution did not affect the protein binding of brequinar to HSA. The protein binding determined in the plasma of cancer patients was not quantitatively different, except for variability, from that observed in the plasma of healthy donors. Examination of relationships between the unbound brequinar fraction and pharmacokinetics suggested that plasma protein binding was not a major determinant of brequinar disposition in cancer patients.     

Short-term neurobehavioural effects in anaesthetists with low exposure to nitrous oxide

The aim of this study was to assess whether a sample of 37 anaesthetists occupationally exposed only to N2O showed any deterioration in vigilance and/or mood. The anaesthetists were examined with three neurobehavioural tests (Simple Reaction Time and Colour Word Vigilance to measure the vigilance and Mood Rating Scale to evaluate the level of stress and arousal) and underwent N2O biological monitoring (to correlate the test results with the N2O exposure) on the first and on the last day of the work week, before and after work in the operating room. No significant relationship was found between the biological monitoring and the test results. The only significant statistical difference was found between the beginning and the end of each workday in the arousal level, regardless of the result of the biological monitoring.     

Criteria for diagnosis and attribution of an occupational musculoskeletal disease

Background:Criteria for diagnosis and compensation of occupational musculoskeletal diseases varies widely between countries as demonstrated by the large differences between countries with comparable economics and social systems (for example, within the European Union). Several countries have a list of occupational diseases and sometimes these lists include diagnostic and attribution criteria, but these criteria are usually not very specific, and they may also be very different.Objectives:The aim of this paper is to explicitly define what are the information needed for an evidence-based diagnosis and attribution of an occupational musculoskeletal disease.Methods:Based on the general framework of evidence-based medicine, a review is presented of the information required to define: - when a musculoskeletal disease is present, according to the best available techniques; - how to define a relevant exposure to biomechanical risk factors, according to the best available techniques.Results:Criteria are presented to combine information regarding the diagnosis of a musculoskeletal disease and exposure to biomechanical risk factors for an evidence-based attribution of the disease to the occupational exposure. The criteria use a probabilistic model that combine epidemiologic and medical findings, workplace exposure assessment, and non-occupational factors evaluation.Discussion:The use of the proposed criteria may improve the process of diagnosis and attribution of an occupational musculoskeletal disease. In addition, it makes possible to associate a probability rank to the attribution and, ultimately, it may improve the overall quality of the decisional process of the occupational physician.Key words: Criteria, occupational disease, musculoskeletal system     

Pseudotumoral pulmonary cryptococcosis in association with Cushing's syndrome

Opportunistic infections in endogenous Cushing's syndrome are associated with severe cortisol excess and carry a high mortality. Pulmonary cryptococcosis is one of these opportunistic infections and can mimic a lung neoplasm, therefore making its diagnosis difficult. We report a case of a young male with ACTH-dependent Cushing's syndrome and severe hypercortisolism. The patient achieved cure after the transfenoidal surgery, but developed a febrile state. A chest computed tomography showed a pulmonary nodule that did not change in serial chest radiographs. Diagnosis of tuberculosis, fungal and bacterial infections were inconclusive, so the hypothesis of lung neoplasm became more probable. The necropsy, however, disclosed a pseudotumoral cryptococcosis. Opportunistic infections, like Cryptococcus neoformans, should be considered in patients with Cushing's syndrome and a pulmonary infiltrate.     

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

Nuclear receptor coactivator 4 (NCOA4) promotes ferritin degradation and Ncoa4-ko mice in a C57BL/6 background show microcytosis and mild anemia, aggravated by iron deficiency. To understand tissue-specific contributions of NCOA4-mediated ferritinophagy we explored the effect of Ncoa4 genetic ablation in the iron-rich Sv129/J strain. Increased body iron content protects these mice from anemia and, in basal conditions, Sv129/J Ncoa4-ko mice show only microcytosis; nevertheless, when fed a low-iron diet they develop a more severe anemia compared to that of wild-type animals. Reciprocal bone marrow (BM) transplantation from wild-type donors into Ncoa4-ko and from Ncoa4-ko into wild-type mice revealed that microcytosis and susceptibility to iron deficiency anemia depend on BM-derived cells. Reconstitution of erythropoiesis with normalization of red blood count and hemoglobin concentration occurred at the same rate in transplanted animals independently of the genotype. Importantly, NCOA4 loss did not affect terminal erythropoiesis in iron deficiency, both in total and specific BM Ncoa4-ko animals compared to controls. On the contrary, upon a low iron diet, spleen from wild-type animals with Ncoa4-ko BM displayed marked iron retention compared to (wild-type BM) controls, indicating defective macrophage iron release in the former. Thus, erythropoietin administration failed to mobilize iron from stores in Ncoa4-ko animals. Furthermore, Ncoa4 inactivation in thalassemic mice did not worsen the hematologic phenotype. Overall our data reveal a major role for NCOA4-mediated ferritinophagy in macrophages to favor iron release for erythropoiesis, especially in iron deficiency.     

A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism

We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.     

Gyrification,cortical and subcortical morphometry in neurofibromatosis type 1: an uneven profile of developmental abnormalities

Background

Neurofibromatosis type 1 (NF1) is a monogenic disorder associated with cognitive impairments. In order to understand how mutations in the NF1 gene impact brain structure it is essential to characterize in detail the brain structural abnormalities in patients with NF1. Previous studies have reported contradictory findings and have focused only on volumetric measurements. Here, we investigated the volumes of subcortical structures and the composite dimensions of the cortex through analysis of cortical volume, cortical thickness, cortical surface area and gyrification.

Methods

We studied 14 children with NF1 and 14 typically developing children matched for age, gender, IQ and right/left-handedness. Regional subcortical volumes and cortical gyral measurements were obtained using the FreeSurfer software. Between-group differences were evaluated while controlling for the increase in total intracranial volume observed in NF1.

Results

Subcortical analysis revealed disproportionately larger thalami, right caudate and middle corpus callosum in patients with NF1. Cortical analyses on volume, thickness and surface area were however not indicative of significant alterations in patients. Interestingly, patients with NF1 had significantly lower gyrification indices than typically developing children primarily in the frontal and temporal lobes, but also affecting the insula, cingulate cortex, parietal and occipital regions.

Conclusions

The neuroanatomic abnormalities observed were localized to specific brain regions, indicating that particular areas might constitute selective targets for NF1 gene mutations. Furthermore, the lower gyrification indices were accompanied by a disproportionate increase in brain size without the corresponding increase in folding in patients with NF1. Taken together these findings suggest that specific neurodevelopmental processes, such as gyrification, are more vulnerable to NF1 dysfunction than others. The identified changes in brain organization are consistent with the patterns of cognitive dysfunction in the NF1 phenotype.