Preliminary insights into RNA in CSF of pediatric SMA patients after 6 months of nusinersen.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare autosomal-recessive neurodegenerative disorder caused by mutations in survival motor neuron 1 (SMN1) gene, and consequent loss of function of SMN protein, which results in progressive loss of lower motor neurons, and muscular wasting. Antisense oligonucleotide (ASO) nusinersen (Spinraza®) modulates the pre-mRNA splicing of the SMN2 gene, allowing rebalance of biologically active SMN. It is administered intrathecally via lumbar puncture after removing an equal amount of cerebrospinal fluid (CSF). Its effect was proven beneficial and approved since 2017 for SMA treatment. Given the direct effect of nusinersen on RNA metabolism, the aim of this project was to evaluate cell-free RNA (cfRNA) in CSF of SMA patients under ASOs treatment for biomarker discovery. METHODS: By RNA-sequencing approach, RNA obtained from CSF of pediatric SMA type 2 and 3 patients was processed after 6 months of nusinersen treatment, at fifth intrathecal injection (T6), and compared to baseline (T0). RESULTS: We observed the deregulation of cfRNAs in patients at T6 and we were able to classify these RNAs into disease specific, treatment specific and treatment dependent. Moreover, we subdivided patients into "homogeneous" and "heterogeneous" according to their gene expression pattern. The "heterogeneous" group showed peculiar activation of genes coding for ribosomal components, meaning that in these patients a different molecular effect of nusinersen is observable, even if this specific molecular response was not referable to a clinical pattern. CONCLUSIONS: This study provides preliminary insights into modulation of gene expression dependent on nusinersen treatment and lays the foundation for biomarkers discovery.

Self-perceived attention difficulties are associated with sensory hypersensitivity in migraine.

BACKGROUND: Attention is the process which enables to preferentially select salient or relevant stimuli and to attenuate the response to irrelevant incoming stimuli. Migraine is characterized by both attentional alterations and an abnormal sensory processing to external stimulations. The aim of the study was to investigate potential interactions between self-perceived attentional difficulties and sensory hypersensitivity in migraine patients. METHODS: Forty-six episodic migraineurs without aura and 46 healthy controls filled out questionnaires on self-perceived attention difficulties and self-reported sensitivity to visual, auditory and olfactory stimulations. RESULTS: Compared to controls, migraineurs reported significantly higher levels of attention difficulty and sensory sensitivity. Sensory hypersensitivity correlated significantly with self-perceived attentional difficulties in migraineurs (P=0.002), but not with migraine disability or levels of anxiety or depression. Ictal and interictal sensory sensitivities were significantly correlated in migraineurs within visual (P<0.001), auditory (P<0.001) and olfactory (P=0.001) modalities. CONCLUSION: This study shows for the first time an association between self-reported attentional difficulties and multimodal sensory hypersensitivity. Studies combining behavioral and physiological measures of sensory processing and attention processes are necessary to further understand the peculiar vulnerability of migraineurs to sensory stimuli.

[Cutaneous loxoscelism, about an exceptional observation of 9 consecutive cases]. / Le loxoscelisme cutané, à propos d'une observation exceptionnelle de 9 cas consécutifs.

INTRODUCTION: Loxosceles spiders are ubiquitous and responsible for many cases of envenomation in the world. The kind rufescens is present in the Provence and Occitan regions in France. During the summer 2015, we faced many Loxosceles rufescens cases of bites having led to extensive integumental necrosis whose features and singular evolution seems important to report. MATERIAL AND METHODS: We report the cases of nine patients who experienced a spider bite in the summer of 2015 in the Languedoc Roussillon. RESULTS: Of nine patients, eight patients had skin necrosis and five required surgical care. Five patients had a fever and had five other general signs such as important asthenia, joint pain, nausea and dizziness. CRP was very low normal in all patients. Finally, five of the nine patients reported a residual pain. DISCUSSION: L. rufescens is a small spider (7 to 15mm in diameter) having a cytotoxic venom. Loxoscelism diagnosis is usually made by removing a front necrotic skin lesion. Of systemic loxoscelism that have been described, some American species had fatal outcomes. The treatment remains controversial with various options: surgery, antibiotics, antihistaminics, antivenom. CONCLUSION: The diagnosis must be made in endemic areas when confronted to a necrosic integumentary infectious rapidly progressive, unresponsive to antibiotic treatment associated with atypical general signs.

Early white matter involvement in an infant carrying a novel mutation in ACOX1.

We describe the clinical findings and MRI features observed in a child who presented a two-step disease course: he was hypotonic at birth and soon afterwards developed seizures, which were partially responsive to treatment; he subsequently showed developmental delay and a progressive neurological deterioration with the onset of severe seizures at around three years of age. Head MRI at age 20 days was unremarkable, whereas at 25 months it showed bilateral hyperintensity of the deep cerebellar nuclei; five months later, the signal hyperintensity was also present in the cerebellar white matter and ventral pontine fibre tracts. Molecular analysis revealed a novel ACOX1 mutation, predicting a largely truncated protein. The white matter involvement, which followed an ascending trajectory from cerebellar and brainstem structures to the cerebral hemispheres, seemed to originate from the perinuclear white matter of the deep cerebellar nuclei.

Diagnosing pelvic osteomyelitis beneath pressure ulcers in spinal cord injured patients: a prospective study.

There is no consensus on a diagnostic strategy for osteomyelitis underlying pressure ulcers. We conducted a prospective study to assess the accuracy of multiple bone biopsies and imaging to diagnose pelvic osteomyelitis. Patients with clinically suspected osteomyelitis beneath pelvic pressure ulcers were enrolled. Bone magnetic resonance imaging (MRI) and surgical bone biopsies (three or more for microbiology and one for histology per ulcer) were performed. Bacterial osteomyelitis diagnosis relied upon the association of positive histology and microbiology (at least one positive culture for non-commensal microorganisms or three or more for commensal microorganisms of the skin). From 2011 to 2014, 34 patients with 44 pressure ulcers were included. Bacterial osteomyelitis was diagnosed for 28 (82.3%) patients and 35 (79.5%) ulcers according to the composite criterion. Discrepancy was observed between histology and microbiology for 5 (11.4%) ulcers. Most common isolates were Staphylococcus aureus (77.1%), Peptostreptococcus (48.6%) and Bacteroides (40%), cultured in three or more samples in 42.9% of ulcers for S. aureus and ≥20% for anaerobes. Only 2.8% of ulcers had three or more positive specimens with coagulase-negative staphylococci, group B Streptococcus, and nil with enterococci and Pseudomonas aeruginosa. Staphylococcus aureus, Proteus and group milleri Streptococcus were recovered from one sample in 22.8%, 11.4% and 11.4% of ulcers, respectively. Agreement was poor between biopsies and MRI (κ 0.2). Sensitivity of MRI was 94.3% and specificity was 22.2%. The diagnosis of pelvic osteomyelitis relies on multiple surgical bone biopsies with microbiological and histological analyses. At least three bone samples allows the detection of pathogens and exclusion of contaminants. MRI is not routinely useful for diagnosis.

Avaliação da atividade antimicrobiana da planta Tradescantia pallida Munt (Taboquinha Roxa) / Evaluation of antimicrobial activity of the Tradescantia pallida Munt plant (Taboquinha Roxa)

RESUMO O objetivo deste estudo foi pesquisar o efeito antimicrobiano in vitro do extrato hidroalcóolico das folhas Tradescantia pallida Munt conhecida como Taboquinha roxa. Foram realizados testes em meio sólido, onde não observou qualquer halo de inibição, e o método de microdiluição, em que os resultados foram expressivos, com determinação da Concentração Inibitória Mínima (CIM) e Concentração Bactericida Mínima (CBM), com resultados em diferentes concentrações. Foram utilizadas cepas padrão de bactérias Gram positivas e Gram negativas. De acordo com os resultados, sugere-se que essa planta apresenta um potencial antimicrobiano.

ABSTRACT The aim of this study was to investigate the in vitro antimicrobial effect of the hydroalcoholic extract of the Tradescantia pallida Munt leaves,known as Taboquinha roxa. The tests were both conducted on solid mean, where it was not observed any zone of inhibition, and by the micro dilution method, in which the results of the Minimum Inhibitory Concentration (MIC) and the Minimum Bactericidal Concentration (MBC) were significant and related with the different concentrations. Standard strains of bacteria type Gram positive and Gram negative were employed. According to the results, this plant has an antimicrobial potential.

NK cytotoxicity and alloreactivity against neuroblastoma cell lines in vitro: comparison of Europium fluorometry assay and quantification by RT-PCR.

UNLABELLED: New therapies for children with high risk neuroblastoma are needed, and haploidentical stem cell transplantation with NK post-graft injections is a potential option. To develop this strategy, we compared and correlated two methods of NK cytotoxicity assay. The aim of this work is to optimize in vitro NK cytotoxicity assays, investigate the effect of interleukin stimulation on NK cells and use of antiGD2 antibodies against tumor target cells and finally establish an in vitro model for haploidentical stem cell transplantation. EXPERIMENTAL DESIGN: We evaluated NK cell cytotoxicity in vitro against NB cell lines (IMR-32 and SK-NSH) in different culture conditions using a Europium BATDA fluorescence test, and correlated the results with quantification of TH, Phox2B, and DCX transcripts evaluated by RT-PCR. RESULTS: Both IMR-32 and SK-N-SH neuroblastoma cell lines were sensitive to NK cells and particularly when NK cells were stimulated by interleukin IL-2 and IL-15 or when using anti-GD2 antibodies against tumor target cells. All these results were observed either with Europium fluorometry assay or with RT-PCR quantification. There is a clear correlation between the two methods, for the three transcripts at the ratio effector/target 50/1 (TH r=0.75, Phox2B r=0.79 and DCX r=0.8), for all the values whatever the cell line. Besides for all three transcripts, the correlations were significantly independent of the cell line and the ratio E/T (all p values non-significant) even if the best correlation was observed for the ratio 50/1. After prolonged incubation times of effector and target cells (24 h), which could be evaluated only by RT-PCR, all the transcripts clearly decreased, confirming the haploidentical effect of NK against the two neuroblastoma cell lines in our two in vitro haploidentical models but no advantage of mismatch. CONCLUSIONS: NK cytotoxicity against neuroblastoma cell lines can be evaluated by Europium assay and by RT-PCR with clear correlation for the three transcripts TH, Phox2B and DCX whatever the ratio E/T and cell line used. This new method of RT-PCR is simple and suitable for large-scale conditions like study of adherent tumor cells or prolonged incubations of target/effector cells which allowed us to observe haploidentical effect.

Hematopoietic progenitor cell mobilization and harvesting in children with malignancies: do the advantages of pegfilgrastim really translate into clinical benefit?

Our purpose was to assess success rates in children of achieving optimal hematopoietic progenitor cells (HPCs) harvest after mobilization with 300 microg/kg pegfilgrastim. Between January 2005 and January 2007, 26 children with solid malignancies who were referred for HPC collection were consecutively included. Hematopoietic progenitor cell mobilization consisted of one s.c. injection of 300 microg/kg body weight (BW) of pegfilgrastim. The success criterion was defined as at least 5 x 10(6) CD34+ cells/kg during the first standard apheresis (less than 3 blood volumes processed (BVP)). After 26 inclusions, the Bayesian analysis gave a mean estimated success rate of 60.7% (95% credibility interval: 42.0-78.0%). The first apheresis allowed the collection of 8.3 x 10(6) CD34+ cells/kg BW (range 0.6-37.8), with a median of 2.8 BVP (range 1.4-3.0). Overall, the median of CD34+ cells collected was 12.4 x 10(6)/kg (range 2.7-37.8). The cumulative dose of anthracyclin was the only variable associated with the total number of CD34+ collected cells (P<0.05). Mobilization was clinically well tolerated in 20 patients. No drug-related adverse events of grade > or =3 occurred. We conclude that a single injection of 300 microg/kg pegfilgrastim in the hematological steady state is an efficient and well-tolerated method of HPC mobilization in children with solid malignancies.

Receptor activated C kinase is down-regulated in the male gonad of the marine bivalve mollusc Mya arenaria exposed to tributyltin (TBT).

This study was aimed at investigating the molecular mechanisms by which tributyltin (TBT) impairs the reproductive processes in the marine bivalve Mya arenaria. The suppression polymerase chain reaction subtractive hybridization (SSH) method was used to identify differentially expressed transcripts in the gonads of adult M. arenaria 72 h after a single injection of 160 ng TBT in the adductor muscle. Subtractive cDNA libraries comprising 322 clones were obtained. These clones were sequenced and corresponded to 55 female and 26 single male non-redundant cDNAs. Following similarity searches in genome databases, some of the transcripts could be assigned to cellular functions including mitochondrial respiration, structural proteins, structure of cytoskeleton, nucleic acid regulation, general metabolism and signal transduction. Among the potentially differentially regulated transcripts, Receptor for activated C kinase 1 (RACK1) represented 6% of the total down-regulated clones in males and the corresponding protein exhibited a high degree of similarity (80%) with the human polypeptide. The RACK1 cDNA from M. arenaria consists of 1085 bp, encoding a 318 deduced polypeptide which contains five internal tryptophan-aspartate (WD) repeats, six putative PKC phosphorylation sites, one tyrosine kinase site, four putative N-myristoylation sites as well as a transmembrane segment spanning amino acid 228-251. A significant down-regulation (by approximately 30% (p<0.05)) of RACK1 expression in male gonads exposed to TBT was confirmed by quantitative real-time RT-PCR. Transcript levels of RACK1 were higher in the female gonads than in the mantle, gills and male gonads. Gene expression as detected by in situ hybridization was strong in mature oocytes comparatively to primary germ cells. RACK1 may be a useful biomarker for TBT exposure in the reproductive system of bivalve molluscs.

[Pediatric cases in preclinical emergency medicine: critical aspects in the range of missions covered by ground ambulance and air rescue services]. / Pädiatrische Notfälle in der präklinischen Notfallmedizin: Schwerpunkte des Einsatzspektrums im bodengebundenen Rettungsdienst und in der Luftrettung.

BACKGROUND: The aim of this study was to demonstrate differences in structure and severity of pediatric emergencies treated by aeromedical (air rescue) or ground ambulances services. Conclusions for the training of emergency physicians are discussed. PATIENTS AND METHODS: In a 3-year study period, a total of 9,274 pediatric emergencies covered by the ADAC air rescue service are compared to 4,344 pediatric patients of ground ambulance services in Saarland. RESULTS: In aeromedical services pediatric emergencies are more frequent (12.9% vs. 6.4%), trauma predominates (59.9% vs. 35.6%) and severe injuries or diseases occur more frequently (30.5% vs. 15.0%). In both groups pediatric emergency cases are concentrated into very few diagnostic groups: more than one third of the cases involving pre-school children is due to convulsions. Respiratory diseases and intoxication are the next most frequent causes and are more common in ground ambulance patients. Head trauma is the most common diagnosis in cases of pediatric trauma, followed by musculoskeletal and thoracoabdominal trauma. All types of severe trauma are more frequent in pediatric patients of the aeromedical services. CONCLUSIONS: Training of emergency physicians should include pediatric life support and specific information about frequent pediatric emergency situations. For emergency physicians in aeromedical services, an intensive training in pediatric trauma life support is also necessary.

High cancer cell death in syngeneic tumors developed in host mice deficient for the stromelysin-3 matrix metalloproteinase.

Matrix metalloproteinases (MMPs) are extracellular enzymes. Some of them are known to be involved in tumor development and/or progression. Several cellular functions have been proposed for MMPs during malignant processes. Notably, they may be involved in tissue-remodeling processes through their ability to digest matrix components or to participate in tumor neoangiogenesis and, subsequently, in cancer cell proliferation. One of these MMPs, stromelysin-3 (ST3/MMP11), although devoid of enzymatic activity against the matrix components, is associated with human tumor progression and poor patient clinical outcome. Using several in vivo experimental models, it has been demonstrated that ST3 expression by the fibroblastic cells surrounding malignant epithelial cells promotes tumorigenesis in a paracrine manner. The present study was devoted to the identification of the cellular function underlying this ST3-induced tumor promotion using a syngeneic tumorigenesis model in mice. Our results show that ST3 exhibits a new and unexpected role for a MMP, because ST3-increased tumorigenesis does not result from increased neoangiogenesis or cancer cell proliferation but from decreased cancer cell death through apoptosis and necrosis. Thus, during malignancy, the cellular function of ST3 is to favor cancer cell survival in the stromal environment.

Identification and characterization of a novel gastric peptide hormone: the motilin-related peptide.

BACKGROUND & AIMS: This study looked for new proteins with expression restricted to the gastric epithelium that may provide insight to the differentiation and function of the gastric unit. METHODS: A novel complementary DNA was isolated and sequenced, and its expression was examined in mouse tissues at both messenger RNA and protein levels. Subcellular localization was studied using immunoelectron microscopy. The posttraductional processing of the protein was analyzed in vitro by protein microsequencing and in vivo by Western blotting. RESULTS: We identified a novel protein that is mainly expressed by the secretory granules of the stomach enteroendocrine cells. This protein has sequence similarity with prepromotilin, the precursor of the motilin hormone and the motilin-associated peptide. As for the prepromotilin, a posttraductional maturation leads to a secreted peptide that is further cleaved at a dibasic site and gives rise to the motilin-related peptide (MTLRP) and MTLRP-associated peptide. CONCLUSIONS: We have identified and characterized a novel gene encoding the preproMTLRP protein. MTLRP presents similarity to motilin and is specifically expressed by enteroendocrine cells of the stomach and therefore represents a novel hormone.

pS2/TFF1 interacts directly with the VWFC cysteine-rich domains of mucins.

BACKGROUND & AIMS: Trefoil factors (TFFs) are secreted gastrointestinal proteins that have been shown to protect and promote healing of the gastrointestinal tract. Moreover, pS2/TFF1 is essential for normal differentiation of the gastric mucosa because deficient mice develop antropyloric adenomas. To date, it is unclear how TFFs mediate their functions. METHODS: Using the yeast 2-hybrid system, we attempted to identify murine TFF1 interacting proteins by screening a stomach and duodenum complementary DNA (cDNA) expression library. RESULTS: Four positive clones were isolated. Sequence and expression studies showed that they corresponded to the murine counterpart of human cDNA sequences encoding carboxy-terminal fragments of mMuc2 (489 residues) and mMuc5AC (427, 430, and 894 residues) mucin proteins. Mutagenesis experiments showed that TFF1 interacts with the 2 mucins through binding with their VWFC1 and VWFC2 (von Willebrand factor C) cysteine-rich domains. CONCLUSIONS: These results show that the gastrointestinal protective effect of TFF1, and presumably of the other TFFs, is caused at least partially by their participation, via mucin binding, in the correct organization of the mucous layer that protects the apical side of the mucosa from deleterious luminal agents.

Expression of matrix metalloproteinases during murine chorioallantoic placenta maturation.

A large body of experimental evidence supports the participation of two groups of extracellular proteases, matrix metalloproteinases (MMPs), and plasminogen activators/plasmin, in tissue remodeling in physiological and pathological invasion. In the late mouse placenta, several tissue remodeling and cell invasion processes take place. Spongiotrophoblast migration into maternal decidua, as well as decidual extracellular matrix remodeling require the coordinated action of extracellular proteolytic enzymes. Via Northern and in situ hybridization, we have analyzed the spatio-temporal expression patterns of members of the MMP family (stromelysin-3, gelatinases A and B), as well as their inhibitors TIMP-1, -2 and -3 in late murine placenta (days 10.5 to 18.5 of gestation). Gelatinase activity in placental extracts was assessed by substrate zymography. Gelatinase A and stromelysin-3 were found to be prominently expressed in decidual tissue; shortly after midpregnancy, the decidual expression patterns of gelatinase A and stromelysin-3 became overlapping with each other, as well as with the expression domain of TIMP-2. On the other hand, gelatinase B transcripts were expressed only by trophoblast giant cells at day 10.5, and were downregulated at later stages. TIMP-1 and TIMP-3 transcripts were detected in decidual periphery at day 10.5, while later the expression was restricted to the endometrial stroma and spongiotrophoblasts, respectively. The areas of stromelysin-3 expression were the same (giant trophoblasts) or adjacent (decidua) to those where urokinase (uPA) transcripts were detected, suggesting a possible cooperation between these proteinases in placental remodeling. We generated mice doubly deficient for stromelysin-3 and uPA, and report here that these mice are viable and fertile. Furthermore, these animals do not manifest obvious placental abnormalities, thereby suggesting the existence of compensatory/redundant mechanisms involving other proteolytic enzymes. Our findings document the participation of MMPs and their inhibitors in the process of late murine placenta maturation, and warrant the characterization of other members of the MMP family, like membrane type-MMPs, in this process.

[Extracellular proteases of stromal origin: contribution to tumor progression and therapeutic perspectives]. / Les protéases extracellulaires d'origine stromale: contribution à la progression cancéreuse et perspectives thérapeutiques.

For a long time, extracellular proteinases were thought to be expressed by the cancerous cells and only able to cleave extracellular matrix components, in order to promote tumor cell invasion. Recent works have now demonstrated that these proteinases are currently synthesized by stromal fibroblastic cells and that some of them may exhibit additive function(s). These findings lead to a new therapeutical concept leading to target the activity of stromal proteinases, and most notably of the matrix metalloproteinases.

Tumor necrosis factor receptor associated factor 4 (TRAF4) expression pattern during mouse development.

This is the first in situ hybridization analysis of expression of a tumor necrosis factor (TNF) receptor associated factor (TRAF) during development. TRAF4 is observed throughout mouse embryogenesis, most notably during ontogenesis of the central (CNS) and peripheral (PNS) nervous system, and of nervous tissues of sensory organs. TRAF4 is preferentially expressed by post-mitotic undifferentiated neurons. Interestingly, TRAF4 remains expressed in the adult hippocampus and olfactory bulb, known to contain multipotential cells responsible for neoneurogenesis.

In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy.

Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699-704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3-/-) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7, 12-dimethylbenzanthracene-induced tumorigenesis in ST3-/- mice. Moreover, ST3-/- fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas.

Chromosomal assignment and expression pattern of the murine Lasp-1 gene.

The human Lasp-1 (LIM and SH3 protein) gene was previously identified by differential screening of a breast cancer-derived metastatic lymph node cDNA library. It was located on the q12-q21 region of human chromosome 17 and was shown to be amplified and overexpressed in 12% of breast tumors. Lasp-1 defines a new LIM-protein subfamily, as it associates a C-terminal Src homology 3 (SH3) domain to a N-terminal LIM motif. In this study, the isolation and characterization of the cDNA encoding the mouse Lasp-1 protein are described, and it is shown to be highly conserved with its human counterpart. In addition to the LIM and SH3 domains, both human and mouse Lasp-1 contain an actin-binding domain. The mouse gene was mapped by in situ hybridization to the 11C-11D region of chromosome 11. Northern blot analysis shows that this gene is expressed from 7.5 to 17.5 days post-coitum of mouse embryogenesis and in almost all adult tissues.

Spontaneous iron overload in Sprague-Dawley rats.

In a review of the toxicological studies performed in our laboratory during the period 1986-1995, we occasionally observed significant iron overloading in the liver. Liver tissue was examined by light and electron microscopy, and the results were analyzed by sex and age (7, 9, 11, 19, 31, 59, and 111 wk). The intensity of iron overload increased with age: the accumulation began in pericanalicular siderosomes of periportal hepatocytes and extended progressively to the entire lobule and also to nonhepatocytic cells (Kupffer cells in sinusoids and macrophages around bile ducts in portal tracts) and occasionally with distortion of sinusoids by sideroblastic nodules and moderate enlargement of portal tracts in the oldest animals. No significant inflammatory infiltrates, degeneration, necrosis or fibrosis were noted. Hepatocyte pigmentation alone was prominent at 9 and 11 wk. The frequency of pigmentation of parenchymal and nonhepatocytic cells increased from 9 wk for females; in males, this was seen only at 111 wk. The intensity of pigmentation of nonhepatocytic cells versus parenchymal cells increased with aging. The frequency of those different types of iron overloading was higher for females up to 111 wk. The pathology of spontaneous iron overloading in the Sprague-Dawley rat, described here in spite of differences, has some similarities to that of human hereditary hemochromatosis.