Dimensions of irritability in adolescents: longitudinal associations with psychopathology in adulthood.

BACKGROUND: There is an emerging consensus in developmental psychopathology that irritable youth are at risk for developing internalizing problems later in life. The current study explored if irritability in youth is multifactorial and the impact of irritability dimensions on psychopathology outcomes in adulthood. METHODS: We conducted exploratory factor analysis on irritability symptom items from a semi-structured diagnostic interview administered to a community sample of adolescents (ages 14-19; 42.7% male; 89.1% white). The analysis identified two factors corresponding to items from the mood disorders v. the oppositional defiant disorder (ODD) (Leibenluft and Stoddard) sections of the interview. These factors were then entered together into regression models predicting psychopathology assessed at age 24 (N = 941) and again at age 30 (N = 816). All models controlled for concurrent psychopathology in youth. RESULTS: The two irritability dimensions demonstrated different patterns of prospective relationships, with items from the ODD section primarily predicting externalizing psychopathology, items from the mood disorder sections predicting depression at age 24 but not 30, and both dimensions predicting borderline personality disorder symptoms. CONCLUSIONS: These results suggest that the current standard of extracting and compositing irritability symptom items from diagnostic interviews masks distinct dimensions of irritability with different psychopathological outcomes. Additionally, these findings add nuance to the prevailing notion that irritability in youth is specifically linked to later internalizing problems. Further investigation using more sensitive and multifaceted measures of irritability are needed to parse the meaning and clinical implications of these dimensions.

Renal Papillary Rarefaction: An Artifact Mimicking Papillary Necrosis.

In histopathology, the presence of a tissue change that does not represent the tissue's normal appearance can often lead to an incorrect diagnosis and interpretation. These changes are collectively known as "artifacts" resulting from postmortem autolysis, improper fixation, problems with tissue handling or slide preparation procedures. Most tissue artifacts are obvious, yet some artifacts may be subtle, occur in relatively well-fixed tissue, and demand careful observation to avoid confusion with real biological lesions. The kidney often contains artifacts that may be observed throughout all regions of the renal parenchyma. Cortical tubule artifacts present the greatest challenge when discerning an artifact versus an induced lesion following exposure to a xenobiotic. However, confounding artifacts observed at the tip of the renal papilla may also be problematic for the pathologist. An uncommon artifact involving tinctorial alteration and rarefaction affecting the papillary tip of the rat kidney is described here and differentiated from treatment induced lesions of renal papillary necrosis.

Histology Atlas of the Developing Mouse Urinary System With Emphasis on Prenatal Days E10.5-E18.5.

Congenital abnormalities of the urinary tract are some of the most common human developmental abnormalities. Several genetically engineered mouse models have been developed to mimic these abnormalities and aim to better understand the molecular mechanisms of disease. This atlas has been developed as an aid to pathologists and other biomedical scientists for identification of abnormalities in the developing murine urinary tract by cataloguing normal structures at each stage of development. Hematoxylin and eosin- and immunohistochemical-stained sections are provided, with a focus on E10.5-E18.5, as well as a brief discussion of postnatal events in urinary tract development. A section on abnormalities in the development of the urinary tract is also provided, and molecular mechanisms are presented as supplementary material. Additionally, overviews of the 2 key processes of kidney development, branching morphogenesis and nephrogenesis, are provided to aid in the understanding of the complex organogenesis of the kidney. One of the key findings of this atlas is the histological identification of the ureteric bud at E10.5, as previous literature has provided conflicting reports on the initial point of budding. Furthermore, attention is paid to points where murine development is significantly distinct from human development, namely, in the cessation of nephrogenesis.

High x-ray resolving power utilizing asymmetric diffraction from a quartz transmission crystal measured in the 6 keV to 22 keV energy range.

A Cauchois-type spectrometer utilizing the (203) lattice planes at an oblique angle of 11.53° to the normal to the surface of a quartz transmission crystal recorded the Kα and Kß spectral lines of six elements from Fe to Ag in the 6-22 keV energy range from a laboratory x-ray source. After deconvolving the natural lifetime widths and the image plate detector broadening from the observed spectral linewidths, the intrinsic crystal resolving power was determined to be 4000 at the lower energies and decreasing to 1000 at the higher energies. Previously, a Si wafer crystal exhibited twice this resolving power when the (331) planes had been used in asymmetric geometry. The investigation of diffraction with this quartz crystal, with a very similar lattice spacing and therefore spectral coverage, was motivated by the larger integrated reflectivity of quartz due to its well-known quasimosaicity upon elastic bending. The measured spectral linewidths were in good agreement with the widths calculated by accounting for various broadening mechanisms, including source size, crystal thickness, crystal height, crystal rocking curve width, geometrical aberrations, and possible spectrometer configuration errors. This is the first, to the best of our knowledge, demonstration of high resolving power achieved by asymmetric diffraction over a wide energy range (6-22 keV) and with detailed comparisons with theoretical broadenings. Based on these results, Cauchois spectrometers employing asymmetric planes of perfect quartz and silicon crystals can be reliably designed and optimized for high-resolution spectroscopy in the >6 keV energy range.

Uterine Paramesonephric Cysts in Sprague-Dawley Rats from National Toxicology Program Studies.

Congenital uterine wall cysts arising from paramesonephric (Müllerian) and mesonephric (Wolffian) ducts are typically incidental findings in most species. We used immunohistochemistry to characterize and determine the origin of uterine cysts in Sprague-Dawley (SD) rats from multigeneration studies conducted by the National Toxicology Program. Subserosal uterine cysts were observed in 20 of the 2,400 SD rats evaluated in five studies, and 10 cysts were characterized for this study. Single cysts were unilocular, fluid-filled, and occurred throughout the uterus. Microscopically, all cysts had a well-developed smooth muscle wall, lined by flattened to cuboidal, sometimes ciliated, epithelium that stained intensely positive for cytokeratin 18 and paired box protein 8 (PAX8). Most cyst epithelia displayed weak to moderate positivity for progesterone receptor (PR) and/or estrogen receptor α (ER-α), as well as were negative for GATA binding protein 3 (GATA3). Cyst lumens contained basophilic flocculent material. The cysts appeared to be developmental anomalies arising from paramesonephric tissue based on positive PAX8 and ER-α and/or PR staining. Additionally, 70% of the cysts lacked GATA3 expression. Taken together, the subserosal uterine cysts observed in adult rats in these studies most likely arose from the paramesonephric duct.

High-efficiency echelle gratings for MIGHTI, the spatial heterodyne interferometers for the ICON mission.

Development of a new generation of low-groove density-blazed echelle gratings optimized for MIGHTI, a space-borne spatial heterodyne interferometer operating in the visible and near infrared is described. Special demands are placed on the wavefront accuracy, groove profile, and efficiency of these gratings. These demands required a new ruling for this application, with significant improvements over existing gratings. Properties of a new generation of highly efficient, plane gratings with 64 grooves/mm blazed at 8.2° are reported.

A brief review of kidney development, maturation, developmental abnormalities, and drug toxicity: juvenile animal relevancy.

Nonclinical juvenile animal tests perform a valuable role in determining adverse drug effects during periods of organogenesis and/or functional maturation. Developmental anatomic and functional maturation time points are important to consider between juveniles and adults when regarding different organ toxicities in response to drug administration. The kidney is an example of a major organ that has differences in these time points in comparing juveniles to adults and in contrasting humans to laboratory animal species. Toxicologic pathologists, involved in juvenile studies, need to be aware of these time points which are age-related exposure periods of sensitivity to drug toxicity. Age-related developmental anatomic and functional maturation are factors which can affect the way that a drug is absorbed, distributed, metabolized, and excreted (ADME). Changes to any component of ADME may alter drug toxicity resulting in kidney abnormalities, nephrotoxicity, or maturational disorders. Juvenile animal kidneys may either be less resistant or more resistant to known adult nephrotoxic drug effects. Furthermore, drug toxicity observed in juvenile animal kidneys may not always correspond to similar toxicities in humans. Juvenile animal nonclinical toxicology studies targeting the kidneys have to be carefully planned to attain the maximum knowledge from each study.

A Survey of Mesenchyme-related Tumors of the Rat Kidney in the National Toxicology Program Archives, with Particular Reference to Renal Mesenchymal Tumor.

In order to harmonize diagnostic terminology, confirm diagnostic criteria, and describe aspects of tumor biology characteristic of different tumor types, a total of 165 cases of mesenchyme-related tumors and nephroblastomas of the rat kidney were reexamined from the National Toxicology Program (NTP) Archives. This survey demonstrated that renal mesenchymal tumor (RMT) was the most common spontaneous nonepithelial tumor in the rat kidney, also occurring more frequently in the NTP studies than nephroblastoma. Renal sarcoma was a distinct but very rare tumor entity, representing a malignant, monomorphous population of densely crowded, fibroblast-like cells, in which, unlike RMT, preexisting tubules did not persist. Nephroblastoma was characterized by early death of affected animals, suggesting an embryonal origin for this tumor type. Male and female rats were equally disposed to developing RMT, but most of the cases of nephroblastoma occurred in female rats and liposarcoma occurred mostly in male rats. This survey confirmed discrete histopathological and biological differences between the mesenchyme-related renal tumor types and between RMT and nephroblastoma. Statistical analysis also demonstrated a lack of any relationship of these renal tumor types to test article administration in the NTP data bank.

Spontaneous Age-related Lesions of the Kidney Fornices in Sprague-Dawley Rats.

The upper portion of the rat kidney pelvis has specialized anatomic structures referred to as fornices. Fornices have a role in urine concentration. Spontaneous lesions including mineralization, epithelial hyperplasia, and inflammatory cell infiltration may occur in the area of the fornices. However, little information regarding specific historical control data or the spontaneous development of these findings in male and female fornices is known. Understanding spontaneous age-related lesions in the area of the fornices versus other portions of the kidney pelvis may be relevant in the identification of test article-induced changes. A retrospective study was conducted of male and female Sprague-Dawley rat kidney fornices over several time points to determine the incidence and severity of mineralization, epithelial hyperplasia, and inflammatory cell infiltration. Based on this investigation, these lesions appeared to increase over time and, in general, occurred earlier and with a greater incidence in females. Regarding those chemicals that may result in lesions of the kidney pelvis, it may be important for pathologists to separately diagnose lesions of the fornices from other portions of the kidney pelvis to help differentiate between any spontaneous age-related and induced changes.

Renal Tumors in 26-Week Tg.Rash2 Mice Carcinogenicity Studies.

We report renal tubular adenomas and a carcinoma in 26-week Tg.rasH2 mouse carcinogenicity studies, which have not been reported to date either at our facility or in other published data. However, during the year 2014, renal tubular tumors were present in 4 studies conducted at our facility. Because of their morphological similarity to the amphophilic-vacuolar (AV) phenotypic variant of renal tubule tumors noted in Sprague-Dawley and Fischer 344 rats, which are thought to be familial, as well as the genetic homogeneity of Tg.rasH2 mice, we tracked the parents of these mice with tumors in each study. The origin of these tumors could not be traced back to any of the parents or even an animal barrier, and these tumors were not attributed to the vehicle or test article. Although the exact mechanism of tumorigenesis was not known, based on the available information, the development of renal tumors in these mice was considered random and spontaneous.

Regulatory Forum Opinion Piece*: Dispelling Confusing Pathology Terminology: Recognition and Interpretation of Selected Rodent Renal Tubule Lesions.

Renal tubule lesions often prove troublesome for toxicologic pathologists because of the diverse nature and interrelated cell types within the kidney and the presence of spontaneous lesions with overlapping morphologies similar to those induced by renal toxicants. Although there are a number of guidance documents available citing straightforward diagnostic criteria of tubule lesions for the pathologist to refer to, most are presented without further advice on the when to or to the why and the why not of diagnosing one lesion over another. Documents presenting diagnostic perspectives and recommendations derived from an author's experience are limited since guidance documents are generally based on descriptive observations. In this Regulatory Forum opinion piece, the authors attempt to dispel confusing renal tubule lesion terminology in laboratory animal species by suggesting histological advice on the recognition and interpretation of these complex entities.

Ultra-thin curved transmission crystals for high resolving power (up to E/ΔE = 6300) x-ray spectroscopy in the 6-13 keV energy range.

Ultra-thin curved transmission crystals operating in the Cauchois spectrometer geometry were evaluated for the purpose of achieving high spectral resolution in the 6-13 keV x-ray energy range. The crystals were silicon (111) and sapphire R-cut wafers, each 18 µm thick, and a silicon (100) wafer of 50-µm thickness. The W Lα(1) spectral line at 8.398 keV from a laboratory source was used to evaluate the resolution. The highest crystal resolving power, E/ΔE=6300, was achieved by diffraction from the (33-1) planes of the Si(100) wafer that was cylindrically bent to a radius of curvature of 254 mm, where the (33-1) planes have an asymmetric angle of 13.26° from the normal of the crystal surface facing the x-ray source. This work demonstrates the ability to measure highly resolved line shapes of the K transitions of the elements Fe through Kr and the L transitions of the elements Gd through Th using a relatively compact spectrometer optical system and readily available thin commercial wafers. The intended application is as a diagnostic of laser-produced plasmas where the presence of multiple charged states and broadenings from high temperature and density requires high-resolution methods that are robust in a noisy source environment.

Spontaneous incidence of oncocytic proliferative lesions in control rat kidney.

The spontaneous incidence of foci of oncocytic proliferation (oncocytic hyperplasia and oncocytoma) was assessed in a histopathological reevaluation of the kidneys of 2,391 male and female Fischer 344 (F344) groups of control rats from long-term carcinogenicity studies (involving 24 chemicals) that had been conducted by the National Toxicology Program. The overall incidence of oncocytic proliferation was 0.3%, with a male preponderance over females at 0.5% (6/1,236) versus 0.09% (1/1,155), respectively. In males, there appeared to be an association of oncocytic proliferation with advanced spontaneous chronic progressive nephropathy. Oncocytoma or oncocytic hyperplasia appear to be rare lesions in F344 rats, and observations from these carcinogenicity studies suggest that they are slow growing and tend to occur late in a rodent's life span.

Evaluation of hydroxyatrazine in the endocrine disruptor screening and testing program's male and female pubertal protocols.

Two critical components of the validation of any in vivo screening assay are to demonstrate sensitivity and specificity. Although the Endocrine Disruptor Screening Program's Tier 1 Male and Female Pubertal Protocols have been shown to be sensitive assays for the detection of weak endocrine disrupting chemicals (EDCs), there are concerns that the assays lack specificity for EDC effects when a chemical induces systemic toxicity. A lack of specificity, or the ability to correctly identify an inactive or "negative" chemical, would increase the probability of identifying false positives. Here, we orally exposed rats to hydroxyatrazine (OH-ATR), a biotransformation by-product of the chlorotriazine herbicides that produced nephrotoxicity following a 13-week dietary exposure. Based on a previous study in our laboratory, males were dosed with 11.4 to 183.4 mg/kg OH-ATR and females were dosed with 45.75 to 183.4 mg/kg OH-ATR. Following exposure in both sexes, there was a dose-response increase in mean kidney weights and the incidence and severity of kidney lesions. These lesions included the deposition of mineralized renal tubule concretions, hydronephrosis, renal tubule dilatation, and pyelonephritis. However, no differences in body weight, liver weight, or reproductive tissue weights, reproductive or thyroid histology, hormone concentrations or the age of pubertal onset were observed. Therefore, the results demonstrate that the endpoints included in the pubertal assay are useful for nonendocrine (systemic) effects that define an no observable effect level (NOEL) or lowest observable effect level (LOEL) and provide one example where an impact on kidney function does not alter any of the endocrine-specific endpoints of the assay.

Association of advanced chronic progressive nephropathy (CPN) with renal tubule tumors and precursor hyperplasia in control F344 rats from two-year carcinogenicity studies.

From the archives of the National Toxicology Program, National Institutes of Health, kidney sections from twenty-four carcinogenicity studies (representing twenty-three chemicals) in male and female F344 rats were histopathologically re-evaluated to grade the severity of chronic progressive nephropathy (CPN) on an expanded scale of 0-8, and to record the presence of renal tubule tumors (RTT) and their precursor, atypical tubule hyperplasia (ATH). The data were statistically analyzed using SAS software for logistic regression analysis. This histopathological survey of 2,436 F344 rats showed clear evidence of a qualitative and statistically significant association between advanced stages of CPN severity and the development of low-grade RTT and ATH. Advanced CPN severity therefore represents a risk factor for the development of RTT and appears to be an underlying basis for spontaneous occurrence of RTT in the F344 rat. The difference in incidence and severity of CPN between the sexes also explains the 9:1 male-to-female sex difference in the spontaneous occurrence of ATH and RTT observed here. The regulatory significance of this finding is that chemicals exacerbating CPN as their only renal effect are likely to show a numerical increase in RTT with dose, which does not represent a direct tumorigenic effect of the chemical.

Proliferative and nonproliferative lesions of the rat and mouse urinary system.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in the urinary tract of rats and mice. The standardized nomenclature of urinary tract lesions presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as those induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for urinary tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Spontaneous renal tumors suspected of being familial in sprague-dawley rats.

Spontaneous renal tubule tumors (RTTs), with a distinctive morphological phenotype, were present in three Sprague-Dawley rats, 1 male and 2 females, out a total of 120 animals of each sex from untreated and placebo control groups in a 2-year carcinogenicity study. One female had one carcinoma, adenoma and hyperplasia, and the other female had five adenomas and many hyperplastic lesions; the male case had one carcinoma. From these cases, a biological continuum of hyperplasia, adenoma and carcinoma could be recognized. The tumors were present in the renal cortex and appeared as solid lobulated growths with occasional central necrosis. The lobules were divided by a small amount of fibrovascular tissue. Occasionally the larger tumors contained a cystic area. Tumor cells appeared distinctive and exhibited variable amounts of eosinophilic/amphophilic and vacuolated cytoplasm. Nuclei were round to oval with a prominent nucleolus. Mitotic figures were uncommon, and no distant metastasis was noted. The tumors were seen as multiple and bilateral lesions in two animals and had no apparent relationship to chronic progressive nephropathy (CPN). Foci of tubule hyperplasia were also noted to contain the same type of cellular morphology. The morphological and biological features of these 3 cases resembled the amphophilic-vacuolar (AV) variant of RTT that has been posited to be of familial origin. This is a report of spontaneous familial renal tumors in Sprague-Dawley rats from Japan.

Hard x-ray spectrometer calibrations using a portable 120 kV x-ray source.

A Cauchois transmission-crystal hard x-ray spectrometer was calibrated by using a portable, compact, battery-powered tungsten x-ray source having 120 peak kilovoltage. The source emission region was characterized by recording high-resolution 2D x-ray images and was found to be composed of three emission regions having a 400 µm overall extent. The absolutely calibrated source fluence was measured by using a calibrated silicon drift detector and was in good agreement with the spectrum calculated by the SpekPy code. High-resolution spectra of the W Kα and Kß lines in the 57-70 keV energy range were recorded on image plate detectors by the Cauchois spectrometer and provided excellent calibrations of the spectrometer's dispersion and spectral resolution. The minimal effect of the source size in the spectral lines recorded on the spectrometer's Rowland circle and the source-size broadening of the spatial lines recorded well beyond the Rowland circle were analyzed. The integrated reflectivity of the spectrometer's quartz (101) crystal was measured by using the absolutely calibrated 59.318 keV W Kα1 spectral line emission and was in agreement with previous integrated reflectivity measurements performed at the National Institute of Standards and Technology. The well-characterized portable 120 kV x-ray source provides a convenient and cost-effective way to accurately calibrate the sensitivity, dispersion, spectral resolution, and source-size broadening in the spectra recorded by high-resolution x-ray spectrometers operating in the hard x-ray range. The absolutely calibrated source fluence can also be used to calibrate x-ray detectors at energies in the 40-100 keV energy range.

Crystal response measurement of the x-ray transmission crystals used by the Imaging Spectroscopy Snout at the National Ignition Facility.

The Imaging Spectroscopy Snout (ISS) used at the National Ignition Facility is able to simultaneously collect neutron pinhole images, 1D spatially resolved x-ray spectra, and time resolved x-ray pinhole images. To measure the x-ray spectra, the ISS can be equipped with up to four different transmission crystals, each offering different energy ranges from ∼7.5 to ∼12 keV and different resolutions. Characterizing and calibrating such instruments is of paramount importance in order to extract meaningful results from experiments. More specifically, we characterized different ISS transmission-type alpha-Quartz crystals by measuring their responses as a function of photon energy, from which we inferred the angle-integrated reflectivity for each crystal's working reflections. These measurements were made at the Lawrence Livermore National Laboratory calibration station dedicated to the characterization of x-ray spectrometers. The sources used covered a wide x-ray range-from a few to 30 keV; the source diameter was ∼0.6 mm. The experimental results are discussed alongside theoretical calculations using the pyTTE model.

Efficiency calibrations of cylindrically bent transmission crystals in the 20 to 80 keV x-ray energy range.

Two quartz (10-11) crystals were cylindrically bent to a 25.4 cm radius of curvature and were mounted in identical Cauchois-type transmission spectrometers, and the crystal diffraction efficiencies were measured to 5% absolute accuracy using narrow bandwidth x-ray source fluences in the 20 to 80 keV energy range. The measured integrated reflectivity values were compared to calculations performed using a computational model that accounts for the diffraction geometry of the bent transmission crystal. These crystal calibrations enable the accurate measurement of absolute hard x-ray emission levels from laser-produced plasmas and other laboratory sources.