Pain is a complex constellation of cognitive, unpleasant sensory, and emotional experiences that primarily serves as a survival mechanism. Pain arises in the peripheral nervous system and pain signals synapse with nerve tracts extending into the central nervous system. Several different schemes are used to classify pain, including the underlying mechanism, tissues primarily affected, and time-course. Numerous animal models of pain, which should be employed with appropriate Institutional Animal Care and Use approvals, have been developed to elucidate pathophysiology mechanisms and aid in identification of novel therapeutic targets. The variety of available models underscores the observations that pain phenotypes are driven by several distinct mechanisms. Pain outcome measurement encompasses both reflexive (responses to heat, cold, mechanical and electrical stimuli) and nonreflexive (spontaneous pain responses to stimuli) behaviors. However, the question of translatability to human pain conditions and potential treatment outcomes remains a topic of continued scrutiny. In this review we discuss the different types of pain and their mechanisms and pathways, available rodent pain models with an emphasis on type of pain stimulations and pain outcome measures and discuss the role of pathologists in assessing and validating pain models.

Calcitonin gene-related peptide (CGRP) and its receptor have been implicated as a key mediator in the pathophysiology of migraine. Thus, erenumab, a monoclonal antibody antagonist of the CGRP receptor, administered as a once monthly dose of 70 or 140 mg has been approved for the preventive treatment of migraine in adults. Due to the species specificity of erenumab, the cynomolgus monkey was used in the pharmacology, pharmacokinetics, and toxicology studies to support the clinical program. There were no effects of erenumab on platelets in vitro (by binding, activation or phagocytosis assays). Specific staining of human tissues with erenumab did not indicated any off-target binding. There were no erenumab-related findings in a cardiovascular safety pharmacology study in cynomolgus monkeys or in vitro in human isolated coronary arteries. Repeat-dose toxicology studies conducted in cynomolgus monkeys at dose levels up to 225 mg/kg (1 month) or up to 150 mg/kg (up to 6 months) with twice weekly subcutaneous (SC) doses showed no evidence of erenumab-mediated adverse toxicity. There were no effects on pregnancy, embryo-fetal or postnatal growth and development in an enhanced pre-postnatal development study in the cynomolgus monkey. There was evidence of placental transfer of erenumab based on measurable serum concentrations in the infants up to 3 months post birth. The maternal and developmental no-observed-effect level (NOEL) was the highest dose tested (50 mg/kg SC Q2W). These nonclinical data in total indicate no safety signal of concern to date and provide adequate margins of exposure between the observed safe doses in animals and clinical dose levels.

Sustained elevation of parathyroid hormone (PTH) is catabolic to cortical bone, as evidenced by deterioration in bone structure (cortical porosity), and is a major factor for increased fracture risk in chronic kidney disease (CKD). Etelcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces PTH levels in subtotal nephrectomized (Nx) rats and in hemodialysis patients with secondary hyperparathyroidism (SHPT) in clinical studies; however, effects of etelcalcetide on bone have not been determined. In a rat model of established SHPT with renal osteodystrophy, etelcalcetide or vehicle was administered by subcutaneous (s.c.) injection to subtotal Nx rats with elevated PTH (>750pg/mL) once per day for 6weeks. Sham-operated rats receiving vehicle (s.c.) served as non-SHPT controls. Prior to treatment, significant increases in serum creatinine (2-fold), blood urea nitrogen (BUN, 3-fold), PTH (5-fold), fibroblast growth factor-23 (FGF23; 13-fold) and osteocalcin (12-fold) were observed in SHPT rats compared to non-SHPT controls. Elevations in serum creatinine and BUN were unaffected by treatment with vehicle or etelcalcetide. In contrast, etelcalcetide significantly decreased PTH, FGF23 and osteocalcin, whereas vehicle treatment did not. Cortical bone porosity increased and bone strength decreased in vehicle-treated SHPT rats compared to non-SHPT controls. Cortical bone structure improved and energy to failure was significantly greater in SHPT rats treated with etelcalcetide compared to vehicle. Mineralization lag time and marrow fibrosis were significantly reduced by etelcalcetide. In conclusion, etelcalcetide reduced bone turnover, attenuated mineralization defect and marrow fibrosis, and preserved cortical bone structure and bone strength by lowering PTH in subtotal Nx rats with established SHPT.

Etelcalcetide, a novel peptide agonist of the calcium-sensing receptor, prevents vascular calcification in a rat model of renal insufficiency with secondary hyperparathyroidism. Vascular calcification occurs frequently in patients with chronic kidney disease (CKD) and is a consequence of impaired mineral homeostasis and secondary hyperparathyroidism (SHPT). Etelcalcetide substantially lowers parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) levels in SHPT patients on hemodialysis. This study compared the effects of etelcalcetide and paricalcitol on vascular calcification in rats with adenine-induced CKD and SHPT. Uremia and SHPT were induced in male Wistar rats fed a diet supplemented with 0.75% adenine for 4 weeks. Rats were injected with vehicle, etelcalcetide, or paricalcitol for 4 weeks from the beginning of adenine diet. Rats fed an adenine-free diet were included as nonuremic controls. Similar reductions in plasma PTH and parathyroid chief cell proliferation were observed in both etelcalcetide- and paricalcitol-treated rats. Serum calcium and phosphorus were significantly lower in etelcalcetide-treated uremic rats and was unchanged in paricalcitol-treated rats. Both serum FGF23 and aortic calcium content were significantly lower in etelcalcetide-treated uremic rats compared with either vehicle- or paricalcitol-treated uremic rats. The degree of aortic calcium content for etelcalcetide-treated rats was similar to that in nonuremic controls and corroborated findings of lack of histologic aortic mineralization in those groups. In conclusion, etelcalcetide and paricalcitol similarly attenuated progression of SHPT in an adenine rat model of CKD. However, etelcalcetide differentially prevented vascular calcification, at least in part, due to reductions in serum FGF23, calcium, and phosphorus levels.

Etelcalcetide is a novel d-amino acid peptide that functions as an allosteric activator of the calcium-sensing receptor and is being developed as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on hemodialysis. To support clinical development and marketing authorization, a comprehensive nonclinical safety package was generated. Primary adverse effects included hypocalcemia, tremoring, and convulsions. Other adverse effects were considered sequelae of stress associated with hypocalcemia. Cardiovascular safety evaluations in the dog revealed an anticipated prolongation of the corrected QT interval that was related to reductions in serum calcium. Etelcalcetide did not affect the human ether-a-go-go gene ion channel current. Etelcalcetide was mutagenic in some strains of Salmonella, however, based on the negative results in 2 in vitro and 2 in vivo mammalian genotoxicity assays, including a 28-day Muta mouse study, etelcalcetide is considered nongenotoxic. Further support for a lack of genotoxicity was provided due to the fact that etelcalcetide was not carcinogenic in a 6-month transgenic rasH2 mouse model or a 2-year study in rats. There were no effects on fertility, embryo-fetal development, and prenatal and postnatal development. All of the adverse effects observed in both rat and dog were considered directly or secondarily related to the pharmacologic activity of etelcalcetide and the expected sequelae associated with dose-related reductions in serum calcium due to suppression of parathyroid hormone secretion. These nonclinical data indicate no safety signal of concern for human risk beyond that associated with hypocalcemia and associated QT prolongation.

This article reviews the regulatory guidelines that provide for the inclusion of recovery groups in toxicology studies, presents the challenges in the design and interpretation of nonclinical recovery studies, and summarizes the best practices for the role of an anatomic pathologist regarding toxicology studies with recovery groups. Evaluating the potential recovery of histopathologic findings induced by a biopharmaceutical requires the active participation of one or more anatomic pathologists. Their expertise is critical in risk assessment regarding the potential for recovery as well as providing scientific guidance in the design and evaluation of studies with recovery groups.

γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aβ42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aβ42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described.

Psoriasis is a common immune-mediated disease in European populations; it is characterized by inflammation and altered epidermal differentiation leading to redness and scaling. T cells are thought to be the main driver, but there is also evidence for an epidermal contribution. In this article, we show that treatment of mouse skin overexpressing the IL-1 family member, IL-1F6, with phorbol ester leads to an inflammatory condition with macroscopic and histological similarities to human psoriasis. Inflammatory cytokines thought to be important in psoriasis, such as TNF-α, IL-17A, and IL-23, are upregulated in the mouse skin. These cytokines are induced by and can induce IL-1F6 and related IL-1 family cytokines. Inhibition of TNF or IL-23 inhibits the increased epidermal thickness, inflammation, and cytokine production. Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice. These data suggest a role for IL-1F family members in psoriasis.

Abstract Radiometric soundings from the Wave Propagation Laboratory's ground-based Profiler, the NOAA 6/7 satellites, and the combination of the two, were compared in their ability to derive temperature and moisture profiles. Radiosonde data for the period December 1981-December 1982, taken by the National Weather Service at Stapleton International Airport, Denver, Colorado, were used as “ground-truth” for the comparison; in all, 460 soundings were analyzed. The set of soundings contained 216 clear, 173 partly cloudy and 71 cloudy cases. Comparisons show that Profiler retrievals were more accurate than those of the satellite in the lowest 500 mb of the atmosphere, with the converse being true above that level. The combined temperature retrievals were more accurate, in the rms sense, than either of the separate retrievals at every level from the surface to 10 mb. Below 50 mb, the maximum rms difference of the combined system from radiosondes was 2.7 K; below 300 mb, it was 2.0 K. Geopotential heights and p...

The receptor-interacting protein (RIP) family kinase RIP4 interacts with protein kinase C (PKC) isoforms and is implicated in PKC-dependent signaling pathways. RIP4−/− mice die at birth with epidermal differentiation defects, causing fusions of all external orifices and loss of the esophageal lumen. To further understand RIP4 function in the skin, we generated transgenic mice with epidermal-specific expression of RIP4 using the human keratin-14 promoter (K14-RIP4). The K14-RIP4 transgene rescued the epidermal phenotype of RIP4−/− mice, showing that RIP4 acts autonomously in the epidermis to regulate differentiation. Although RIP4−/− mice share many phenotypic similarities with inhibitor κB kinase (IKK)α−/− mice and stratifin repeated epilation (SfnEr/Er) mice, the K14-RIP4 transgene failed to promote epidermal differentiation in these mutant backgrounds. Unexpectedly, topical treatment of K14-RIP4 mice with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced dramatic, neutrophilic inflammation, an effect that was independent of tumor necrosis factor type 1 receptor (TNFR1/p55) function. Despite their enhanced sensitivity to TPA, K14-RIP4 mice did not have an altered frequency of tumor formation in TPA-promoted skin cancer initiated with 7,12-dimethylbenz[a]anthracene (DMBA). These data suggest that RIP4 functions in the epidermis through PKC-specific signaling pathways to regulate differentiation and inflammation.

A study of the improvement in cloud-masking capability of data from a Moderate Resolution Imaging Spectroradiometer (MODIS) relative to data from an Advanced Very High Resolution Radiometer (AVHRR) is performed. MODIS offers significant advances over AVHRR in spatial resolution and spectral information. Three MODIS scenes that present a range of cloudiness, surface type, and illumination conditions are analyzed. AVHRR local area coverage (LAC) and global area coverage (GAC) data were synthesized from the most spectrally comparable MODIS channels. This study explores the benefits to cloud masking offered by MODIS beyond that offered by AVHRR. No global generalization can be inferred from this limited analysis, but this study does attempt to quantify the added benefit of MODIS over AVHRR for three scenes. The sole focus is on the levels of cloud contamination in clear AVHRR pixels; the misclassification of clear pixels as cloudy is not addressed. For the scenes studied, the results of the additional MODIS tests revealed measurable residual cloud contamination in both AVHRR LAC and GAC clear pixels. From this analysis, the contamination of the clear pixels in AVHRR LAC data was between 1% and 3% for the cases studied. The levels of contamination of the clear GAC pixels revealed by MODIS cloud tests ranged from 2% to 4%. MODIS was able to reveal roughly 2% more cloud contamination of clear GAC pixels than was revealed by LAC. This result indicates that the increase in spatial resolution offered by MODIS may be as significant to reducing cloud contamination as is the increase in spectral information. Inclusion of the results of AVHRR spatial uniformity tests applied to MODIS or LAC pixels revealed potentially much more cloud contamination of clear GAC pixels. The larger values of potential cloud contamination revealed by spatial uniformity tests were not apparent in the clear-sky products.An analysis of the derived SST, land surface temperature (LST), and normalized difference vegetation index (NDVI) fields was conducted to explore the impact of the MODIS-inferred cloud contamination on these products. The results indicated minimal effects on the distribution of SST, LST, and NDVI derived from AVHRR LAC data. Errors in the GAC SST and LST had standard deviations of 0.1 and 0.3 K, respectively. The GAC NDVI error distribution has a standard deviation of 0.03 for all scenes. The GAC error distributions showed little bias, indicating that cloud-masking differences between the AVHRR and MODIS should not introduce a discontinuity in the AVHRR/MODIS/Visible Infrared Imaging Radiometer Suite (VIIRS) SST and NDVI data records.

During the 1990s, the United States experienced a rise in the popularity of nocturnal juvenile curfews as a method of crime prevention. Prior research has not, however, found curfews to be particularly effective in achieving their goals, and concerns have been raised about discriminatory enforcement. In this article we examine the implementation of a juvenile curfew in a large southern city, Charlotte, North Carolina, and investigate its impact on different racial groups. The background characteristics of curfew violators were found to mirror those of juvenile offenders in general, and different types of violators were cited in different areas of town. However, although the curfew had a positive or at least a neutral effect on some offenders, it had an escalation effect on Asian and Hispanic youth. The policy implications of the findings are discussed.

Offending specialization has received considerable attention in past research on criminal careers. Relatively little attention has been given to examining the relationships between various sub-group differences and the extent to which individuals tend toward specialization or versatility in their criminal careers. In the present analysis, we examine hypotheses derived from Moffitt's recent developmental theory that bear directly on offending specialization. Our analysis examines direct relationships between gender, onset age, persistence and offending specialization as well as the interaction of these influences and offending specialization. Our findings reveal results that are both consistent and inconsistent with Moffitt's dual taxonomy of offending behavior.

For both public policy and theoretical reasons, criminologists have been interested in the degree to which criminal offenders specialize in particular crimes. Traditionally, offense specialization has been measured with the forward specialization coefficient (FSC). Recently, the FSC has been criticized for being interpretationally obtuse and having no known sampling distribution. In this paper we examine both the interpretational and the statistical properties of the FSC. We conclude that (1) it has an intuitive interpretation that is no less useful than either a standard correlation coefficient or its competitors, (2) its sampling distribution is approximately normal, and (3) the conventional formula for the estimated standard error of the FSC may underestimate the true standard error in some circumstances. With these results behind us, we propose and illustrate both a parametric statistical test for the difference between two independent FSCs and two nonparametric alternatives.

A number of criminological theories make either implicit or explicit predictions about the empirical relationship between prior and future offending behavior. Some argue that time-stable characteristics such as criminal propensity should account for any positive correlation between past and future criminal behavior for all individuals. Others contend that the positive association between offending behavior at different points in time are partly causal and partly spurious. Still others anticipate that different patterns will emerge for different groups (distinguished by their ciminal propensity) of individuals. Using a longitudinal data set comprised of 848 training school releasees, we test various hypotheses emanating from these different theoretical perspectives. The results indicate that (1) both stability and change have causal implications for one's offending behavior and (2) with but one exception, these effects do not vary between high and low criminal propensity groups.

Disposition data were collected in ten counties to examine overrepresentation in the North Carolina justice system of juveniles from minority racial groups. The analysis proceeded in two phases. The first phase examined whether minority juveniles were at greater risk of adjudication than their white counterparts, The second phase assessed the probability of confinement in a Division of Youth Services training school facility by race. In both instances, offender characteristics such as gender, age, type of offense, and prior official offending record were held constant. In the commitment analysis, an array of other control variables were available for study as well. Four primary findings emerged: 1) About half of the juveniles referred to intake were African-American, although African-Americans only comprised about one-fourth of the juvenile population in the community; 2) The racial distribution of those juveniles who were adjudicated was similar to the racial distribution of those juveniles who were referred to intake; 3) African-Americans made up about two-thirds of the population of juveniles who were committed even though they comprised less than half of the population of those referred to intake and those who were actually adjudicated; 4) The use of control variables had little effect on these results and the conclusions described above were relatively stable across the various counties included in the study.

The contribution of domestic violence calls to the danger of police work has been a matter of major concern to police, policy makers, and researchers for decades. Building on prior research, the authors examine three years of data on police calls for service, assault, and injury to determine the danger of domestic violence in relation to other types of calls. Of the 10 categories of police activity examined, domestic disturbance ranked fourth in the ratio of assaults to calls for service and fifth in the ratio of injuries to calls for service. No significant differences were observed in the background characteristics of victims and offenders in domestic disturbance and other incidents. Consequently it was recommended that policies to enhance officers' safety be directed mainly at handling incidents in general rather than being geared specifically to responding to domestic disturbances.