Hand Infections in End-Stage Renal Disease-Consider Tumoral Calcinosis.

Tumoral calcinosis (TC) is a rare condition defined by the accumulation of calcium salts in soft tissues surrounding joints, most commonly large joints. Chronic joint inflammation in the setting of local hyperphosphatemia leads to interruption and dysfunction of tissue repair and generates breakdown products that subsequently calcify and accumulate. We present a case of a 42-year-old man with a history of end-stage renal disease on dialysis presenting to the clinic with a painless digital mass of his right long finger at the proximal interphalangeal joint. Our initial impression was a splinter abscess based on presentation and patient history. Although our patient's presentation of traumatic, painless TC of the hand secondary to end-stage renal disease is rare, the pathogenic mechanisms behind TC support this presentation. The authors recommend including TC within the differential of presentations similar to that of chronic abscess or giant cell tumor, especially when their medical history includes end-stage renal disease.

Surgical Management of Iatrogenic Mercury Poisoning From Subcutaneous Injection Into the Arm.

BACKGROUND: Mercury, an element with threats of severe toxic insult to humans and no biological function, has a surprisingly extensive record of human exposure. Regardless of hesitancies toward its harmfulness, it has been historically identified with an almost supernatural power to provide protection from evil and sickness, give good fortune, lend aid in athletic undertakings, or even allow one to achieve immortality. Mercury poisoning is an iatrogenic disease even today as people attempt to achieve these effects through volitional injections into their body by practitioners. Although an uncommon practice in the United States, awareness of patient presentation after volitional injections of elemental mercury is necessary for appropriate treatment of these patients. We aim to increase awareness of the cultural practice of subcutaneous injections of mercury, as it is uncommonly seen in the United States, to contribute a broader understanding to the patient's medical presentation and describe an approach and the impact of medical and surgical intervention. METHODS: In this report, we describe a rare case of elemental mercury poisoning secondary to volitional subcutaneous injection to the arm. Initial management of care through chelation therapy and monitoring of renal and serum mercury levels in addition to symptoms of systemic spread was overseen by an internal medicine physician and poison control. Surgical intervention via full-thickness excision of the visible mercury to the right arm followed by local flap and skin grafting reconstruction was performed. CONCLUSIONS: Mercury poisoning from intentional subcutaneous administration is an uncommon patient presentation in the United States; however, knowledge of management of this rare condition is important for effective management of iatrogenic mercury toxicity.

Implementation of an Enhanced Recovery After Surgery Protocol for Cranial Vault Remodeling Procedures.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been implemented across surgical disciplines, including cranial vault remodeling for craniosynostosis. The authors aim to describe the implementation of an ERAS protocol for cranial vault remodeling procedures performed for patients with craniosynostosis at a tertiary care hospital. DESCRIPTION: Institutional review board approval was received. All patients undergoing a cranial remodeling procedure for craniosynostosis at the authors' institution over a 10-year period were collected (n = 168). Patient and craniosynostosis demographics were collected as well as operative details. Primary outcome measures were intensive care unit length of stay (ICU LOS) and narcotic usage. Chi squared and independent t-tests were employed to determine significance. A significance value of 0.05 was utilized. RESULTS: During the time examined, there were 168 primary cranial vault remodeling procedures performed at the authors' institution - all of which were included in the analysis. Use of the ERAS protocol was associated with decreased initial 24-hour morphine equivalent usage (p < 0.01) and decreased total morphine equivalent usage (p < 0.01). Patients using the ERAS protocol experienced a shorter ICU LOS (p < 0.01), but the total hospital length of stay was unchanged. CONCLUSION: This study reiterates the benefit of developing and implementing an ERAS protocol for patients undergoing cranial vault remodeling procedures. The protocol resulted in an overall decreased ICU LOS and a decrease in narcotic use. This has implications for ways to maximize hospital reimbursement for these procedures, as well as potentially improve outcomes.

Subacute Ulnar Nerve Compression Neuropathy Following Hand Crush Injury in the Setting of Intracanal Accessory Abductor Digiti Minimi: A Double Crush Phenomenon.

Anatomical variations within Guyon's canal such as an accessory abductor digiti minimi are described as causes of ulnar nerve compression. Here we present a unique case of delayed ulnar neuropathy following treatment of left fourth metacarpal base fracture with percutaneous pinning fixation and an uncomplicated two month postoperative course. He returned with new ulnar sensory loss and motor weakness. EMG demonstrated nerve compression with CT identifying an accessory abductor digiti minimi in Guyon's canal. Following Guyon's canal release with partial accessory muscle resection, there was immediate sensory and progressive motor recovery with resolution of clawing. Delayed compression by an accessory abductor digiti minimi following trauma has not been described, suggestive of double-crush phenomenon. The accessory muscle was an asymptomatic variable (first "crush") and with the second "crush" of post-surgical changes resulting in pathological nerve compression. With delayed onset ulnar neuropathy after trauma, surgeons should consider possible accessory structures.

A Dual-Functioning 5'-PPP-NS1shRNA that Activates a RIG-I Antiviral Pathway and Suppresses Influenza NS1.

Retinoic acid-inducible gene-I (RIG-I) is a cytosolic pathogen sensor that is crucial against a number of viral infections. Many viruses have evolved to inhibit pathogen sensors to suppress host innate immune responses. In the case of influenza, nonstructural protein 1 (NS1) suppresses RIG-I function, leading to viral replication, morbidity, and mortality. We show that silencing NS1 with in-vitro-transcribed 5'-triphosphate containing NS1 short hairpin RNA (shRNA) (5'-PPP-NS1shRNA), designed using the conserved region of a number of influenza viruses, not only prevented NS1 expression but also induced RIG-I activation and type I interferon (IFN) expression, resulting in an antiviral state leading to inhibition of influenza virus replication in vitro. In addition, administration of 5'-PPP-NS1shRNA in prophylactic and therapeutic settings resulted in significant inhibition of viral replication following viral challenge in vivo in mice with corresponding increases of RIG-I, IFN-ß, and IFN-λ, as well as a decrease in NS1 expression.

Neurogranin regulates sensorimotor gating through cortico-striatal circuitry.

Glutamate dysregulation is known to contribute to many psychiatric disorders including schizophrenia. Aberrant cortico-striatal activity and therefore glutamate levels might be relevant to this disease characterized by reduced prepulse inhibition (PPI), however, the molecular and behavioral mechanism of the pathophysiology of schizophrenia remains unclear. The focus of this study was to contribute to the current understanding of the glutamate and neurogranin (Ng) pathway, in relation to the cortico-striatal pathology of schizophrenia using a mouse model. A variant of the Ng gene has been detected in people with schizophrenia, implicating maladaptation of cortical glutamate signaling and sensorimotor gating. To test Ng-mediated PPI regulation in the mouse model, we utilized Ng null mice, viral-mediated Ng expression, and genetics approaches. Our results demonstrate that lack of Ng in mice decreases PPI. Ng over-expression in the prefrontal cortex (PFC) increases PPI, while Ng expression in either the nucleus accumbens (NAc) or hippocampus induces no change in PPI. Using optogenetics and chemogenetics, we identified that cortico-striatal activation is involved in PPI regulation. Finally, pharmacological regulation of Ng using glutamate receptor inhibitors demonstrated altered PPI between genotypes. In this study, we have investigated the impact of Ng expression on sensorimotor gating. This study contributes to a better understanding of the glutamatergic theory of schizophrenia, opening novel therapeutic avenues that may lead to glutamatergic treatments to ameliorate the symptoms of schizophrenia.

Neurogranin in the nucleus accumbens regulates NMDA receptor tolerance and motivation for ethanol seeking.

Dysfunction of N-methyl-d-aspartate receptor (NMDAR) signaling in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng), a calmodulin-binding protein, is exclusively expressed in the post-synapse, and mediates NMDAR driven synaptic plasticity by regulating the calcium-calmodulin (Ca2+-CaM) pathway. To study the functional role of Ng in AUD, we administrated behavior tests including Pavlovian instrument transfer (PIT), operant conditioning, and rotarod test using Ng null mice (Ng-/- mice). We used adeno-associated virus (AAV)-mediated Ng expression and pharmacological manipulation to validate behavioral responses in Ng-/- mice. The results from our multidisciplinary approaches demonstrated that deficit of Ng increases tolerance to NMDAR inhibition and elicit faster cue reactivity during PIT without changes in ethanol reward. Operant conditioning results demonstrated that Ng-/- mice self-administered significantly more ethanol and displayed reduced sensitivity to aversive motivation. We identified that ethanol exposure decreases mGluR5 (metabotropic glutamate receptor 5) expression in the NAc of Ng-/- mice and pharmacological inhibition of mGluR5 reverses NMDAR desensitization in Ng-/- mice. Together these findings specifically suggest that accumbal Ng plays an essential role in the counterbalance between NMDAR and mGluR5 signaling; which alters NMDAR resistance, and thereby altering aversive motivation for ethanol and may ultimately contribute to susceptibility for alcohol addiction.

Progressive Renal Disease Established by Renin-Coding Adeno-Associated Virus-Driven Hypertension in Diverse Diabetic Models.

Progress in research and developing therapeutics to prevent diabetic kidney disease (DKD) is limited by a lack of animal models exhibiting progressive kidney disease. Chronic hypertension, a driving factor of disease progression in human patients, is lacking in most available models of diabetes. We hypothesized that superimposition of hypertension on diabetic mouse models would accelerate DKD. To test this possibility, we induced persistent hypertension in three mouse models of type 1 diabetes and two models of type 2 diabetes by adeno-associated virus delivery of renin (ReninAAV). Compared with LacZAAV-treated counterparts, ReninAAV-treated type 1 diabetic Akita/129 mice exhibited a substantial increase in albumin-to-creatinine ratio (ACR) and serum creatinine level and more severe renal lesions. In type 2 models of diabetes (C57BKLS db/db and BTBR ob/ob mice), compared with LacZAAV, ReninAAV induced significant elevations in ACR and increased the incidence and severity of histopathologic findings, with increased serum creatinine detected only in the ReninAAV-treated db/db mice. The uninephrectomized ReninAAV db/db model was the most progressive model examined and further characterized. In this model, separate treatment of hyperglycemia with rosiglitazone or hypertension with lisinopril partially reduced ACR, consistent with independent contributions of these disorders to renal disease. Microarray analysis and comparison with human DKD showed common pathways affected in human disease and this model. These results identify novel models of progressive DKD that provide researchers with a facile and reliable method to study disease pathogenesis and support the development of therapeutics.

High beam headlamp use rates: Effects of rurality, proximity of other traffic, and roadway curvature.

OBJECTIVE: The few observational studies of the prevalence of high beam use indicate the rate of high beam use is about 25% when vehicles are isolated from other vehicles on unlit roads. Recent studies were limited to 2-lane rural roads and used measurement methods that likely overestimated use. The current study examined factors associated with the rate of high beam use of isolated vehicles on a variety of roadways in the Ann Arbor, Michigan area. METHODS: Twenty observation sites were categorized as urban, rural, or on a rural/urban boundary and selected to estimate the effects of street lighting, road curvature, and direction of travel relative to the city on high beam use. Sites were selected in pairs so that a majority of traffic passing one site also passed through the other. Measurement of high beams relied on video data recorded for 2 nights at each site, and the video data also were used to derive a precise measure of the proximity of other traffic. Nearly 3,200 isolated vehicles (10 s or longer from other vehicles) were observed, representing 1,500-plus vehicle pairs. RESULTS: Across the sample, 18% of the vehicles used high beams. Seventy-three percent of the 1,500-plus vehicle pairs used low beams at each paired site, whereas 9% used high beams at both sites. Vehicles at rural sites and sites at the boundaries of Ann Arbor were more likely to use high beams than vehicles at urban sites, but use in rural areas compared with rural/urban boundary areas did not vary significantly. Rates at all sites were much lower than expected, ranging from 0.9 to 52.9%. High beam use generally increased with greater time between subject vehicles and leading vehicles and vehicles in the opposing lane. There were mixed findings associated with street lighting, road curvature, and direction of travel relative to the city. CONCLUSION: Maximizing visibility available to drivers from headlights includes addressing the substantial underuse of high beam headlamps. Advanced technologies such as high beam assist, which switches automatically between high and low beam headlamps depending on the presence of other traffic, can help to address this problem.

Role of TGF-alpha in the progression of diabetic kidney disease.

Transforming growth factor-alpha (TGFA) has been shown to play a role in experimental chronic kidney disease associated with nephron reduction, while its role in diabetic kidney disease (DKD) is unknown. We show here that intrarenal TGFA mRNA expression, as well as urine and serum TGFA, are increased in human DKD. We used a TGFA neutralizing antibody to determine the role of TGFA in two models of renal disease, the remnant surgical reduction model and the uninephrectomized (uniNx) db/db DKD model. In addition, the contribution of TGFA to DKD progression was examined using an adeno-associated virus approach to increase circulating TGFA in experimental DKD. In vivo blockade of TGFA attenuated kidney disease progression in both nondiabetic 129S6 nephron reduction and Type 2 diabetic uniNx db/db models, whereas overexpression of TGFA in uniNx db/db model accelerated renal disease. Therapeutic activity of the TGFA antibody was enhanced with renin angiotensin system inhibition with further improvement in renal parameters. These findings suggest a pathologic contribution of TGFA in DKD and support the possibility that therapeutic administration of neutralizing antibodies could provide a novel treatment for the disease.

Characteristics of turn signal use at intersections in baseline naturalistic driving.

The purpose of this study was to determine whether a driver's use of turn signals is sufficiently reliable to forecast a vehicle's future path around an intersection, when detailed information about the intersection is unavailable. Naturalistic observations of turn signal use among 108 drivers on surface streets were extracted from the baseline portion of a field operational test of a safety system. Left and right turns that resulted in heading changes of between 70 and 110° and turn radii between 18 and 90 m were selected from the dataset. The odds that a driver would signal a turn were modeled as a function of road type, turn direction, presence of a forward vehicle, whether the vehicle stopped before the turn, and driver age and gender. Overall, 25 percent of left turns and 29 percent of right turns were not signaled. Road type, turn direction, and presence of a forward vehicle were found to influence the odds that a turn is signaled, while gender and age of the driver did not. The results suggest that situational factors like road type and turn direction are more powerful predictors of whether a turn will be signaled than either age or gender. Signaling on major and minor surface roads was about 5 times more likely than on local roads and 1.5 times more likely when a forward vehicle was present, suggesting a possible effect of traffic volume. It was concluded that turn signal activation alone may be insufficiently reliable to forecast a driver's path.

Biomarkers of exocrine pancreatic injury in 2 rat acute pancreatitis models.

UNLABELLED: Consistent, sensitive biomarkers of exocrine pancreatic injury (EPIJ) in animal models and humans have historically represented a poorly met need for investigators and clinicians. EXPERIMENTAL DESIGN: Sprague-Dawley CD/International Genetic Standard system (IGS) rats were administered cerulein or cyanohydroxybutene (CHB) to induce EPIJ. Serum samples were taken at time points between 1- and 168-hr postinjection (PI), and rats were sacrificed between 24- and 168-hr PI. METHOD: We investigated a series of serum-based biomarkers including amylase, lipase, pancreas-enriched microRNAs (miRs) and inflammation biomarkers compared with concurrent hematology and pancreatic histology. RESULTS AND CONCLUSION: Microscopic EPIJ was not associated with consistent changes in hematology or inflammation biomarkers. Increased severity scores for EPIJ correlated with increased amylase and lipase values, although severity of EPIJ did not always correlate with the magnitude of enzyme increases. Microscopic EPIJ was most severe at 24 to 48 hr; increases in miR-216a (32-fold) and miR-375 (23-fold) were present at 24 hr and, along with enzymes, were normalized by 48 hr in the cerulein study. MiRs-216a and 375 were increased by ∼800- and 500-fold, respectively, at 24 hr while miR-375 remained elevated until 72 hr in the CHB study. Impact statement: Pancreas-enriched miRs hold promise as novel serum-based biomarkers for EPIJ.

Heavy trucks, conspicuity treatment, and the decline of collision risk in darkness.

INTRODUCTION: The influence of amendments to Federal Motor Vehicle Safety Standard (FMVSS) 108, requiring conspicuity treatments on heavy tractors and trailers, was determined in analyses of the odds of fatal collisions in darkness. METHOD: Comparisons were made between crashes in which conspicuity treatment was likely relevant, and those in which it was likely irrelevant. RESULTS: Over 23years, the odds that a fatal collision involving a heavy truck occurred in darkness declined by 58% among relevant crashes, while little decline was observed for irrelevant crashes. Disaggregation into crash types revealed the largest declines occurred in fatal rear-end and angle collisions. A parallel analysis of light vehicles also found declines but no differences among crash type. Similar trends were also observed for nonfatal rear end collisions. CONCLUSION: The results suggest that detection failure may have contributed to the risk of striking a tractor-semitrailer in darkness, and that conspicuity treatments have reduced this risk. IMPACT ON INDUSTRY: Conspicuity treatments appear to reduce risk of collision into heavy trucks in darkness. It is likely that this benefit would also extend to other vehicles that are not included in the FMVSS 108 regulation (e.g., buses, single unit trucks, recreational vehicles), although many are so equipped, regardless of the regulation.

The influence of rear turn-signal characteristics on crash risk.

INTRODUCTION: The relationship between the relative risk of a rear-end collision during a turn, merge, or lane change maneuver and the characteristics of the rear turn-signal configuration was examined using crash data from seven states in the United States. METHOD: Rear turn-signal characteristics-including color, optics, separation, and light source-were identified for 55 vehicle models and used in a logistic regression analysis to model the odds of a rear-end collision. Additional variables including driver demographics (gender, age), vehicle age, and light condition were also modeled. Risk was assessed using a contrast group of striking vehicles in similar collisions. RESULTS: The results suggest that the odds of being the struck vehicle were 3% to 28% lower among vehicles equipped with amber versus red turn signals. Although the analysis suggests that there may be a safety benefit associated with amber rear turn signals, it is unclear whether turn-signal color alone is responsible. IMPACT ON INDUSTRY: The results suggest that aspects of a vehicle's rear signal characteristics may influence crash risk.

Collaborative evaluation and market research converge: an innovative model agricultural development program evaluation in Southern Sudan.

In June and July 2006 a team of outside experts arrived in Yei, Southern Sudan through an AID project to provide support to a local agricultural development project. The team brought evaluation, agricultural marketing and financial management expertise to the in-country partners looking at steps to rebuild the economy of the war ravaged region. A partnership of local officials, agricultural development staff, and students worked with the outside team to craft a survey of agricultural traders working between northern Uganda and Southern Sudan the steps approach of a collaborative model. The goal was to create a market directory of use to producers, government officials and others interested in stimulating agricultural trade. The directory of agricultural producers and distributors served as an agricultural development and promotion tool as did the collaborative process itself.

Trends and characteristics of animal-vehicle collisions in the United States.

INTRODUCTION: Since 1990, fatal animal-vehicle collisions (AVCs) in the United States have more than doubled. This paper examines annual AVC trends in the United States over a 19-year period, seasonal and diurnal patterns of AVC risk, the geographic distribution of crash risk by state, and the association between posted speed limit and AVC crash risk in darkness. METHOD: AVCs were compiled from the Fatality Analysis Reporting System (FARS) and the General Estimates System (GES) for the years 1990-2008 to examine annual crash trends for fatal and nonfatal crashes. Seasonal trends for fatal AVCs were examined with the aggregated FARS dataset; seasonal trends for fatal and nonfatal AVCs were also examined by aggregating four years of Michigan crash data. State-by-state distributions of fatal AVCs were also described with the aggregated FARS dataset. Finally, the relationship between posted speed limit and the odds that a fatal or nonfatal AVC occurred in darkness were examined with logistic regressions using the aggregated FARS and Michigan datasets. RESULTS: Between 1990 and 2008, fatal AVCs increased by 104% and by 1.3 crashes per trillion vehicle miles travelled per year. Although not all AVCs involve deer, daily and seasonal AVC crash trends follow the general activity pattern of deer populations, consistent with prior reports. The odds that a fatal AVC occurred in darkness were also found to increase by 2.3% for each mile-per-hour increase in speed; a similar, albeit smaller, effect was also observed in the aggregated Michigan dataset, among nonfatal crashes. CONCLUSION: AVCs represent a small but increasing share of crashes in the United States. Seasonal and daily variation in the pattern of AVCs seem to follow variation in deer exposure and ambient light level. Finally, the relative risk that a fatal and nonfatal AVC occurred in darkness is influenced by posted speed limit, suggesting that a driver's limited forward vision at night plays a role in AVCs, as it does in pedestrian collisions. IMPACT ON INDUSTRY: The association between speed limit and crash risk in darkness suggests that AVC risk might be reduced with countermeasures that improve a driver's forward view of the road.

Differences in geometry of pedestrian crashes in daylight and darkness.

INTRODUCTION: Previous studies have shown that increased risk in darkness is particularly great for pedestrian crashes, suggesting that attempts to improve headlighting should focus on factors that likely influence those crashes. The current analysis was designed to provide information about how details of pedestrian crashes may differ between daylight and darkness. METHOD: All pedestrian crashes that occurred in daylight or dark conditions in Michigan during 2004 were analyzed in terms of the variables included in the State of Michigan crash database. Additional analysis of the narratives and diagrams in police accident reports was performed for a subset of 400 of those crashes-200 sampled from daylight and 200 sampled from darkness. RESULTS: Several differences were found that appear to be related to the characteristic asymmetry of low-beam headlamps, which (in the United States) distributes more light on the passenger's side than the driver's side of the vehicle. These results provide preliminary quantification of the how the photometric differences between the right and left sides of typical headlamps may affect pedestrian crash risk. IMPACT ON INDUSTRY: The results suggest that efforts to provide supplemental forward vehicle lighting in turns may have safety benefits for pedestrians.

Automatic cropping of MRI rat brain volumes using pulse coupled neural networks.

The Pulse Coupled Neural Network (PCNN) was developed by Eckhorn to model the observed synchronization of neural assemblies in the visual cortex of small mammals such as a cat. In this paper we show the use of the PCNN as an image segmentation strategy to crop MR images of rat brain volumes. We then show the use of the associated PCNN image 'signature' to automate the brain cropping process with a trained artificial neural network. We tested this novel algorithm on three T2 weighted acquisition configurations comprising a total of 42 rat brain volumes. The datasets included 40 ms, 48 ms and 53 ms effective TEs, acquisition field strengths of 4.7 T and 9.4 T, image resolutions from 64x64 to 256x256, slice locations ranging from +6 mm to -11 mm AP, two different surface coil manufacturers and imaging protocols. The results were compared against manually segmented gold standards and Brain Extraction Tool (BET) V2.1 results. The Jaccard similarity index was used for numerical evaluation of the proposed algorithm. Our novel PCNN cropping system averaged 0.93 compared to BET scores circa 0.84.

Warning reliability and driver performance in naturalistic driving.

OBJECTIVE: This study examines how naturalistic driving performance is influenced by the perceived reliability of an in-vehicle warning system using a unique measure of perceived reliability. BACKGROUND: Prior studies of warning reliability conducted in simulator and test-track experiments demonstrate that the objective reliability of a warning can influence a driver's responsiveness to that warning. METHODS: Driver responses to lateral drift warnings (LDWs) were examined to determine if the latency to initiate a corrective steering response was related to the subjective reliability of prior system performance. An operational definition of subjective reliability was developed based on measures of the proportion of LDWs responded to by a steering correction in the preceding 24-hr period - the day proportion. Age, gender, weather condition, light level, road class, weekday status, and day proportion were used to model correction latency in a linear model. RESULTS: A main effect of day proportion was found, suggesting that reaction time to respond decreases by about 375 ms as the day proportion increases from 0 to 1. CONCLUSION: The study illustrates a method of quantifying subjective reliability and performance using naturalistic data. The results suggest that latency to make a steering correction is inversely related to the perceived reliability of the warning system in the 24 hr preceding the warning. APPLICATION: The results have direct application to the method of assessing the efficacy of in-vehicle collision warning systems, suggesting that use of a perceived reliability measure may better predict a driver's disposition to respond to a warning.

Screening a novel class of anticoagulants for multi-organ toxicity using Fischer 344 rats: involvement of clinical and anatomic pathologists in the early drug development process.

BACKGROUND: Veterinary clinical and anatomic pathologists play a critical role in assessing the safety of new molecules. The process for evaluation of candidate molecules in drug discovery may vary markedly, depending on the unique characteristics of the compound class. OBJECTIVES: The goal of this report is to describe the evaluation process for assessing the potential toxicity of 2 anticoagulant compounds that were representative of molecules tested in early screening studies in Fisher rats, and to use these studies as an example of the strategic approach used by veterinary pathologists in pharmaceutical safety assessment. METHODS: Groups of 3 rats were given vehicle alone or one of several doses of compound A or B by oral gavage daily for 4 consecutive days. Survival; clinical signs; body and organ weight measurements; hematologic, coagulation, and clinical biochemical testing; and gross and histologic findings at necropsy were assessed. Transmission electron microscopy was used to characterize unique findings in the liver of rats treated with compound B. RESULTS: Both compounds caused dose-dependent prolongation of the prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin clotting time (TCT). Hepatobiliary and intestinal toxicity were identified by alterations in serum chemistry data, and by histopathologic findings. Electron microscopy and tissue inorganic phosphorus analysis revealed phospholipidosis in rats treated with compound B. CONCLUSIONS: Pharmacologically mediated or "on target" effects for these molecules were characterized by dose-progressive prolongation of the PT, APTT, and TCT. Nonpharmacologically mediated or "off-target" toxicity consisted of hepatoxicity and enterotoxicity. These liabilities required that scientists alter the original molecular scaffold to reach the desired therapeutic target and minimize toxicity.