Pilot Study: Colostomy and Urine Collection Protocol for Investigating Potential Inciting Causes of Hen Diuresis Syndrome.

Hen diuresis syndrome has emerged over the past 5 yr as a significant cause of mortality in the U.S. broiler breeder industry. The condition affects hens in production and is characterized by transient muscle weakness in the vent region, transient diuresis, and often urate deposits on the skin below the vent. Affected hens are often seen straining to lay an egg, which suggests oviduct contraction is also impaired. Related hen mortality, often reaching 1% or more a week, is believed to be primarily the result of male aggression of the vent region (Turner et al., "Investigating Causes of Excessive Urate Production in Broiler Breeder Hens Associated with Peritonitis and Cannibalism Mortality," Oral Presentation at The American Association of Avian Pathologists Annual Meeting, p. 139, 2010). The exact association between the cause of mortality and this syndrome is unknown, but it may be the consequence of transient partial to full oviduct prolapse, which predisposes or stimulates cannibalism and aggression. Based on unpublished work done prior to this study (Turner et al., ibid.), the evidence suggests the underlying problem is metabolic. We feel that urine collection and analysis is an essential component to understanding this condition. This study serves as a pilot study for future investigations that attempt to identify the nature and cause of the metabolic disturbance through paired urine and serum collection and analysis. For the purpose of this study, a small sample of 10 affected and 10 unaffected birds was used for sample collection. In order to collect pure urine, the birds were surgically colostomized. Colostomy did prove to be a useful means of collecting urine free of feces, and for the purposes of our study it yielded adequate urine samples for analysis. There were statistically relevant urine values observed. Affected birds had a higher presence of blood in the urine, a lower uric acid excretion rate (mg/hr), higher concentration (mEq/L) of urine Na+, and a lower concentration (mEq/L) of urine K+ than unaffected birds. This pilot study helps to address some of the pitfalls previously associated with colostomy and to determine when collection can begin postoperatively so that we can better understand when and how to begin our sampling in future trials to address the etiology of this condition.

Investigations into Outbreaks of Black Fly Attacks and Subsequent Avian Haemosporidians in Backyard-Type Poultry and Other Exposed Avian Species.

In late spring of 2009 and 2010, there were reports of severe black fly (Simulium spp., shown in Fig. 1) outbreaks in various counties in Mississippi, especially those in and around the Mississippi River Delta. Complaints were of black flies attacking multiple species of backyard poultry and causing high morbidity and mortality in affected flocks. At several affected locations, black flies were readily observed swarming around and feeding on birds. A large number of these parasites were easily trapped on fly strips (Fig. 2). Multifocal to coalescing cutaneous hemorrhagic lesions, consistent with fly bites, were seen on the birds. Upon necropsy examination, a large number of black flies were also observed in the digestive tract (Fig. 3). Although black flies may cause disease directly, such as cardiopulmonary collapse and anaphylactoid reactions, detection of Leucocytozoon in blood smears (Fig. 4) of affected birds prompted further investigations of this protozoan as a cause of disease. Leucocytozoon spp. are known to be transmitted by black flies and may be associated with morbidity and mortality in birds such as poultry. From June 2009 through July 2012, the investigation included a total collection of 1068 individual blood samples, representing 371 individual premises in 89 counties/parishes across Mississippi (59), Alabama (10), Louisiana (4), and Tennessee (16). Of the 371 premises where blood samples were collected, 96 (26%) were either positive or highly suspected to be positive for Leucocytozoon spp. by blood smear analysis, and 5 (1.2%) were positive for Haemoproteus spp. by blood smear analysis. Attempts to diagnose Leucocytozoon spp. by PCR analysis and sequencing were complicated by coinfections with two closely related haemosporidians (Haemoproteus spp. and Plasmodium spp.). A novel technique involving flow cytometry was also explored. This study discusses the black fly field outbreak, the involvement of haemosporidians, molecular methods for detection of both the black flies and blood parasites, and initial attempts at flow cytometry.

Glucose monitoring as an impediment to Improving glycemic control: a case report.

Diabetes mellitus is increasing in frequency and is associated with disabling acute and chronic complications. There is evidence to indicate that excellent glucose control may retard the development and/or progression of these complications. In order to optimize diabetic control, patients are encouraged to monitor their glucose frequently We describe a patient who provided inaccurate glucose monitoring results, delaying effective management of his progressively increasing glycosylated hemoglobin level. The diagnostic clue to his erroneous glucose monitoring results was the lack of intra-day variation in this patient on insulin therapy. Moreover, glucose records within the patient's glucometer pointed to a much less frequent glucose monitoring than the written data provided by the patient. The glucometer was accurate when used by the patient under direct observation. It remains unclear whether this patient deliberately misled his providers or if the erroneous data reflected underlying cognitive dysfunction. Providers are encouraged to approximate average blood sugars based on glycosylated hemoglobin values and compare this to home monitoring results provided by the patient. Primary providers should also expect a certain degree of variability when reviewing home blood sugar values with their patients (on insulin therapy) and consider further investigation should the numbers lack such variation. Clinicians are urged to inspect the actual glucose readings on the patient's glucometer as well as inspecting written glucose records. Observing the patient's technique and accuracy when using their personal glucometer should also be considered.

Glucose monitoring as an impediment to improving glycemic control: a case report.

Diabetes mellitus is increasing in frequency and is associated with disabling acute and chronic complications. There is evidence to indicate that excellent glucose control may retard the development and/or progression of these complications. In order to optimize diabetic control, patients are encouraged to monitor their glucose frequently. We describe a patient who provided inaccurate glucose monitoring results, delaying effective management of hisprogressively increasing glycosylated hemoglobin level. The diagnostic due to his erroneous glucose monitoring results was the lack of intra-day variation in this patient on insulin therapy. Moreover, glucose records within the patient's glucometer pointed to a much less frequent glucose monitoring than the written data provided by the patient. The glucometer was accurate when used by the patient under direct observation. It remains unclear whether this patient deliberately misled his providers or if the erroneous data reflected underlying cognitive dysfunction. Providers are encouraged to approximate average blood sugars based on glycosylated hemoglobin values and compare this to home monitoring results provided by the patient. Primary providers should also expect a certain degree of variability when reviewing home blood sugar values with their patients (on insulin therapy) and consider further investigation should the numbers lack such variation. Clinicians are urged to inspect the actual glucose readings on the patient's glucometer as well as inspecting written glucoserecords. Observing the patient's technique and accuracy when using their personal glucometer should also be considered.

Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively.

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called Regulated Induced Proximity Targeting Chimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.

A natural outbreak of clinical toxoplasmosis in a backyard flock of guinea fowl in Mississippi.

A case of a naturally occurring infection with Toxoplasma gondii in a backyard flock of guinea fowl in north Mississippi is reported. To our knowledge, this is the first worldwide report of a natural clinical infection in a flock of guinea fowl. This case was two of seven birds lost out of approximately 20 guinea fowl present in the flock. Birds reportedly exhibited lethargy prior to death. Necropsy examinations were performed on two of the dead birds. There were no gross lesions; however, intralesional protozoan cysts suggestive of T. gondii were observed microscopically. One of two guinea fowl demonstrated dramatic microscopic pathology consisting of variable multifocal necrosis, fibrin exudation, and inflammation of spleen, lung, and heart associated with protozoa cysts and tachyzoites compatible with toxoplasmosis. The bone marrow also exhibited multifocal necrosis and fibrin exudation, as well as marked erythroid and lesser granulocytic hyperplasia with intralesional protozoan cysts. The diagnosis of toxoplasmosis was confirmed with immunohistochemistry and PCR.

Antigen-independent tumor targeting by CBX-12 (alphalex™-exatecan) induces long-term antitumor immunity.

Aims: To determine whether antigen-independent targeting of the TOP1 inhibitor exatecan to tumor with a pH-sensitive peptide (CBX-12) produces superior synergy with immunotherapy compared with unconjugated exatecan. Materials & methods: In vitro and ex vivo functional assays were performed via FACS and ELISA assays. In vivo efficacy was evaluated in the syngeneic CT26 model. Results: CBX-12 combined with anti-PD-1 or anti-CTLA4 results in delayed tumor growth and complete response, with cured animals displaying long-term antitumor immunity. CBX-12 stimulates expression of MHC 1 and PD-L1 and is an inducer of immunogenic cell death, producing long-term immune recognition of tumor cells and resultant antitumor immunity. Conclusion: The authors' data provide the rationale for exploring immunotherapy combinations with CBX-12 in clinical trials.

Although combinations of chemotherapy and immunotherapy have shown great promise for cancer treatment, they have also demonstrated significant safety concerns that require dose reductions. Targeting chemotherapy to the tumor can avoid these safety issues, thereby enhancing efficacy of combination therapies. CBX-12 is a novel peptide-drug agent targeting the TOP1-inhibiting drug exatecan to tumor via pH-sensitive peptide. Unlike tumor targeting via antibody, CBX-12 universally targets all solid tumors. CBX-12 avoids the immune cell toxicity of nontumor-targeted exatecan and safely synergizes with immunotherapies. CBX-12 treatment causes tumor cells to express and secrete molecules that result in activation of immune components to recognize and eliminate tumor cells. These data support the upcoming clinical trials of CBX-12 in combination with immunotherapy.

Testicular Atrophy and Epididymitis-Orchitis Associated with Infectious Bronchitis Virus in Broiler Breeder Roosters.

Infectious bronchitis is a respiratory disease of chickens caused by a gammacoronavirus named infectious bronchitis virus (IBV). In addition to affecting the respiratory tract, IBV may also induce urogenital infections, leading to nephropathogenic disease, false layer syndrome in laying hens, and epididymal lithiasis and epididymitis in males. Here, we report a case of decreased reproductive efficiency due to male infertility in 33- to 38-wk-old broiler breeders. At necropsy, the males presented with urates deposited on the skin around the vent and testicular asymmetry due to marked unilateral atrophy. Histopathology revealed lymphocytic epididymitis, epididymal lithiasis, and orchitis. IBV antigen was detected within collecting and efferent ducts of epididymides by immunohistochemistry. IBV strain DMV/1639 was detected by reverse transcription-quantitative PCR in pools of testes, oviducts, tracheas, cecal tonsils, and kidneys from a 37-wk-old affected flock. This report shows evidence of the role of IBV in male chicken infertility and highlights the importance of performing molecular surveillance of IBV to monitor vaccine strains and to detect emerging variants that can potentially hinder production.

Reporte de caso- Atrofia testicular y epididimitis-orquitis asociadas con el virus de la bronquitis infecciosa en gallos reproductores pesados. La bronquitis infecciosa es una enfermedad respiratoria del pollo causada por un gammacoronavirus llamado virus de la bronquitis infecciosa (con las siglas en inglés IBV). Además de afectar el tracto respiratorio, el IBV también puede inducir infecciones urogenitales, lo que conduce a enfermedad nefropatogénica, síndrome de la falsa ponedora en gallinas de postura y litiasis epididimaria y epididimitis en machos. En este reporte se describe un caso de disminución de la eficiencia reproductiva debido a la infertilidad de machos en reproductores pesados de 33 a 38 semanas de edad. En la necropsia, los machos presentaron depósitos de uratos sobre la piel alrededor de la cloaca y asimetría testicular por atrofia unilateral marcada. La histopatología reveló epididimitis linfocítica, litiasis epididimaria y orquitis. Antígenos del virus de la bronquitis infecciosa se detectaron dentro de los conductos colectores y eferentes de los epidídimos mediante inmunohistoquímica. La cepa del virus de la bronquitis DMV/1639 se detectó mediante transcripción reversa y PCR cuantitativa en muestras agrupadas de testículos, oviductos, tráqueas, tonsilas cecales y riñones de una parvada afectada de 37 semanas de edad. Este reporte muestra evidencia del papel del virus de la bronquitis infecciosa en la infertilidad de los pollos machos y destaca la importancia de realizar una vigilancia molecular de este virus para monitorear las cepas vacunales y detectar variantes emergentes que potencialmente pueden dificultar la producción.

Acute Neurotoxicity of Antisense Oligonucleotides After Intracerebroventricular Injection Into Mouse Brain Can Be Predicted from Sequence Features.

Antisense oligonucleotides are a relatively new therapeutic modality and safety evaluation is still a developing area of research. We have observed that some oligonucleotides can produce acute, nonhybridization dependent, neurobehavioral side effects after intracerebroventricular (ICV) dosing in mice. In this study, we use a combination of in vitro, in vivo, and bioinformatics approaches to identify a sequence design algorithm, which can reduce the number of acutely toxic molecules synthesized and tested in mice. We find a cellular assay measuring spontaneous calcium oscillations in neuronal cells can predict the behavioral side effects after ICV dosing, and may provide a mechanistic explanation for these observations. We identify sequence features that are overrepresented or underrepresented among oligonucleotides causing these reductions in calcium oscillations. A weighted linear combination of the five most informative sequence features predicts the outcome of ICV dosing with >80% accuracy. From this, we develop a bioinformatics tool that allows oligonucleotide designs with acceptable acute neurotoxic potential to be identified, thereby reducing the number of toxic molecules entering drug discovery pipelines. The informative sequence features we identified also suggest areas in which to focus future medicinal chemistry efforts.

TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor.

Exatecan and deruxtecan are antineoplastic camptothecin derivatives in development as tumor-targeted-delivery warheads in various formulations including peptides, liposomes, polyethylene glycol nanoparticles, and antibody-drug conjugates. Here, we report the molecular pharmacology of exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors. Modeling exatecan binding at the interface of a TOP1 cleavage complex suggests two novel molecular interactions with the flanking DNA base and the TOP1 residue N352, in addition to the three known interactions of camptothecins with the TOP1 residues R364, D533, and N722. Accordingly, exatecan showed much stronger TOP1 trapping, higher DNA damage, and apoptotic cell death than the classical TOP1 inhibitors used clinically. We demonstrate the value of SLFN11 expression and homologous recombination (HR) deficiency (HRD) as predictive biomarkers of response to exatecan. We also show that exatecan kills cancer cells synergistically with the clinical ATR inhibitor ceralasertib (AZD6738). To establish the translational potential of this combination, we tested CBX-12, a clinically developed pH-sensitive peptide-exatecan conjugate that selectively targets cancer cells and is currently in clinical trials. The combination of CBX-12 with ceralasertib significantly suppressed tumor growth in mouse xenografts. Collectively, our results demonstrate the potency of exatecan as a TOP1 inhibitor and its clinical potential in combination with ATR inhibitors, using SLFN11 and HRD as predictive biomarkers.

Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies.

Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic-acid (LNA)-modified antisense oligonucleotides (ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3' UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well tolerated and produced a robust, long-lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post injection and corresponded with tau protein reduction in the cerebrospinal fluid (CSF). Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.

Correction to 'Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity'.

[This corrects the article DOI: 10.1093/narcan/zcab021.].

Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity.

Topoisomerase inhibitors are potent DNA damaging agents which are widely used in oncology, and they demonstrate robust synergistic tumor cell killing in combination with DNA repair inhibitors, including poly(ADP)-ribose polymerase (PARP) inhibitors. However, their use has been severely limited by the inability to achieve a favorable therapeutic index due to severe systemic toxicities. Antibody-drug conjugates address this issue via antigen-dependent targeting and delivery of their payloads, but this approach requires specific antigens and yet still suffers from off-target toxicities. There is a high unmet need for a more universal tumor targeting technology to broaden the application of cytotoxic payloads. Acidification of the extracellular milieu arises from metabolic adaptions associated with the Warburg effect in cancer. Here we report the development of a pH-sensitive peptide-drug conjugate to deliver the topoisomerase inhibitor, exatecan, selectively to tumors in an antigen-independent manner. Using this approach, we demonstrate potent in vivo cytotoxicity, complete suppression of tumor growth across multiple human tumor models, and synergistic interactions with a PARP inhibitor. These data highlight the identification of a peptide-topoisomerase inhibitor conjugate for cancer therapy that provides a high therapeutic index, and is applicable to all types of human solid tumors in an antigen-independent manner.

The potential to improve diabetes control with vitamin D replacement in African American patients: case report and literature review.

African Americans have a higher prevalence of Diabetes mellitus and associated complications. The prevalence of Vitamin D deficiency is also higher in African Americans. We report an African American veteran who was followed for a period of 10 years in the Endocrine clinic for insulin-requiring diabetes. Despite intensive, medical, nutritional and educational efforts during that period, no discernible progress was made in achieving any improvement in glycemic control. The patient appeared to be noncompliant with recommended strategies to improve glycemia. The patient was seen recently and was found to be profoundly Vitamin D deficient with a 25 (OH) Vitamin D level of 11.6 ng/ml [30-100 ng/ml]. While patient did not wish to change his insulin regimen or diabetic management, he was willing to accept Vitamin D therapy. Replacement with Vitamin D was associated with significant improvement in glycosylated hemoglobin to previously unmatched levels of glycemic control. We discuss the multiple potential mechanisms by which improved Vitamin D status may result in improved diabetes control. Given the current pandemic of Vitamin D deficiency and the plethora of potential benefits, we recommend maintaining adequate Vitamin D reserves in diabetic patients with a special emphasis on minority populations.

P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from AD patients, genetic analysis of mutations that cause early onset forms of AD, and preclinical studies. Based on this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors are an attractive therapeutic approach for AD because cleavage of the APP by BACE1 is required to form Abeta. In this study, three potent BACE1 inhibitors are characterized. All three inhibitors decrease Abeta formation in cultured cells with IC(50) values less than 10 nM. Analysis of APP C-terminal fragments by immunoblotting and Abeta peptides by mass spectrometry showed that these inhibitors decreased Abeta by inhibiting BACE1. An assay for Abeta1-40 in mice was developed and used to show that these BACE1 inhibitors decreased plasma Abeta1-40, but not brain Abeta1-40, in wild-type mice. Because these BACE1 inhibitors were substrates for P-glycoprotein (P-gp), a member of the ATP-binding cassette superfamily of efflux transporters, these inhibitors were administered to P-gp knockout (KO) mice. These studies showed that all three BACE1 inhibitors decreased brain Abeta1-40 in P-gp KO mice, demonstrating that P-gp is a major limitation for development of BACE1 inhibitors to test the amyloid hypothesis. A comparison of plasma Abeta1-40 and brain Abeta1-40 dose responses for these three compounds revealed differences in relative ED(50) values, indicating that factors other than P-gp can also contribute to poor brain activity by BACE1 inhibitors.

Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents.

The α7 nicotinic acetylcholine receptor is thought to play an important role in human cognition. Here we describe the in vivo effects of BMS-902483, a selective potent α7 nicotinic acetylcholine receptor partial agonist, in relationship to α7 nicotinic acetylcholine receptor occupancy. BMS-902483 has low nanomolar affinity for rat and human α7 nicotinic acetylcholine receptors and elicits currents in cells expressing human or rat α7 nicotinic acetylcholine receptors that are about 60% of the maximal acetylcholine response. BMS-902483 improved 24h novel object recognition memory in mice with a minimal effective dose (MED) of 0.1mg/kg and reversed MK-801-induced deficits in a rat attentional set-shifting model of executive function with an MED of 3mg/kg. Enhancement of novel object recognition was blocked by the silent α7 nicotinic acetylcholine receptor agonist, NS6740, demonstrating that activity of BMS-902483 was mediated by α7 nicotinic acetylcholine receptors. BMS-902483 also reversed ketamine-induced deficits in auditory gating in rats, and enhanced ex vivo hippocampal long-term potentiation examined 24h after dosing in mice. Results from an ex vivo brain homogenate binding assay showed that α7 receptor occupancy ranged from 64% (novel object recognition) to ~90% (set shift and gating) at the MED for behavioral and sensory processing effects of BMS-902483.

Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping.

RATIONALE: Alzheimer's dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions. OBJECTIVES: The objective of the present experiments was to explore the effects of donepezil (Aricepttrade mark), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction. MATERIALS AND METHODS: The effects of donepezil were assessed in Sprague-Dawley rats with scopolamine-induced deficits in a battery of cognitive/behavioral tests. RESULTS: Scopolamine produced deficits in contextual and cued fear conditioning, the 5-choice serial reaction time test, delayed nonmatching to position, the radial arm maze, and the Morris water maze. Analyses of the pattern and size of the effects revealed that donepezil produced very large effects on scopolamine-induced deficits in psychomotor function (approximately 20-50% of the variance), moderate-sized effects on scopolamine-induced deficits in simple conditioning and attention (approximately 3-10% of the variance), but only small effects on scopolamine-induced deficits in higher cognitive functions of working memory and spatial mapping (approximately 1% of the variance). CONCLUSIONS: These results are consistent with the limited efficacy of donepezil on higher cognitive function in AD patients, and suggest that preclinical behavioral models could be used not only to determine if novel treatments have some therapeutic potential, but also to predict more precisely what the pattern and size of the effects might be.

Morphometric Documentation of a High Prevalence of Left Ventricular Dilated Cardiomyopathy in Both Clinically Normal and Cyanotic Mature Commercial Broiler Breeder Roosters with Comparisons to Market-Age Broilers.

Previous studies documented the common occurrence of transitory cyanosis and echocardiographic aortic insufficiency in mature commercial broiler breeder roosters. During further investigations, we observed a high prevalence of hearts exhibiting extensive dilation of the left ventricle chamber compatible with dilated left ventricular cardiomyopathy present in both cyanotic and normal subpopulations. We conducted quantitative studies focused on documentation of cardiac ventricle parameters by using simple gross morphometric methods performed on formalin-fixed hearts obtained from both clinically normal roosters and those exhibiting variable transitory cyanosis, echocardiographic aortic insufficiency, or both. A high prevalence of often dramatic left ventricular dilation reflected in enlarged left ventricular chamber areas and elevated left ventricle-to-total ventricle area ratios was morphometrically documented. However, no statistically significant differences in the occurrence of ventricular abnormalities were observed between normal and cyanotic roosters. Age-associated changes were also demonstrated by comparative morphometric studies on hearts from normal market-age broilers (average age of 7 wk) and those of mature roosters (average age of 42 wk). Elevation in both left and right ventricular weight-to-total heart weight ratios dramatically increased with aging. In addition, values (average ± SD) for the left ventricle chamber area-to-total ventricle area ratios increased from 3.2 ± 2.0% in broilers up to 10.0 ± 8.8% in roosters. None of the normal broilers studied demonstrated left ventricular volume ratios above 10%, whereas 33% of the roosters had left ventricular volume ratios above 10%, including 13% with ratios of 20% or higher. However, the left ventricle wall area-to-body weight ratios were much closer for the two age groups (0.85 ± 0.18 cm(2)/kg in broilers and 0.79 ± 0.13 cm(2)/kg in roosters). Also, the standard right ventricle-to-total ventricle weight ratio (RV/TV) went from 0.18 ± 0.04 in broilers to 0.25 ± 0.12 in roosters, whereas the left ventricle-to-total ventricle weight ratios were similar for the two age groups (0.74 ± 0.12 and 0.75 ± 0.08 in broilers and roosters, respectively). Our results for RV/TV in normal broilers were similar to the reported values for normal market-age broilers. In contrast, 36% of the roosters had RV/TV above values reported for broilers considered reflective of right ventricular hypertrophy due to pulmonary hypertension, whereas 4% had values above the reported threshold for broilers dying with ascites (ratios greater than 0.0249 and 0.299, respectively). However, ascites was not observed for any of the roosters. Although essentially all cardiac morphometric parameters demonstrated statistically significant correlations with the age-class group comparisons, significance could not be documented for comparisons between cardiomorphometrics and the subjective occurrences of transitory cyanosis or echocardiographic aortic insufficiency.

Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5.

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.