Patient characteristics, prognostic factors and outcome of dogs with high-grade primary mediastinal lymphoma.

The goals of this retrospective study were to determine the patient characteristics of dogs with high-grade primary mediastinal lymphoma and to determine outcome and associated prognostic factors. A total of 42 dogs were identified, in which 36 received treatment and had follow-up information available. The most common clinical signs included lethargy, anorexia and polyuria/polydipsia. Hypercalcemia and pleural effusion were common findings at diagnosis. The phenotype was almost exclusively T-cell, most often in association with lymphoblastic cytomorphology as defined by the World Health Organization (WHO) lymphoma classification scheme. The overall progression-free survival (PFS) and overall survival (OS) were 133 and 183 days, respectively. Treatment with a CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) protocol was associated with an improved PFS (144 days) and OS (194 days) when compared with dogs that received other medical therapies (P = .005 and P = .002, respectively); the absence of pleural effusion at diagnosis was associated with an increased OS but not PFS. These results suggest that while the prognosis for dogs with mediastinal lymphoma is poor, survival may be improved with treatment using a CHOP-based protocol.

Mapping the CGRP receptor ligand binding domain: tryptophan-84 of RAMP1 is critical for agonist and antagonist binding.

The calcitonin receptor-like receptor (CLR) associates with the accessory protein RAMP1 to form a receptor for the neuropeptide calcitonin gene-related peptide (CGRP). Multiple lines of evidence have implicated CGRP in the pathophysiology of migraine headache making the CGRP receptor an attractive target for development of small-molecule antagonists as a novel treatment for this debilitating condition. The CGRP receptor antagonists telcagepant and olcegepant (BIBN4096BS) have demonstrated clinical efficacy in the treatment of migraine and there is now a need to better understand how these molecules interact with the receptor. Previous work has shown the extracellular portion of RAMP1 to be important for binding of these antagonists, with tryptophan-74 being a key interaction site. The crystal structure of the extracellular portion of human RAMP1 placed tryptophan-74 in a hydrophobic patch hypothesized to interact with CGRP receptor ligands and also identified nearby residues that may be important for ligand binding. In this study we explored the role played by these residues of RAMP1 using an alanine replacement strategy. We confirmed a role for tryptophan-74 in antagonist binding and also identified arginine-67 as being important for binding of telcagepant but not compound 3, a close analog of BIBN4096BS. We also identified tryptophan-84 as being critical for both high-affinity binding of the non-peptide antagonists as well as the peptides CGRP and CGRP(8-37). These data for the first time pinpoint a specific RAMP1 residue important for both antagonist and agonist potency and are consistent with the N-terminal domain of RAMP1 forming the binding pocket interface with CLR.

Safety assessment of Lactobacillus brevis KB290 as a probiotic strain.

Lactobacillus brevis KB290 (KB290), a plant-derived probiotic lactic acid bacterium, reportedly improves gut health and stimulates immune function. Here we extensively investigated the geno-, acute, subacute, and subchronic toxicity of KB290 and its bacterial translocation potential. KB290 was non-mutagenic in the bacterial reverse mutation assay by the preincubation method. In the single oral dose toxicity test, KB290 at 10(9) cfu/ml was nontoxic at maximum capacity (20 ml/kg). When 10(8), 10(9), or 10(10) cfu/kg was administered daily to rats by gavage for 2 weeks (subacute assay), we observed no clear treatment-related effect and no evidence of bacterial translocation from the gastrointestinal tract. When it was administered for 13 weeks (subchronic assay), we again observed no clear treatment-related effect and no significant toxicological effect. Based on those results, we consider 10(10) cfu/kg per day, the highest dose tested, to be the no observed adverse effect level (NOAEL). These results suggest that KB290 is safe for human consumption.

Risk of incident age-related eye diseases in people with an affected sibling : The Beaver Dam Eye Study.

The purpose of this investigation was to determine whether age-related cataract and maculopathy in older siblings predicts development of the same in younger siblings. A population-based study of age-related eye diseases was conducted in 1988--1990 in Beaver Dam, Wisconsin, and a follow-up examination was performed 5 years later. Diagnoses of age-related eye diseases were assigned on the basis of gradings of study photographs. There were 1,088 people from 488 sibships with at least two siblings who could contribute information for these analyses. The authors computed odds ratios and 95% confidence intervals for developing the specific lesion and identifying it 5 years later if an older sibling had it at baseline. The odds ratios were 1.65 (95% confidence interval (CI): 0.91, 2.99) for nuclear cataract, 1.62 (95% CI: 0.92, 2.85) for cortical cataract, 1.95 (95% CI: 0.48, 7.95) for posterior subcapsular cataract, 1.82 (95% CI: 0.91, 3.66) for soft drusen, 8.18 (95% CI: 3.34, 20.08) for retinal pigment epithelium depigmentation, 3.59 (95% CI: 1.71, 7.57) for increased retinal pigment, and 10.32 (95% CI: 0.83, 128.58) for exudative age-related maculopathy. These findings suggest that strong family determinants of lesions of age-related maculopathy are likely, less so for age-related cataract, which confer risk of the same lesion in a younger sibling.

Effects of chronic ethanol ingestion on mid-latency auditory evoked potentials depend on length of exposure.

We hypothesized that chronic ethanol ingestion is associated with modifications in components of mid-latency auditory evoked potentials (MAEPs). To test this, male Long Evans rats were administered 10% ethanol in drinking water as the sole fluid source for 3, 6, or 9 months. MAEPs were obtained and compared to age-matched control groups. MAEPs were obtained from additional rats after 4 weeks of abstinence. Data were obtained for varying frequencies (4, 8, 16, 24, 32 kHz) and intensities (65, 75, 85 dB SPL). Three months of ethanol exposure was associated with increased latencies and amplitudes of Na and Pa. MAEP components recovered and returned to control values after 4 weeks' abstinence following 3 months of EtOH exposure. Few significant differences were observed in the ethanol-treated or abstinent group after 6 months' exposure. However, 9 months of ethanol exposure revealed a significant increase in latencies and decrease in amplitudes of both Na and Pa components. After 4 weeks of abstinence, the Na and Pa component peak latencies appeared earlier than age-matched controls. The Na and Pa peak amplitudes were slightly greater than the ethanol-treated group; however, they did not recover to control values. These findings suggest that chronic ethanol consumption may produce time-dependent structural and/or neurochemical alterations in substrates for cortical information processing, which may be irreversible. In the present paradigm, this irreversibility may occur after 6 or more months of ethanol intake, and may be detected with the use of MAEPs.

Chronic ethanol ingestion produces cholinergic hypofunction in rat brain.

Alterations in cholinergic function due to prolonged ethanol exposure (up to 9 months) were assessed by choline acetyltransferase (ChAT) activity and high-affinity choline uptake (HAChU) in three brain regions of the Long-Evans rat: frontal cortex, parietal cortex, and region of the nucleus basalis of Meynert (NbM). No statistically significant changes were found in ChAT activity in the 3-month group; however, ChAT activity was decreased in both the frontal cortex (-32%) and NbM region (-22%) after 6 months of ethanol exposure. ChAT activity in the parietal cortex was increased 30% after 6 months. Nine months of exposure significantly decreased ChAT activity in all three brain regions. No significant differences were observed in high-affinity choline uptake after 3 months of ethanol exposure. However, after 6 months of ethanol exposure HAChU was decreased to 51% of control values in the frontal cortex. There was a simultaneous increase in HAChU to 43% and 178% of control values in the NbM and parietal cortex, respectively. However, choline uptake was significantly decreased in the frontal cortex and NbM region after 9 months of exposure. The results indicate a neurotoxic effect of prolonged intake of ethanol on the basal forebrain cholinergic projection system, which may cause impairment of cholinergic innervation of target areas of the basal nucleus complex.

Cardiac response of domestic chickens to hawk and goose models.

The response of precocial birds to configurational stimuli has been a source of controversy for decades. In this experiment we measured cardiac response of domestic chicks to "hawk" and "goose" silhouettes. The chicks' heart rates varied more in response to the hawk model than to the goose model, suggesting that the hawk silhouette is a more fearful stimulus than that of the goose. Our data document the recognition of a configurational stimulus without prior, pertinent experience.