A Novel α-Hemolytic Streptococcus Species (Streptococcus azizii sp. nov.) Associated with Meningoencephalitis in Na?ve Weanling C57BL/6 Mice

During 1 year, experimentally naïve C57BL/6NCrl weanlings born to timed-pregnant dams from a single vendor demonstrated markedly increased mortality associated with runting, abnormal gait, and decreased activity. Gram-positive, aerobic, α-hemolytic, coccoid bacteria were isolated from the meninges (n = 16), blood (n = 1), and kidneys (n = 1) of clinically affected weanlings (n = 15); from the uterus (n = 1), meninges (n = 1), and oral cavity (n = 2) of 3 dams; and from the meninges and oral cavity of a clinically affected 86-d-old mouse in the same colony. Multifocal, necrosuppurative meningoencephalitis and ventriculitis with intralesional gram-positive coccoid bacteria were present in all but 2 affected animals. The bacterium also was isolated from the oral cavity of an asymptomatic timed-pregnant dam (1 of 23) from the same vendor and from 8 mice at the vendor''s facility. All isolates (n = 25) were identified by using 2 semiautomated rapid-identification systems, one of which consistently identified the causative bacterium as Aerococcus viridans 2 (n = 12) or 3 (n = 13), with probabilities of 55.7% to 98.3%. The bacterium did not grow in 6.5% NaCl at 10 °C, thus suggesting a Streptococcus species. Partial 16S rRNA sequencing of 4 isolates suggested S. hyointestinalis (probability, 93.4%) and S. gallinaceus (99.5%). Full 16S rRNA sequences for 3 isolates identified the bacterium as a novel Streptococcus species most closely related to S. acidominimus strain LGM (96.5%) and Streptococcus species strain Smarlab 3301444 (96.3%) and for which we propose the name S. azizii.Streptococcus species adversely affect both immunocompetent and immunocompromised mice.^2,16,30,31 As commensal bacteria, these gram-positive cocci inhabit the nose, mouth, intestine, genital tract, and skin. In general, pathogenic streptococci belong to Lancefield groups A, B, C, and G and are associated with suppurative lesions in the kidneys, heart, spleen, liver, uterus, thorax, lymph nodes, and lungs of affected mice.² C57BL/6 mice serve as a well-characterized model for S. pneumoniae, the cause of pneumococcal disease in humans.²⁵ Although C57BL/6 mice are highly susceptible to experimental infection with α-hemolytic Streptococcus pneumoniae, natural infections remain undocumented.² In humans, 10 of the most common subtypes of S. pneumoniae account for 62% of invasive bacterial disease worldwide and can cause clinical syndromes ranging from meningitis to pneumonia. Mouse models have been instrumental in developing pneumococcal vaccines for at-risk populations.²⁵Many of the Streptococcus species that cause dental caries and that can lead to bacteremia are α-hemolytic, such as S. mutans and S. sanguinis.¹² In addition, S. suis causes clinical signs in swine similar to those of S. pneumoniae in humans and poses a significant zoonotic risk.^34,35 Naturally occurring disease caused by other α-hemolytic Streptococcus species is extremely rare in mice.³⁰ When described, these infections occurred in immunodeficient mice, and, to our knowledge, there are no reports of α-hemolytic Streptococcus species causing clinical disease in immunocompetent mice.In this report, we describe meningoencephalitis associated with a novel α-hemolytic Streptococcus species in a colony of C57BL/6NCrl mice. The bacterium appeared to be enzootic in at least some of the vendor''s barrier breeding colonies. The pathogenesis of the disease associated with this bacterium remains to be fully elucidated.     

A cellular perspective of bias at G protein‐coupled receptors

G protein‐coupled receptors (GPCRs) modulate cell function over short‐ and long‐term timescales. GPCR signaling depends on biochemical parameters that define the what, when, and where of receptor function: what proteins mediate and regulate receptor signaling, where within the cell these interactions occur, and how long these interactions persist. These parameters can vary significantly depending on the activating ligand. Collectivity, differential agonist activity at a GPCR is called bias or functional selectivity. Here we review agonist bias at GPCRs with a focus on ligands that show dramatically different cellular responses from their unbiased counterparts.     

Distinguishing type 2 diabetes from type 1 diabetes in African American and Hispanic American pediatric patients

Objective

To test the hypothesis that clinical observations made at patient presentation can distinguish type 2 diabetes (T2D) from type 1 diabetes (T1D) in pediatric patients aged 2 to 18.

Subjects and Methods

Medical records of 227 African American and 112 Hispanic American pediatric patients diagnosed as T1D or T2D were examined to compare parameters in the two diseases. Age at presentation, BMI z-score, and gender were the variables used in logistic regression analysis to create models for T2D prediction.

Results

The regression-based model created from African American data had a sensitivity of 92% and a specificity of 89%; testing of a replication cohort showed 91% sensitivity and 93% specificity. A model based on the Hispanic American data showed 92% sensitivity and 90% specificity. Similarities between African American and Hispanic American patients include: (1) age at onset for both T1D and T2D decreased from the 1980s to the 2000s; (2) risk of T2D increased markedly with obesity. Racial/ethnic-specific observations included: (1) in African American patients, the proportion of females was significantly higher than that of males for T2D compared to T1D (p<0.0001); (2) in Hispanic Americans, the level of glycated hemoglobin (HbA1c) was significantly higher in T1D than in T2D (p<0.002) at presentation; (3) the strongest contributor to T2D risk was female gender in African Americans, while the strongest contributor to T2D risk was BMI z-score in Hispanic Americans.

Conclusions

Distinction of T2D from T1D at patient presentation was possible with good sensitivity and specificity using only three easily-assessed variables: age, gender, and BMI z-score. In African American pediatric diabetes patients, gender was the strongest predictor of T2D, while in Hispanic patients, BMI z-score was the strongest predictor. This suggests that race/ethnic specific models may be useful to optimize distinction of T1D from T2D at presentation.     

Identification of an Abbreviated Test Battery for Detection of HIV-Associated Neurocognitive Impairment in an Early-Managed HIV-Infected Cohort

Background

HIV-associated neurocognitive disorders (HAND) remain prevalent despite improved antiretroviral treatment (ART), and it is essential to have a sensitive and specific HAND screening tool.

Methods

Participants were 200 HIV-infected US military beneficiaries, managed early in the course of HIV infection, had few comorbidities, and had open access to ART. Participants completed a comprehensive, seven-domain (16-test), neuropsychological battery (∼120 min); neurocognitive impairment (NCI) was determined using a standardized score derived from demographically adjusted T-scores (global deficit score ≥0.5). Restricting the estimated administration time of the screening battery to < = 20 minutes, we examined the sensitivity and specificity of detecting NCI for all possible combinations of 2-, 3-, and 4- tests from the comprehensive battery.

Results

Participants were relatively healthy (median CD4 count: 546 cells/mm³) with 64% receiving ART. Prevalence of NCI was low (19%). The best 2-test screener included the Stroop Color Test and the Hopkins Verbal Learning Test-Revised (11 min; sensitivity = 73%; specificity = 83%); the best 3-test screener included the above measures plus the Paced Auditory Serial Addition Test (PASAT; 16 min; sensitivity = 86%; specificity = 75%). The addition of Action Fluency to the above three tests improved specificity (18 min; sensitivity = 86%; specificity = 87%).

Conclusions

Combinations of widely accepted neuropsychological tests with brief implementation time demonstrated good sensitivity and specificity compared to a time intensive neuropsychological test battery. Tests of verbal learning, attention/working memory, and processing speed are particularly useful in detecting NCI. Utilizing validated, easy to administer, traditional neuropsychological tests with established normative data may represent an excellent approach to screening for NCI in HIV.     

Continuous estrone treatment impairs spatial memory and does not impact number of basal forebrain cholinergic neurons in the surgically menopausal middle-aged rat

CEE (conjugated equine estrogens) is the most widely prescribed estrogen-only menopausal hormone therapy in the United States, and is comprised of over 50% estrone (E1) sulfate. Following CEE administration, E1 is the principal circulating estrogen. However, the cognitive and neurobiological effects of E1 in a middle-aged rodent model have not yet been evaluated. We assessed cognitive effects of continuous E1 treatment in middle-aged surgically menopausal rats using a maze battery. We also quantified number of choline acetyltransferase-immunoreactive (ChAT-IR) neurons in distinct basal forebrain regions known in earlier studies in to be impacted by the most potent naturally-circulating estrogen in rodents and women, 17β-estradiol (17β-E2), as well as CEE. On the spatial working memory delayed-match-to-sample water maze, the highest E1 dose impaired memory performance during acquisition and after delay challenge. E1 did not impact ChAT-IR neuron number in the medial septum (MS) or horizontal/vertical diagonal bands. In a comparison study, 17β-E2 increased MS ChAT-IR neuron number. Findings indicate that E1 negatively impacts spatial working memory and memory retention, and does not increase ChAT-IR neuron number in basal forebrain, as does 17β-E2. Thus, data from prior studies suggest that 17β-E2 and CEE can enhance cognition and increase number of ChAT-IR basal forebrain neurons, while here we show that E1 does not induce these effects. Findings from preclinical basic science studies can inform the design of specific combinations of estrogens that could be beneficial to the brain and cognition. Accumulating data suggest that E1 is not likely to be among these key beneficial estrogens.     

New genes of Xanthomonas citri subsp. citri involved in pathogenesis and adaptation revealed by a transposon-based mutant library

Background  

Citrus canker is a disease caused by the phytopathogens Xanthomonas citri subsp. citri, Xanthomonas fuscans subsp. aurantifolli and Xanthomonas alfalfae subsp. citrumelonis. The first of the three species, which causes citrus bacterial canker type A, is the most widely spread and severe, attacking all citrus species. In Brazil, this species is the most important, being found in practically all areas where citrus canker has been detected. Like most phytobacterioses, there is no efficient way to control citrus canker. Considering the importance of the disease worldwide, investigation is needed to accurately detect which genes are related to the pathogen-host adaptation process and which are associated with pathogenesis.     

Luteal function in mares following administration of oxytocin,cloprostenol or saline on day 0, 1 or 2 post-ovulation

Mares (n = 30) were treated in the post-ovulatory period with saline, oxytocin, or cloprostenol (Clo). Dose, administration frequency and treatment day (Day 0, 1 or 2 post-ovulation) were evaluated. Interovulatory interval of control cycles was 22.7 (+/-0.36) days with a range of 20.6 (+/-1.44) to 23.8 (+/-1.39) days among all treatment groups. Mares treated with two micro-doses of cloprostenol on Day 2 post-ovulation had the shortest interovulatory interval. This group also had the lowest mean circulating progesterone concentrations on Days 3-7 and 13, and was the slowest group to reach concentrations of 5 ng/ml. Repeated administration of cloprostenol over 24 h in the early post-ovulatory period may more effectively impair luteal function than single doses. This could negatively affect pregnancy outcome but may be effective for lysing the early post-ovulatory luteal structure when mares are not bred.