Clinical Applications of Prostaglandins in Dogs and Cats

In the biological sciences today there are few substances that generate as much interest as prostaglandins. They have found widespread use in veterinary medicine, yet are only approved by the FDA for specific uses in cattle and horses. However, practical applications in the dog and cat have been reported by clinicians and have been evaluated in clinical research projects

Antigen-Independent Selection of T15 Idiotype During B-Cell Ontogeny In Mice

Precursors of B cells capable of responding to a T-independent form of phosphorylcholine (PC) in splenic focus assays were detected in the spleens of neonatal mice as early as 4 days after birth. The earliest anti-PC B cells were T15-. T15+ foci-forming B cells were first detected 6 days after birth and expanded rapidly to constitute greater than 80% of the total PC-specific foci by day 10. Injection of heat-killed S. pneumoniae (R36A) into neonatal mice resulted in priming of the antibody response to PC, with an idiotype profile reflecting that of precursors of foci-forming B cells at the time of antigen administration. Priming of 2-dayold mice with 2 X106 and 2 X107 R36A induced a five- and ten-fold increase in the antibody response to phosphorylcholine 6 to 8 weeks later. However, only 10 to 15% of the serum antibodies expressed the normally dominant T15 idiotype. Doses below 2 x105 R36A showed no detectable priming activity. PC-specific hybridomas derived from mice injected with 2 X107 R36A 2 days after birth lacked the idiotypic and molecular characteristics typical of T15+ antibodies. Antibodies to phosphorylcholine, raised by immunization of 6-week-old mice are normally protective against pneumococcal infection. However, serum antibodies from mice treated with R36A 2 days after birth and responding to phosphorylcholine following challenge with R36A at 6 weeks of age failed to protect against deliberate infection with virulent S. pneumoniae. These observations imply that the antigen phosphorylcholine does not play a role in the selective expansion and dominant expression of the T15 idiotype

DNA adjuvants for potent mucosal immunity

In order to develop safe vaccines for effective mucosal immunity to major pulmonary bacterial infections, one must consider appropriate vaccine antigens (Ags), delivery systems and nontoxic molecular adjuvants. Such vaccine constructs can induce Ag-specific immune responses which provide effective protection from mucosal infections. In particular, it has been shown that adjuvant-based mucosal vaccine preparations are relatively easy to construct by simply mixing the adjuvant with the bacterial Ag, and the resulting vaccine can elicit protective immunity. We have studied DNA-based nasal adjuvants targeting mucosal dendritic cells (DCs) in order to induce Ag-specific mucosal and systemic immune responses that provide essential protection against microbial pathogens which invade our mucosal surfaces. In this review, we initially introduce a plasmid encoding the cDNA of Flt3 ligand (pFL), a molecule which is a growth factor for DCs as an effective adjuvant for mucosal immunity to pneumococcal infections. Next, we discuss the potential of adding unmethylated CpG oligodeoxynucleotide together with pFL together with a pneumococcal Ag for protection from pneumococcal infections. To do this, we have used pneumococcal surface protein A as vaccine for the restoration of mucosal immunity in aging. Further, we have also used our nasal pFL adjuvant system with phosphorylcholine-keyhole limpet hemocyanin (PC-KLH) in pneumococcal vaccine development, to successfully induce complete protection from nasal carriage by Streptococcus pneumoniae. Finally, we discuss the possibility that anti-PC antibodies induced by nasal delivery of pFL plus PC-KLH may play a protective role for prevention of atherogenesis and thus block the subsequent development of cardiovascular disease

Stably accessing octave-spanning microresonator frequency combs in the soliton regime

Microresonator frequency combs can be an enabling technology for optical frequency synthesis and timekeeping in low size, weight, and power architectures. Such systems require comb operation in low-noise, phase-coherent states such as solitons, with broad spectral bandwidths (e.g., octave-spanning) for self-referencing to detect the carrier-envelope offset frequency. However, stably accessing such states is complicated by thermo-optic dispersion. For example, in the Si3N4 platform, precisely dispersion-engineered structures can support broadband operation, but microsecond thermal time constants have necessitated fast pump power or frequency control to stabilize the solitons. In contrast, here we consider how broadband soliton states can be accessed with simple pump laser frequency tuning, at a rate much slower than the thermal dynamics. We demonstrate octave-spanning soliton frequency combs in Si3N4 microresonators, including the generation of a multi-soliton state with a pump power near 40 mW and a single-soliton state with a pump power near 120 mW. We also develop a simplified two-step analysis to explain how these states are accessed in a thermally stable way without fast control of the pump laser, and outline the required thermal properties for such operation. Our model agrees with experimental results as well as numerical simulations based on a Lugiato-Lefever equation that incorporates thermo-optic dispersion. Moreover, it also explains an experimental observation that a member of an adjacent mode family on the red-detuned side of the pump mode can mitigate the thermal requirements for accessing soliton states

A Kerr-microresonator optical clockwork

Kerr microresonators generate interesting and useful fundamental states of electromagnetic radiation through nonlinear interactions of continuous-wave (CW) laser light. Using photonic-integration techniques, functional devices with low noise, small size, low-power consumption, scalable fabrication, and heterogeneous combinations of photonics and electronics can be realized. Kerr solitons, which stably circulate in a Kerr microresonator, have emerged as a source of coherent, ultrafast pulse trains and ultra-broadband optical-frequency combs. Using the f-2f technique, Kerr combs support carrier-envelope-offset phase stabilization for optical synthesis and metrology. In this paper, we introduce a Kerr-microresonator optical clockwork based on optical-frequency division (OFD), which is a powerful technique to transfer the fractional-frequency stability of an optical clock to a lower frequency electronic clock signal. The clockwork presented here is based on a silicon-nitride (Si$_3$N$_4$) microresonator that supports an optical-frequency comb composed of soliton pulses at 1 THz repetition rate. By electro-optic phase modulation of the entire Si$_3$N$_4$ comb, we arbitrarily generate additional CW modes between the Si$_3$N$_4$ comb modes; operationally, this reduces the pulse train repetition frequency and can be used to implement OFD to the microwave domain. Our experiments characterize the residual frequency noise of this Kerr-microresonator clockwork to one part in $10^{17}$, which opens the possibility of using Kerr combs with high performance optical clocks. In addition, the photonic integration and 1 THz resolution of the Si$_3$N$_4$ frequency comb makes it appealing for broadband, low-resolution liquid-phase absorption spectroscopy, which we demonstrate with near infrared measurements of water, lipids, and organic solvents

Pneumococcal surface protein A of invasive Streptococcus pneumoniae isolates from Colombian children.

Pneumococcal surface protein A (PspA) elicits protection in mice against fatal bacteremia and sepsis caused by genetically diverse pneumococci and protects against carriage and lung infection. We determined the PspA families of invasive isolates of Streptococcus pneumoniae recovered from Colombian children <5 years of age. That 97.5% of Colombian isolates belong to PspA families 1 and 2 supports the hypothesis that a human PspA vaccine covering a few PspA families could be broadly effective

Immunizations with pneumococcal surface protein A and pneumolysin are protective against pneumonia in a murine model of pulmonary infection with Streptococcus pneumoniae

Intranasal infection of mice with certain strains of capsular group 19 Streptococcus pneumoniae can result in focal pneumonia in the absence of bacteremia. Using this model of murine pneumonia, we demonstrated that immunization with recombinant forms of either pneumococcal surface protein A (PspA) or PdB (a genetically detoxified derivative of pneumolysin) elicited significant protection against focal pulmonary infection. This may be the first demonstration that a proposed vaccine antigen can protect against pneumococcal pneumonia. The best protection was obtained by immunizing mice with a mixture of PspA and PdB, indicating that the protection elicited by these antigens can complement each other. This result is in agreement with previous studies that used pneumococcal sepsis and nasal colonization models and demonstrate that the best protein vaccines for prevention of infection may be those that include more than one protection-eliciting pneumococcal protein.David E. Briles, Susan K. Hollingshead, James C. Paton, Edwin W. Ades, Lea Novak, Frederik W. van Ginkel, and William H. Benjamin, Jr

Relative Fitness of Fluoroquinolone-resistant Streptococcus pneumoniae

Fluoroquinolone resistance in Streptococcus pneumoniae is primarily mediated by point mutations in the quinolone resistance–determining regions of gyrA and parC. Antimicrobial resistance mutations in housekeeping genes often decrease fitness of microorganisms. To investigate the fitness of quinolone-resistant S. pneumoniae (QRSP), the relative growth efficiencies of 2 isogenic QRSP double mutants were compared with that of their fluoroquinolone-susceptible parent, EF3030, by using murine nasopharyngeal colonization and pneumonia models. Strains containing the GyrA: Ser81Phe, ParC: Ser79Phe double mutations, which are frequently seen in clinical QRSP, competed poorly with EF3030 in competitive colonization or competitive lung infections. However, they efficiently produced lung infection even in the absence of EF3030. The strain containing the GyrA: Ser81Phe, ParC: Ser79Tyr double mutations, which is seen more frequently in laboratory-derived QRSP than in clinical QRSP, demonstrated reduced nasal colonization in competitive or noncompetitive lung infections. However, the strain was equally able to cause competitive or noncompetitive lung infections as well as EF3030