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College/university campuses comprise a distinct type of urban interface, with their generally expansive spatial pattern of alternating permanent structures, parking lots, and green spaces. The campus of the University of West Florida (UWF) in Pensacola, Florida, was constructed among second-growth longleaf pine stands recovering from extensive logging in the western-most extent of the Panhandle, with the original campus design deliberately carried out to maintain original contours and minimize tree removal. The extended campus includes a fire-excluded, longleaf-dominated landscape with active gopher tortoise populations confined to power line right-of-ways. This study (1) examined burrowing effects on soils and plant communities, and (2) estimated the age of longleaf pine stems (trees) around campus to assess the influence of human activity on population structure. Gopher tortoise sampling was confined to three discrete areas (types) for each burrow: apron (redistributed soil outside burrow), burrow (soil above burrowed cavity), and matrix (unaltered surrounding area). Within one 0.1 m2 quadrat/sample type for each of 16 burrows, density was determined for all vascular species; mineral soil was taken to a 5-cm depth. Air-dried soil was analyzed for pH, organic matter (OM), cation exchange capacity (CEC), extractable macro- and micronutrients, and extractable aluminum. All longleaf stems >2.5 cm diameter at breast height (DBH) were measured for DBH. Stem age was estimated with an allometric equation. Plant density was reduced by burrowing 7-fold on apron versus burrow and matrix sites, which did not vary between each other. Soil variables did not vary between burrow and matrix samples. Apron soils were significantly lower in pH, OM, CEC, and cations. Soil NO3− was ~3-fold higher in apron soils. Age structure of longleaf pine on campus revealed that nearly 2/3 of all stems are between 75 and 125 years old, consistent with the cessation of extensive logging of longleaf in this region.

An efficient process to synthesize Monobactam 1 from intermediates 2, 3, and 4 was developed. The process was initially enabled to deliver 500 g of 1 for exploratory toxicity studies and further im...

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Process development and multikilogram synthesis of the monocyclic β-lactam core 17 for a novel pyridone-conjugated monobactam antibiotic is described. Starting with commercially available 2-(2,2-diethoxyethyl)isoindoline-1,3-dione, the five-step synthesis features several telescoped operations and direct isolations to provide significant improvement in throughput and reduced solvent usage over initial scale-up campaigns. A particular highlight in this effort includes the development of an efficient Staudinger ketene–imine [2 + 2] cycloaddition reaction of N-Boc-glycine ketene 12 and imine 9 to form racemic β-lactam 13 in good isolated yield (66%) and purity (97%). Another key feature in the synthesis involves a classical resolution of racemic amine 15 to afford single enantiomer salt 17 in excellent isolated yield (45%) with high enantiomeric excess (98%).

This work describes the optimization and scale-up of a Buchwald–Hartwig amination reaction for the preparation of a pharmaceutical intermediate. This C–N bond formation is challenged by the use of a chiral primary amine, which both adds cost and favors formation of biaryl byproducts. In order to develop a scalable process, a number of factors had to be investigated including catalyst selection and stoichiometry of the chiral amine. These all needed to be optimized while maintaining low palladium levels in the isolated product. The reaction was found to be most effective using Pd(dba)2 with BINAP and Cs2CO3 in THF. When executed on 2.5 kg scale, these conditions provided 2.06 kg of the desired product in 80% yield with only 73 ppm residual palladium. To date, this process has been successfully executed to produce more than 12 kg of compound (S)-3.

A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate 6. A highly selective Suzuki reaction between 6 and pinacol boronate 8, followed by Boc deprotection, completed the synthesis of crizotinib 1.

Early process development work toward a promising pyrazole-based HMG-CoA reductase inhibitor is described. PF-03052334-02 (1) was prepared in 14 synthetic steps with a 21% overall yield, highlighted by a modified three-step hydroxypyrazole formation in which the yield was improved from 37% to 73%, a Suzuki/ozonolysis pathway that streamlined the downstream chemistry, and a reversed Wittig olefination strategy that improved the key coupling step from 50% to 95% yield. Multiple process hazards and most chromatography steps were removed, and a highly effective active pharmaceutical ingredient (API) salt formation, purification, and isolation protocol was also developed.

A chiral β-amino acid containing three contiguous chiral centers was synthesized efficiently in 11 steps, employing enantio-enriched β-ketoester as a key intermediate, via stereoselective catalytic hydrogenation of the corresponding enamide. Stereoselective 1,4-addition of a methyl group and protonation were key to the preparation of the desired acid 12. Mild and efficient reaction conditions were applied to the enamine formation and protection to avoid epimerization at C-4 of compounds 13 and 14. The final compound was found to display potent affinity for the α2δ-protein that is a recognized drug target for the treatment of a variety of diseases.

Development work toward an enabling synthesis of preparative scale batches of an imidazole-based HMG-CoA reductase inhibitor is described. The desired target was synthesized in 16% yield over 7 steps, highlighted by an imidazole-forming condensation reaction in which the yield was improved from 20% to >70% via modification of the solvent, acid, and amine equivalents. The step 2 acylation was improved, and a problematic benzyl ester in step 4 was converted into the corresponding benzyl amide to decrease trans-amidation during the step 5 imidazole formation. A highly effective salt formation and crystallization protocol was also developed.

This paper describes the synthesis of two amino-quinazolinediones which are potent gyrase/topoisomerase inhibitors and useful as antibacterial agents. The early scale-up work to prepare a chiral side chain on multigram scale and two different amino-quinazolinedione cores is detailed. The enabling synthesis for the side chain employed a previously reported Michael addition of MeNO2 to an enantiomerically enriched δ-amino-enoate and a two-step de-oxygenation of a lactam. Key synthetic steps for core preparation and completion of the amino-quinazolinediones include dianion-promoted cyclization via intramolecular, nucleophilic aromatic substitution, electrophilic amination, nucleophilic aromatic substitution of the side chain to the core, deprotection and isolation of the hydrochloride salt in acceptable yield.

The preparation of a few (nitrophenyl)hydroxylamines and reaction with two quinazoline-2,4-diones is described. The electrophilic aminating agents were assessed in terms of yield for the N-amination of two quinazoline-2,4-diones and safety considerations for rapid scale-up. For the amination of the described system, the best yield and the highest onset temperature were found in the same aminating agent, specifically, (4-nitrophenyl)hydroxylamine.

High resolution He(I) photoelectron spectra are reported for a racemic mixture of bromochlorofluoromethane molecules. The samples were cooled using nozzle jet expansion of the pure gas. The adiabatic and vertical ionization potentials are determinedtobe 10⋅98±0⋅05 eV and 11⋅13±0⋅06 eV,respectively.

This paper describes base-promoted reactions of N-alkoxycarbonyl-O-(nitrophenyl)hydroxylamines which contain a halogen attached to the aromatic ring. The reaction is promoted under mild conditions (NaHCO3 or K2CO3) and provides the N-alkoxycarbonyl-N-hydroxyaniline. In a crossover experiment, some scrambling was observed which suggests that the reaction is inter- and intramolecular in nature. N-Boc-(2,6-di-Cl-4-NO2-phenyl)hydroxylamine was also found to N-Boc aminate Bn2NH to form the protected hydrazine in modest yield.

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.

This paper describes base-promoted reactions of N-alkoxycarbonyl-O-(nitrophenyl)hydroxylamines which contain a halogen attached to the aromatic ring. The reaction is promoted under mild conditions (NaHCO3 or K2CO3) and provides the N-alkoxycarbonyl-N-hydroxyaniline. In a crossover experiment, some scrambling was observed which suggests that the reaction is inter- and intramolecular in nature. N-Boc-(2,6-di-Cl-4-NO2-phenyl)hydroxylamine was also found to N-Boc aminate Bn2NH to form the protected hydrazine in modest yield.

This paper describes the development of an efficient and scalable second generation synthesis of novel, pyrrole-based HMG-CoA reductase inhibitors. Compound 1 was identified as part of a discovery program aimed at finding improved treatments for hypercholesterolemia. Herein, we describe an efficient synthesis of its highly functionalized pyrrole core followed by attachment of the 3,5-dihydroxyhexanoic acid side chain via ylide olefination chemistry.

Aim The Paediatric High Dependency Audit was commissioned by the regional network to identify paediatric high dependency (PHD) activity within a specific region that has 4 funded HDU beds. Method Details of patients fulfilling the HDU criteria were collected on each site. The anonymised data was analysed centrally. Each site was visited by the lead nurse for quality purposes. Each patient fulfilling audit criteria was confirmed by the local investigator and final data checked by the lead nurse and lead clinician. PHD activity was recorded by type, diagnosis, location and length of stay (LoS) according to HRG criteria (Paediatric Minimal Care Dataset 2007) and additional criteria agreed relevant by the nine network Hospitals. A lead audit nurse was employed for audit development, analysis and data collection. A similar audit has been performed in the South West region of England. Results The network covers a paediatric population of approximately 500 000 children with nine hospitals all referring to one Paediatric Intensive Care Unit. The network crosses the SHA boundaries. Over a 12 month period, 2500 HDU activities were recorded. Within the HRG criteria the commonest indication for HDU care was oxygen therapy with saturation recording (1100). Within this group 210 had this identified as a single HDU criteria. The remainder had other interventions noted. For example, intravenous or continuous nebulised salbutamol (708), high oxygen requirements exceeding 40% (707), prolonged or recurrent convulsions (110), DKA with electrolyte abnormalities (96) and meningococcal sepsis (57) were identified most frequently as HDU activity by diagnosis. We believe there was significant underreporting of isolated oxygen therapy. LoS per patient varied between units with the individual unit median times ranging between 21.5 and 45 h. Over 1600 episodes were managed on the general paediatric ward or HDU areas utilizing the ward based staff. Conclusions HDU activity is common on general paediatric wards. It is underrecognised and better recording of activity is a prerequisite to improved funding. Training and organisational needs are apparent.

Background: To date there has not been a national consensus on the Paediatric Intensive Care nursing research priorities for the UK and Ireland. A nursing subgroup of the Paediatric Intensive Care Society (PICS) study group (SG) was established in 2007 with representation from as many UK and Irish units as possible. The aims of the group were to survey national PICU practice (through audit), acquire new knowledge by structured observation (through audit) and improve patient care by conducting rigorous research studies. PICS-SG is predominantly a medically-driven group, this subgroup intended to provide a strong nursing voice fostering an environment of collegiality and collaboration amongst PICU research-interested nurses. The group wants to develop links with European PIC nurse researchers and international links. Aims: The group met March 2010 to establish research priorities for PIC nursing research. A brainstorming session elicited a number of broad themes, which were then voted on to achieve six top priority themes. Further discussion led to specific areas/questions for audit or research. Results: The six priority research themes were: patient deterioration, PIC nursing workforce, family/parent/psychosocial issues in PIC, pain/sedation and withdrawal, risk reduction in PIC and nutrition/feeding in PIC. Implications: UK and Irish PIC nurses have now agreed upon priority nursing research areas, with a view to take this forward and collaborate nationally and internationally.

New technology is giving researchers greater independence in their use of bibliographic databases. Art librarians should promote ‘end-user services’ which provide library users with direct access to online databases, although there are a number of problems which are liable to detract from the efficiency and thoroughness associated with computer-assisted searching.

A major functional problem for the postpolio patient is the loss of ambulation ability. A retrospective study of lower extremity orthotic management for ambulation was made of 104 subjects with histories of paralytic poliomyelitis who received treatment and evaluation in a postpolio clinic. Thirty-six patients (35%) had a remote history of a surgical arthrodesis of the ankle. Fifty-six subjects (54%) reported using lower extremity orthoses after the onset of their polio. At initial postpolio clinic evaluation 19 subjects (18%) were using lower extremity orthoses, and all of these patients had a remote history of orthotic use. After clinical evaluation, a new lower extremity orthosis was recommended for 37 subjects (36%). Nine of these patients had never used orthotic devices. New orthoses for a previously braced limb or an additional orthosis for a previously unbraced limb were prescribed more frequently in previously braced patients (28 of 56 vs 9 of 48, p less than 0.02). Seventy-two percent of subjects with ankle fusion required new orthoses; 19% of those without fusion required one (p less than 0.001). A questionnaire returned by 81 subjects (78%) indicated that appropriate orthotic prescription significantly improved the ability to walk, increased perceived walking safety, and reduced knee and overall pain (p = 0.04 to 0.008).

Forty-nine men performed progressive submaximal treadmill exercise to determine the cardiopulmonary and subjective response to added resistance to breathing. Twenty subjects (controls), FEV1/FVC% = 79.2 +/- 1.4 (mean +/- SEM), were compared with 19 mildly obstructed men (OB1), FEV1/FVC% = 66.9 +/- 0.5, and 10 with moderate obstruction (OB2), FEV1/FVC% = 53.7 +/- 1.9. Separate exercise trials were performed with no added resistance (NAR), R1 = 3.5 cm H2O/L/s inspiratory and 1.5 cm H2O/L/s expiratory resistance, and R2 = 5 cm HKO/L/s inspiratory and 1.5 cm H2O/L/s expiratory resistance. Analysis of cardiopulmonary parameters was made at an oxygen consumption rate of VO2 = 1.5 L/min for all 3 obstruction groups at all 3 resistances. With NAR, all 3 groups had similar respiratory rate (RR), tidal volume (VT), minute ventilation (VE), end-tidal PCO2 (PETCO2), respiratory exchange ratio (R), heart rate (HR), and mouth pressure swing (Poral). With both R1 and R2 compared with NAR, control and OB1 subjects (at VO2 = 1.5 L/min) had reduced RR, VE, and R, and increased VT and Poral (p less than 0.01 for all). Changes with added resistance for OB2 subjects were in the same directions, but were significant only for VE and with R1 for RR. Heart rate did not change; PETCO2 increased in control subjects and with R2 in OB1 subjects. Separate analysis showed that except for the smaller increase in PETCO2 in OB2 subjects, none of the changes with added resistance in the OB1 or OB2 groups were different from changes in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)