Expedient and Diastereodivergent Assembly of Terpenoid Decalin Subunits having Quaternary Stereocenters through Organocatalytic Robinson Annulation of Nazarov Reagent.

We report an expedient approach to highly functionalized cis- and trans-decalines that could function as key structural subunits toward the synthesis of various classes of terpenoids. Key to the strategy is an organocatalyzed Robinson annulation reaction of the Nazarov reagent that affords chiral enone building blocks with high enantioselectivities. The quaternary carbon stereogenic center can direct the subsequent reactions and allow the rapid and diastereoconvergent assembly of complex decalines with contiguous stereocenters.

Drugs against Mycobacterium tuberculosis 3-isopropylmalate dehydrogenase can be developed using homologous enzymes as surrogate targets.

3-Isopropylmalate dehydrogenase (IPMDH) from Mycobacterium tuberculosis (Mtb) may be a target for specific drugs against this pathogenic bacterium. We have expressed and purified Mtb IPMDH and determined its physicalchemical and enzymological properties. Size-exclusion chromatography and dynamic light scattering measurements (DLS) suggest a tetrameric structure for Mtb IPMDH, in contrast to the dimeric structure of most IPMDHs. The kinetic properties (kcat and Km values) of Mtb IPMDH and the pH-dependence of kcat are very similar to both Escherichia coli (Ec) and Thermus thermophilus (Tt) IPMDHs. The stability of Mtb IPMDH in 8 M urea is close to that of the mesophilic counterpart, Ec IPMDH, both of them being much less stable than the thermophilic (Tt) enzyme. Two known IPMDH inhibitors, O-methyl oxalohydroxamate and 3-methylmercaptomalate, have been synthesised. Their inhibitory effects were found to be independent of the origin of IPMDHs. Thus, experiments with either Ec or Tt IPMDH would be equally relevant for designing specific inhibitory drugs against Mtb IPMDH.

Understanding why patients with immune thrombocytopenia are deeply divided on splenectomy.

BACKGROUND: Splenectomy is an effective treatment for chronic immune thrombocytopenia (ITP); however, patients' willingness to accept splenectomy is variable. OBJECTIVE: To explore why some ITP patients accepted splenectomy when recommended by their physician while others refused. DESIGN: Qualitative descriptive study using one-to-one, in-depth patient interviews and a team-based approach to thematic analysis. RESULTS: Of 25 patients interviewed, 15 refused splenectomy and 10 accepted and were awaiting surgery. Themes about the influences on splenectomy decision making that emerged from patient interviews were (i) the perceived impact of ITP on quality of life, (ii) patients' view of splenectomy as a last resort treatment, (iii) patients' interpretations of the rates of treatment success and failure and (iv) a perceived lack of familiarity about ITP. Patients who accepted splenectomy perceived their disease as having a negative impact on their quality of life, whereas patients who refused felt their situation was not severe enough to warrant surgery. Patients developed their own experiential interpretations of the success rates of splenectomy quoted to them. A general lack of awareness of the clinical impact of ITP and its cause was identified by patients as barriers to choosing splenectomy. CONCLUSIONS: Patients' disease experience, perceptions of the lack of treatment alternatives, interpretations of treatment success and failure rates and a general lack of awareness about ITP influenced treatment choice. This study represents a first step towards contextualizing treatment decision making in ITP, focusing on patient preferences and values.

Substituent effect on the photoreduction kinetics of benzophenone.

The kinetics of the photoreduction of four benzophenone derivatives by isopropyl alcohol was examined in acetonitrile, namely, tetra-meta-trifluoromethyl-, di-para-trifluoromethyl-, di-para-methoxy benzophenone, and, for comparison, the unsubstituted molecule itself. The basic spectroscopic (absorption and phosphorescence spectra) and photophysical (quantum yields and excited state energies) properties were established, and the key kinetic parameters were determined by the laser flash photolysis transient absorption technique. The rate coefficients of both the primary and secondary photoreduction reaction show remarkable dependence on ring substitution. This substantial effect is caused by the considerable change in the activation energy of the corresponding process. The experimental results as well as DFT quantum chemical calculations clearly indicate that these benzophenone derivatives all react as n-π* excited ketones, and the rate as well as the activation energy of the reduction steps change parallel with the reaction enthalpies, the determining factor being the stability of the forming aromatic ketyl radicals. The secondary photoreduction of benzophenones by the aliphatic ketyl radical formed in the primary step occurs via a hydrogen bonded complex. The binding energy of the hydrogen bonded complex between the aliphatic ketyl radical reactant and a solvent molecule is a critical parameter influencing the observable rate of the secondary photoreduction.

Benchmarking: applications to transfusion medicine.

Benchmarking is as a structured continuous collaborative process in which comparisons for selected indicators are used to identify factors that, when implemented, will improve transfusion practices. This study aimed to identify transfusion medicine studies reporting on benchmarking, summarize the benchmarking approaches used, and identify important considerations to move the concept of benchmarking forward in the field of transfusion medicine. A systematic review of published literature was performed to identify transfusion medicine-related studies that compared at least 2 separate institutions or regions with the intention of benchmarking focusing on 4 areas: blood utilization, safety, operational aspects, and blood donation. Forty-five studies were included: blood utilization (n = 35), safety (n = 5), operational aspects of transfusion medicine (n = 5), and blood donation (n = 0). Based on predefined criteria, 7 publications were classified as benchmarking, 2 as trending, and 36 as single-event studies. Three models of benchmarking are described: (1) a regional benchmarking program that collects and links relevant data from existing electronic sources, (2) a sentinel site model where data from a limited number of sites are collected, and (3) an institutional-initiated model where a site identifies indicators of interest and approaches other institutions. Benchmarking approaches are needed in the field of transfusion medicine. Major challenges include defining best practices and developing cost-effective methods of data collection. For those interested in initiating a benchmarking program, the sentinel site model may be most effective and sustainable as a starting point, although the regional model would be the ideal goal.

Utilization of platelet transfusions in the intensive care unit: indications, transfusion triggers, and platelet count responses.

BACKGROUND: A description of current platelet (PLT) transfusion practice in the intensive care unit (ICU) is needed. STUDY DESIGN AND METHODS: All thrombocytopenic patients (PLT count, <150 x 10(9)/L) who received PLT transfusions were identified from a previous prospective study of consecutive medical-surgical ICU patients; trauma, orthopedic, and cardiac surgery were exclusions. Risk factors for ineffective transfusions were examined. RESULTS: Of 261 ICU patients, 118 (45.2%) had thrombocytopenia and a PLT count nadir of less than 50 x 10(9) per L (n = 22), 50 to 99 x 10(9) per L (n = 37), and 100 to 149 x 10(9) per L (n = 59). Twenty-seven (22.9%) patients received PLT transfusions (n = 76 transfusions) and 37 (31.4%) had major bleeding. PLT dose was approximately 3 to 4 x 10(11) per L transfusion. Therapeutic (n = 24) and prophylactic (n = 52) PLT transfusion triggers were 51 x 10(9) per L (interquartile range [IQR], 26 to 68) and 41 x 10(9) per L (IQR, 20 to 57), respectively, as measured at a median of 4.5 hours (IQR, <1.6 to 6.9) before transfusion. A single PLT transfusion resulted in a median PLT increase of 14 x 10(9) per L (IQR, -2 to 30) measured at 5.2 hours (IQR, 1.8 to 8.8) after the transfusion; however, no PLT count increase was observed after 17 transfusions given to 13 (48.1%) patients. No risk factors for ineffective transfusions were identified. CONCLUSIONS: Among critically ill patients, most PLT transfusions were administered to prevent, rather than to treat, bleeding, with a transfusion trigger of 40 to 50 x 10(9) per L. Nearly half of ICU patients who received transfusions failed to mount a PLT count increase after a single transfusion. Prospective studies are needed to determine the effects of PLT transfusions on bleeding and predictors of ineffective transfusions in the ICU.