Miracle-dz/UniFAR-FTUs huggingface dataset:
Extractive Biotransformation for Production of Metabolites of Poorly Soluble Compounds: Synthesis of 32-Hydroxy-rifalazil

A novel reaction system was developed for the production of metabolites of poorly water-soluble parent compounds using mammalian liver microsomes. The system includes the selection and use of an appropriate hydrophobic polymeric resin as a reservoir for the hydrophobic parent compounds and its metabolites. The utility of the extractive biotransformation approach was shown for the production of a low-yielding, synthetically challenging 32-hydroxylated metabolite of the antibiotic rifalazil using mouse liver microsomes. To address the low solubility and reactivity of rifalazil in the predominantly aqueous microsomal catalytic system, a variety of strategies were tested for the enhanced delivery of hydrophobic substrates, including the addition of mild detergents, polyvinylpyrrolidone, glycerol, bovine serum albumin, and hydrophobic polymeric resins. The latter strategy was identified as the most suitable for the production of 32-hydroxy-rifalazil, resulting in up to 13-fold enhancement of the volumetric productivity compared with the standard aqueous system operating at the solubility limit of rifalazil. The production process was optimized for a wide range of reaction parameters; the most important for improving volumetric productivity included the type and amount of the polymeric resin, cofactor recycling system, concentrations of the biocatalyst and rifalazil, reaction temperature, and agitation rate. The optimized extractive biotransformation system was used to synthesize 32-hydroxy-rifalazil on a multimilligram scale.
Goal-directed therapy in cardiac surgery: a systematic review and meta-analysis.

BACKGROUND Perioperative mortality after cardiac surgery has decreased in recent years although postoperative morbidity is still significant. Although there is evidence that perioperative goal-directed haemodynamic therapy (GDT) may reduce surgical mortality and morbidity in non-cardiac surgical patients, the data are less clear after cardiac surgery. The objective of this review is to perform a meta-analysis on the effects of perioperative GDT on mortality, morbidity, and length of hospital stay in cardiac surgical patients. METHODS We conducted a systematic review using Medline, EMBASE, and the Cochrane Controlled Clinical Trials Register. Additional sources were sought from experts. The inclusion criteria were randomized controlled trials, mortality reported as an outcome, pre-emptive haemodynamic intervention, and cardiac surgical population. Included studies were examined in full and subjected to quantifiable analysis, subgroup analysis, and sensitivity analysis where possible. Data synthesis was obtained by using odds ratio (OR) and mean difference (MD) for continuous data with 95% confidence interval (CI) utilizing a random-effects model. RESULTS From 4986 potential studies, 5 met all the inclusion criteria (699 patients). The quantitative analysis showed that the use of GDT reduced the postoperative complication rate (OR 0.33, 95% CI 0.15-0.73; P=0,006) and hospital length of stay (MD -2.44, 95% CI -4.03 to -0.84; P=0,003). There was no significant reduction in mortality. CONCLUSION The use of pre-emptive GDT in cardiac surgery reduces morbidity and hospital length of stay.
Risks associated with permanent discontinuation of blood pressure-lowering medications in patients with type 2 diabetes

Objective: The associations of discontinuation of the study medication on major outcomes were assessed in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Trial. Methods: ADVANCE was a factorial randomized controlled trial of blood pressure lowering (a fixed combination of perindopril and indapamide vs. placebo) and intensive glucose control (vs. standard glucose control) in patients with type 2 diabetes. Patients who permanently discontinued the randomized blood pressure-lowering medication during the study period (n = 1557) were compared with others (n = 9583). Cox's proportional hazards models were used to estimate the effects of the discontinuation on the risks of macrovascular events, microvascular events together and separately and all-cause mortality, using discontinuation as a time-dependent covariate. Results: In multivariable analyses, discontinuation was associated with increased risks of combined macro and microvascular events (hazard ratio 2.24, 95% CI 1.96–2.57), macrovascular events (3.23, 2.75–3.79), microvascular events (1.38, 1.11–1.71), and all-cause mortality (7.99, 6.92–9.21) compared to continuing administration of randomized medications during the trial period, which were highest in the first year after discontinuation. These associations were similar in active and placebo groups, except in the first year after discontinuation during which event rates were lower in the active group than in the placebo group (P ⩽ 0.01). Conclusion: Discontinuation of study medication is a potent risk marker for identifying high-risk patients. Thus it is important that clinicians seek to identify such patients early after discontinuation of treatment. Although some short-term residual effects of previous active treatment can be expected, patients who discontinue require further urgent investigation and management.
Methods used by dental practice-based research network dentists to diagnose dental caries.

OBJECTIVES To (1) identify the methods that dentists in The Dental Practice-based Research Network (DPBRN) use to diagnose dental caries; (2) quantify their frequency of use, and (3) test the hypothesis that certain dentist and dental practice characteristics are significantly associated with their use. METHODS A questionnaire about methods used for caries diagnosis was sent to DPBRN dentists who reported doing some restorative dentistry; 522 dentists participated. Questions included the use of dental radiographs, the dental explorer, laser fluorescence, air-drying and fiber-optic devices and magnification as used when diagnosing primary, secondary/recurrent or non-specific caries lesions. Variations on the frequency of their use were tested using multivariate analysis and Bonferroni tests. RESULTS Overall, the dental explorer was the instrument most commonly used to detect primary occlusal caries and caries at the margins of existing restorations. In contrast, laser fluorescence was rarely used to help diagnose occlusal primary caries. For proximal caries, radiographs were used to help diagnose 75%-100% of lesions by 96% of the DPBRN dentists. Dentists who use radiographs most often to assess proximal surfaces of posterior teeth were significantly more likely to also report providing a higher percentage of patients with individualized caries prevention (p = .040) and seeing a higher percentage of pediatric patients (p = .001). CONCLUSION The use of specific diagnostic methods varied substantially. The dental explorer and radiographs are still the most commonly used diagnostic methods.
Collisional Activation by MALDI Tandem Time-of-flight Mass Spectrometry Induces Intramolecular Migration of Amide Hydrogens in Protonated Peptides*

Considerable controversy exists in the literature as to the occurrence of intramolecular migration of amide hydrogens upon collisional activation of protonated peptides and proteins. This phenomenon has important implications for the application of CID as an experimental tool to obtain site-specific information about the incorporation of deuterium into peptides and proteins in solution. Using a unique set of peptides with their carboxyl-terminal half labeled with deuterium we have shown unambiguously that hydrogen (1H/2H) scrambling is such a dominating factor during low energy collisional activation of doubly protonated peptides that the original regioselective deuterium pattern of these peptides is completely erased (Jørgensen, T. J. D., Gårdsvoll, H., Ploug, M., and Roepstorff, P. (2005) Intramolecular migration of amide hydrogens in protonated peptides upon collisional activation. J. Am. Chem. Soc.127, 2785–2793). Taking further advantage of this unique test system we have now investigated the influence of the charge state and collision energy on the occurrence of scrambling in protonated peptides. Our MALDI tandem time-of-flight experiments clearly demonstrate that complete positional randomization among all exchangeable sites (i.e. all N- and O-linked hydrogens) also occurs upon high energy collisional activation of singly protonated peptides. This intense proton/deuteron traffic precludes the use of MALDI tandem time-of-flight mass spectrometry to obtain reliable information on the specific incorporation pattern of deuterons obtained during exchange experiments in solution.
Hepatitis B vaccination: Risk‐benefit profile and the role of systematic reviews in the assessment of causality of adverse events following immunisation

Since the early 1990s, several cases of demyelinating diseases were reported in France in association with the vaccination against hepatitis B. A large scientific, regulatory, and public debate took place to reassure the growing concern of the population. The objective of this paper is to examine the decision process undertaken both in France and in Italy; to outline the main findings of the studies conducted before and after the French decision to suspend the vaccination campaign among adolescents; and to describe the contribution of systematic review and causality criteria in the evaluation of the risk‐benefit profile of vaccines. Even on the basis of the early findings, which appeared to be compatible with a low increase in the risk associated with the vaccination, it was apparent that the risk‐benefit profile was unchanged for newborns, and was essentially unchanged for adolescents and for high‐risk adults. The availability of subsequent negative association studies provided further reassurance. It is essential to rely on well‐conducted systematic reviews to produce valid and reliable estimates of the risk‐benefit profile. J. Med. Virol. 67:451–453, 2002. © 2002 Wiley‐Liss, Inc.
Quadriceps EMG in Open and Closed Kinetic Chain Tasks in Women With Patellofemoral Pain

The authors investigated whether the discrepancy noted in the literature regarding delayed and decreased activity in vastus medialis obliquus (VMO) in people with patellofemoral pain (PFP) depends on the nature of the open kinetic chain (OKC) and the closed kinetic chain (CKC) in the experimental task. They hypothesized that activity in VMO would be more delayed and decreased in CKC tasks than in OKC tasks. Women with PFP (n = 17) and healthy controls (n = 17) performed isometric quadriceps contractions in CKC and OKC tasks. The authors manipulated only the application of resistance. Electromyographs (EMGs) showed that participants with PFP reacted later and activated the quadriceps more in the CKC task but had intramuscular quadriceps coordination similar to that of controls. The nature of the OKC task or the CKC task does not seem to explain contradictory findings regarding VMO activation.
Fibular aplasia, tibial campomelia, and oligosyndactyly in a male newborn infant: A case report and review of the literature

We report on a male newborn with a rarely described congenital limb deficiency syndrome consisting of shortening and anterior bowing of the right lower limb at the distal third of the tibia with associated overlying soft tissue dimpling, oligodactyly of the right foot, and a left‐sided oligosyndactyly of the hand. The right hand and left lower limb were clinically normal. Radiographic examination revealed complete absence of the right fibula, absence of the right‐sided Vth ray, and anterior bowing and shortening of the right‐sided tibia. Femora, humeri, ulnae, and radii were normal. The infant had neither facial dysmorphia nor other associated anomalies. A limb deficiency syndrome comparable to this case has been reported in a female by Hecht and Scott [1981; Clin Genet 20:432–437], the only report classified under OMIM 246570 so far. We found two other reports describing three cases comparable to our case and the female reported by Hecht and Scott [1981], and reviewed these cases. The major common findings in all the five cases consist of fibular aplasia, tibial campomelia, and oligosyndactyly. Therefore, we propose to name it fibular aplasia‐tibial campomelia‐oligosyndactyly (FATCO) syndrome. Additional case reports are needed for further delineation of this rare limb deficiency syndrome. © 2005 Wiley‐Liss, Inc.
Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension

ObjectiveTo determine whether inhalation of aerosolized sildenafil with and without inhaled nitric oxide (NO) causes selective pulmonary vasodilation in a sheep model of pulmonary hypertension. DesignA controlled laboratory study in instrumented, awake, spontaneously breathing lambs. SettingAnimal research laboratory affiliated with a university hospital. SubjectTwenty Suffolk lambs. InterventionsLambs were instrumented with a carotid artery catheter, a pulmonary artery catheter, and a tracheostomy tube and studied awake. After baseline measurements, pulmonary hypertension was induced by the continuous infusion of U46619, a thromboxane A2 analog. After breathing three concentrations of inhaled NO (2, 5, and 20 ppm), lambs were divided into two groups. Group 1 (n = 7) breathed aerosols containing 1, 10, and 30 mg of sildenafil alone, and group 2 (n = 4) simultaneously breathed NO (2 and 5 ppm) and aerosols containing 10 mg of sildenafil. Hemodynamic measurements were obtained before and at the end of each drug administration. Venous admixture was calculated, and plasma cyclic guanosine monophosphate and sildenafil concentrations were measured. Measurements and Main Results Aerosols containing 10 mg and 30 mg of sildenafil selectively decreased the pulmonary artery pressure by 21% ± 3% and 26% ± 3%, respectively (p < .05 vs. baseline pulmonary hypertension). When 10 mg of sildenafil was inhaled while simultaneously breathing 2 ppm and 5 ppm NO, the pulmonary artery pressure decreased by 35% ± 3% and 43% ± 2% (p < .05 vs. baseline pulmonary hypertension). Inhaled sildenafil did not impair systemic oxygenation, increase right-to-left intrapulmonary shunting, or impair the ability of inhaled NO to reduce right-to-left shunting. ConclusionsNebulized sildenafil is a selective pulmonary vasodilator that can potentiate the pulmonary vasodilating effects of inhaled NO.
Evaluation of the quality of radiotherapy randomized trials for painful bone metastases

The quality of randomized radiotherapy studies investigating the palliation of painful bone metastases has been questioned, with some authors recognizing the potential impact of bias on result interpretation. However, there has been no published comprehensive evaluation of quality assessment. The goals of the current study were to evaluate the quality of randomized studies using a validated checklist and to discuss implications and future directions.
Norgestomet and gonadotropin-releasing hormone enhance corpus luteum function and fertility of postpartum suckled beef cows.

In Exp. 1,101 suckled beef cows were administered two injections of prostaglandin F2 alpha (PGF2 alpha) 11 d apart. Cows in Group 1 received no additional treatment. Cows in Groups 2 and 3 received 250 micrograms of GnRH plus 47-h calf removal. Cows in Group 3 also received a norgestomet ear implant that was inserted 4 d after the first PGF2 alpha injection and left in situ for 8 d. The second PGF2 alpha injection was administered approximately 28 h before the time of norgestomet implant removal. The GnRH was administered approximately 30 h after the time of norgestomet implant removal (or 58 h after the second PGF2 alpha injection). Calf removal was the period from the time of implant removal to AI. All cows were artificially inseminated once 75 h after the second PGF2 alpha injection (47 h after implant removal). Reproductive status before the time of GnRH treatment (presynchronization) was determined by multiple sampling (2, 13, and 23 d before GnRH treatment) for blood progesterone concentrations (62% anestrous and 38% cyclic). The GnRH treatment increased (P < .01) the ovulation response and norgestomet reduced (P < .01) the incidence of short luteal phases in the presynchronization anestrous cows. Norgestomet treatment increased (P < .05) the timed breeding pregnancy rates for both presynchronization anestrous and cyclic cows. In Exp. 2, 174 suckled beef cows were administered Syncro-Mate B (which includes norgestomet). Cows in Group 1 received no additional treatment, whereas cows in Group 2 received 250 micrograms of GnRH (30 h after norgestomet implant removal). (ABSTRACT TRUNCATED AT 250 WORDS)
Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1–dependent

Discodermolide is a microtubule-stabilizing agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, reintroduction of a nonphosphorylatable mutant (Thr-37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32-resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation, and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence.
Effect of meningitis and probenecid on the penetration of vancomycin into cerebrospinal fluid in rabbits

This study examined the effects of experimental pneumococcal meningitis and probenecid administration on the penetration of parenterally administered vancomycin into cerebrospinal fluid in rabbits. Bacterial killing was also examined in infected animals. Meningitis was induced by intracisternal inoculation of Streptococcus pneumoniae. Vancomycin was administered in a loading dose followed by a continuous intravenous infusion for 6 h. Serum and cerebrospinal fluid samples were obtained at 0, 2, 4, and 6 h for antibiotic assays and quantitative cultures. Meningitis significantly enhanced the penetration of vancomycin into cerebrospinal fluid, but probenecid administration had no effect. In normal rabbits, at 6 h the mean percent penetration (cerebrospinal fluid concentration/serum concentration x 100%) +/- the standard deviation was 1.9 +/- 0.9% in the nonprobenecid group (n = 10) and 1.9 +/- 1.1% in the probenecid group (n = 9). In rabbits with experimental pneumococcal meningitis, the mean percent penetration at 6 h was 3.9 +/- 2.6% in the nonprobenecid group (n = 11) and 4.3 +/- 2.1% in the probenecid group (n = 9). Mean bacterial titers in the cerebrospinal fluid of infected animals decreased by more than 3.0 log 10 colony-forming units per ml in both the nonprobenecid and the probenecid groups.
Small-Molecule Probes Targeting the Viral PPxY-Host Nedd4 Interface Block Egress of a Broad Range of RNA Viruses

ABSTRACT Budding of filoviruses, arenaviruses, and rhabdoviruses is facilitated by subversion of host proteins, such as Nedd4 E3 ubiquitin ligase, by viral PPxY late (L) budding domains expressed within the matrix proteins of these RNA viruses. As L domains are important for budding and are highly conserved in a wide array of RNA viruses, they represent potential broad-spectrum targets for the development of antiviral drugs. To identify potential competitive blockers, we used the known Nedd4 WW domain-PPxY interaction interface as the basis of an in silico screen. Using PPxY-dependent budding of Marburg (MARV) VP40 virus-like particles (VLPs) as our model system, we identified small-molecule hit 1 that inhibited Nedd4-PPxY interaction and PPxY-dependent budding. This lead candidate was subsequently improved with additional structure-activity relationship (SAR) analog testing which enhanced antibudding activity into the nanomolar range. Current lead compounds 4 and 5 exhibit on-target effects by specifically blocking the MARV VP40 PPxY-host Nedd4 interaction and subsequent PPxY-dependent egress of MARV VP40 VLPs. In addition, lead compounds 4 and 5 exhibited antibudding activity against Ebola and Lassa fever VLPs, as well as vesicular stomatitis and rabies viruses (VSV and RABV, respectively). These data provide target validation and suggest that inhibition of the PPxY-Nedd4 interaction can serve as the basis for the development of a novel class of broad-spectrum, host-oriented antivirals targeting viruses that depend on a functional PPxY L domain for efficient egress. IMPORTANCE There is an urgent and unmet need for the development of safe and effective therapeutics against biodefense and high-priority pathogens, including filoviruses (Ebola and Marburg) and arenaviruses (e.g., Lassa and Junin) which cause severe hemorrhagic fever syndromes with high mortality rates. We along with others have established that efficient budding of filoviruses, arenaviruses, and other viruses is critically dependent on the subversion of host proteins. As disruption of virus budding would prevent virus dissemination, identification of small-molecule compounds that block these critical viral-host interactions should effectively block disease progression and transmission. Our findings provide validation for targeting these virus-host interactions as we have identified lead inhibitors with broad-spectrum antiviral activity. In addition, such inhibitors might prove useful for newly emerging RNA viruses for which no therapeutics would be available.