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The development of transforming growth factor β receptor inhibitors (TGF β Ri) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGF β RI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGF β in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGF β Ri classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring. SIGNIFICANCE STATEMENT: Only a few TGF β Ri have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. The potential translations of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule, PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use S9-compliant profile for the intended-to-treat cancer patients., (Copyright © 2024 by The Author(s).)

Using orthopedic devices or prosthetic joints to treat various conditions is expected in a Traumatology and Orthopedics Unit. Recently, the materials used to build these different devices have evolved; however, pathogens can still infect these materials. Additionally, the immune system has limitations when defending against these pathogens, which results in bacterial infections like Staphylococcus aureus , Methicillin-susceptible Staphylococcus aureus ( MSSA ) and Methicillin-resistant Staphylococcus aureus ( MRSA ). A total of 276 patients who attended the Traumatology and Orthopedics Unit of our hospital from 1 June 2018 to 1 June 2019, were included in the present study. Our study analyzed the incidence of S. aureus and other bacterial pathogens in the surgical sites of patients with orthopedic implants, as well as the most used types of implants and implant materials. The specimens obtained from the surgical sites of the patients were cultured in anaerobic and aerobic media for subsequent identification using their phenotypic characteristics. Subsequently, antibiotic susceptibility tests were performed to establish the appropriate treatment. The primary pathogens identified were Staphylococcus aureus (26.4%), followed by Escherichia coli (21.0%) and Staphylococcus epidermidis (15.8%). The most commonly used implants were plates (41.7%), followed by endomedullary nails (20%), Kirschner wires (14.1%), and fixators (10.1%). As for the anatomical regions of the implants, the most frequent sites were the legs, followed by the thighs, wrists, and ankles. The pathogens were more susceptible to ciprofloxacin (95%), clindamycin (89%), and cefotaxime (86%). S. aureus is the primary infectious agent in our hospital, with an incidence of 26.4% after the placement of orthopedic implants. Although its incidence was lower compared to other tertiary hospitals, it is necessary to improve aseptic techniques in such a way as to reduce the incidence of this pathogen further.

Compound 1 is a potent TGF-β receptor type-1 (TGFβR1 or ALK5) inhibitor but is metabolically unstable. A solvent-exposed part of this molecule was used to analogue and modulate cell activity, liver microsome stability and mouse pharmacokinetics. The evolution of SAR that led to the selection of 2 (MDV6058 / PF-06952229) as a preclinical lead compound is described., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Transcriptional regulation, determined by the chromatin structure and regulatory elements interacting at promoter regions, is a key step in plant responses to environmental cues. Nitrate (NO 3 - ) is a nutrient signal that regulates the expression of hundreds of genes in Arabidopsis thaliana. Here, we integrate mRNA sequencing, genome-wide RNA polymerase II (RNPII), chromatin immunoprecipitation sequencing, and DNase sequencing datasets to establish the relationship between RNPII occupancy and chromatin accessibility in response to NO 3 - treatments in Arabidopsis roots. Genomic footprinting allowed us to identify in vivo regulatory elements controlling gene expression in response to NO 3 - treatments. NO 3 - -modulated transcription factor (TF) footprints are important for a rapid increase in RNPII occupancy and transcript accumulation over time. We mapped key TF regulatory interactions and functionally validated the role of NAP, an NAC-domain containing TF, as a new regulatory factor in NO 3 - transport. Taken together, our study provides a comprehensive view of transcriptional networks in response to a nutrient signal in Arabidopsis roots., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The metabolic activity of endogenous nitric oxide (NO) and the medical use of nitrovasodilatory drugs like isosorbide dinitrate have been shown to be potential inducers inducers of cervical ripening prior to surgical evacuation of the uterus., Objective: To assess the therapeutic efficacy and safety of combined isosorbide dinitrate-oxytocin in the management of intrauterine foetal death (IUFD)., Methods: Sixty women with IUFD after 20 weeks of gestation requesting uterine evacuation were randomly selected to receive isosorbide dinitrate gel solution (80 mg/1.5 mL; n = 30) or misoprostol gel solution (100 mcg/1.5 mL; n = 30) every 3 h with a maximum of four doses or until a Bishop score >7 was reached. Subsequently, patients received a high dose of intravenous oxytocin until complete uterus evacuation was achieved. Therapeutic efficacy was evaluated by mean the relative risk of the foetal expulsion based on comparison of event rates, and the proportion of women induced to labor at 7, 10 and 15 h after the administration of isosorbide dinitrate or misoprostol. Safety was assessed on the basis of woman´s vital signs and evaluation of adverse effects, including headache, abdominal pain, pelvic pain, lower back pain, nausea, dizziness and vomiting., Results: The foetal expulsion rate using the isosorbide dinitrate-oxytocin combination was approximately 4.4 times, and at least 2.1 times, the foetal expulsion rate with the misoprostol-oxytocin regimen at any given point in time. The proportion of women achieved vaginal delivery at 15 hours was 100% for the isosorbide dinitrate-oxytocin group and 86.7% for the misoprostol-oxytocin group. The average delivery induction interval was significantly lower when isosorbide dinitrate-oxytocin was used (8.7 ± 3.1 h) than when misoprostol-oxytocin (11.9 ± 3.1 h) was used. A total of 20% of patients in the isosorbide dinitrate-oxytocin group recorded headache, and no cases of uterine tachysystole, haemorrhage or coagulopathy were recorded., Conclusion: This study indicates that intravaginal isosorbide dinitrate followed by intravenous oxytocin was more effective than the conventional method used to induce labour in the medical management of foetal death in pregnancies after 20 weeks of gestation., Trial Registration: Clinicaltrials.gov NCT02488642., Competing Interests: The authors have declared that no competing interests exist.

Human leptospirosis is an infection that most often affects tropical countries. Since 2007, Colombia requires the notification of disease cases, enabling the observation of an increase in cases in recent years. The objectives of this article were to analyze environmental and socioeconomic variables and to evaluate their relationship with human leptospirosis cases. This is an ecological study on human leptospirosis cases aggregated by municipality and reported between 2007 and 2016. Spatial aggregation assessment was made using the Getis-Ord Gi method, and negative binomial regression was used to evaluate the relationship between environmental and socioeconomic variables with human leptospirosis. During the study period, 9,928 cases of human leptospirosis were reported, and 58.9% of municipalities reported at least one case. Four hotspots of human leptospirosis, including 18 municipalities, were identified. The results of the negative binomial model confirmed the importance of the effects of education, poverty and some climatic variables on the decadal incidence rate of human leptospirosis. Our results confirm the importance of socioeconomic determinants such as social marginality associated with violence and education, as well as ecological variables such as rainfall, height above sea level and forest coverage on the incidence rate of human leptospirosis at municipal scale.

Breast cancer surgery can benefit from regional anaesthesia techniques, which can be used as a sole anaesthetic procedure in some cases where risk for general anaesthesia is high. Regional anaesthesia allows early recovery, reduces postoperative opioid and non opioid analgesics consumption and helps early home discharge, reducing thus costs. We present a case of an 87-year-old woman with multiple comorbidities who underwent breast cancer surgery. The patient was successfully surgically treated under serratus intercostal plane block anaesthesia. We discuss the use and benefits of the serratus intercostal plane block in thoracic procedures., (Copyright © 2018 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.)

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core. Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity against EZH2, while also improving solubility and oxidative metabolic stability., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Emerging evidence points to an unexpected diversification of core promoter recognition complexes that serve as important regulators of cell-type specific gene transcription. Here, we report that the orphan TBP-associated factor TAF9B is selectively up-regulated upon in vitro motor neuron differentiation, and is required for the transcriptional induction of specific neuronal genes, while dispensable for global gene expression in murine ES cells. TAF9B binds to both promoters and distal enhancers of neuronal genes, partially co-localizing at binding sites of OLIG2, a key activator of motor neuron differentiation. Surprisingly, in this neuronal context TAF9B becomes preferentially associated with PCAF rather than the canonical TFIID complex. Analysis of dissected spinal column from Taf9b KO mice confirmed that TAF9B also regulates neuronal gene transcription in vivo. Our findings suggest that alternative core promoter complexes may provide a key mechanism to lock in and maintain specific transcriptional programs in terminally differentiated cell types.DOI: http://dx.doi.org/10.7554/eLife.02559.001., (Copyright © 2014, Herrera et al.)

Nowadays society is demanding more and more smart healthcare services that allow monitoring patient status in a non-invasive way, anywhere and anytime. Thus, healthcare applications are currently facing important challenges guided by the u-health (ubiquitous health) and p-health (pervasive health) paradigms. New emerging technologies can be combined with other widely deployed ones to develop such next-generation healthcare systems. The main objective of this paper is to review and provide more details on the work presented in "LOBIN: E-Textile and Wireless-Sensor-Network-Based Platform for Healthcare Monitoring in Future Hospital Environments", published in the IEEE Transactions on Information Technology in Biomedicine, as well as to extend and update the comparison with other similar systems. As a result, the paper discusses the main advantages and disadvantages of using different architectures and communications technologies to develop wearable systems for pervasive healthcare applications.

Important risk of groundwater pollution has been observed as a result of rapid leaching of highly soluble pesticides when used in agronomic practices as conventional formulations. This risk can be minimized through the application of the pesticide at a set rate using controlled release formulations (CRFs). In this research, CRFs of isoproturon, imidacloprid and cyromazine have been evaluated in a calcareous soil. The effects of two natural polymers (alginate and lignin) and two modifying sorbents (bentonite and activated carbon) on pesticide release kinetics from CRFs have been investigated, as well as mobility of pesticides using soil columns. The rate of pesticide release in soil from CRFs diminished in all cases in relation to technical products. From the analysis of the time taken for 50% of the active ingredient to be released into soil (T(50 soil)), it can be deduced that the release rate of pesticides can be controlled by using activated carbon in the alginate-based CRFs and mixing the pesticide with kraft lignin. Mobility experiments showed that the use of CRFs clearly reduces the presence of isoproturon and imidacloprid in the leachate compared to technical products, and to a lesser extent for cyromacine due to its high water solubility., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The pesticides isoproturon, imidacloprid and cyromazine, identified as groundwater pollutants, were incorporated in lignin-based formulations to obtain controlled release (CR) properties. The formulations were prepared by mixing the pesticide with a commercially available pine kraft lignin under melting conditions. A high efficiency of the preparations was therefore reached; it oscillated between 93.36% and 98.20% for the cyromazine and the isoproturon formulations. Kinetic-release experiments carried out in water showed that the release rate of isoproturon, imidacloprid and cyromazine from CR granules diminished in all cases in relation to the technical products. From the analysis of the time taken for 50% of the active ingredient to be released into water (T(50)), it can be deduced that the release rates were much higher in cyromazine CR formulations than in those prepared with isoproturon. However, imidacloprid showed an intermediate release rate. The obtained linear regression between T(50) values and granule size can be suitable to select the most appropriate formulation to avoid the isoproturon, imidacloprid and ciromazine tendency to leach.

Objective: To assess current management of renal cell carcinoma (RCC) extending into the inferior vena cava (IVC): staging, diagnosis, surgical approach, adjuvant therapy, prognostic factors and survival rate., Materials and Methods: Nineteen cases of RCC extending into the IVC undergoing surgical resection from January 1988 to August 2008 were reviewed. TNM staging and Neves-Zincke grading of the tumor were also assessed. Surgical approach depended on thrombus level., Results: With a perioperative mortality rate of 10.5% and a mean follow-up of 22.65 months (range 2-79), 5 patients are still alive, while 11 patients died from the disease, 1 from an unrelated cause, and 2 were lost to follow-up. Patients with metastatic disease received adjuvant treatment with immunotherapy or kinase inhibitors. Mean survival was 15.1 months. Significant differences were found in 3- and 5-year survival rates in patients staged as N0M0 as compared to all other stages (N+M0, N0M+, N+M+). No differences were found depending on thrombus level., Conclusions: RCC with thrombus in the IVC is a tumor with a high mortality rate. Surgery continues to be the best option, and requires adequate preoperative evaluation and the support of an experienced and well trained multidisciplinary team. Survival depends on disease extension.

Background: Mortality and morbidity in ambulatory surgery are rare, and thus the patient's quality of life (i.e., the ability to resume normal activities after discharge home) should be considered one of the principle end-points after ambulatory surgery and anesthesia. We conducted a systematic review of the instruments to measure the quality of recovery of ambulatory surgical patients in order to advise on the selection of appropriate measures for research and quality assurance., Methods: A systematic literature search of MEDLINE, EMBASE, CINAHL, HAPI, PsycINFO, Web of Science Search History, Biosys Previews Search, HealthStar, and ASSIA was performed to identify patient-based outcome measures to assess postoperative recovery from ambulatory anesthesia. The instruments were assessed for eight criteria: appropriateness, reliability, validity, responsiveness, precision, interpretability, acceptability, and feasibility., Results: Seven articles met the inclusion criteria set for the review. The quality of the identified instruments was variable., Conclusion: Only one instrument, 40-item Quality of recovery score, fulfilled all eight criteria, however this instrument was not specifically designed for ambulatory surgery and anesthesia.

The Interactive Module for Cavity Navigation (IMCA) was created in order to enhance the Web Environment for Surgical Skills Training in Otolaryngology (WESST--OT); later, it was found that it could be used as an independent module which allowed the practice of path navigation in any medical cavity, and its potential use with patients was evidenced. This paper describes the making of IMCA and the potential use of genetic algorithms in path generation.

Different alginate-based systems of isoproturon, imidacloprid, and cyromazine have been investigated in order to obtain controlled release (CR) properties. The basic formulation [sodium alginate (1.50%), pesticide (0.30%), and water] was modified using different amounts of bentonite and activated carbon. The higher values of encapsulation efficiency corresponded to those formulations prepared with higher percentages of activated carbon, showing higher encapsulation efficiency values for isoproturon and imidacloprid than for cyromazine, which has a higher water solubility. The kinetic experiments of imidacloprid/isoproturon release in water have shown us that the release rate is higher in imidacloprid systems than in those prepared with isoproturon. Moreover, it can be deduced that the use of bentonite and/or activated carbon sorbents reduces the release rate of the isoproturon and imidacloprid in comparison with the technical product and with alginate formulation without modifying agents. The highest decrease in release rate corresponds to the formulations prepared with the highest percentage of activated carbon. The water uptake, permeability, and time taken for 50% of the active ingredient to be released into water, T50, were calculated to compare the formulations. On the basis of a parameter of an empirical equation used to fit the pesticide release data, the release of isoproturon and imidacloprid from the various formulations into water is controlled by a diffusion mechanism. The sorption capacity of the sorbents and the permeability of the formulations were the most important factors modulating pesticide release. Finally, a linear correlation of the T50 values and the content of activated carbon in formulations were obtained.

VP16 is a virion phosphoprotein of herpes simplex virus and a transcriptional activator of the viral immediate-early (IE) genes. We identified four novel VP16 phosphorylation sites (Ser18, Ser353, Ser411, and Ser452) at late times in infection but found no evidence of phosphorylation of Ser375, a residue reportedly phosphorylated when VP16 is expressed from a transfected plasmid. A virus carrying a Ser375Ala mutation of VP16 was viable in cell culture but with a slow growth rate. The association of the mutant VP16 protein with IE gene promoters and subsequent IE gene expression was markedly reduced during infection, consistent with prior transfection and in vitro results. Surprisingly, the association of Oct-1 with IE promoters was also diminished during infection by the mutant strain. We propose that Ser375 is important for the interaction of VP16 with Oct-1, and that the interaction is required to enable both proteins to bind to IE promoters.

Objective: To determine the therapeutic efficacy and safety of a nitric oxide (NO) isosorbide dinitrate donor to induce cervical ripening of women with missed abortions before surgical evacuation of the uterus., Design: A prospective, randomised, double-blind controlled trial., Setting: Tertiary referral maternity teaching hospital. Population Sixty women with missed abortions and no cervical dilation., Methods: Women requesting surgical evacuation of the uterus were randomly selected to receive endocervical 80 mg/1.5 mL isosorbide dinitrate gel solution (n= 30) or 400 mug/1.5 mL misoprostol gel solution (n= 30) every 3 hours to a maximum of four doses or until reaching cervical ripening. Vital signs and symptoms were recorded at baseline and then every 3 hours until finishing therapy. Adverse events, such as headache, abdominal pain, pelvic pain, backache, nausea and vomiting, were evaluated., Main Outcome Measures: Probability of reaching cervical ripening >8 mm Hegar dilator; evaluated at 3, 6, 9 and 12 hours after application of isosorbide dinitrate or misoprostol., Results: The probabilities of induction of cervical ripening by isosorbide dinitrate and misoprostol after four repeated doses at 3-hour intervals were significantly different (P<0.001). Efficacy of therapy after 12 hours was 97% for the isosorbide dinitrate group and 70% for the misoprostol group. Systolic and diastolic blood pressures were lower after administration of isosorbide dinitrate than prostaglandin analogues. The difference in the mean systolic and diastolic blood pressure between treatment groups was greatest at 3 hours, with a difference of 7.7 mmHg (P<0.001) and 5.9 mmHg (P<0.003), respectively. The most frequent side effect associated with isosorbide dinitrate administration was headache, which occurred in 18 out of 30 patients, compared with only 5 out of 30 women in the misoprostol group [relative risk (RR) 2.41, 95% confidence interval (CI) 1.45-4.03, P<0.001). Women treated with misoprostol reported mainly pelvic pain (RR 3.24, 95% CI 1.99-5.27, P<0.001)., Conclusions: Intracervical administration of 80 mg isosorbide dinitrate in women with missed abortions appears to be effective for cervical ripening prior to surgical evacuation of the uterus. Differences in the incidence of non-serious adverse events are not likely to be clinically significant.

Controlled release systems (CRS), unlike the conventional formulations, facilitate a gradual and controlled discharge of the pesticides, reducing the losses by evaporation and leaching and minimizing pesticide pollution. In this study, carbofuran-an insecticide-nematicide identified as a groundwater pollutant-was incorporated in alginate-based granules to obtain controlled release properties. The effect on carbofuran release rate caused by the incorporation of bentonite, activated carbon, and different mixtures of both sorbents in alginate basic formulation was studied by immersion of the granules in water. The water uptake, sorption capacity of the sorbent, permeability, and time taken for 50% of the active ingredient to be released into water, T(50), were calculated by the comparison of the preparations. T(50) values were higher for those formulations containing bentonite and/or activated carbon (T(50) values range from 14.76 h for the alginate formulation containing only bentonite as the sorbent to 29.5 weeks for the alginate formulation containing only activated carbon as the sorbent) than for the preparation without these sorbents (11.72 h). On the basis of a parameter of an empirical equation used to fit the insecticide-nematicide release data, it appears that the release of carbofuran from the various formulations into water is controlled by a diffusion mechanism. The sorption capacity of the sorbents for carbofuran was the most important factor modulating carbofuran release. In addition, it was observed that there is a linear correlation of the T(50) values and the content of activated carbon in dry granules.

During infection by herpes simplex virus type 1 (HSV-1), the virion protein VP16 activates the transcription of viral immediate-early (IE) genes. Genetic and biochemical assays have shown that the potent transcriptional activation domain of VP16 can associate with general transcription factors and with chromatin-modifying coactivator proteins of several types. The latter interactions are particularly intriguing because previous reports indicate that HSV-1 DNA does not become nucleosomal during lytic infection. In the present work, chemical cross-linking and immunoprecipitation assays were used to probe the presence of activators, general transcription factors, and chromatin-modifying coactivators at IE gene promoters during infection of HeLa cells by wild-type HSV-1 and by RP5, a viral strain lacking the VP16 transcriptional activation domain. The presence of VP16 and Oct-1 at IE promoters did not depend on the activation domain. In contrast, association of RNA polymerase II, TATA-binding protein, histone acetyltransferases (p300 and CBP), and ATP-dependent remodeling proteins (BRG1 and hBRM) with IE gene promoters was observed in wild-type infections but was absent or reduced in cells infected by RP5. In contrast to the previous evidence for nonnucleosomal HSV-1 DNA, histone H3 was found associated with viral DNA at early times of infection. Interestingly, histone H3 was underrepresented on IE promoters in a manner dependent on the VP16 activation domain. Thus, the VP16 activation domain is responsible for recruiting general transcription factors and coactivators to IE promoters and also for dramatically reducing the association of histones with those promoters., (Copyright 2004 American Society for Microbiology)

Ubiquitin, the peptide 'tag' that targets eukaryotic proteins for degradation by the proteasome, has also been implicated in transcriptional activation. The mechanism of gene activation might include recruitment of a transcriptional elongation factor by ubiquitinated activators.

The herbicide atrazine (6-chloro-N2-ethyl-N4-isopropyl-1,3,5-triazine-2,4-diamine) was incorporated in alginate-based granules to obtain controlled-release (CR) properties. The basic formulation [sodium alginate (1.40%)-atrazine (0.60%)-water] was modified by the addition of sorbents. The effect on atrazine release rate caused by the incorporation of acid-treated bentonite (0.5 and 2.5 M H2SO4) in alginate formulation was studied by immersion of the granules in water under static conditions. The water uptake, sorption capacity of the sorbent, permeability, and time taken for 50% of the active ingredient to be released into water, t50, were calculated for the comparison of the preparations. t50 values were longer for those formulations containing acid-treated bentonite (36.78 and 29.01 days for 0.5 and 2.5 M H2SO4 treatments, respectively) than for the preparation without bentonite (9.69 days). On the basis of a parameter of an empirical equation used to fit the herbicide release data, it appears that the release of atrazine from the various formulations into water is controlled by diffusion mechanism. The sorption capacity of the sorbents and the permeability of the formulations (ranging from 4.99 to 20.83 mg day(-1) mm(-1)) were the most important factors affecting herbicide release.

Cyclodepsipeptides comprise a wide variety of cyclic peptides of natural origin and are characterized by the occurrence of at least one ester linkage. The great interest that this class of natural products has elicited in scientific community is explained by their wide range of biological activities, intriguing mechanisms of action and attractive molecular architecture. For example, they display a variety of biological effects, such as immunosuppressant, antibiotic, antifungi, antiinflammatory or antitumoral activities. In addition, many of these cyclic depsipeptides represent useful tools for the research of biological processes involved in cellular regulation. The present review deals with the most interesting aspects of the biology and the chemistry of some of these compounds.

A synthetic approach to the tunicamycins, a complex family of nucleosides with potent antibiotic and antiviral activities is reported based on diazo chemistry. The corresponding precursors for the synthesis of tunicaminyl uracil derivatives, the non-stabilized diazo derived from 13 and the aldehyde derivative of uridine, compound 4, were prepared efficiently from commercially available D-galactal and uridine, respectively. After a high yielding coupling reaction to obtain the ketone 14, a stereoselective reduction provided the corresponding tunicaminyl uracil derivative 17a and its C-7 epimer 17b. The interconversion of the diazo and aldehyde functional groups in the requisite building blocks was similarly achieved to obtain the ketone 32, which after reduction yielded the corresponding 7-deoxy-6-hydroxy tunicaminyl uracil analogs 33a and 33b.

[reaction: see text] A synthetic approach toward the liposidomycins, a family of complex nucleoside-type antibiotics, is reported based on the synthesis of epoxy-amides derived from the reaction of sulfur ylides with the uridyl aldehyde derivative 6. To this end, the epoxy-amide derivative of indoline 14 was stereoselectively prepared and, after treatment with DDQ, transformed into the corresponding N-indole epoxyamide 15. The indole 15 provides ready access to a variety of structures related to the diazepanone core present in the liposidomycins by reaction with a variety of amines.

The microbial contamination of carcasses and equipment has been studied in an industrial slaughterhouse of Iberian pigs. Samples of the surface of carcasses were taken at different stages of the process and aerobic plate count at 37 degrees C (APC), Enterobacteriaceae-count (E-count) and Escherichia coli-count (EC-count) were determined. It was demonstrated that in scalding and singeing the APC decreased (P < 0.01), while in the dehairing it increased (P < 0.01). The E-count and EC-count decreased in the scalding but increased in the evisceration (P < 0.001). The implementation of good manufacturing practices (GMP) in the stages of closure of the anus and evisceration significantly decreased the EC-count. It changed from 61.1% in carcasses without GMP that had counts higher than 1 log CFU/cm2 to only 7.4% in GMP carcasses. A final wash of the carcasses with potable water at high pressure (the only decontaminating treatment permitted in the European Union) was tested and failed to decrease the counts. It was also demonstrated that cleaning and disinfection of the dehairing and scraping machines is not effective.

We reacted N,N-diethyl-2-(dimethylsulfuranylidene)acetamide with 4,6-O-alkylidene-glycopyranoses under several experimental conditions and obtained, stereoselectively, derivatives of acyclic 3-(polyhydroxyalkyl)-alpha,beta-epoxyamides. In this way, and in one stage, we introduced, highly stereoselectively, two new chiral carbons with a substituted asymmetric epoxide group that could then be regioselectively transformed and, in addition, obtained highly functionalized acyclic structures starting from easily obtained cyclohemiacetalic monosaccharides. The configuration of the new chiral carbons of the resulting trans-epoxyamides was determined by comparing the IR, NMR, and polarimetric data with another epoxyamide of known configuration. We attempted to explain the stereochemistry of the major products by proposing a preferential conformation for the different starting aldehyde sugars in the basic reaction medium that took into account, at first, the principal electrical interactions between the carbonyl group and those unprotected hydroxyl groups with partial hydroxylate character and, secondarily, the preferred equatorial approach (exo) of the nucleophile. Finally, we studied the cyclization of the reaction products by an initial Payne transposition of the gamma-hydroxy-alpha,beta-epoxide to alpha-hydroxy-beta,gamma-epoxide, followed by its cyclization to a C-glycofuranoside.

Orthotopic liver transplantation was performed in 20 pigs. Serum total bile acids (STBA) were determined and their profile compared with standard early function parameters: total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactic acid. In phase I, the STBA level was 32.89 +/- 1.29 mumol/l. In phase II, STBA accumulated to 84.46 +/- 15.25 mumol/l (p less than 0.01), followed by hepatic clearance in phase III (63.61 +/- 9.71 mumol/1; NS). Between phase III and 6- and 12-hour samples, STBA decreased progressively, reaching values of 33.63 +/- 7.05 mumol/l at 24 h. AST was elevated in phases I, II, III, and at 6, 12 and 24 h (p less than 0.001), as was ALT (but with insignificant differences). Thus, STBA and their profile appear to be earlier and more specific indicators of early graft function than conventional parameters.