L-arginine-containing mesoporous silica nanoparticles embedded in dental adhesive (Arg@MSN@DAdh) for targeting cariogenic bacteria.

Dental caries is the major biofilm-mediated oral disease in the world. The main treatment to restore caries lesions consists of the use of adhesive resin composites due to their good properties. However, the progressive degradation of the adhesive in the medium term makes possible the proliferation of cariogenic bacteria allowing secondary caries to emerge. In this study, a dental adhesive incorporating a drug delivery system based on L-arginine-containing mesoporous silica nanoparticles (MSNs) was used to release this essential amino acid as a source of basicity to neutralize the harmful acidic conditions that mediate the development of dental secondary caries. The in vitro and bacterial culture experiments proved that L-arginine was released in a sustained way from MSNs and diffused out from the dental adhesive, effectively contributing to the reduction of the bacterial strains Streptococcus mutans and Lactobacillus casei. Furthermore, the mechanical and bonding properties of the dental adhesive did not change significantly after the incorporation of L-arginine-containing MSNs. These results are yielding glimmers of promise for the cost-effective prevention of secondary caries.

Kidney-Protector Lipidic Cilastatin Derivatives as Structure-Directing Agents for the Synthesis of Mesoporous Silica Nanoparticles for Drug Delivery.

Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.

Versatile Route to trans-Platinum(II) Complexes via Manipulation of a Coordinated 3-(Pyridin-3-yl)propanoic Acid Ligand.

We describe the direct coupling of alcohols and amines to a 3-(pyridin-3-yl)propanoic acid ligand coordinated to a Pt(II) to afford ester and amide derivatives. Using this approach, a family of trans-Pt(II) compounds with amine ligands bearing long perfluorinated chains was prepared, as these chains potentially endow the complexes with thermoactivatable properties. Related compounds with alkyl chains in place of the perfluorinated chains were also prepared as controls using the same direct coupling method. The stability of the complexes in solution, their reactivity with DNA and proteins, and their antiproliferative activity evaluated in tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK293) cells at 37 °C and following exposure to elevated temperatures (that mimic the temperatures employed in thermotherapy) were also studied to assess their utility as putative (thermoactivated) anticancer agents.

Influence of a preventive program on the oral health-related quality of life (OHRQoL) of European pregnant women: a cohort study.

The aim of this study was to compare the impact of oral health on quality of life of a group of pregnant women enrolled in a program of oral health with respect to a control group of non-pregnant women. A cross-sectional study involving a sociodental indicator OHIP-14 and a dental examination was completed to assess pregnant women's knowledge of oral health, hygienic habits, periodontal and caries index. Data were collected from 113 pregnant women and 113 non-pregnant women. Sociodemographic data for both groups were homogeneous. Pregnant women have better values of general and oral health, even though they have not perceived need for dental treatment, compared with control group. A worse periodontal health was observed for the control group. Our results showed that quality of life in pregnant women has been influenced with a statistical significance (p < 0.05) by the variables age, unemployment, level of education, immigration, frequency of brushing, type of dental practice, self-reported general and oral health and perceived treatment needs. The oral quality of life of pregnant women seems to be positively influenced by the incorporation of preventive oral programs during pregnancy.

Enhanced Cytotoxicity and Reactivity of a Novel Platinum(IV) Family with DNA-Targeting Naphthalimide Ligands.

Pt(IV) complexes are known as prodrugs that can potentially overcome cisplatin limitations by slowing down its reactivity and, once reduced, act as the corresponding Pt(II) drugs. We report a new approach toward trans Pt(IV) complexes, conceived to afford nonconventional active trans Pt(II) complexes with dual-targeting properties. The reduction of the complexes has been studied in the presence of ascorbic acid and glutathione, showing that different species are formed in the process. The interaction with DNA after reduction has been also studied and correlated to the formation of Pt(II) species. The cytotoxicity profile of the Pt(IV) complexes corroborated the rationale behind this approach.

Intravascular Papillary Endothelial Hyperplasia at Foot Level: A Case Report and Literature Review.

Intravascular papillary endothelial hyperplasia is a benign vascular lesion. Its importance lies in the differential diagnosis of malignant vascular neoplasms, such as angiosarcoma, to avoid unnecessary aggressive treatment. We present a case report on this type of tumor at the dorsal region of the foot to describe the pathogenic and histologic features of this lesion.

[Translated article] Adjusted indirect comparison of zanubrutinib and ibrutinib in first-line treatment of chronic lymphocytic leukemia.

OBJECTIVE: The aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. METHOD: A literature search was conducted in Pubmed and Embase on November 10, 2022 for phase III clinical trials studying Bruton tyrosine kinase inhibitors in monotherapy in the first-line setting for chronic lymphocytic leukemia. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. RESULT: Of the 39 studies obtained in the review, 2 clinical trials were selected: 1 for zanubrutinib and 1 for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were atrial fibrillation, hypertension, and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the equivalent therapeutic alternatives guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives. CONCLUSIONS: Assuming the uncertainty associated with the adjusted indirect comparison, zanubrutinib could be considered equivalent in efficacy to ibrutinib, however, the presence of differentiating safety features precludes assigning the 2 alternatives as equivalent therapeutic alternatives.

Adjusted indirect comparison of zanubrutinib and ibrutinib in first-line treatment of chronic lymphocytic leukemia. / Comparación indirecta ajustada de zanubrutinib e ibrutinib en el tratamiento de primera línea de la leucemia linfocítica crónica.

OBJECTIVE: The aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. METHOD: A literature search was conducted in Pubmed and Embase on 10 November 2022 for phase III clinical trials studying Bruton's tyrosine kinase inhibitors in monotherapy in the first-line setting for CLL. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. RESULT: Of the 39 studies obtained in the review, two clinical trials were selected: one for zanubrutinib and one for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were auricular fibrillation, hypertension and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the ATE guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives. CONCLUSIONS: Assuming the uncertainty associated with the adjusted indirect comparison, zanubrutinib could be considered equivalent in efficacy to ibrutinib, however, the presence of differentiating safety features precludes assigning the two alternatives as equivalent therapeutic alternatives.

Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bis-organosilane Ligands in Axial Positions.

We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: cis-dichloro(diamine)-trans-[3-(triethoxysilyl)propylcarbamate]platinum(IV) (Pt(IV)-biSi-1) and cis-dichloro(diisopropylamine)-trans-[3-(triethoxysilyl) propyl carbamate]platinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt(IV)-biSi-2 outperformed cisplatin in reducing tumor growth at lower concentrations, with reduced side effects. Mechanistically, Pt(IV)-biSi-2 induced permanent DNA damage independent of p53 levels. DNA damage such as double-strand breaks marked by histone gH2Ax was permanent after treatment with Pt(IV)-biSi-2, in contrast to cisplatin's transient effects. Pt(IV)-biSi-2's faster reduction to Pt(II) species upon exposure to biological reductants supports its superior biological response. These findings unveil a novel strategy for designing Pt(IV) anticancer prodrugs with enhanced activity and specificity, offering therapeutic opportunities beyond conventional Pt drugs.

Systematic review and meta-analysis of interleulin-6 inhibitors in reducing mortality for hospitalized patients with COVID-19.

OBJECTIVE: One year after the declaration of the SARS-CoV-2 pandemic, only  dexamethasone has clearly shown a reduction in mortality for COVID-19  hospitalized patients. For interleukin-6 inhibitors, results are variable and  nclear. The objective was to review and analyze the effect of tocilizumab and  sarilumab on survival in this setting. METHOD: The PRISMA statements were fulfilled for the systematic review. A  systematic search in Medline, Embase and medRxiv was conducted to identify  randomized controlled trials with tocilizumab or sarilumab in hospitalized  patients with COVID-19. Mortality data from non-critical and critical patients  were extracted. A random-effects (DerSimonian-Laird) meta-analysis was  performed for both subgroups and the whole population using MAVIS software  v. 1.1.3. Similarity and homogeneity among trials were assessed. RESULTS: Twenty-five and 23 articles were identified in Medline and Embase,  respectively, five were trials with tocilizumab and/or sarilumab; two more were  identified at medRxiv. Seven randomized clinical trials fulfilled the  inclusion criteria. Another trial was pre-published and included post-hoc. The  meta-analysis, with eight randomized clinical trials and 6,340 patients, showed  a benefit on mortality for interleukin-6  heterogeneity (I2 = 7%), but  a low similarity among studies. The results showed no differences among  critical and non-critical patients. A sensitivity analysis excluding non-similar or  heterogeneous studies showed different results, without benefit and with low  precision of the result in non-critical patients. CONCLUSIONS: A benefit in mortality for interleukine-6 inhibitors was found, but  with important differences among the scenarios analyzed in the clinical  trials. Positive results are mainly caused by two randomized clinical trials which  are similar in concomitant use of steroids and veryhigh mortality in  critical patents. Sarilumab was poorly represented in the meta-analysis.  Nevertheless, an association between the benefit and the critical/non-critical  condition was not found. More randomized clinical trials, mainly focused in  atients at high mortality risk, are needed to confirm the benefit of interleukine- 6 inhibitors for COVID-19. Sarilumab was underrepresented in the meta- analysis.

OBJETIVO: Un año después de la declaración de la pandemia por SARS­CoV-2,  solo dexametasona había mostrado claramente una reducción de la mortalidad  en pacientes hospitalizados por COVID-19. Los resultados de los inhibidores de  interleucina 6 son diversos y poco claros. El objetivo de este trabajo es  revisar y analizar el efecto de tocilizumab y sarilumab sobre la supervivencia  de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA. Se  realizó una búsqueda sistemática en Medline, Embase y medRxiv para identificar ensayos controlados aleatorizados con tocilizumab o sarilumab  en pacientes hospitalizados con COVID-19. Se recopilaron los datos de mortalidad de pacientes críticos y no críticos y se llevó a cabo un metaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos  subgrupos y para toda la población, usando el software MAVIS v. 1.1.3. La similitud y homogeneidad entre los ensayos fue evaluada. RESULTADOS: Se identificaron 25 y 23 artículos en Medline y Embase, respectivamente; cinco eran ensayos con tocilizumab y/o sarilumab;  se identificaron dos más en medRxiv. En total, siete ensayos clínicos  aleatorizados cumplieron los criterios de inclusión. Posteriormente, se  prepublicó otro ensayo que cumplía los criterios de inclusión y se incorporó al  análisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y 6.340  pacientes, mostró un beneficio sobre la mortalidad para los inhibidores de  interleucina-6 (hazard ratio 0,85; intervalo de confianza al 95% 0,74-0,99),  con baja heterogeneidad (I2 = 7%), pero reducida similitud entre los estudios.  Los resultados no mostraron diferencias entre pacientes críticos y no  críticos. Un análisis de sensibilidad excluyendo estudios heterogéneos o no  similares mostró resultados diferentes, sin beneficio y con baja precisión del  resultado en pacientes no críticos. CONCLUSIONES: Se encontró un beneficio en la mortalidad de los inhibidores de  la interleucina 6, pero con importantes diferencias entre los escenarios analizados en los ensayos clínicos. Los resultados positivos se  eben principalmente a dos ensayos que son similares en el uso concomitante  de esteroides y una mortalidad muy alta en pacientes críticos. Sarilumab estuvo escasamente representado en el metaanálisis. Sin embargo, el metaanálisis por subescenarios no encontró una relación entre  el beneficio y la condición de pacientes críticos/no críticos. Se necesitan más ensayos clínicos aleatorizados, principalmente enfocados en  pacientes con alto riesgo de mortalidad, para confirmar el beneficio de los  inhibidores de interleucina-6 en COVID-19.

Selenium and Vitamin E Concentrations in Miranda Jennies and Foals (Equus asinus) in Northeast Portugal.

The increase in donkeys treated by practitioners in recent years has led to an increased interest in finding more information on basic biochemical preliminary reference values. The aims of this study were to measure Se and Vit E levels in plasma from Miranda jennies peripartum and postpartum and in their foals to compare blood profiles of the jenny and foal related to the overall foal's health. Twenty-two healthy peripartum and postpartum Miranda donkeys were sampled (12 jennies and 10 foals) in the northeast of Portugal (Atenor and Paradela) from May to November, 2018. Amounts of selenium in soil were significantly correlated (0.97) to concentrations of selenium in jennies (42.412 µg/L in Atenor and 9.612 µg/L in Paradela) and foals (19.378 µg/L in Atenor and 6.430 µg/L in Paradela). Selenium levels were lower in foals than adults and in males than females. Vitamin E was associated with overall foal health. Foals with a mean vitamin E of 3.585-5.307 mg/L showed signs of weakness, but carpal flexural deformities were observed when the average vitamin E was 11.520 mg/L. Low vitamin E levels (5.307 mg/L) in jennies were related to foal mortality. Diets, location, parity, and age affect blood profiles of jennies and, ultimately, foal health.

A three-year large scale study on the risk of honey bee colony exposure to blooming sunflowers grown from seeds treated with thiamethoxam and clothianidin neonicotinoids.

Despite the restriction of the use of neonicotinoids in the EU, including thiamethoxam and clothianidin, the debate over their risk on honey bees has not been fully settled. This study presents results of a three-year study working with 180 honey bee colonies in ten replicates. Colonies were sorted into three treatments (60 colonies per treatment) exposed to sunflower blooms grown from seeds treated with thiamethoxam, clothianidin and a non-treated control. Each colony was assessed at six moments: one before to exposition to sunflower, two during the exposition (short-time risk), two after exposition (medium-time risk) and one after wintering (long-time risk). The health and development of the colonies were assessed by monitoring adult bee population, brood development, status of the queen, food reserves and survival. No significant difference among treatments when raw data was considered. However, when evolution from initial status of the colony was evaluated, a significant difference was observed from the first week of exposure to sunflower blooms. In this period, the number of adult bees and the amount of brood were slightly lower in the bee hives exposed to neonicotinoids, although such differences disappeared in subsequent evaluations. The concentration of residues in samples of beebread and adult bees was at the level of ng·g-1. Magnitude of the effect of the treatment factor on the variability of colony health and development related parameters was low. The most important factor was the hive, followed by the replicate and year, and to a lesser extent the initial strength of the colonies.

Synthesis, biological evaluation, in silico modeling and crystallization of novel small monocationic molecules with potent antiproliferative activity by dual mechanism.

Seeking for new anticancer drugs with strong antiproliferative activity and simple molecular structure, we designed a novel series of compounds based on our previous reported pharmacophore model composed of five moieties. Antiproliferative assays on four tumoral cell lines and evaluation of Human Choline Kinase CKα1 enzymatic activity was performed for these compounds. Among tested molecules, those ones with biphenyl spacer showed betters enzymatic and antiproliferative activities (n-v). Docking and crystallization studies validate the hypothesis and confirm the results. The most active compound (t) induces a significant arrest of the cell cycle in G0/G1 phase that ultimately lead to apoptosis, following the mitochondrial pathway, as demonstrated for other choline kinase inhibitors. However additional assays reveal that the inhibition of choline uptake could also be involved in the antiproliferative outcome of this class of compounds.

Calcifying aponeurotic fibroma of the sole of the foot in an elderly patient.

Calcifying aponeurotic fibroma (CAF) is a rare, locally aggressive fibroblastic lesion that occurs predominantly in the distal extremities of children and adolescents. In the present study, a case of pathologically proven CAF arising in the sole of the right foot of a 84-year-old man is presented. Physical examination revealed a firm, immobile, non-tender mass. Plain radiographs showed a faintly calcified soft tissue mass without bone involvement. Magnetic resonance imaging (MRI) revealed a well circumscribed subcutaneous mass. The patient underwent an excisional biopsy. Histologically, the tumor showed a biphasic pattern, composed of a moderately cellular fibromatosis-like component and irregular calcified areas with polygonal epithelioid cells. There has been no evidence of local recurrence six months following surgery. To the best of our knowledge, this case describes the oldest patient with this condition.

Using phosphine ligands with a biological role to modulate reactivity in novel platinum complexes.

Three platinum complexes with cis and trans configuration cis-[Pt(TCEP)2Cl2], cis-[Pt(tmTCEP)2Cl2] and trans-[Pt(TCEP)2Cl2], where TCEP is tris(2-carboxyethyl)phosphine, have been synthesized and fully characterized by usual techniques including single-crystal X-ray diffraction for trans-[Pt(TCEP)2Cl2] and cis-[Pt(tmTCEP)2Cl2]. Here, we also report on an esterification process of TCEP, which takes place in the presence of alcohols, leading to a platinum complex coordinated to an ester tmTCEP (2-methoxycarbonylethyl phosphine) ligand. The stability in solution of the three compounds and their interaction with biological models such as DNA (pBR322 and calf thymus DNA) and proteins (lysozyme and RNase) have also been studied.

C24-hydroxylated stigmastane derivatives as Liver X Receptor agonists.

Phytosterols are stucturally correlated to the endogenous ligands of Liver X Receptor (LXR), a ligand-activated nuclear receptor that has emerged as an attractive drug target due to its ability to integrate metabolic and inflammatory signaling. Natural and semi-synthetic phytosterol derivatives characterized by the presence of side-chain oxygenated functions have shown to be able to modulate LXR activity. Here, we describe the efficient synthesis of four stigmastane derivatives, endowed with a hydroxyl group at C24 position, namely (24R)- and (24S)-stigmasta-5,28-diene-3ß,24-ols (also referred to as saringosterols, 10a and 10b) and (24R)- and (24S)-stigmasta-5-ene-3ß,24-ols (11a and 11b), starting from the readily available stigmasterol. Thanks to X-ray crystallography the absolute configuration of the newly created chiral centers was definitively assigned for all the four compounds. The subsequent luciferase assays with GAL-4 chimeric receptors evidenced the ability of the two 24(S)-epimers, 10b and 11b, to interact with LXRs, showing the same degree of affinity as (22R)-hydroxycholesterol (1). With regard to the isoform selectivity both the derivatives 10b and 11b showed a preference for LXRß, up to 4-fold in terms of efficacy for 11b. The gene expression profiling of (24S)-stigmasta-5,28-diene-3ß,24-ol (10a) and (24S)-stigmasta-5-ene-3ß,24-ol (11a) demonstrated the capability of both the compounds to induce the expression of four well-known LXR target genes, such as ABCA1, SREBP1c, FASN, and SCD1 in U937 monocytic cell line, thus supporting the hypothesis they were LXR positive modulators.

Reactions of a tetranuclear Pt-thiosemicarbazone complex with model proteins.

The tetranuclear Pt complex (PtL)4 (where L2- is the anion derived from para-isopropyl thiosemicarbazone) was first described in A.G. Quiroga et al., J. Med. Chem. 41, 1998, 1399-1408. (PtL)4 manifests antiproliferative properties toward various cancer cell lines being a promising anticancer drug candidate. Yet, details of its reactivity with biomolecules have not been elucidated. To this end, we investigated the reactions of (PtL)4 with a few model proteins, i.e. bovine pancreatic ribonuclease (RNase A), cytochrome c (Cyt c) and hen egg white lysozyme (Lysozyme), through electrospray ionization mass spectrometry and other biophysical methods. A rich reactivity of (PtL)4 with the above-mentioned model proteins is observed, leading to the formation of numerous metallodrug-protein adducts. The tetranuclear complex breaks down and various fragments bind proteins up to high metal/protein ratios; this typically results into very complicated mass spectral patterns. However, some of the main mass peaks could be assigned in the case of the Lysozyme adduct. In addition, crystallographic data were obtained for the (PtL)4/Lysozyme and (PtL)4/RNase A adducts pointing at His side chains as the primary binding sites for monometallic Pt fragments. Notably, a few selected features of the interactions observed in the (PtL)4/protein adducts were reproduced by reacting (PtL)4 with a small molecule, i.e. N-methylimidazole. In conclusion, the present study confirms the prodrug nature of the tetraplatinum complex, clarifies one possible pathway for its activation through cluster disassembly and allows initial identification of adducts formed with a representative protein.

Measuring and modeling for the assessment of the genetic background behind cognitive processes in donkeys.

New productive niches can offer new commercial perspectives linked to donkeys' products and human therapeutic or leisure applications. However, no assessment for selection criteria has been carried out yet. First, we assessed the animal inherent features and environmental factors that may potentially influence several cognitive processes in donkeys. Then, we aimed at describing a practical methodology to quantify such cognitive processes, seeking their inclusion in breeding and conservation programmes, through a multifactorial linear model. Sixteen cognitive process-related traits were scored on a problem-solving test in a sample of 300 Andalusian donkeys for three consecutive years from 2013 to 2015. The linear model assessed the influence and interactions of four environmental factors, sex as an animal-inherent factor, age as a covariable, and the interactions between these factors. Analyses of variance were performed with GLM procedure of SPSS Statistics for Windows, Version 24.0 software to assess the relative importance of each factor. All traits were significantly (P<0.05) affected by all factors in the model except for sex that was not significant for some of the cognitive processes, and stimulus which was not significant (P<0.05) for all of them except for the coping style related ones. The interaction between all factors within the model was non-significant (P<0.05) for almost all cognitive processes. The development of complex multifactorial models to study cognitive processes may counteract the inherent variability in behavior genetics and the estimation and prediction of related breeding parameters, key for the implementation of successful conservation programmes in apparently functionally misplaced endangered breeds.

Transverse Cervicothoracic Stabbing: Multidisciplinary Management of a Surgical Emergency.

Tracheobronchial injuries are closely related to orotracheal intubations and chest traumas. Stabbing injuries are very rare and often life threatening because of the damage to vital structures such as the respiratory tract and large arterial or venous vessels. Early diagnosis and treatment of penetrating neck injuries increase survival rates. We report a case of the tracheobronchial section with a penetrating stabbing wound on the left laterocervical area associated with contralateral pneumothorax, requiring urgent surgical pulmonary repair, tracheal suture, and tracheotomy. Prompt action with a multidisciplinary approach resulted in a favorable outcome.

Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists.

A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRß isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRß, while it was virtually inactive at LXRα (EC50 = 14.51 µM). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively.