Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.

External auditory canal exostoses: long-term surgical satisfaction and its relationship with surgical complications.

OBJECTIVE: The main purpose of the present study was to evaluate whether complications related to surgery for exostoses are associated with a decrease in patients' quality of life. METHODS: This was a retrospective study for which the following information was collected: sex, age, pre- and post-operative symptoms, pre- and post-operative audiological evaluation results, surgical approach, instruments used, complications, and Glasgow Benefit Inventory score. RESULTS: The study included 67 patients (94 ears). The three main complaints reported were wax retention, otitis externa and hearing loss. Surgical complications occurred in 14.9 per cent of patients. Patients experienced a significant benefit from surgery, especially in relation to somatic state, with a global Glasgow Benefit Inventory score of + 44.3. No significant difference was found between the global Glasgow Benefit Inventory changes and surgery-related complications (p = 0.093). CONCLUSION: After surgery for exostoses, the vast majority of patients showed improvement. Complications related to surgery in general do not seem to influence patients' satisfaction with surgery.

Amifostine protects from the peripheral sensory neuropathy induced by oxaliplatin in mice.

Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.

Amifostine protects from the peripheral sensory neuropathy induced by oxaliplatin in mice

Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.

Dynamic Modeling of Silicon Bioavailability, Uptake, Transport, and Accumulation: Applicability in Improving the Nutritional Quality of Tomato.

Silicon is an essential nutrient for humans, additionally is beneficial for terrestrial plants. In plants Si enhances tolerance to different types of stress; in humans, it improves the metabolism and increases the strength of skeletal and connective tissues as well as of the immune system. Most of the Si intake of humans come from edible plants creating a double benefit: first, because the absorption of Si increases the antioxidants and other phytochemicals in plants, thereby increasing its functional value, and second because the higher concentration of Si in plants increases intake in human consumers. Therefore, it is desirable to raise the availability of Si in the human diet through the agronomic management of Si accumulator species, such as corn, wheat, rice, soybeans, and beans. But also in such species as tomatoes, carrots, and other vegetables, whose per capita consumption has increased. However, there are few systematized recommendations for the application and management of Si fertilizers based on the physicochemical factors that determine their availability, absorption, transport, and deposition in cells and tissues. This study presents updated information about edaphic and plant factors, which determine the absorption, transport, and deposition rates in edible organs. The information was integrated into an estimated dynamic model that approximates the processes previously mentioned in a model that represents a tomato crop in soil and soilless conditions. In the model, on the other hand, was integrated the available information about key environmental factors related to Si absorption and mobilization, such as the temperature, pH, and soil organic matter. The output data of the model were compared against information collected in the literature, finding an adequate adjustment. The use of the model for educational or technical purposes, including the possibility of extending it to other horticultural crops, can increase the understanding of the agronomic management of Si in plants.

Solvent-Controlled, Site-Selective N-Alkylation Reactions of Azolo-Fused Ring Heterocycles at N1-, N2-, and N3-Positions, Including Pyrazolo[3,4- d]pyrimidines, Purines, [1,2,3]Triazolo[4,5]pyridines, and Related Deaza-Compounds.

Alkylation of 4-methoxy-1 H-pyrazolo[3,4- d]pyrimidine (1b) with iodomethane in THF using NaHMDS as base selectively provided N2-methyl product 4-methoxy-2-methyl-2 H-pyrazolo[3,4- d]pyrimidine (3b) in an 8/1 ratio over N1-methyl product (2b). Interestingly, conducting the reaction in DMSO reversed selectivity to provide a 4/1 ratio of N1/N2 methylated products. Crystal structures of product 3b with N1 and N7 coordinated to sodium indicated a potential role for the latter reinforcing the N2-selectivity. Limits of selectivity were tested with 26 heterocycles which revealed that N7 was a controlling element directing alkylations to favor N2 for pyrazolo- and N3 for imidazo- and triazolo-fused ring heterocycles when conducted in THF. Use of 1H-detected pulsed field gradient-stimulated echo (PFG-STE) NMR defined the molecular weights of ionic reactive complexes. This data and DFT charge distribution calculations suggest close ion pairs (CIPs) or tight ion pairs (TIPs) control alkylation selectivity in THF and solvent-separated ion pairs (SIPs) are the reactive species in DMSO.

Adenoma pleomórfico em mucosa jugal: relato de caso / Pleomorphic adenoma on the buccal mucosa: a case report

O adenoma pleomórfico, que é uma neoplasia mista de glândula salivar, é uma morbidade relativamente comum. Apresenta prevalência dominante como neoplasia em glândula parótida, podendo acometer também glândulas salivares menores. É derivado de uma mistura de elementos ductais e mioepiteliais. O tumor geralmente é solitário e apresenta umcrescimento lento e indolor, como massa nodular única, independentedo sítio de origem. Quando intraoral é mais comum em palato duro e lábio superior, sendo relativamente incomum em mucosa jugal. Nesse trabalho, relata-se um caso clínico de adenoma pleomórfico em mucosa jugal, apresentando sete anos de evolução, com completa resolução após o tratamento cirúrgico conservador.

The pleomorphic adenoma, which is a mixed salivary gland neoplasm, is a relatively common disease. It has dominant prevalence such as neoplasm on parotid gland may also affect the minor salivary glands. It is derived from a mixture of ductal and myoepithelial elements. The tumor is usually solitary and presents a slow and pain less growth, being a single mass, independent of site of origin. When intraoral, it is more common onthe hard palate and upper lip. It is relatively uncommon on the buccal mucosa. In this paper, we report a case of pleomorphic adenoma in the buccal mucosa, with seven years of evolution, with complete resolution after conservatory surgical treatment.

[Interactions of DNA bases with individual water molecules. Molecular mechanics and quantum mechanics computation results vs. experimental data].

To elucidate details of the DNA-water interactions we performed the calculations and systemaitic search for minima of interaction energy of the systems consisting of one of DNA bases and one or two water molecules. The results of calculations using two force fields of molecular mechanics (MM) and correlated ab initio method MP2/6-31G(d, p) of quantum mechanics (QM) have been compared with one another and with experimental data. The calculations demonstrated a qualitative agreement between geometry characteristics of the most of local energy minima obtained via different methods. The deepest minima revealed by MM and QM methods correspond to water molecule position between two neighbor hydrophilic centers of the base and to the formation by water molecule of hydrogen bonds with them. Nevertheless, the relative depth of some minima and peculiarities of mutual water-base positions in' these minima depend on the method used. The analysis revealed insignificance of some differences in the results of calculations performed via different methods and the importance of other ones for the description of DNA hydration. The calculations via MM methods enable us to reproduce quantitatively all the experimental data on the enthalpies of complex formation of single water molecule with the set of mono-, di-, and trimethylated bases, as well as on water molecule locations near base hydrophilic atoms in the crystals of DNA duplex fragments, while some of these data cannot be rationalized by QM calculations.

A novel chiral GC/MS method for the analysis of fluoxetine and norfluoxetine enantiomers in biological fluids.

AIMS: A novel robust chiral gas chromatographic/mass spectrometric (GC/MS) method for the separation and measurement of fluoxetine and norfluoxetine enantiomers in urine and plasma was developed. MATERIALS AND METHODS: The drug was extracted from the samples by a liquid-liquid technique, using chloroform, and the enantiomers were separated and measured on a chiral gas chromatographic column (HYDRODEX ß-6TBDM(®), 0.25 µm × 0.25 mm × 50 m). GC/MS instrumentation was used for the acquisition of data in the electron impact selective-ion monitoring mode. RESULTS: The ions chosen were of a mass-to-charge ratio (m/z) exactly equal to 44 units, in order to measure fluoxetine enantiomers, 134 units in order to measure norfluoxetine enantiomers, and 58 units in order to measure diphenhydramine, the internal standard. The method was found to be linear and reproducible in the 50-500 ng/mL concentration range for both urine samples and plasma samples and for both fluoxetine and norfluoxetine, with correlation coefficients ranging between 0.994 and 0.997. CONCLUSIONS: This methodology has an enormous potential for application in pharmacokinetic studies of the enantiomers of fluoxetine.

Nonsteroidal 2,3-dihydroquinoline glucocorticoid receptor agonists with reduced PEPCK activation.

Continuing studies based on dihydroquinoline glucocorticoid receptor agonists lead to the discovery of a series of C4-oxime analogs. Representative compounds exhibited potent transrepression activity with minimal transactivation of phosphoenolpyruvate caboxykinase (PEPCK), a key protein in the gluconeogenesis pathway. These compounds represent promising leads in identifying GR agonists with high anti-inflammatory activity and attenuated potential for glucose elevation.

Full description of copper uptake by algal biomass combining an equilibrium NICA model with a kinetic intraparticle diffusion driving force approach.

In this work kinetic and equilibrium studies related to copper binding to the protonated macroalga Sargassum muticum are reported. An intraparticle-diffusion linear driving force (LDF) model has been chosen for the quantitative description of the kinetics at several initial metal concentrations. Copper intraparticle homogeneous diffusion coefficient (D(h)) obtained is in the range 0.2-0.9×10(-10) m(2) s(-1). NICA isotherm is demonstrated to constitute a substantial improvement with respect to a simpler Langmuir competitive equation. The binding parameters were chosen to provide the best simultaneous description of the equilibrium experiments. Values of log K(Cu) (4.3), n(Cu) (1) and p (0.31) in NICA isotherm, and log K(Cu) (3.5-5) in Langmuir competitive model, have been obtained. These parameters have been also used to predict the competition between copper and cadmium for binding sites. Two acids, HNO(3) and HCl, have been tested to evaluate their effectiveness to release copper from the metal-laden biomass.

Titanium implants: a removal torque study in osteopenic rabbits.

CONTEXT: Osteoporosis is a skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue. It may affect the craniomaxillofacial complex and result in less bone-implant contact. AIMS: The objective of this study was to measure the endosseous integration of titanium implants using the removal torque test in low-mineral density experimental animal models. MATERIALS AND METHODS: Thirty female New Zealand white rabbits were divided into two groups: control (n=14), sham-operated; and test (n=16), ovariectomized. All animals received 2.2 mm Χ 4.0 mm titanium implants in the right tibia, 120 days after ovariectomy or sham surgery. Animals were killed at 7 and 14 weeks of postimplant insertion, when implants were removed by reverse torque rotation using a digital torque meter. Statistical analysis used was Student's t-test. RESULTS AND CONCLUSION: At the 7-week period, the mean torque values for the control and test groups were 11.6 Ncm and 10.4 Ncm, respectively, with no statistical significance. Implant removal torque analysis showed statistically lower values (P < 0.05) for the test group at the 14-week period (control=16.7 Ncm and test=9.7 Ncm). The results of this study indicate that hormonal privacy compromise implants biomechanical performance.

Synthesis and characterization of nonsteroidal glucocorticoid receptor modulators for multiple myeloma.

Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.

Sequential analysis for quality control in the neonatal intensive care unit.

OBJECTIVE: This article describes a novel application of a statistical technique for continuous quality assurance in the NICU. METHODS: We used prospective analysis of rates of survival to 28 days of life, without major IVH in ELBW infants in a single tertiary NICU, before and after the introduction of an evidence-based treatment protocol. By using the CUSUM function, each infant's results were sequentially plotted, and significant changes in outcomes were noted when the plot crossed predetermined boundary lines. RESULTS: Significant changes in outcomes were evident with this method sooner than traditional analyses on the basis of year-end or other arbitrary intervals. The introduction of the ELBW protocol was temporally associated with significant improvement in intact short-term survival. CONCLUSION: Sequential analysis techniques are useful tools for ongoing quality assurance; deviations in outcomes may be detected more quickly, which should assist in the identification of improvements or decrements in performance of the NICU.

[Extra-lobar pulmonary sequestration with broncho-esophageal fistula]. / Sequestro pulmonar extra-lobar com fístula bronco-esofágica.

We describe a case of extra-lobar pulmonary sequestration with broncho-esophageal fistula in a newborn male who presented respiratory distress, cyanosis and feeding difficulties. The diagnosis was made with a swallowed contrast examination, nuclear magnetic resonance, digital subtraction angiography and confirmed by gross and histologic examination. The work of a multidisciplinary team was essential for an early diagnosis and the correct and effective treatment of this Cuncommon condition.

[Hemangioma of the right ventricle]. / Hemangioma do ventrículo direito.

A 36-year-old male with unspecific symptoms and normal physical examination had right cardiac enlargement on chest X-ray. Two-dimensional echocardiographic and thoracic computed tomography demonstrated an intracardiac mass. The tumor was surgically resected and the pathological diagnosis was mixed-type epicardial hemangioma. We discuss this case and review the literature.