Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile.

Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.

Human Vascular Microphysiological System for in vitro Drug Screening.

In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400-800 µM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction, and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture. Vasodilation was blocked with the addition of the nitric oxide synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME). TEBVs elicited reversible activation to acute inflammatory stimulation by TNF-α which had a transient effect upon acetylcholine-induced relaxation, and exhibited dose-dependent vasodilation in response to caffeine and theophylline. Treatment of TEBVs with 1 µM lovastatin for three days prior to addition of Tumor necrosis factor - α (TNF-α) blocked the injury response and maintained vasodilation. These results indicate the potential to develop a rapidly-producible, endothelialized TEBV for microphysiological systems capable of producing physiological responses to both pharmaceutical and immunological stimuli.

Hippocampal interneuron transplants reverse aberrant dopamine system function and behavior in a rodent model of schizophrenia.

Schizophrenia patients exhibit increased hippocampal activity that is correlated with positive symptoms. Although the cause of this hippocampal hyperactivity has not been demonstrated, it likely involves a decrease in GABAergic signaling. Thus, we posit that restoring GABAergic function may provide a novel therapeutic approach for the treatment of schizophrenia. It has been demonstrated that transplanted GABAergic precursor cells from the medial ganglionic eminence (MGE) can migrate and differentiate into mature interneurons. Here, we demonstrate that ventral hippocampal MGE transplants can restore hippocampal function and normalize downstream dopamine neuron activity in a rodent model of schizophrenia. Furthermore, MGE transplants also reverse the hyper-responsive locomotor response to amphetamine. Taken together, these data demonstrate that restoring interneuron function reverses neurophysiological and behavioral deficits in a rodent model of schizophrenia and moreover, demonstrate the feasibility of a neuronal transplant procedure as a potential novel therapeutic approach for the treatment of schizophrenia.

First Report of Shoot Blight and Canker Caused by Diplodia coryli in Hazelnut Trees in Chile.

Shoot blight, twig and branch cankers with grayish discoloration, roughened tissue, and dieback were observed in 5-year-old European hazelnut trees (Corylus avellana L.) cv. Barcelona at two commercial plantations in the Allipén locality, Region de La Araucanía (38° 59' 24.76″ S, 72° 29' 35.58″ W), Chile, during the 2011 to 2012 growing season. In addition, discoloration of the wood was observed in cross-sections. In order to isolate the causal agent, entire twigs and shoot fragments with cankers were sterilized in 0.5% sodium hypochlorite for 2 minutes, followed by two rinses with sterile distilled water. The tissues were then stored in a humid chamber. Sub-epidermal black pycnidia with sporulation were detected on the symptomatic tissue. Conidia were transferred to potato dextrose agar (PDA) (Difco, Lawrence, KS) and incubated at 25°C in the dark. The mycelia were black, creeping, and compact in appearance. The mature conidia were dark brown with a single septum, slightly constricted at the septum, and ovoid with a broadly rounded apex; some had a truncated base. Conidia had the following measurements: (20.0-) 23.1 ± 1.9 (-28.0) × (10-) 11.9 ± 1.2 (-15) µm with an average length/width ratio of 1.95 ± 0.17 (n = 50). These morphometric characteristics correspond to those of Diplodia coryli Fuckel (1870), teleomorph: Botryosphaeria sensu lato. The identity of the fungus was confirmed using internal transcribed spacer (ITS) rDNA sequencing completed at CABI, United Kingdom. The sequencing report indicated that the isolate (IMI-501235a) had 100% homology with a reference strain (CBS 242.51) in the CBS collection. The obtained sequence was deposited in GenBank (Accession No. JX163116). The anamorphs of Botryosphaeria have been divided into up to 18 genera (1), many of which are not clearly defined. Diplodia (3), including D. coryli (CBS 242.51) and D. juglandis (CBS 188.87), have been included within the genus Dothiorella (2), but the taxon names have not been formally changed. A pathogenicity test was conducted with one isolate (IMI-501235a) and four 1-year-old plants of hazelnut cultivar Barcelona. Plants were maintained in individual bags in greenhouse conditions (14/10 hours dark/light, 20°C; 70% RH). Prior to inoculation, plant tissues were externally disinfected with sodium hypochlorite (2%) and rinsed with sterile distilled water. Each plant was inoculated at fresh wound sites on two shoots and three twigs around each vegetative bud. The inoculum consisted of an agar plug with mycelia (5 mm) from the margin of an actively growing colony cultured on PDA media for 7 days. Each wound was covered with moistened cotton and sealed with Parafilm; a control plant was inoculated in the same way with agar only. After 3 months, fragments of necrotic and discolored vascular system tissues from inoculated shoots were removed and incubated on PDA. D. coryli was consistently recovered from these tissues, satisfying Koch's postulates. The control plant showed no symptoms of the disease. D. coryli has been reported to cause symptoms of dieback (dead branches) in Italy and Spain. To our knowledge, this is the first report of D. coryli on C. avellana cv. Barcelona in Chile. European hazelnut is an emerging crop in Chile, grown mainly for export, and management strategies for this disease will need to be developed. References: (1) S. Denman et al. Stud. Mycol. 45:129, 2000. (2) A. J. L. Phillips et al. Persoonia 21:29, 2008. (3) A. J. L. Phillips et al. Mycologia 97:513, 2005.

Signo radiológico: el lirio caído / Radiology sign: the drooping lily

Abstract: the drooping lily sign, also known as wilting flower, corresponds to an imaginological alteration reported over 40 years ago. Initially described in excretory urography, it represents the appearance of the inferior ureteropelvic renal system with a duplicated collecting system, in which the renal pelvis is horizontal and calices are discreetly directed towards caudal. Despite the current limited use of excretory urography, the drooping lily sign remains valid and of diagnostic use in voiding cystourethrograms (VCUG) (also micturating cystourethrogram (MCUG)), computed tomography urography (CTU) and magnetic resonance urography (MRU).

El signo del lirio caído (drooping lily en la literatura anglosajona), también llamado "flor marchita", corresponde a una alteración imaginológica reportada hace más de 40 años. Inicialmente descrito en pielografía de eliminación, representa el aspecto que adquiere el sistema pieloureteral inferior de un riñón con doble sistema excretor, dado por una pelvis renal de orientación horizontal y cálices que se dirigen discretamente hacia caudal. A pesar de la escasa utilización de la pielografía de eliminación en la actualidad, el signo de lirio caído sigue vigente y resulta de utilidad diagnóstica en uretrocistografía miccional, urografía por tomografía computarizada (UroTC) y urografía por resonancia magnética (UroRM).

Selective deletion of the leptin receptor in dopamine neurons produces anxiogenic-like behavior and increases dopaminergic activity in amygdala.

The leptin receptor (Lepr) is expressed on midbrain dopamine neurons. However, the specific role of Lepr signaling in dopamine neurons remains to be clarified. In the present study, we generated a line of conditional knockout mice lacking functional Lepr selectively on dopamine neurons (Lepr(DAT-Cre)). These mice exhibit normal body weight and feeding. Behaviorally, Lepr(DAT-Cre) mice display an anxiogenic-like phenotype in the elevated plus-maze, light-dark box, social interaction and novelty-suppressed feeding tests. Depression-related behaviors, as assessed by chronic stress-induced anhedonia, forced swim and tail-suspension tests, were not affected by deletion of Lepr in dopamine neurons. In vivo electrophysiological recordings of dopamine neurons in the ventral tegmental area revealed an increase in burst firing in Lepr(DAT-Cre) mice. Moreover, blockade of D1-dependent dopamine transmission in the central amygdala by local microinjection of the D1 antagonist SCH23390 attenuated the anxiogenic phenotype of Lepr(DAT-Cre) mice. These findings suggest that Lepr signaling in midbrain dopamine neurons has a crucial role for the expression of anxiety and for the dopamine modulation of amygdala function.

Erythrocytes dynamic viscoelasticity in beta-thalassaemia minor.

Beta-thalassaemia is a hereditary hemolytic disease, in which each clinic phenotype encompasses a heterogenic group of genetic alterations resulting in beta-globin chain synthesis decrease or absence in red blood cells. Studies on beta-thalassaemia carriers suggest the existence of decreased red cell deformability. The erythrocyte deformability in the blood stream is a well-known fact regarding blood circulation efficiency. Red blood cells may be considered to be viscoelastic and their behavior may be described according to complex viscoelastic parameters when they undergo oscillatory stresses. This dynamic behavior is physiologically important due to the in vivo pulsatile blood flow. The aim of the present work was to evaluate complex erythrocyte viscoelastic parameters in patients suffering from heterozygous beta-thalassaemia in comparison with healthy individuals. Our results reveal that even though thalassaemia erythrocytes show a decreased deformability in the stationary state, in a dynamic state, hemorheological alterations are only evident at low oscillatory frequencies, i.e., at lower frequencies in contrast with the normal heart rate (60 cycles/min = 1 Hz), producing no significant alterations at increased heart rate.

Interpretation of correlations between nuclear observables in rare-earth nuclei.

We have recently obtained the optimal core-cluster decompositions for an extensive set of heavy even-even nuclei in the rare-earth region. The core-cluster charge products thus deduced are found to be closely correlated with the corresponding B(E2) values. We investigate here the strong resemblance of these correlations to the corresponding Casten plots, and find that the cluster model also predicts a further correlation between core-cluster charge products and the nuclear excitation energies, suggesting a new form of Casten plot for these energies.

Morbilidad y recurrencia de la disección inguino-femoral con incisión limitada en carcinoma epidermoide de vulva / Morbidity and recurrence of the inguino-femoral dissection with limited incision in epidermoid vulvar carcinoma

Tradicionalmente la disección radical ganglionar inguinal ha sido el tratamiento en el carcinoma de vulva, sin embargo, la morbilidad asociada al procedimiento es alta. Recientemente se han propuesto nuevas opciones en el manejo. De tal manera que tanto los procedimientos radicales versus conservadores no han demostrado diferencias en la supervivencia. Objetivo. Comparar la morbilidad y recurrencia tumoral entre dos tipos de abordajes para la disección ganglionar inguino-femoral mediante incisiones cl sicas radicales versus limitadas de tipo conservador. Material y métodos. Retrospectivamente analizamos los expedientes clínicos de pacientes con el diagnóstico de carcinoma epidermoide de la vulva tratados con disección ganglionar con incisión radical versus limitada, durante el periodo de enero de 1986 a diciembre de 1996, en el Instituto Nacional de Cancerología de México (INCan). Se seleccionaron nueve pacientes tratadas con vulvectomía o hemivulvectomía e incisión inguino-femoral limitada (Grupo I), uni o bilateral y 18 pacientes tratadas con vulvectomía o hemivulvectomía con incisiones separadas de la disección ganglionar inguino-femoral pero con incisión radical clásica (Grupo II). Resultados. Durante los 10 años de evaluación, 27 pacientes con carcinoma de vulva fueron identificadas. Para el grupo I el promedio de edad fue de 68.4 años versus 72.5 del grupo II (p= NS). El número de ganglios disecados y recurrencias locales no mostró diferencias con significancia estadística para ambos grupos. La supervivencia para las pacientes del grupo I fue del 66.7 por ciento y 42 por ciento para las del grupo II. Los únicos parámetros con p significativas fueron la frecuencia de bencrosis del colgajo (p= 0.03), infección de la herida quirúrgica (p= 0.05) a favor del grupo I (p= 0.07). Conclusiones. En nuestro Análisis la incisión limitada para realizar la disección ganglionar inguino-femoral ofrece menor morbilidad que la incisión radical clásica, sin repercusión en el control oncológico y supervivencia de las pacientes.

Monarch butterflies (Danaus plexippus L.) use a magnetic compass for navigation.

Fall migratory monarch butterflies, tested for their directional responses to magnetic cues under three conditions, amagnetic, normal, and reversed magnetic fields, showed three distinct patterns. In the absence of a magnetic field, monarchs lacked directionality as a group. In the normal magnetic field, monarchs oriented to the southwest with a group pattern typical for migrants. When the horizontal component of the magnetic field was reversed, the butterflies oriented to the northeast. In contrast, nonmigratory monarchs lacked directionality in the normal magnetic field. The results are a direct demonstration of magnetic compass orientation in migratory insects.

Hematologic study of newborn umbilical cord blood.

Hematological parameters in newborn umbilical cord blood samples (n = 476), collected at the Hospital Provincial del Centenario, Rosario, were studied. They were divided into 3 groups: (I) full term newborns with weight according to gestational age; (II) low weight and normal gestational age; (III) preterm newborns. The results were as follows: group (I) Hb: 15.5 +/- 1.1 g/dl; RBC; 4.66 +/- 0.33 x 10(12)/l; PCV: 49% +/- 4.3%, MCV 105.1 +/- 5.3 fl; MHC: 33.2 +/- 1.2 pg. Decreased Hb concentration (p < 0.05) and increased MCV (p < 0.01) were observed in preterm newborns in comparison with normal ones, and a slight PCV increase and RBC values in low weight newborns compared to the control group (p < 0.05). Erythrocyte morphology was normal as well as reticulocyte values in these samples. The electrophoretic pattern was (FA) with the following Hb F values 66.3 +/- 6.8%, and Hb A2 0.45 +/- 0.3% in group (I), with a significant increase of Hb F in 30-35 weeks preterm newborns. Group (I) values are considered as normal hematological parameters in newborns in our country, whereas MCV < 94.7 fl is considered as a neonatal microcytosis marker, consequently an alert to investigate alpha-thalassemia. There was no influence on Hb concentration due to maternal smoking habit. The present work could be of relevance for our region since up to the present time there are no similar records.

Silane-coated silica particle colloid processing of human sperm.

PURPOSE: The purpose of this study was to determine differences in the quality of human sperm processed through different lots of silane-coated silica particle colloid solutions. The objectives were to compare (a) sperm kinematic parameters, (b) the sperm acrosome status, (c) the membrane integrity of the head and tail regions, (d) the DNA normality, and (e) the heat-inducible hyperactivation motility after processing sperm through either a Silane-coated silica particle colloid solution, a Percoll solution, or a simple centrifuge sperm wash (control). METHODS: Sperm cells were derived from pooled cryopreserved-thawed specimens of several donors (n = 10). The pooled sperm were divided and processed through either the centrifuge wash, the 90:47% two-layer Percoll, or one of three lots of silane-coated silica particle colloidal solutions from three vendors. Aliquots of sperm cells were analyzed using the Hamilton-Thorn HTM-C motility analyzer for differences in kinematics and hyperactivation. Sperm were also analyzed for membrane integrity at both head and tail regions, normal morphology, acrosome status, and viability. Sperm undergoing apoptosis were determined using the acridine orange stain. Processed sperm were also incubated at 40 degrees C for 4 hr and the quality of the sperm was assessed using the heat-induced hyperactivation and motility parameter. RESULTS: The data showed that after sperm processing, the number of sperm recovered was higher for the three lots of colloids (silane-coated silica particle colloid solutions) compared with Percoll processing. Total sperm motility was higher in the colloidal washes compared with the control. There were no differences in motility between Percoll- and colloid-processed sperm. In contrast, the percentages of sperm exhibiting progressive motility or hyperactivation varied among the different lots of colloid solutions. The Percoll wash solution yielded the highest percentage of sperm with intact tail membranes, whereas some lots of colloid solutions disrupted sperm head membranes. The percentages of sperm undergoing apoptosis varied for the different lots of colloid solutions. There was a marked increase in hyperactivation associated with one colloid solution after heat induction. CONCLUSIONS: The results demonstrated variability in the different lots of silane-coated silica particle colloid solutions for processing sperm. Each lot of colloid solution excelled at improving different sperm parameters. The silane-coated silica particle colloid solutions were shown to be effective in recovering motile sperm compared with Percoll but the types of motility and sperm quality varied for the different lots of colloid solutions. Due to the variability in lots of silane-coated silica colloid solutions, reported studies based on only one lot or one source of colloid solution may be difficult to interpret. Furthermore, it may be advantageous to select the best lot of silane-coated silica particle colloid solution to produce the highest number of sperm exhibiting the ideal parameters for use in assisted reproduction technologies.

[Paget's disease with temporal bone involvement, hypoacusis and vertigo. Apropos a case]. / Enfermedad de Paget con afectación del hueso temporal, hipoacusia y vértigos. A propósito de un caso.

The Paget disease is a chronic osteodystrophy of unknown etiology, very frequent in 50 years of age and above. It's an anatomo-radiologic syndrome that sometimes, is accompanied by clinical symptoms. May be monostotic or polyostotic but never generalized. Occasionally it affects the temporal bone producing deafness, tinnitus and vertigo. We report a case with important temporal bone demineralization, deafness and vertigo.