Frontostriatal Circuits Alterations Associated with Cognitive Flexibility Deterioration in Huntington's Disease.

BACKGROUND: Recent resting-state functional magnetic resonance imaging studies have reported abnormal functional connectivity (FC) in the prefrontal cortex (PFC)-striatum circuit in patients with premanifest Huntington's disease (HD). However, there is a lack of evidence showing persistence of abnormal frontostriatal FC and its relation to cognitive flexibility performance in patients with clinically manifest HD. OBJECTIVE: The aim of this study was to evaluate the resting-state FC integrity of the frontostriatal circuit and its relation to cognitive flexibility in HD patients and healthy controls (HCs). METHOD: Eighteen patients with early clinical HD manifestation and 18 HCs matched for age, sex, and education participated in this study. Both groups performed the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional (IED) set-shift task, which measures cognitive flexibility. Resting-state functional magnetic resonance images were also acquired to examine the FC in specific frontostriatal circuits. Eight regions of interest were preselected based on regions previously associated with extradimensional (ED) shifting in patients with premanifest HD. RESULTS: Significant negative correlations between the number of attentional set-shifting errors and the ventral striatum-ventrolateral PFC FC were found in the HD group. This group also showed negative FC correlations between the total errors and the FC between right ventral striatum-right ventrolateral PFC, left ventral striatum-left ventrolateral PFC, and right ventral striatum-left ventrolateral PFC. Negative correlations between the ED errors and left ventral striatum-left ventrolateral PFC and right ventral striatum-right ventrolateral PFC FC were also found. Finally, a positive correlation between the number of stages completed and left ventral striatum-left ventrolateral PFC FC was found. CONCLUSIONS: Manifest HD patients show significant cognitive flexibility deficits in attentional set-shifting that are associated with FC alterations in the frontostriatal circuit. These results show that FC abnormalities found in the prodromal stage of the disease can also be associated with cognitive flexibility deficits at a later clinical stage, making them good candidates to be explored in longitudinal studies.

Cerebellar Degeneration Signature in Huntington's Disease.

Recent findings suggest a significant effect of the cerebellar circuit deterioration on the clinical manifestation of Huntington's disease, calling for a better understanding of the cerebellar degeneration in this disorder. Recent brain imaging analyses have provided conflicting results regarding the cerebellar changes during the progression of this disease. To help in resolving this controversy, we examined the cerebellar gray matter structural integrity from a cohort of HD patients. Whole brain voxel-based morphometry (VBM) and spatially unbiased atlas template of the human cerebellum (SUIT) analyses were done from T1-weighted brain images. Our results showed a significant cerebellar degeneration without any sign of volume increase. The highest cerebellar degeneration was identified in Crus I right lobule, Crus II bilaterally, and left VIIb, and left VIIIa lobules. The cerebellar degeneration signature, which controls for severity of degeneration, showed a degeneration pattern that included regions I-IV, Crus II, VIIb, VIIIa, VIIIb and X.

[Atypical hemolytic uremic syndrome. Report of two cases treated with Eculizumab]. / Síndrome hemolítico urémico atípico en tratamiento con eculizumab. Casos clínicos.

Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy where organic damage predominates in the kidney. Atypical HUS (aHUS) is a rare disease that affects young adults and causes terminal chronic renal failure ending in dialysis, in most cases. It also recurs after kidney transplantation. aHUS is associated with genetic defects of the alternative complement pathway or its activation by other factors such as drugs, autoimmune diseases, infections, malignant hypertension and ischemia-reperfusion. We report two women aged 17 and 25 years old with catastrophic aHUS. In both cases, complement amplifying factors (drugs and infections) were added and acted on a genetic vulnerability to precipitate complement activation and produce aHUS. Both patients developed terminal renal failure and had to undergo hemodialysis. Fortunately, after a broad etiological study, it was possible to make the diagnosis of aHUS and start treatment with Eculizumab, a monoclonal antibody that changed the natural history of aHUS. It inhibits complement activity controlling microangiopathy and preventing the development of end-stage renal disease. It also improves the success rate in kidney transplantation. In the case of our patients, both discontinued dialysis after chronic treatment with Eculizumab.

Theoretical charge plots as a tool for targeted and accelerated ion exchange chromatography method development of NANOBODYⓇ molecules.

NANOBODYⓇ molecules are an innovative class of biotherapeutics based on heavy chain only VHH immunoglobulins. Much like canonical antibodies, they are prone to the formation of charge variants and other post-translational modifications, which can potentially impact their critical quality attributes. Therefore, establishing high-resolution product-specific methods, such as IEX chromatography, is essential for evaluating the purity of these molecules. However, due to the lower surface charge of NANOBODYⓇ molecules, their charge-based elution behavior can differ considerably from that of classical antibodies, resulting in a more extensive method development set-up for these smaller molecules. Using an initial pH screening gradient based on theoretical protein charge plots, we investigated the IEX retention behavior of eight NANOBODYⓇ molecules with a wide range of pI values (pI 5.0 to 10.0). Our findings reveal that the charge-based chromatographic behavior of NANOBODYⓇ molecules cannot be solely attributed to the isoelectric point (pI) of the protein. Rather, a molecule-specific charge threshold was identified as a critical parameter for NANOBODYⓇ molecule retention. Furthermore, the protein charge plot also showed that NANOBODYⓇ molecule elution can be characterized by a charge plateau where the net charge of the protein remains constant over a certain pH range (∼ pH 5.5 to pH 8.0), further challenging the paradigm that elution pH and pI are fixed values. The application of this theoretical approach using protein charge plots to define NANOBODYⓇ molecule charge threshold and charge plateau parameters, can reduce overall IEX method development turnaround time by at least 2-fold.

AlterORF: a database of alternate open reading frames.

AlterORF is a searchable database that contains information regarding alternate open reading frames (ORFs) for over 1.5 million genes in 481 prokaryotic genomes. The objective of the database is to provide a platform for improving genome annotation and to serve as an aid for the identification of prokaryotic genes that potentially encode proteins in more than one reading frame. The AlterORF Database can be accessed through a web interface at www.alterorf.cl.

Application of Nanoparticle Technology to Reduce the Anti-Microbial Resistance through ß-Lactam Antibiotic-Polymer Inclusion Nano-Complex.

Biocompatible polymeric materials with potential to form functional structures in association with different therapeutic molecules have a high potential for biological, medical and pharmaceutical applications. Therefore, the capability of the inclusion of nano-Complex formed between the sodium salt of poly(maleic acid-alt-octadecene) and a ß-lactam drug (ampicillin trihydrate) to avoid the chemical and enzymatic degradation and enhance the biological activity were evaluated. PAM-18Na was produced and characterized, as reported previously. The formation of polymeric hydrophobic aggregates in aqueous solution was determined, using pyrene as a fluorescent probe. Furthermore, the formation of polymer-drug nano-complexes was characterized by Differential Scanning Calorimetry-DSC, viscometric, ultrafiltration/centrifugation assays, zeta potential and size measurements were determined by dynamic light scattering-DLS. The PAM-18Na capacity to avoid the chemical degradation was studied through stress stability tests. The enzymatic degradation was evaluated from a pure ß-lactamase, while the biological degradation was determined by different ß-lactamase producing Staphylococcus aureus strains. When ampicillin was associated with PAM-18Na, the half-life time in acidic conditions increased, whereas both the enzymatic degradation and the minimum inhibitory concentration decreased to a 90 and 75%, respectively. These results suggest a promissory capability of this polymer to protect the ß-lactam drugs against chemical, enzymatic and biological degradation.

Physicochemical characterization of in situ drug-polymer nanocomplex formed between zwitterionic drug and ionomeric material in aqueous solution.

Biocompatible polymeric materials with the potential to form functional structures, in association with different therapeutic molecules, in physiological media, represent a great potential for biological and pharmaceutical applications. Therefore, here the formation of a nano-complex between a synthetic cationic polymer and model drug (ampicillin trihydrate) was studied. The formed complex was characterized by size and zeta potential measurements, using dynamic light scattering and capillary electrophoresis. Moreover, the chemical and thermodynamically stability of these complexes were studied. The ionomeric material, here referred as EuCl, was obtained by equimolar reaction between Eudragit E and HCl. The structural characterization was carried out by potentiometric titration, FTIR spectroscopy, and DSC. The effect of pH, time, polymer concentration and ampicillin/polymer molar ratio over the hydrodynamic diameter and zeta potential were established. The results show that EuCl ionomer in aqueous media presents two different populations of nanoparticles; one of this tends to form flocculated aggregates in high pH and concentrations, by acquiring different conformations in solution by changing from a compact to an extended conformation. Moreover, the formation of an in situ interfacial polymer-drug complex was demonstrated, this could slightly reduce the hydrolytic degradation of the drug while affecting its solubility, mainly under acidic conditions.

Síndrome hemolítico urémico atípico en tratamiento con eculizumab: casos clínicos / Atypical hemolytic uremic syndrome: report of two cases treated with Eculizumab

Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy where organic damage predominates in the kidney. Atypical HUS (aHUS) is a rare disease that affects young adults and causes terminal chronic renal failure ending in dialysis, in most cases. It also recurs after kidney transplantation. aHUS is associated with genetic defects of the alternative complement pathway or its activation by other factors such as drugs, autoimmune diseases, infections, malignant hypertension and ischemia-reperfusion. We report two women aged 17 and 25 years old with catastrophic aHUS. In both cases, complement amplifying factors (drugs and infections) were added and acted on a genetic vulnerability to precipitate complement activation and produce aHUS. Both patients developed terminal renal failure and had to undergo hemodialysis. Fortunately, after a broad etiological study, it was possible to make the diagnosis of aHUS and start treatment with Eculizumab, a monoclonal antibody that changed the natural history of aHUS. It inhibits complement activity controlling microangiopathy and preventing the development of end-stage renal disease. It also improves the success rate in kidney transplantation. In the case of our patients, both discontinued dialysis after chronic treatment with Eculizumab.

Cuadrilatero venoso de Rogie: variantes anatómicas / Rogie's Venous Quadrilateral: Anatomical Variants

El cuadrilátero venoso de Rogie es una región ana- tómica en donde las venas mesentérica inferior, esplénica y mesentérica superior van a tributar en la vena porta hepática. La vena porta hepática es un vaso de gran calibre que recoge la sangre ve- nosa del estómago, yeyuno, íleon, duodeno, colon y parte del sigmoide. En el laboratorio de anatomía macroscópica humana de la Universidad Nacional Autónoma de Honduras en el Valle de Sula (UNAH- VS) encontramos dos variantes anatómicas de las estructuras que componen el cuadrilátero venoso de Rogie en relación a la aorta abdominal y en la manera en que tributa la vena mesentérica inferior. La primera variante que se encontró fue la vena mesentérica inferior drenando directamente al án- gulo de unión entre la vena mesentérica superior y la vena esplénica. La segunda variante se encontró en la misma región del mismo cadáver, en el límite posteroinferior del cuadrilátero de Rogie, en donde la vena renal izquierda discurre posterior a la aorta abdominal. La posición retroaórtica de la vena renal izquierda puede resultar perjudicial para la persona en caso de ser comprimida por la aorta abdominal...(AU)

Factores de riesgo asociados a infecciones por Acinetobacter baumannii en una unidad de cuidados intensivos pediátricos / Risk factors associated to Acinetobacter baumannii in a PICU

El Acinetobacter baumannii (Ab) es un germen nosocomial, multiresistente, afecta especialmente a pacientes críticamente enfermos, contribuyendo en la mortalidad; su impacto en nuestro medio es desconocido. Objetivos: el presente estudio pretende determinar la incidencia de infección por Ab y los principales factores de riesgo asociados. Métodos: se realizó un estudio observacional, de tipo caso y control en 257 niños internados en la UTIP del Hospital del Niño Manuel Ascencio Villarroel. Resultados: encontrándose 4 brotes a lo largo del año y una incidencia de 7,8/100 internados; el germen fue aislado en superficies inanimadas, no así en el personal. Se evidenciaron los siguientes factores de riesgo tras 10 días de exposición: Días de internación en UTIP (OR=10,09; p=0,000), uso de ventilador mecánico (OR=15,75; p=0,000), intubación endotraqueal (OR=17,09; p=0,000), catéter urinario (OR=11,9; p=0,000), catéter venoso central (OR=12,9; p=0,000), catéter venoso periférico (OR=14,2; p=0,000), sonda naso u orogástrico (OR=13; p=0,000). La mortalidad observada no varía significativamente de la mortalidad general. Conclusiones: concluimos que el Ab es el principal agente bacteriano nosocomial en la UTIP, la estancia prolongada en el servicio, y los días de invasividad aumentan el riesgo de adquirir este germen; se requieren medidas de control de los brotes para disminuir su incidencia.

Acinetobacter baumannii (Ab) is a nosocomial, multiresistent pathogen, affecting especially critically ill patients, leading to mortality; is unknown its impact in our hospital. Objectives: this study pretends to determinate infection incidence of Ab and its risk factors associated. Methods: it was performed an observational, case and control study, in 257 children admitted to Manuel Ascencio Villarroel Children Hospital; we found 4 spreads in a year, the incidence was 7,8/100 of admitted patients. Ab was isolated in environmental cultures, but was not found in personal cultures. Results: we found following risk factors after 10 days exposure: PICU days internship (OR=10,09; p=0,000), mechanical ventilation (OR=15,75; p=0,000), endothacheal tube (OR=17,09; p=0,000), urinary catheter (OR=11,9; p=0,000), central venous catheter (OR=12,9; p=0,000), peripherical venous catheter (OR=14,2; p=0,000), oro or nasogastric catheter (OR=13; p=0,000); mortality found associated to Ab was similar to the found in the control group Conclusions: we concluded that Ab is the most frequent pathogen isolated in our PICU, prolonged stay and invasive methods increase risk to be infected by this pathogen; control measures are necessary to decrease its incidence.

Enhanced apomorphine sensitivity and increased binding of dopamine D2 receptors in nucleus accumbens in prepubertal rats after neonatal blockade of the dopamine D3 receptors by (+)-S14297.

The role of dopamine (DA) D3 receptors is controversial in early developmental stages of specially locomotor activity. Past studies have only tested behavioral changes induced by neonatal administration of nonselective dopamine antagonist such as haloperidol or sulpiride in adult rats. We investigated the role of neonatal blockade of DA D3 receptors at (postnatal day, P1 to P12) using the DA D3 receptor antagonist (+)-S14297 on paradigms related to DA behaviors including locomotor activity in novel environment and after administration of the DA nonspecific agonists d-amphetamine, and apomorphine. Additionally, autoradiographic studies were performed to correlate behavioral alterations with DA D1-like, D2-like, and D3 receptors. All studies were performed at two critical ages, prepubertal (P35) and postpubertal (P60). The quantitative autoradiogaphic study revealed increases in the expression of DA D2-like receptor expression in the nucleus accumbens (NAcc) in prepubertal animals that received the DA D3 antagonist (+)-S14297 at neonatal age. In addition, novel environment and apomorphine administration (0.5 mg/kg, s.c.), induced increases of locomotor activity in prepubertal animals that received the DA D3 antagonist (+)-S14297. Autoradiographic and behavioral results suggest that blockade of DA D3 receptors after birth may mediate different neurodevelopmental aspects of the dopaminergic pathway before and after puberty.

Tumores pituitarios: adenoma somatotropos (acromegalia) / Pituitarios tumors: adenoma somatotropos (acromegaly)

Los adenomas hipofisiarios productores de hormona de crecimiento (HC), son la causa más usual de la acromegalia pituitaria y, en frecuencia, le sigue a los prolactinomas. El estudio involucró 34 pacientes acromegálicos, 24 mujeres y 10 varones con edades entre 21 y 76 años (x 45,94 años) del Hospital Nacional del Sur, EsSalud, Arequipa. El tiempo de enfermedad en promedio, fue de 6,82 años con un rango de 1 a 20 años. Diecisiete pacientes (50 por ciento) nacieron en la sierra. Los síntomas y signos más importantes, en orden decreciente fueron: cambios acrofaciales, cefalea, artropatía, diastema, defectos del campo visual, parestesias y síndrome del túnel carpiano e hiperbidrosis. Los niveles séricos del HC y prolactina antes y después del tratamiento fueron 23,99 ng/mL y 11,31 ng/mL, 43.17 ng/mL, respectivamente. De 12 pacients sometidos a PTGO, seis resultaron intolerantes a la glucosa y uno francamente diabético. La TC de hipófisis reveló en 30 casos macroadenoma y en 4 microadenomas, luego del tratamiento hubo 14 y 4 macro y microadenomas, respectivamente. De los 30 pacientes tratados, 23 con hipofisectomía - 14 vía transcraneal y 9 vía transesfenoidal - y 7 con tratamiento farmacológico, los resultados, según criterios de evaluación, fueron favorables en 9, desfavorables en 2 y sin cambio en 16. Se refuerza que la cirugía, especialmente la transfenoidal, es la primera opción terapéutica a la acromegalia, complementada con octreotida.

Evaluación de los tumores pituitarios en el Hospital Nacional de Sur Arequipa, EsSalud (ex IPSS). I: Prolactinomas / Evaluation of pituitary tumors. Hospital Nacional del Sur Arequipa, EsSalud(ex IPSS). I Prolactinomas

Los adenomas pituitarios representan 10 al 15 por ciento de las neoplasias intracraneales, y los prolactinomas son los más comunes de los tumores pituitarios secretores. Las características clínicas niveles de prolactina y el estudio de la fosa pituitaria por medio de TC, fueron evaluados en 101 pacientes (91 mujeres y 10 hombres), portadores de adenomas secretores de prolactina, antes y después de tratamiento con bromocriptina y/o hipofisectomía, quienes acudieron a los servicios de endocrinología y/o neurocirugia entre setiembre de 1992 y junio de 1997. El nivel promedio de prolactina antes del tratamiento fue de 106,9 ng/ml, el cual descendió hasta 20,0 ng/ml después de tratamiento médico con bromocriptina por un tiempo promedio de 23,6 meses. Cefalea, galactorrea, alteraciones en el ciclo menstrual, alteraciones en el campo visual, infertilidad y disminución de la líbido estuvieron presentes en 80,2 por ciento; 71,3 por ciento; 51,6 por ciento; 23,8; 7,9 por ciento y 6,9 por ciento; respectivamente. El estudio tomográfico reveló 63 microadenomas y 37 macroadenomas, cifras que disminuyeron después del uso de bromocriptina, a 26 y 24, respectivamente. Aproximadamente 69 por ciento de los pacientes respondieron a la bromocriptina en términos de disminución de los niveles de prolactina a su valor normal, disminución del tamaño tumoral, cese de la galactorrea y retorno de la menstruación, en 21 por ciento no hubo cambio y en 9 por ciento los prolactinomas crecieron a pesar de la disminución en los niveles de prolactina.