[Acute interstitial pneumonia in a patient treated with methotrexate: Late-onset with neutrophilia and eosinophilia in bronchoalveolar lavage fluid]. / Pneumopathie interstitielle aiguë chez une patiente traitée par méthotrexate : atteinte tardive avec neutrophilie et éosinophilie dans le lavage bronchoalvéolaire.

INTRODUCTION: Methotrexate-induced pneumonitis is a rare but potentially fatal side effect. It is a diagnosis of exclusion. There are early and late forms and different cell patterns in the bronchoalveolar lavage (BAL). CASE REPORT: We present a case of acute interstitial lung disease in a 54-year-old patient who had been taking methotrexate for a year and a half for rheumatoid arthritis. After excluding other causes and based on the diagnostic criteria of Searles and McKendry, we could reasonably identify methotrexate as the cause of the lung disease. It was of late onset and the BAL showed neutrophilia and eosinophilia. CONCLUSION: Methotrexate-induced pneumonitis is a diagnosis of exclusion. A late onset combined with the predominance of neutrophils and eosinophils in BAL is rare in the literature, demonstrating the wide heterogeneity of methotrexate-related interstitial lung disease.

Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas).

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

Abnormalities in skilled reaching movements are improved by peripheral anesthetization of the less-affected forelimb after sensorimotor cortical infarcts in rats.

Unilateral damage to sensorimotor cortical (SMC) regions can profoundly impair skilled reaching function in the contralesional forelimb. Such damage also results in impairments and compensatory changes in the less-affected/ipsilesional forelimb, but these effects remain poorly understood. Furthermore, anesthetization of the ipsilesional hand in humans with cerebral infarcts has been reported to produce transient functional improvements in the paretic hand [Floel A, Nagorsen U, Werhahn KJ, Ravindran S, Birbaumer N, Knecht S, et al. Influence of somatosensory input on motor function in patients with chronic stroke. Ann Neurol 2004;56:206-12; Voller B, Floel A, Werhahn KJ, Ravindran S, Wu CW, Cohen LG. Contralateral hand anesthesia transiently improves poststroke sensory deficits. Ann Neurol 2006;59:385-8]. One aim of this study was to sensitively assay the bilateral effects of unilateral ischemic SMC damage on performance of a unimanual skilled reaching task (the single pellet retrieval task) that rats had acquired pre-operatively with each forelimb. The second aim was to determine whether partially recovered contralesional reaching function is influenced by anesthetization of the ipsilesional forelimb. Unilateral SMC lesions were found to result in transient ipsilesional impairments in reaching success and significant ipsilesional abnormalities in reaching movements compared with sham-operates. There were major contralesional reaching impairments which improved during a 4 week training period, but movements remained significantly abnormal. Anesthetization of the ipsilesional forelimb with lidocaine at this time attenuated the contralesional movement abnormalities. These findings indicate that unilateral ischemic SMC lesions impair skilled reaching behavior in both forelimbs. Furthermore, after partial recovery in the contralesional forelimb, additional improvements can be induced by transient anesthetization of the ipsilesional forelimb. This is consistent with the effects of unilateral anesthetization in humans which have been attributed to the modulation of competitive interhemispheric interactions. The present findings suggest that such interactions are also likely to influence skilled reaching function in rats.

Uretrolisis transvaginal / Transvaginal urethrolysis

La incidencia de obstrucción después de cirugía para corregir la incontinencia de orina en la mujer se desconoce. Varía de acuerdo al tipo de pacientes operadas, la técnica utilizada y las patologías asociadas. Se estima entre 2,5 por ciento y 24 por ciento. Material y método: Estudio retrospectivo de las historias clínicas de las pacientes con obstrucción posterior a cirugía de corrección de la incontinencia urinaria con TVT (Johnson & Johnson). Resultados: Durante el período de julio de 2000 a abril de 2004 se realizaron 95 cirugías para corrección de la incontinencia de orina con TVT. Hubo 3 pacientes con sintomatología obstructiva y/o urgeincontinencia de novo. La evaluación de las pacientes incluyó anamnesis, examen físico, cartilla miccional, cistoscopia y urodinamia. La cistoscopia fue normal en todas ellas. Los parámetros urodinámicos fueron concluyentes de obstrucción en 2 de las 3 pacientes. La corrección quirúrgica fue realizada por uretrolisis transvaginal que fue exitosa en todas las pacientes. No hubo complicaciones quirúrgicas intra o postoperatorias. Conclusiones: Hubo 3,2 por ciento de complicación obstructiva en nuestra serie de 95 pacientes, que se encuentra dentro de las series clínicas publicadas. Consideramos que la uretrolisis transvaginal es una técnica adecuada para la corrección de la obstrucción uretral posterior a la cirugía TVT. Es un procedimiento quirúrgico seguro y técnicamente fácil. Nuestra serie clínica no nos permitió identificar factores de riesgo a considerar en las pacientes que van a ser operadas.

Reelin mRNA expression during embryonic brain development in the chick.

The expression of reelin mRNA was studied during embryonic brain development in the chick, by using in situ hybridization. Reelin was highly expressed in the olfactory bulb and in subpial neurons in the marginal zone of the cerebral cortex. In the diencephalon, the ventral division of lateral geniculate nuclei and perirotundal nuclei were strongly positive. High levels of expression were associated with some layers of the tectum and with the external granule cell layer of the cerebellum. A more moderate signal was detected in the septal nuclei, hyperstriatal fields, retina, habenular nuclei and hypothalamus, in some reticular nuclei of the mid- and hindbrain, and in the spinal cord. Little or no expression was observed in the cortical plate, Purkinje cells, or the inferior olivary complex. Comparison with reelin expression during mammalian and reptilian brain development reveals several evolutionarily conserved features that presumably define a homology. In addition, significant differences are noted, particularly in telencephalic fields. Most importantly, the developing chick cortex does not exhibit high levels of reelin expression in subpial Cajal-Retzius cells characteristic of the mammalian brain. These observations are compatible with an action of reelin on adhesion and/or of nucleokinesis at the level of target cells. They further suggest that, whereas the telencephalon of birds and archosaurs evolved primarily from dorsal ventricular ridge derivatives in which reelin is probably secondary, the increase in number of reelin-positive cells, and amplification of reelin expression played a key part in the evolution of the cortex in the synapsid lineage leading to mammals.

Reelin expression during embryonic brain development in lacertilian lizards.

The expression of reelin mRNA and protein was studied during embryonic brain development in the lacertilian lizards L. viridis and L. galloti, by using radioactive in situ hybridization and immunohistochemistry. At all stages studied, high reelin expression was consistently found in the olfactory bulb, in the lateral cortex, and in neurons of the marginal zone and subplate of medial and dorsal cortical sectors. In the dorsal ventricular ridge (DVR), reelin expression was confined to deeply located, large cells which were more abundant in the caudal than the rostral part of the DVR. In the diencephalon, the ventral lateral geniculate complex and the perirotundal were strongly positive, whereas other nuclei were mostly negative. High reelin signal was associated with some layers in the tectum, with the torus semicircularis, cerebellar granule cell layers, and the ventral horn of the spinal cord. A more moderate signal was detected in the septal nuclei, striatum, retina, habenular nuclei, preoptic and periventricular hypothalamic components, and in reticular nuclei of the mid- and hindbrain. The medial and dorsal cortical plate and Purkinje cells were reelin-negative but expressed disabled-1 (Dab1) mRNA. When they are compared with reelin expression during mammalian brain development, our data reveal an evolutionarily conserved canvas of reelin expression, as well as significant differences, particularly in developing cortical fields. The developing lizard cortex differs from that of turtles, birds, crocodiles, and mammals in that it displays heavy reelin expression not only in neurons of the marginal zone that might be homologous to mammalian Cajal-Retzius cells, but also in subplate neurons. This difference in the pattern of reelin expression suggests that the elaborate radial organization of the lacertilian cortical plate, somewhat reminiscent of its mammalian counterpart, results from evolutionary convergence. Our data lend support to the hypothesis that the reelin signaling pathway played a significant role during cortical evolution.

Reelin mRNA expression during embryonic brain development in the turtle Emys orbicularis.

The expression of reelin messenger ribonucleic acid (mRNA) was studied during embryonic brain development in the turtle Emys orbicularis, by using radioactive in situ hybridization. A high expression was consistently found in the olfactory bulb and in a few neurons in the marginal zone and, to a lesser extent, in the subplate of the dorsal and medial cortical sectors. In the diencephalon, the ventral division of lateral geniculate nuclei and the prospective reticular thalamic nuclei were strongly positive. High reelin signal was also associated with some layers of the tectum and with the external granule cell layer of the cerebellum. A more moderate signal was detected in the septal nuclei, striatum, dorsal ventricular ridge, retina, habenular nuclei, and hypothalamus, and in some reticular nuclei of the midbrain and hindbrain and in ventral spinal cord. The cortical plate, basal forebrain, amygdala, and tegmentum were weakly labeled. When they are compared to reelin expression during mammalian brain development, our data reveal an evolutionarily conserved canvas of reelin expression and significant differences, particularly in developing cortical fields. Most significantly, the developing turtle cortex does not display the heavy reelin expression in subpial Cajal-Retzius cells that is so typical of its mammalian counterpart. Given the key role of reelin in laminar cortical development, our data suggest that the increase in the number of reelin-producing cells and/or the amplification of reelin expression in the cortical marginal zone might have been a driving factor during the evolution of the laminated cerebral cortex from stem reptiles to mammals, as indicated in previous comparative analyses.

Axonal neurofilaments are resistant to calpain-mediated degradation in the WLD(S) mouse.

The biological basis for the phenotype of delayed Wallerian degeneration in the WLDs mouse has yet to be elucidated, although it is known that the characteristic is intrinsic to the axon. Previous data suggested that nerves from the WLD(S) are relatively resistant to proteolytic degradation. We investigated the time-course of neurofilament degradation in response to addition of the calcium-activated protease m-calpain, comparing nerves from WLD(S) and wild-type mice. During 10 min of in vitro proteolysis, neurofilaments from the WLD(S) were consistently slower to degrade than were neurofilaments from wild-type mice. Direct comparisons were performed on Western blots, with statistically significant differences in neurofilament immunoreactivity at 2, 4, and 6 min of reaction time (p < 0.01). These findings suggest that the mutation leading to the WLD(S) phenotype may affect the proteolytic interaction between calpain and neurofilaments.

Evolutionarily conserved, alternative splicing of reelin during brain development.

Reelin is the protein defective in reeler mutant mice and plays a pivotal role in brain development. However, some uncertainties remain about the relationship between reelin and the reeler phenotype. It is generally believed that reelin, secreted by specific neuronal types such as Cajal-Retzius cells, acts at short distance via the extracellular matrix on target neurons, the response of which requires the Dab1 gene product. However, the pattern of reelin expression in some structures such as olfactory bulb, retina, and spinal cord suggests that the protein might be endowed with different functions. In the present study, we identify two uncommon, evolutionarily conserved splicing events in the 3' part of the transcript that result in different forms of the protein. First, a 6-nucleotide, brain-specific microexon is skipped in about 10% of reelin RNA. In addition, an alternative polyadenylation event involving 10-25% of reelin mRNA results in secretion of a truncated protein lacking the terminal, highly basic stretch. This alternative reelin is generally expressed in the same cells as the major form, but is almost undetectable in retina and spinal cord. Both alternative splicing events are present in mouse, rat, and man, suggesting that the corresponding reelin forms are functionally important.

Reln(rl-Alb2), an allele of reeler isolated from a chlorambucil screen, is due to an IAP insertion with exon skipping.

The reeler Albany2 mutation (Reln(rl-Alb2) in the mouse is an allele of reeler isolated during a chlorambucil mutagenesis screen. Homozygous animals had drastically reduced concentrations of reelin mRNA, in which an 85-nt exon was absent. At the genomic level, the mutation was shown to be due to an intracisternal A-particle insertion leading to exon skipping. This appears to be the first observation of retrotransposon insertion during chlorambucil mutagenesis.

Reelin mRNA expression during mouse brain development.

Using in situ hybridization, expression of the mRNA for reelin, the gene most probably responsible for the reeler trait, was studied during mouse brain development, from embryonic day 13 to maturity. The highest level of expression was found in Cajal-Retzius neurons, while a high signal was also seen in the olfactory bulb, the external granular layer of the cerebellum and, particularly at early developmental stages, in hypothalamic differentiation fields, tectum and spinal cord. A moderate to low level of expression was found in the septal area, striatal fields, habenular nuclei, some thalamic nuclei, particularly the lateral geniculate, the retina and some nuclei of the reticular formation in the central field of the medulla. Paradoxically, no reelin expression was detected in radial glial cells, the cortical plate, Purkinje cells, inferior olivary neurons and many other areas that are characteristically abnormal in reeler mutant mice. Together with other preliminary studies, the present observations suggest that the action of reelin is indirect, possibly mediated by the extracellular matrix. Most of the data can be explained by supposing that reelin is a cell-repulsive molecule which prevents migrating neurons from invading reelin-rich areas, and thus facilitates the deployment of radial glial cell processes and the formation of early architectonic patterns.

Targeting the maize T-urf13 product into tobacco mitochondria confers methomyl sensitivity to mitochondrial respiration.

The URF13 protein, which is encoded by the maize mitochondrial T-urf13 gene, is thought to be responsible for pathotoxin and methomyl sensitivity and male sterility. We have investigated whether T-urf13 confers toxin sensitivity and male sterility when expressed in another plant species. The coding sequence of T-urf13 was fused to a mitochondrial targeting presequence, placed under the control of the cauliflower mosaic virus 35S promoter, and introduced into tobacco by Agrobacterium tumefaciens-mediated transformation. Plants expressing high levels of URF13 were methomyl sensitive. Subcellular analysis indicated that URF13 is mainly associated with the mitochondria. Adding methomyl to isolated mitochondria stimulated NADH-linked respiration and uncoupled oxidative phosphorylation, indicating that URF13 was imported into the mitochondria, and conferred toxin sensitivity. Most control plants, which expressed the T-urf13c construct lacking the mitochondrial presequence, were methomyl sensitive and contained URF13 in a membrane fraction. Subcellular fractionation by sucrose gradient centrifugation showed that URF13 sedimented at several positions, suggesting the protein is associated with various organelles, including mitochondria. No methomyl effect was observed in isolated mitochondria, however, indicating that URF13 was not imported and did not confer toxin sensitivity to the mitochondria. Thus, URF13 confers toxin sensitivity to transgenic tobacco with or without import into the mitochondria. There was no correlation between the expression of URF13 and male sterility, suggesting either that URF13 does not cause male sterility in transgenic tobacco or that URF13 is not expressed in sufficient amounts in the appropriate anther cells.

Individual chaperones required for Yop secretion by Yersinia.

Pathogenic yersiniae secrete anti-host proteins called Yops, by a recently discovered Sec-independent pathway. The Yops do not have a classical signal peptide at their N terminus and they are not processed during membrane translocation. The secretion domain is nevertheless contained in their N-terminal part but these domains do not resemble each other in the different Yops. We have previously shown that YopE secretion requires SycE, a 15-kDa acidic protein acting as a specific cytosolic chaperone. Here we show that the gene downstream from yopH encodes a 16-kDa acidic protein that binds to hybrid proteins made of the N-terminal part of YopH and either the bacterial alkaline phosphatase or the cholera toxin B subunit. Loss of this protein by mutagenesis led to accumulation of YopH in the cytoplasm and to a severe and selective reduction of YopH secretion. This protein thus behaves like the counterpart of SycE and we called it SycH. We also engineered a mutation in lcrH, the gene upstream from yopB and yopD, known to encode a 19-kDa acidic protein. Although this mutation was nonpolar, the mutant no longer secreted YopB and YopD. The product of lcrH could be immunoprecipitated together with cytoplasmic YopD. lcrH therefore seems to encode a YopD-specific chaperone, which we called SycD. Determination of the dependence of YopB on SycD requires further investigation. SycE, SycH, and SycD appear to be members of a new family of cytosolic chaperones required for Yop secretion.

Studies of a neurochemical link between depression, anxiety, and stress from [3H]imipramine and [3H]paroxetine binding on human platelets.

We measured platelet [3H]imipramine and [3H]paroxetine binding in patients with major depression (n = 11), dysthymia (n = 9), generalized anxiety (n = 18) and panic disorder (n = 10), and in healthy controls (n = 13). The [3H]imipramine binding capacity (Bmax) was lower in all patient groups; [3H]paroxetine binding was reduced in anxiety disorders, however, decreases in depression and dysthymia were not significant. There were no differences in the affinity constant (Kd) for either radioligand. We also examined the effects of examination stress on platelet binding in medical students. Compared to after vacation, when binding was similar to controls, [3H]imipramine (n = 19) and [3H]paroxetine (n = 14) Bmax values were significantly decreased during examinations and similar to patient values. Examinations were also associated with an increase in plasma cortisol levels. These findings suggest that there is a neurochemical link between depression, anxiety, and stress, and that disturbances in neurochemical functioning may be associated with specific symptomatology, independent of psychiatric diagnosis.

Relationship of social support to [3H]imipramine binding during and after examination stress.

The relationship between social support, depressive symptoms and the maximal binding capacity of [3H]imipramine (Bmax) in platelets was examined in medical students during and after a period of examination stress. There was a positive correlation between the students' perception of their social support and [3H]imipramine Bmax values during examinations, and their perception of social support contributed significantly to the prediction of Bmax by depressive symptomatology. The results suggest that psychosocial factors may be associated with alterations in serotonergic neurotransmission, rendering an individual more physiologically vulnerable to psychological disturbances.

Invaginación intestinal en el niño / Intestinal intussusception in child

Se revisaron 52 fichas de pacientes con diagnóstico de invaginación intestinal entre los años 1978-1987 en el Hospital Roberto del Río de Santiago. La mayor frecuencia se concentra en lactantes eutróficos entre los 3 a 8 meses de edad. En el cuadro clínico predominan vómitos, dolor abdominal cólico, enterorragia y masa abdominal palpable. La mitad de los casos había consultado previamente, el error diagnóstico mas frecuente fue síndrome diarreico agudo siendo la radiología el examen que aclaró el diagnóstico. Se intentó reducción hidrostática en 7 casos lográndose éxito en dos. Se encontró causa orgánica de invaginación en 12%. La morbilidad alcanzó un 14% y no hubo mortalidad. Se discute y compara los aspectos relevantes de este cuadro con lo publicado por otros autores y destaca la importancia de la sospecha clínica, estudio diagnóstico y tratamiento médico-quirúrgico oportuno

Crecimiento en relación a menarquia en mujeres de nivel socioeconómico medio y bajo / Growth related to menarche in middle and low socioeconomic level women

Se describe el crecimiento postmenarquia en 149 niñas, correspondientes a un seguimiento longitudinal de crecimiento y desarrollo de 6 a 20 años de edad, área norte de Santiago. La diferencia de promedios entre estatura al momento de menarquia y estatura adulta fue de 6,40 ñ 2,70 cm. Existió una amplia dispersión, creciendo tres niñas más de 15 cm y una de ellas 22 cm. Los autores concluyen que la predicción de la magnitud del crecimiento después de la menarquia es bastante incierta

Crecimiento postnatal del recién nacido de muy bajo peso: II. Antropometría a un año plazo, estudio longitudinal / Postnatal growth in very low birth weight infants II. One-year term anthropometry, longitudinal study

Se estudia en forma prospectiva, hasta el año de edad, el crecimento longitudinal de 154 RN de peso inferior a 1.501 g atendidos en el Hospital Roberto del Río entre 1983 y 1987. Para el análisis se dividen los sujetos en tres grupos: el grupo A incluye 44 RN de peso inferior a 1.001 g; el grupo B, 68 de 1.000 a 1.250 g, y el grupo C, 42 de 1.251 a 1.500 g. Para comparar los resultados se usan las curvas de crecimiento de Patrí y colaboradores, de niños sanos con un peso promedio de nacimiento de 3.318 g, pertenecientes al mismo medio socioeconómico y área geográfica. Los RN del grupo A pesan, al año, 6.724 +- 804 g, los del grupo B, 7.782 +- 927 g, y los del grupo C, 7.941 +- 903 g. Estos valores, lo mismo que los de la talla , están bajo 2 DE del promedio normal, en los niños del grupo A. Entre 1 y 2 DS en los de los grupos B y C. El perímetro cefálico, al año de edad postnatal, se acerca más a los canales normales en los grupos B y C. Sólo los de peso inferior a 1.000 g tienen una circunferencia craneana bajo 2 DE del promedio normal. Aparentemente el crecimiento postnatal no logra reproducir el del feto in utero. Al año de edad el peso promedio de todo el grupo está muy por debajo del esperado para un niño nacido a término. La talla y sobre todo, el perímetro cefálico se acercan más a lo considerado como normal. Las tablas de crecimiento propuestas para niños de menos de 1.501 g podrían permitir determinar el peso, la talla, el perímetro cefálico promedio y el mínimo aceptable correspondiente a 1 DE para cualquier edad postnatal cuando sólo se conoce el peso de nacimiento. Es necesario seguir estudiando en forma colaborativa el crecimiento "típico" del ENMBP que sobrevive en las actuales tecnologías

Alimentación del recién nacido de muy bajo peso (RNMBP) con una fórmula láctea especial / Feeding of newborn infant of very low birth weight with a special formula

Se estudió en forma prospectiva el crecimiento y algunas variables bioquímicas en 13 recién nacidos de peso inferior a 1.500 g, alimentados con una fórmula especial (Similac Special Care, (SSC) y se compararon los resultados con los de 13 niños de idénticas características alimentados con leche humana de banco. El incremento de peso promedio en el grupo de estudio fué de 26.3 g y 17.1 g en el grupo control. Los niños del primer grupo recuperaron su peso de nacimiento a los 18.8 días y alcanzaron a los 2.000 g a los 46.4 días mientras que en el grupo control la recuperación de peso ocurrió los 22,5 días y los 2.000 g se alcanzó a los 66,4 días. Los incrementos de talla y perímetro cefálicos fueron también mayores en los niños del grupo en estudio pero las diferencias fueron estadísticanmente significativas sólo para esta última medida. No se observó diferencia en la incidencia de osteopenia, ni en los niveles séricos de calcio, fósforo y fosfatasa alcalinas. El test de hemólisis por peróxido de hidrógeno fué normal en los niños alimentados con SSC. El uso de esta fórmula especial fué más conveniente que la leche humana de banco para alimentar a los RNMBP. El peso aumentó más rapidamente lo que disminuyó en forma significativa la permanencia de los niños en el hospital