Role of HDAC6-STAT3 in immunomodulatory pathways in Colorectal cancer cells.

Colorectal cancer (CRC) is one of the most common malignant neoplasms and the second leading cause of death from tumors worldwide. Therefore, there is a great need to study new therapeutical strategies, such as effective immunotherapies against these malignancies. Unfortunately, many CRC patients do not respond to current standard immunotherapies, making it necessary to search for adjuvant treatments. Histone deacetylase 6 (HDAC6) is involved in several processes, including immune response and tumor progression. Specifically, it has been observed that HDAC6 is required to activate the Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor involved in immunogenicity, by activating different genes in these pathways, such as PD-L1. Over-expression of immunosuppressive pathways in cancer cells deregulates T-cell activation. Therefore, we focused on the pharmacological inhibition of HDAC6 in CRC cells because of its potential as an adjuvant to avoid immunotolerance in immunotherapy. We investigated whether HDAC6 inhibitors (HDAC6is), such as Nexturastat A (NextA), affected STAT3 activation in CRC cells. First, we found that NextA is less cytotoxic than the non-selective HDACis panobinostat. Then, NextA modified STAT3 and decreased the mRNA and protein expression levels of PD-L1. Importantly, transcriptomic analysis showed that NextA treatment affected the expression of critical genes involved in immunomodulatory pathways in CRC malignancies. These results suggest that treatments with NextA reduce the functionality of STAT3 in CRC cells, impacting the expression of immunomodulatory genes involved in the inflammatory and immune responses. Therefore, targeting HDAC6 may represent an interesting adjuvant strategy in combination with immunotherapy.

The Chilean socio-ethno-genomic cline.

Studies of the current Chilean population performed using classical genetic markers have established that the Chilean population originated primarily from the admixture of European people, particularly Spaniards, and Amerindians. A socioeconomic-ethno-genetic cline was established soon after the conquest. Spaniards born in Spain or Chile occupied the highest Socioeconomic Strata, while Amerindians belonged to the lowest. The intermediate strata consisted of people with different degrees of ethnic admixture; the larger the European admixture, the higher the Socioeconomic Level. The present study of molecular genomic markers sought to calculate the percentage of Amerindian admixture and revealed a finer distribution of this cline, as well as differences between two Amerindian groups: Aymara and Mapuche. The use of two socioeconomic classifications - Class and Socioeconomic Level - reveals important differences. Furthermore, Self-reported Ethnicity (self-assignment to an ethnic group) and Self-reported Ancestry (self-recognition of Amerindian ancestors) show variations and differing relationships between socioeconomic classifications and genomic Amerindian Admixture. These data constitute a valuable input for the formulation of public healthcare policy and show that the notions of Ethnicity, Socioeconomic Strata and Class should always be a consideration in policy development.

Fluctuaciones de presión intraocular en pacientes operados con implante de implantable collamer lens (ICL V4c). Seguimiento a 3 meses / Intraocular pressure fluctuations in patients implanted with an implantable collamer lens (ICL V4c). Three-month follow-up

Introducción: Una de las complicaciones del implante de ICL es la elevación de la presión intraocular (PIO), la cual es fluctuante y su alteración es un factor predictivo para el desarrollo de glaucoma. Material y métodos: Estudio prospectivo, transversal y analítico, en pacientes candidatos a implante de ICL. Previa valoración clínica completa, biometría y curva de PIO nocturna, posición supina, con 4 tomas, determinando la fluctuación, considerándose anormal por encima de 5 mmHg. Se les sometió a cirugía mediante técnica convencional. A los 3 meses se repitió valoración clínica completa, biometría y curva de PIO, para determinar si había cambios en las fluctuaciones de PIO. Resultados: Se estudiaron 31 ojos de 16 pacientes. El promedio de fluctuación preoperatorio fue de 3,35 ± 2 mmHg, mientras en el postoperatorio fue de 3,0 ± 2,2 mmHg, sin que esta diferencia fuera estadísticamente significativa. La agudeza, capacidad visual y equivalente esférico mostraron una mejoría estadísticamente significativa. Hubo 6 casos con complicaciones, las cuales se relacionaron con un vault alto y un ICL de mayor tamaño. No hubo relación entre estos hallazgos con el grado del ángulo camerular, el grado de pigmento o el nivel de entrenamiento del cirujano. Conclusión: Se exploró por primera vez el efecto del implante de ICL en las fluctuaciones de PIO, encontrando que no es estadísticamente significativo. Se mostró la seguridad y reproducibilidad del procedimiento, como en publicaciones previas, agregando que el nivel de entrenamiento del cirujano no es un factor determinante en estos hallazgos

Introduction: Fluctuating elevated intraocular pressure (IOP) is one of the complications of an implantable collamer lens (ICL), and its alteration is a predictive factor for the development of glaucoma. Material and methods: A prospective, cross-sectional analytic study was conducted on patients suitable for ICL implantation. Complete clinical and biometric work-ups were performed, as well as night-time IOP curve, in supine position, with 4 determinations, in order to assess fluctuation, considering abnormal with a value higher than 5 mmHg. Patients underwent surgery with conventional technique and three months after the work-ups were repeated, including a night-time IOP curve to assess any changes in IOP fluctuations. Results: A total of 31 eyes of 16 patients were studied. Mean IOP fluctuation in the preoperative assessment was 3.35 ± 2 mmHg, whereas the postoperative mean was 3.0 ± 2.2 mmHg, with the difference not being statistically significant. Visual acuity and capacity, as well as spheric equivalent did show a statistically significant improvement. There were 6 cases of complications, which were related to a higher vault and a greater ICL size. There was no relationship between these findings and the angle grade, pigment, and the level of training of the surgeon. Conclusions: The effect of an ICL on IOP fluctuations, has been studied for the first time, which was found to be not statistically significant. As in previous publications, the procedure was safe and reproducible, adding the fact that the level of training of the surgeon is not a determining factor in these findings

Intraocular pressure fluctuations in patients implanted with an implantable collamer lens (ICL V4c). Three-month follow-up. / Fluctuaciones de presión intraocular en pacientes operados con implante de implantable collamer lens (ICL V4c). Seguimiento a 3 meses.

INTRODUCTION: Fluctuating elevated intraocular pressure (IOP) is one of the complications of an implantable collamer lens (ICL), and its alteration is a predictive factor for the development of glaucoma. MATERIAL AND METHODS: A prospective, cross-sectional analytic study was conducted on patients suitable for ICL implantation. Complete clinical and biometric work-ups were performed, as well as night-time IOP curve, in supine position, with 4 determinations, in order to assess fluctuation, considering abnormal with a value higher than 5 mmHg. Patients underwent surgery with conventional technique and three months after the work-ups were repeated, including a night-time IOP curve to assess any changes in IOP fluctuations. RESULTS: A total of 31 eyes of 16 patients were studied. Mean IOP fluctuation in the preoperative assessment was 3.35 ± 2 mmHg, whereas the postoperative mean was 3.0 ± 2.2 mmHg, with the difference not being statistically significant. Visual acuity and capacity, as well as spheric equivalent did show a statistically significant improvement. There were 6 cases of complications, which were related to a higher vault and a greater ICL size. There was no relationship between these findings and the angle grade, pigment, and the level of training of the surgeon. CONCLUSIONS: The effect of an ICL on IOP fluctuations, has been studied for the first time, which was found to be not statistically significant. As in previous publications, the procedure was safe and reproducible, adding the fact that the level of training of the surgeon is not a determining factor in these findings.

Mapping of quantitative trait locus associated with maize tolerance to high seed drying temperature.

quantitative trait locus (QTL) mapping and identification of traits of agronomic importance is important in the process of molecular marker-assisted selection in breeding programs. The molecular map of maize is well saturated and QTL and simple sequence repeat (SSR) markers have been identified, whereas few markers linked to seed quality traits are included. The present study aimed to identify QTL and the gene action and to quantify the effects of these regions in the phenotypic variation related to maize tolerance to high seed drying temperature. SSR markers and 129 segregating families of F2 plants of the cross of intolerant and tolerant lines were used in regression and composite interval mapping methods. Three maize QTL associated with tolerance to high seed drying temperature were identified and mapped to chromosomes 6 and 8, explaining 39% of the phenotypic variation of the trait with additive, dominance and overdominance gene action. These markers seem to be effectively associated with the evaluated trait, since all were mapped near genes whose expression products were associated with seed desiccation tolerance.

Transcranial near-infrared light therapy improves motor function following embolic strokes in rabbits: an extended therapeutic window study using continuous and pulse frequency delivery modes.

Photon or near-infrared light therapy (NILT) may be an effective neuroprotective method to reduce behavioral dysfunction following an acute ischemic stroke. We evaluated the effects of continuous wave (CW) or pulse wave (P) NILT administered transcranially either 6 or 12 h following embolization, on behavioral outcome. For the studies, we used the rabbit small clot embolic stroke model (RSCEM) using three different treatment regimens: 1) CW power density of 7.5 mW/cm(2); 2) P1 using a frequency of 300 mus pulse at 1 kHz or 3) P2 using a frequency of 2 ms pulse at 100 Hz. Behavioral analysis was conducted 48 h after embolization, allowing for the determination of the effective stroke dose (P(50)) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Using the RSCEM, a treatment is considered beneficial if it significantly increases the P(50) compared with the control group. Quantal dose-response analysis showed that the control group P(50) value was 1.01+/-0.25 mg (n=31). NILT initiated 6 h following embolization resulted in the following P(50) values: (CW) 2.06+/-0.59 mg (n=29, P=0.099); (P1) 1.89+/-0.29 mg (n=25, P=0.0248) and (P2) 1.92+/-0.15 mg (n=33, P=0.0024). NILT started 12 h following embolization resulted in the following P(50) values: (CW) 2.89+/-1.76 mg (n=29, P=0.279); (P1) 2.40+/-0.99 mg (n=24, P=0.134). At the 6-h post-embolization treatment time, there was a statistically significant increase in P(50) values compared with control for both pulse P1 and P2 modes, but not the CW mode. At the 12-h post-embolization treatment time, neither the CW nor the P1 regimens resulted in statistically significant effect, although there was a trend for an improvement. The results show that P mode NILT can result in significant clinical improvement when administered 6 h following embolic strokes in rabbits and should be considered for clinical development.

Mechanisms of antinociception of spinal galanin: how does galanin inhibit spinal sensitization?

Galanin by a spinal action has been shown to have an antihyperalgesic action. Thus, in rats with lumbar intrathecal (IT) catheters, the thermal hyperalgesia evoked by carrageenan paw injection was blocked by IT delivery of galanin(1-29) (Gal(1-29)) and galanin(2-11) (Gal(2-11)) with the rank order of activity being Gal(1-29)>Gal(2-11). We sought to determine whether this spinal action reflects an effect upon afferent transmitter release, e.g., substance P (SP), and/or on secondary neurons, e.g., signaling postsynaptic to neurokinin 1 (NK1) receptor activation. To address the question on afferent release, we investigated the effect of IT administration of galanin on tissue injury-induced spinal NK1 internalization (an indicator of SP release). Noxious stimulation (paw compression) produced an increase in NK1 internalization in dorsal horn lamina I. IT pretreatment of rats with Gal(1-29) and Gal(2-11) significantly attenuated the evoked NK1 internalization, with the rank order of activity being Gal(1-29)>Gal(2-11)>saline. To address the question of postsynaptic action, we examined the effects of IT galanin upon IT SP-induced thermal hyperalgesia and spinal PGE2 release. Application of SP (30 nmol) directly to spinal cord led to a decrease in thermal thresholds and a profound increase in PGE(2) concentration in spinal dialysates. Both phenomena were reversed by Gal(1-29) and Gal(2-11) (10nmol, IT). These findings suggest that the antihyperalgesic effect of spinal galanin is due to its action on sites both presynaptic (inhibition of SP release) and postsynaptic (blockade of SP-evoked hyperalgesia and PGE2 production) to the primary afferents.

A rare case of intramedullary lipoma associated with cyst.

Intramedullary lipomas are benign tumours of the spinal cord corresponding to 1% of all primitive intramedullary tumours. We report a rare case of "true" intramedullary lipoma associated with cyst. The patient underwent subtotal resection and the diagnosis was made by histopathological examination. There was postoperative neurological improvement.

Clonally related penicillin-nonsusceptible Streptococcus pneumoniae serotype 14 from cases of meningitis in Salvador, Brazil.

Active hospital-based surveillance in the city of Salvador, Brazil, from December 1995 through October 1998, identified 221 patients with confirmed pneumococcal meningitis. Of these 221 patients, 29 (13%) had isolates with intermediate-level resistance to penicillin. Infection with these penicillin-nonsusceptible isolates was significantly associated with age of <2 years (P<.0019), previous antibiotic use (P<.0006), and coresistance to trimethoprim-sulfamethoxazole (P<.0000). Serotype 14 was the most prevalent serotype (55.2%) of penicillin-nonsusceptible isolates. Strain typing by repetitive element BOX polymerase chain reaction (PCR) analysis showed that penicillin-nonsusceptible serotype 14 isolates had closely related BOX PCR patterns, whereas penicillin-susceptible serotype 14 isolates each had distinct, unrelated patterns. Penicillin-nonsusceptible serotype 14 isolates from Salvador and other Brazilian cities had similar BOX PCR patterns. These observations indicate that in Brazil a large proportion of cases of penicillin-nonsusceptible pneumococcal meningitis appear to be caused by a closely related group of serotype 14 strains that may have disseminated to widely separate geographic areas.

[Increase in the frequency of norfloxacin and ciprofloxacin resistance of bacteria isolated from urine culture]. / Aumento da freqüência de resistência à norfloxacina e ciprofloxacina em bactérias isoladas em uroculturas.

OBJECTIVE: To assess time trends in the frequency of norfloxacin and ciprofloxacin resistance of bacteria isolated from urine culture. METHODS: Results of all urine cultures with a bacterial growth of at least 10(5) colony-forming units per milliliter, performed at the Renal Service of the Federal University of Bahia, Brazil, from 1983 to 1994 were analyzed. The bacteria considered for this analysis were those most often isolated: Escherichia coli (n = 668), Klebsiella spp. (n = 286), Staphylococcus spp. (n = 186), Proteus spp. (n = 135) and Enterobacter spp. (n = 129). RESULTS: The frequencies of norfloxacin resistance for the periods 1983-1986, 1987-1990 and 1991-1994 were 3.2%, 5.9% and 9.1%, respectively (p-value < 0.05). The most pronounced increases in the frequencies of norfloxacin-resistance were observed for Klebsiella spp. and Enterobacter spp. The frequency of ciprofloxacin resistance was 7.4% in the period 1985-1989 and 16.5% in the period 1990-1994 (p-value < 0.05). This time trend in ciprofloxacin resistance was more striking for Enterobacter spp. and Staphylococcus spp. CONCLUSION: The results show a gradual increase in the frequency of norfloxacin and ciprofloxacin resistance of the bacteria most commonly isolated from urine cultures. The influence of previous treatment with quinolones and characteristics of the infecting bacteria on these findings are important questions to to be addressed in future investigations.

Aumento da frequência de resistência à norfloxacina e ciprofloxacina em bactérias isoladas em uroculturas / Increase in the frequency of norfloxacin and ciprofloxacin resistance of bacteria isolated from urine culture

Objetivo. Avaliar mudanças, ao longo dos anos, na freqüência de resistência à norfloxacina e ciprofloxacina em bactérias isoladas de uroculturas. Métodos. Resultados de todas as uroculturas com crescimento bacteriano de pelo menos 10(5) unidades formadoras de colônias por mL de urina (UFCmL), realizadas no Serviço de Nefrologia da Universidade Federal da Bahia durante o período 1983-1994, foram analisadas. As bactérias incluídas na análise foram aquelas mais freqüentemente isolados: Escherichia coli (n=668), Klebsiella spp. (n=286), Staphylococcus spp. (n=186), Proteus spp. (n=135) e Enterobacter spp. (n=129). Resultados. A freqüência de bactérias resistentes à norfloxacina foi de 3,2 por cento, no período 1983-1986; 5,9 por cento, no período 1987-1990; e 9,1 por cento no período de 1991-1994 (p<0,05). Klebsiella spp. e Enterobacter spp. foram as bactérias que apresentaram maiores aumentos na freqüência de resistência à norfloxacina. Para a ciprofloxacina, constatou-se resistência em 7,4 por cento das bactérias isoladas, no período 1985-1989, e 16,5 por cento, no período 1990-1994 (p<0,05). Esse aumento na freqüência de bactérias resistentes à ciprofloxacina foi mais marcante para Enterobacter spp. e Staphylococcus spp. Conclusoes. Os resultados do presente estudo mostram um aumento gradual na freqüência de resistência à norfloxacina e ciprofloxacina entre as bactérias mais comumente isoladas em uruculturas. A influência do uso prévio de quinolonas e de peculiaridades da bactéria infectante, nesses achados, representa importante questao a ser investigada.

Differentiation of pathogenic Escherichia coli strains in Brazilian children by PCR.

A PCR technique to differentiate pathogenic enteric Escherichia coli strains in a field setting was evaluated. Among 76 children with acute diarrhea, this technique identified 12 children (16%) with enterotoxigenic E. coli, 6 (8%) with enteropathogenic E. coli, and 1 (1%) with enteroinvasive E. coli infection. Compared with the conventional assays, the PCR method proved to be simpler, more rapid, and inexpensive and therefore suitable for application in a developing-country field setting.