Prospective PTCTC trial of myeloablative haplo-BMT with posttransplant cyclophosphamide for pediatric acute leukemias.

Promising results have been reported for adult patients with high-risk hematologic malignancies undergoing haploidentical bone marrow transplant (haploBMT) with posttransplant cyclophosphamide (PTCy). To our knowledge, we report results from the first multicenter trial for pediatric and young adult patients with high-risk acute leukemias and myelodysplastic syndrome (MDS) in the Pediatric Transplantation and Cellular Therapy Consortium. Nine centers performed transplants in 32 patients having acute leukemias or MDS, with myeloablative conditioning (MAC), haploBMT with PTCy, mycophenolate mofetil, and tacrolimus. The median patient age was 12 years. Diagnoses included AML (15), ALL (11), mixed-lineage leukemia (1), and MDS (5). Transplant-related mortality (TRM) at 180 days was 0%. The cumulative incidence (CuI) of grade 2 acute graft-versus-host disease (aGVHD) on day 100 was 13%. No patients developed grades 3-4 aGVHD. The CuI of moderate-to-severe chronic GVHD (cGVHD) at 1 year was 4%. Donor engraftment occurred in 27 patients (84%). Primary graft failures included 3 patients who received suboptimal bone marrow grafts; all successfully engrafted after second transplants. The CuI of relapse at 1 year was 32%, with more relapse among patients MRD positive pre-BMT vs MRD negative. Overall survival rates at 1 and 2 years were 77% and 73%, and event-free survival rate at 1 and 2 years were 68% and 64%. There was no TRM or severe aGVHD, low cGVHD, and favorable relapse and survival rates. This successful pilot trial has led to a phase 3 trial comparing MAC haploBMT vs HLA-matched unrelated donor BMT in the Children's Oncology Group. This trial was registered at www.clinicaltrials.gov as #NCT02120157.

Immunotherapy approaches for rare pediatric solid tumors: advances and future directions.

PURPOSE OF REVIEW: Immunotherapy for pediatric tumors is rapidly evolving. From major successes in pediatric hematologic malignancies, immunotherapy utility increased in the pediatric solid tumor landscape. Numerous pediatric solid tumors are defined as rare with limitations in diagnosis and treatment. This review will describe four major immunotherapies used in pediatrics and discuss results seen in rare pediatric tumors. We will also briefly review the challenges of immunotherapy in solid tumors and opportunities to drive this therapy forward. RECENT FINDINGS: Despite rare success employing immunotherapy for pediatric solid tumors, recently there have been several successes in pediatric rare solid tumors. After describing the evolving landscape of rare pediatric tumors, we will demonstrate the successes or disappointments of immunotherapy. We will describe the mechanism of four immunotherapies used in the pediatrics, followed by the published results. Finally, we will discuss the challenges and opportunities for immunotherapies in pediatric rare tumors. SUMMARY: Pediatric rare tumors are lacking in treatment options. Despite numerous disappointments utilizing immunotherapies in the more common pediatric solid tumors, there have been several successes within the pediatric rare tumor landscape. Much work is still needed to enhance our understanding and knowledge on utilizing these immunotherapies for pediatric rare solid tumors.

Transmission of dengue virus from deceased donors to solid organ transplant recipients: case report and literature review.

Dengue fever is a vector-transmitted viral infection. Non-vectorial forms of transmission can occur through organ transplantation. We reviewed medical records of donors and recipients with suspected dengue in the first post-transplant week. We used serologic and molecular analysis to confirm the infection. Herein, we describe four cases of dengue virus transmission through solid organ transplantation. The recipients had positive serology and RT-PCR. Infection in donors was detected through serology. All cases presented with fever within the first week after transplantation. There were no fatal cases. After these cases, we implemented dengue screening with NS1 antigen detection in donors during dengue outbreaks, and no new cases were detected. In the literature review, additional cases had been published through August 2017. Transmission of Dengue virus can occur through organ donation. In endemic regions, it is important to suspect and screen for dengue in febrile and thrombocytopenic recipients in the postoperative period.

Transmission of dengue virus from deceased donors to solid organ transplant recipients: case report and literature review

ABSTRACT Dengue fever is a vector-transmitted viral infection. Non-vectorial forms of transmission can occur through organ transplantation. We reviewed medical records of donors and recipients with suspected dengue in the first post-transplant week. We used serologic and molecular analysis to confirm the infection. Herein, we describe four cases of dengue virus transmission through solid organ transplantation. The recipients had positive serology and RT-PCR. Infection in donors was detected through serology. All cases presented with fever within the first week after transplantation. There were no fatal cases. After these cases, we implemented dengue screening with NS1 antigen detection in donors during dengue outbreaks, and no new cases were detected. In the literature review, additional cases had been published through August 2017. Transmission of Dengue virus can occur through organ donation. In endemic regions, it is important to suspect and screen for dengue in febrile and thrombocytopenic recipients in the postoperative period.

Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation?

Norepinephrine (NE) is synthesized in the Locus Coeruleus (LC) of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system (CNS) and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework. Since three main families of NE receptors are represented-in order of decreasing affinity for the catecholamine-by: α2 adrenoceptors (α2Rs, high affinity), α1 adrenoceptors (α1Rs, intermediate affinity), and ß adrenoceptors (ßRs, low affinity), on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: (1) sleep: virtual absence of NE, (2) quiet wake: activation of α2Rs, (3) active wake/physiological stress: activation of α2- and α1-Rs, (4) distress: activation of α2-, α1-, and ß-Rs. We postulate that excess intensity and/or duration of states (3) and (4) may lead to maladaptive plasticity, causing-in turn-a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the CNS. While the model has the potential to explain a large number of experimental and clinical findings, a major challenge will be to adapt this hypothesis to integrate the role of other neurotransmitters released during stress in a centralized fashion, like serotonin, acetylcholine, and histamine, as well as those released in a non-centralized fashion, like purines and cytokines.

Pathophysiological Relationship between Infections and Systemic Vasculitis.

The development of autoimmune disorders requires a combination of genetic, immunological, and environmental factors. Infectious agents, such as viruses and bacteria, can trigger autoimmunity through different mechanisms, and for systemic vasculitis in particular, microbial agents have been suggested to be involved in its pathogenesis. Although the exact mechanisms have not been fully elucidated, different theories have been postulated. This review considers the role of infections in the etiology of primary vasculitis, emphasizing their related immunological events.

Immobility time during the forced swimming test predicts sensitivity to amitriptyline, whereas traveled distance in the circular corridor indicates resistance to treatment in female Wistar rats.

Among the main issues in the pharmacological treatment of depression are the wide variation in response to antidepressants among individual patients and the lack of indexes that allow prediction of which drug will be effective in a particular case. We evaluated whether differential sensitivity to amitriptyline is related to dichotomous categorization of individuals on the basis of their behavioral responses to two common paradigms used to evaluate the potential of tricyclic drugs as antidepressants. Hence, we categorized a cohort of 38 female rats on the basis of their immobility time in the conditioning phase of the forced swimming test [FST; high immobility (HI) vs. low immobility (LI) rats] and their locomotor behavior in the circular corridor test [high locomotor response (HR) vs. low locomotor response (LR) rats]. We subjected the rodents to the FST while under the influence of vehicle (n=20) or amitriptyline (15 mg/kg; n=18). We found no statistical evidence of dependence between categorizations of rats on the basis of their behavior in the FST and circular corridor test. Rats categorized as HI/LI and HR/LR significantly differed in their sensitivity/resistance to amitriptyline, as evidenced by changes (or lack thereof) in their immobility time, climbing time, and swimming time during the FST. These results confirm that different behavioral styles among rats are linked to differential sensitivity/resistance to antidepressants. However, we specifically found that categorizing rats as HI/LI better reflected sensitivity to amitriptyline, whereas categorizing them as HR/LR better revealed resistance to the drug. These differential responses should be considered in experimental approaches.

Plasmodium vivax cerebral malaria complicated with venous sinus thrombosis in Colombia.

Complicated malaria is usually due to Plasmodium falciparum. Nevertheless, Plasmodium vivax is infrequently related with life-threatening complications. Few cases have been reported of severe Plasmodium vivax infection, and most of them from Southeast Asia and India. We report the first case of cerebral malaria due to Plasmodium vivax in Latin America, complicated with sagittal sinus thrombosis and confirmed by a molecular method.

Exposure of Red Tilapia (Oreochromis spp.) eggs to 17 α-Methyltestosterone and the sex ratio of the fish offspring / Inmersión de ovas de tilapia roja (Oreochromis spp.) en diferentes estadíos de fertilización en una solución de 17 α- metiltestosterona y la proporción fenotípica del sexo / Efeito da imersão de ovas de tilápia vermelha (Oreochromis spp.) em diferentes fases de fertilização numa solução de 17α- metiltestosterona sobre a proporção fenotípica do sexo

This study evaluated the proportions of sex reversals which occurred after red tilapia (Oreochromis spp.) eggs were immersed into various solutions of 17 α-Methyltestosterone (0, 800 and 1200 ug/L of water). Two fertilization stages of the eggs, i.e., reflecting clear or dark colors, were included in this study. Besides sex proportions, other parameters studied included hatching, fry and fingerling survival, final weight and length. There were no significant differences between the sex proportions obtained relative to hormone concentration or egg color (49.59% males from dark eggs and 46.36% males from light eggsversus the control, which had 55.24% males). In contrast, the percentage of hatching was significantly higher in dark eggs (60.27% ± 11.52). Survival of fry was higher when born from dark eggs compared with clear eggs (51.74% ± 27.01 versus 28.97% ± 1.52, respectively). Fingerling survival was not related to the color of the eggs (59.28% ± 23.73 versus 65.58% ± 9.01 for initially dark and clear eggs, respectively). However, surviving males were longer and heavier (6.75 cm ± 1.29 and 5.45 g ± 3.09) than females. This data suggest a possible interaction between hatching, survival, and egg color.

Este trabajo tuvo como objetivo evaluar la reversión sexual por inmersión de ovas de tilapia roja (Oreochromis spp.) clasificadas por estadíos de fertilización (color de ovas claras y oscuras) a diferentes hormonales 0, 800 y 1200 μg de 17 α- Metil Testosterona (17αMT/L) por litro de agua. El trabajo fue realizado en la estación piscícola de la Universidad de Antioquia, midiendo como variables: proporción sexual, porcentaje de eclosión, sobrevivencia en larva y alevinaje, peso final, longitud total. Para porcentaje de reversión sexual no se encontró diferencia significativa (p>0.05) con respecto a las concentraciones hormonales y al color de ovas, cuyos valores promedio fueron 49.59% de machos para ovas oscuras y 46.36% de machos para ovas claras, respecto al tratamiento testigo que tuvo 55.24% de machos. Para los demás parámetros, tales como porcentaje de eclosión, se encontró diferencia altamente significativa (p<0.01) con respecto al color de las ovas siendo mayor la eclosión en ovas de color oscuro con un valor de 60.27 ± 11.52%. Para sobrevivencia en larva se encontró diferencia significativa (p<0.05) hallándose 51.74 ± 27.01% para las larvas provenientes de ovas oscuras y 28.97 ± 1.52% para las provenientes de ovas claras. Para sobrevivencia en la etapa de alevinaje, no hubo diferencia significativa (p>0.05) con respecto al color de las ovas, encontrándose 59.2 ± 23.73% para los animales provenientes de ovas oscuras y de 65.58 ± 9.01% para los animales provenientes de ovas claras. En las variables peso y longitud se observó diferencia altamente significativa (p<0.001) con respecto al sexo siendo de mayor tamaño y peso los machos con una media de 6.75 ± 1.29 cm y 5.45 ± 3.09 g, respectivamente.

Este estudo teve como objetivo avaliar a reversão sexual por imersão em ovas de tilápia vermelha (Oreochromis spp.), classificadas por fases da fecundação (ovas de cores claras e escuras), com diferentes concentrações hormonais, 0, 800 e 1200 μg17α MT / L de água. Este trabalho foi realizado na Estação Piscícola da Universidade de Antioquia, medindo variáveis, tais como: percentagem de Eclosão, percentagem de Sobrevivência das larvas e alevinagem, Peso fim, Comprimento total, e proporção sexual. Para a variável Eclosão, foi encontrada uma diferença altamente significativa (p<0.01), sendo maior a quantidade de ovas escuras, com uma média de 60.27% e um desvio padrão de ± 11.52%. Na sobrevivencia das larvas não foi encontrada diferença significativa (p<0.05) com respeito a cor das ovas, havendo uma média de 51.74% e um desvio padrão de ± 27.01% para as larvas das ovas escuras; uma média de 28.97% e com desvio padrão de ± 1.52% para as larvas das ovas claras. Durante a etapa da alevinagem não houve diferença significativa (p>0.05), encontrado uma média de 59.28% e um desvio padrão de ± 23.73% para os animais provenientes de ovas escuras; uma média de 65.58% e um desvio padrão de ± 9.01% para animais provenientes de ovas claras. Nas variáveis Peso e Comprimento, foi observada diferença altamente significativa (p <0.001); sendo os machos, de maior tamanho e peso, com uma média de 6.75 centímetros e um desvio padrão de ± 1.29 cm para a variável comprimento. Para a variável peso, ocorreu uma média de 5.45 gr e um desvio de ± 3.09 g. Para a Reversão, não foi encontrada diferença significativa (p>0.05), no que diz respeito ao concentrações hormonais e a cor das ovas.

Long-lasting resistance to haloperidol-induced catalepsy in male rats chronically treated with caffeine.

Chronic caffeine consumption has been inversely associated with the risk of developing Parkinson's disease. Here we assessed whether chronic caffeine treatment increases the resistance of male Wistar rats to haloperidol (1mg/kg, s.c.)-induced catalepsy, measured in the bar test at 15 min intervals during 3h. Caffeine (5mg/kg/day) was delivered for 6 months via drinking water. Control rats received only tap water. Treatments began when animals were 3-4 months old. In order to unveil long-lasting catalepsy refractoriness not attributable to the presence of caffeine in the brains of rats, they were evaluated from day 18 to day 27 after caffeine withdrawal, a time that is far in excess for the full excretion of a caffeine dose in this species. The average cataleptic immobility measured in caffeine-treated rats (n=23) was 1148+/-140 s, a value 34+/-8% lower than that recorded in control animals (n=20), whose mean immobility was 1736+/-137 s (P=0.0026, t-test). The percentage of catalepsy reduction measured in caffeine-treated rats evaluated on days 18-20 after caffeine discontinuation (-32+/-13%, n=12, P<0.05) was comparable to the catalepsy decrease recorded in those animals tested on days 21-27 (-36+/-10%, n=11, P<0.02), a finding compatible with the notion that the effect was indeed mediated by enduring changes of brain functioning and not by the physical presence of caffeine or its metabolites. Caffeine-treated rats also had higher catalepsy latency scores compared with control rats (P<0.01, U-test). The present findings show that chronic consumption of caffeine produces perdurable resistance to catalepsy induced by dopamine receptor blockade, possibly through enhancement of dopamine transmission, giving further support to the epidemiological results indicating that prolonged caffeine consumption affords neuroprotection against Parkinson's disease.

Differential effects of caffeine on the antidepressant-like effect of amitriptyline in female rat subpopulations with low and high immobility in the forced swimming test.

The interaction of caffeine (1 mg/kg) and amitriptyline (15 mg/kg) on the immobility time (IT) during Porsolt's forced swimming test (FST) was investigated in female Wistar rats. Akaike's Information Criterion indicated that the ITs recorded from 142 rats during the first day of the FST followed a bimodal distribution. Hence, the median (125.5 s) was used to classify the animals in subpopulations with low (<125.5 s, LI-rats) or high (>125.5 s, HI-rats) immobility. The paired t-test was used to compare the change of ITs between the first and second swimming sessions. Vehicle-treated animals had a significant increase of ITs during the second day of the test, either in LI-rats (77+/-12 s vs. 196+/-8 s, P<0.0001, n=6) or HI-rats (150+/-8 s vs. 201+/-10 s, P<0.02, n=6). In LI-rats amitriptyline only prevented the increase of ITs during the second session (74+/-27 s vs. 97+/-42 s, n=12), whereas in HI-rats the antidepressant produced a significant decrease of ITs during the second session (161+/-22 s vs. 118+/-32 s, n=7, P<0.02). While caffeine alone prevented the increase of ITs in both groups, the methylxanthine abolished the effect of amitriptyline in HI-rats (165+/-23 s vs. 165+/-46 s, n=9), leaving the antidepressant action unaffected in LI-rats (87+/-23 s vs. 96+/-58 s, n=9). These results suggest that the anti-immobility effect of amitriptyline in HI-rats is mediated in part by endogenous adenosine.

A novel automated rat catalepsy bar test system based on a RISC microcontroller.

Catalepsy tests performed in rodents treated with drugs that interfere with dopaminergic transmission have been widely used for the screening of drugs with therapeutic potential in the treatment of Parkinson's disease. The basic method for measuring catalepsy intensity is the "standard" bar test. We present here an easy to use microcontroller-based automatic system for recording bar test experiments. The design is simple, compact, and has a low cost. Recording intervals and total experimental time can be programmed within a wide range of values. The resulting catalepsy times are stored, and up to five simultaneous experiments can be recorded. A standard personal computer interface is included. The automated system also permits the elimination of human error associated with factors such as fatigue, distraction, and data transcription, occurring during manual recording. Furthermore, a uniform criterion for timing the cataleptic condition can be achieved. Correlation values between the results obtained with the automated system and those reported by two independent observers ranged between 0.88 and 0.99 (P<0.0001; three treatments, nine animals, 144 catalepsy time measurements).

5-HT1A, 5-HT2, and GABAB receptors interact to modulate neurotransmitter release probability in layer 2/3 somatosensory rat cortex as evaluated by the paired pulse protocol.

Activation of gamma-aminobutyric acid B (GABA(B)) and 5-hydroxytryptamine (5-HT) receptors produces presynaptic inhibition at glutamatergic terminals in the rat neocortex. To evaluate interactions between these metabotropic receptors, field potentials were recorded in layer 2/3 of somatosensory cortex. In addition, the paired pulse (PP) protocol was used to measure changes in the ratio of the second/first extracellular synaptic potentials (S(2)/S(1) ratio) as an index of glutamate release probability in the area. Lowering extracellular [Ca(2+)](o) to 0.5 mM, increased the S(2)/S(1) ratio by 318 +/- 134%. 5-HT (1 microM) increased the S(2)/S(1) ratio by 61 +/- 15%. In presence of the GABA(A) antagonist bicuculline (10 microM), 5-HT increased the S(2)/S(1) ratio by 98 +/- 15%. This effect did not desensitize after two consecutive applications of the amine, and was dose dependent in the concentration range between 0.03-1 microM (EC(50) = 2.36 x 10(-7) mol/L). The increase of S(2)/S(1) ratio induced by 5-HT (1 microM) was blocked reversibly by the 5-HT(1A) antagonist NAN-190 (10-30 microM), but was unaffected by the selective GABA(B) antagonist CGP 52432 (1 microM). The action of 5-HT was mimicked by the 5-HT(1A/7) agonist 8OH-DPAT (10 microM), increasing the S(2)/S(1) ratio by 84 +/- 2%, a response that was unaffected by the 5-HT(2/7) antagonist ritanserin (2 microM). The 5-HT(1B) agonist CP93129 (10 microM) had no effect. The GABA(B) agonist baclofen (1 microM) increased the S(2)/S(1) ratio up to 308 +/- 33%, which is similar to that produced by low [Ca(2+)](o). When the effect of baclofen was maximal, application of 5-HT (1 microM) reversed the S(2)/S(1) ratio back to 78 +/- 27%, a result that was blocked by the 5-HT(2/7) antagonist ritanserin (100 nM). Notably, the interaction between the GABA(B) agonist and 5-HT was order dependent, because enhancement of the S(2)/S(1) ratio elicited by baclofen was not inhibited if 5-HT was applied first. These results suggest a complex interaction between GABA(B), 5-HT(1A), and 5-HT(2) receptors in layer 2/3 of rat somatosensory cortex. Activation of GABA(B) receptors induces PP facilitation (inhibits glutamate release) more efficiently than does activation of 5-HT(1A) receptors. When the effect of GABA(B) receptor activation is maximal, however, the influence of 5-HT changes to the opposite direction, inhibiting PP facilitation (increasing glutamate release) through activation of 5-HT(2) receptors.

Caffeine and muscarinic antagonists act in synergy to inhibit haloperidol-induced catalepsy.

The possible synergism between caffeine and muscarinic antagonists to inhibit haloperidol-induced catalepsy was investigated with the bar test in rats. Pretreatment with low doses of caffeine (1-3 mg/kg), a non-selective adenosine antagonist, dose dependently reduced the intensity and increased the onset latency of catalepsy induced by haloperidol (0.5-2 mg/kg). Similar effects were produced by the muscarinic antagonists atropine (4.1 mg/kg), and trihexyphenidyl (THP, 0.01-3 mg/kg). THP inhibited catalepsy intensity with an ED(50) of 0.38 mg/kg, and increased its onset latency with an ED(50) of 0.52 mg/kg. The anticataleptic effect of anticholinergics was potentiated when a low dose of caffeine (1 mg/kg) was applied simultaneously. In the presence of caffeine, THP inhibited catalepsy intensity with an ED(50) of 0.19 mg/kg, and prolonged the latency with an ED(50) of 0.30 mg/kg. The synergism was more evident when THP was administered at subthreshold doses that were unable to modify haloperidol-induced catalepsy when applied alone, but produced a clear inhibition of catalepsy when injected with caffeine. To assess whether repeated administration of caffeine could induce tolerance to the synergism with THP, a group of rats was pretreated with three daily doses of caffeine (1 mg/kg) for seven days, and the catalepsy test was performed on the eighth day. In these animals, caffeine was still able to enhance the anticataleptic actions of THP, suggesting that repeated administration of 1 mg/kg caffeine does not induce tolerance to the synergism with anticholinergics. These results indicate that low doses of caffeine enhance the anticataleptic actions of muscarinic antagonists, and leave open the possibility of using caffeine as adjunctive therapy to reduce the doses and the adverse effects of anticholinergics in Parkinson's disease.