Age-related differences in the response of the brain to dietary melatonin

The aged brain is prone to excessive levels of immune activity, not initiated by an acute response to an extrinsic agent. While dietary melatonin is reported to attenuate the extent of expression of proinflammatory genes, little is known about the extent to which these changes can be translated into altered levels of corresponding proteins. The baseline levels of the proinflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-1 alpha, were greater in older (~29 months old) compared to younger (~7 months old) mouse brains. Acute (3 h) exposure to lipopolysaccharide (LPS) induced activation of nuclear factor kappa B (NF-κB), but not inflammatory cytokines in the brain. The serum level of TNF-α was increased after LPS injection, indicating a systemic immune response to the bacterial cell wall component. Dietary melatonin (40 ppm for 9.3 weeks) did not prevent LPS-induced changes in younger animals but caused an increased systemic TNF-α response in older mice. Melatonin did reduce markers of carbonyl formation in brain proteins of young animals and nitrosylative damage to peptide-bound amino acid residues, in the brains of older animals. Acute LPS challenge did not significantly affect these oxidative markers. Thus, despite lack of clear evidence of attenuation of the NF-κB–cytokine inflammatory trajectory within the CNS by melatonin, this agent did show a protective effect against free radical-initiated injury to amino acid residues within proteins. The results illustrate that previously reported changes in gene expression following melatonin treatment need not be closely paralleled by corresponding changes in protein content.     

Early goal-directed therapy reduces mortality in adult patients with severe sepsis and septic shock: Systematic review and meta-analysis

Introduction:

Survival sepsis campaign guidelines have promoted early goal-directed therapy (EGDT) as a means for reduction of mortality. On the other hand, there were conflicting results coming out of recently published meta-analyses on mortality benefits of EGDT in patients with severe sepsis and septic shock. On top of that, the findings of three recently done randomized clinical trials (RCTs) showed no survival benefit by employing EGDT compared to usual care. Therefore, we aimed to do a meta-analysis to evaluate the effect of EGDT on mortality in severe sepsis and septic shock patients.

Methodology:

We included RCTs that compared EGDT with usual care in our meta-analysis. We searched in Hinari, PubMed, EMBASE, and Cochrane central register of controlled trials electronic databases and other articles manually from lists of references of extracted articles. Our primary end point was overall mortality.

Results:

A total of nine trails comprising 4783 patients included in our analysis. We found that EGDT significantly reduced mortality in a random-effect model (RR, 0.86; 95% confidence interval [CI], 0.72–0.94; P = 0.008;   I² =50%). We also did subgroup analysis stratifying the studies by the socioeconomic status of the country where studies were conducted, risk of bias, the number of sites where the trials were conducted, setting of trials, publication year, and sample size. Accordingly, trials carried out in low to middle economic income countries (RR, 0.078; 95% CI, 0.67–0.91; P = 0.002; I² = 34%) significantly reduced mortality compared to those in higher income countries (RR, 0.93; 95% CI, 0.33–1.06; P = 0.28; I² = 29%). On the other hand, patients receiving EGDT had longer length of hospital stay compared to the usual care (mean difference, 0.49; 95% CI, –0.04–1.02; P = 0.07; I² = 0%).

Conclusion:

The result of our study showed that EGDT significantly reduced mortality in patients with severe sepsis and septic shock. Paradoxically, EGDT increased the length of hospital stay compared to usual routine care.     

Posterior sub-tenon’s bevacizumab injection in diabetic macular edema; a pilot study

Purpose

To evaluate the short-term results of sub-tenon’s injection of bevacizumab in patients with clinically significant macular edema (CSME).

Methods

In this prospective non-comparative interventional case series, sub-tenon’s injection of 2.5 mg/0.1 ml bevacizumab was performed for eyes with CSME. Macular thickness and best corrected visual acuity measurements were performed before and one month after injections.

Results

Nineteen eyes of twelve patients with a mean age of 59.8 ± 5.7 years were evaluated. Thirteen eyes (68.4%) had center-involving macular edema. No significant difference was observed between pre- and post-injection central subfield retinal thickness measurements (P = 0.3). Central subfield thickness measurements improved or remained unchanged in 13 eyes (68.4%). Baseline BCVA of 0.48 ± 0.35 LogMAR improved to 0.36 ± 0.26 LogMAR after injection (P = 0.01). Improvement of >2 lines in BCVA was found in 5 eyes (26.3%), and no eye lost >2 lines of BCVA. No complication associated with sub-tenon’s injection was observed.

Conclusion

Sub-tenon’s injection of bevacizumab resulted in significant short-term visual improvement in eyes with CSME. Retinal thickness changes were not significant.     

Persistence of hepatitis B vaccine immunity in hemodialysis patients

Although the efficacy of hepatitis B vaccines in patients undergoing chronic hemodialysis (HD) treatment has been documented, the persistence of immunity in this population remains largely unknown. In this study we evaluated the persistence of hepatitis B vaccine immunity in HD patients. We followed 37 hepatitis B vaccinated HD patients (following a four-dose vaccination schedule of 40 mug injections intramuscularly in the deltoid muscle at 0, 1, 2, and 6 months) for up to one year to evaluate the persistence of immunity (as indicated by serum levels of hepatitis B surface antibody (anti-HBs) equal to or higher than 10 IU/L). One year after vaccination, 18.9% of patients had lost their anti-HBs (transient responders), while 81.1% still had detectable antibodies in the serum (persistent responders). From 81.1% of persistent responders 11.5% and 88.5% were weak and high responders, respectively. There was no significant difference between persistent and transient responders regarding age, sex, or nutritional factors. We did not find any factors that related to maintaining protective levels of anti-HBs in HD patients. It seems that an antibody titer above 100 IU/L following vaccination is necessary in order to maintain that level of antibody one year later.     

The immunological benefit of higher dose N-acetyl cysteine following mechanical ventilation in critically ill patients

Background

Sepsis complication is a major cause of death in multiple trauma critically ill patients. Defensin (cysteine rich anti-microbial peptides), as an important component of immune system, might play an important role in this process. There is also rising data on immunological effects of N-acetyl-cysteine (NAC), a commonly used anti-oxidant in oxidative stress conditions and glutathione (GSH) deficiencies. The aim of the present study was to evaluate the potential beneficial effects of NAC administration on multiple trauma patients with sepsis.

Methods

In a prospective, randomized controlled study, 44 multiple trauma critically ill patients who were mechanically ventilated and met the criteria of sepsis and admitted to the intensive care unit (ICU) were randomized into two groups . Control group received all standard ICU therapies and NAC group received intravenous NAC 3 gr every 6 hours for 72 hours in addition to standard therapies. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality were recorded. Levels of serum Immunoglobulin M (IgM), Human β-Defensin 2 (HβD2) and GSH were assessed at baseline and 24, 72, 120 hours after intervention.

Results

During a period of 13-month screening, 44 patients underwent randomization but 5 patients had to be excluded. 21 patients in NAC group and 18 patients in control group completed the study. For both groups the length of ICU stay, SOFA score and systemic oxygenation were similar. Mortality rate (40% vs. 22% respectively, p = 0.209) and ventilator days (Mean ± SD 19.82 ± 19.55 days vs. 13.82 ± 11.89 days respectively, p = 0.266) were slightly higher for NAC group. IgM and GSH levels were similar between two groups (p = 0.325, 0.125 respectively), HβD2 levels were higher for NAC group (at day 3).

Conclusion

High dose of NAC administration not only did not improve patients’ outcome, but also raised the risk of inflammation and was associated with increased serum creatinine.     

Evaluation of Alum-Naltrexone Adjuvant Activity,on Efficacy of Anti-Leishmania Immunization with Autoclaved Leishmania major (MRHO/IR/75/ER) Antigens in BALB/C Mice

Background

Naltrexone, an opioid receptor antagonist shifts the immune response toward a Th1 profile. In the current study, we evaluated the efficacy of the mixture of NTX and alum, as a new adjuvant, to enhance immune response and induce protection against Leishmania major in a mouse model.

Methods

BALB/c mice were immunized three times either autoclaved L. major promastigotes’ antigens alone or in combination with the adjuvant alum, naltrexone or the alum–naltrexone mixture. Both humoral and cellular immune responses were assessed two weeks after the last immunization and compared with control mice.

Results

The administration of alum- NTX in combination with the parasite antigen, significantly increased production of IFN-γ IFN-γ /IL-5 ratio, lymphocyte proliferation and improved DTH response against L. major. There was no significant difference in survival following challenge among groups.

Conclusion

Immunization with the alum– naltrexone mixture as an adjuvant, in combination with the autoclaved L. major promastigotes antigens, can enhance cellular immunity and shift the immune responses to a Th1 pattern.     

Preparation and Optimization of Chitosan/pDNA Nanoparticles Using Electrospray

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Chitosan (CS), as a natural polymer, has received a great deal of attention as a carrier for delivery of...     

Simultaneous selection by object-based attention in visual and frontal cortex

Models of visual attention hold that top-down signals from frontal cortex influence information processing in visual cortex. It is unknown whether situations exist in which visual cortex actively participates in attentional selection. To investigate this question, we simultaneously recorded neuronal activity in the frontal eye fields (FEF) and primary visual cortex (V1) during a curve-tracing task in which attention shifts are object-based. We found that accurate performance was associated with similar latencies of attentional selection in both areas and that the latency in both areas increased if the task was made more difficult. The amplitude of the attentional signals in V1 saturated early during a trial, whereas these selection signals kept increasing for a longer time in FEF, until the moment of an eye movement, as if FEF integrated attentional signals present in early visual cortex. In erroneous trials, we observed an interareal latency difference because FEF selected the wrong curve before V1 and imposed its erroneous decision onto visual cortex. The neuronal activity in visual and frontal cortices was correlated across trials, and this trial-to-trial coupling was strongest for the attended curve. These results imply that selective attention relies on reciprocal interactions within a large network of areas that includes V1 and FEF.Visual scenes are usually too complex for all information to be analyzed at once. Selective attention selects a subset of the objects in the visual scene for detailed analysis at the expense of other items. Visual objects compete for selection, and the outcome of this competition depends on bottom-up cues such as saliency and perceptual organization and top-down cues that signal the objects’ behavioral relevance (1). It is not well understood how these different cues interact and which brain areas take the lead in visual selection.The top-down mechanisms for attentional selection are tightly linked to those for the selection of actions (2), and accordingly, cortical areas related to action planning influence the deployment of visual attention. The frontal eye fields (FEF) is one such area that is involved in visual processing, shifts of visual attention (2, 3), and also in the control of eye movements (4, 5). Area FEF contains different types of cells. Visual processing relies on visual and visuomovement cells, whereas the programming of eye movements relies on the activity of visuomovement and movement cells (6, 7). There are several lines of evidence that also implicate FEF in attentional control. First, FEF inactivation impairs attention shifts toward the contralateral visual field (8, 9). Second, subthreshold FEF microstimulation enhances neuronal activity in visual cortex in a manner that is reminiscent of selective attention (10, 11). Third, a role of FEF in the top-down guidance of attention is supported by studies on visual search. In search, selection signals in frontal cortex precede those in area V4 by 50 ms, suggesting that the frontal cortex determines selection and then provides feedback to visual cortex (12, 13). A comparable interareal delay in attentional effects was observed between the lateral intraparietal area and the motion sensitive middle temporal area (14). Thus, the parietal and frontal cortices appear to take the lead in attentional selection and to provide top-down signals to visual cortex. Within the visual cortex, such a reverse hierarchy (15) of attentional effects was observed in a task that required shifts of spatial attention (16) and also in a task demanding shifts between visual and auditory attention (17). Attentional signals in area V4 preceded signals in V2 by 50–250 ms, which in turn preceded attentional effects in the primary visual cortex (V1) by 50–400 ms.However, top-down factors are not the only ones that guide attention. Attention can be object-based, implying that the visual stimulus itself influences the distribution of attention too. If attention is directed to a feature, attention tends to coselect visually related features on the basis of perceptual grouping cues (18) so that entire objects rather than isolated features are attended (19, 20). The influence of perceptual grouping on attentional selection can be investigated with a curve-tracing task that requires grouping of the contour elements of a single curve (21, 22). Attention in this task is directed to the entire curve, implying that the curve’s shape itself influences the distribution of attention (22). Indeed, a traced curve evokes stronger activity in primary visual cortex than an irrelevant curve, revealing a neuronal correlate of object-based attention (23). However, it is not known if the coselection of all image elements of a single object is determined within early visual cortex or is guided by the frontal cortex, just as was shown for other tasks.Here we compare selection signals in areas FEF and V1 in the curve-tracing task with simultaneous recordings in the two areas. A priori, several possibilities exist for the interaction between V1 and FEF. First, the frontal cortex might select the relevant curve and then feed a guiding signal back to visual cortex (24, 25) as in the other tasks described above. If so, attentional selection signals in V1 might arise tens to hundreds of milliseconds later than in FEF. However, the chain of events in the curve-tracing task might differ because visual shape has a profound influence on the distribution of attention (26). Thus, a second possibility is that the visual cortex determines selection so that the attentional modulation in visual cortex precedes that in frontal cortex. A third possibility is that visual and frontal areas jointly determine what is relevant and what is not. In this situation, the selection signals are expected to occur in both areas at approximately the same time. It is also possible that the order of selection in different areas depends on the difficulty of the task. For example, the reverse hierarchy theory of visual perception (15) proposed that easy tasks are usually solved by higher visual areas, whereas lower visual areas are recruited when the picture has to be scrutinized. We therefore varied the difficulty of the curve-tracing task.     

Distribution and molecular analysis of Blastocystis subtypes from gastrointestinal symptomatic and asymptomatic patients in Iran

IntroductionBlastocystis is a common intestinal parasite of human and animal hosts. The parasite has 17 subtypes, and among those at least nine subtypes (ST1-ST9) are found in human hosts.ObjectiveThe aim of the present study was to investigate the presence of different subtypes of Blastocystis spp. among the patients referred to Velayat hospital of Qazvin province, Iran.MethodsOverall, 864 stool samples were examined by using formalin-ethyl acetate concentration method and Trichrome staining. All specimens were cultured in clotted fetal bovine medium. Later, DNA extraction and PCR amplification of 18S ribosomal RNA gene region was conducted and phylogenetic tree constructed.ResultsThe results revealed 7.9% (68/864) of the study population were infected with Blastocystis. Intestinal symptoms were observed in 61% (36/59) of individuals positive for Blastocystis, with abdominal pain in 58% (21/36) of cases which was more frequent than other intestinal signs. No significant relationship was observed among the study variables. By molecular and phylogenetic analysis, three subtypes ST1 (45%), ST2 (30%) and ST3 (23%) of parasite were identified.ConclusionThis study showed ST1 subtype was the predominant subtype among the positive specimens, meanwhile the highest haplotype and nucleotide diversity were clarified in ST3 subtype.